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  1. Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma

    ClinicalTrials.gov

    2016-05-02

    Advanced Pleural Malignant Mesothelioma; HLA-A*0201 Positive Cells Present; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Pleural Malignant Mesothelioma; Stage III Pleural Mesothelioma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Pleural Mesothelioma

  2. PET-Adjusted Intensity Modulated Radiation Therapy and Combination Chemotherapy in Treating Patients With Stage II-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-01-10

    Metastatic Malignant Neoplasm in the Brain; Recurrent Non-Small Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  3. Palliative Care Intervention in Improving Symptom Control and Quality of Life in Patients With Stage II-IV Non-small Cell Lung Cancer and Their Family Caregivers

    ClinicalTrials.gov

    2016-04-06

    Caregiver; Psychological Impact of Cancer and Its Treatment; Recurrent Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  4. Methoxyamine, Pemetrexed Disodium, Cisplatin, and Radiation Therapy in Treating Patients With Stage IIIA-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-04-05

    Metastatic Malignant Neoplasm in the Brain; Stage IIIA Large Cell Lung Carcinoma; Stage IIIA Lung Adenocarcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Large Cell Lung Carcinoma; Stage IIIB Lung Adenocarcinoma; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Large Cell Lung Carcinoma; Stage IV Lung Adenocarcinoma; Stage IV Non-Small Cell Lung Cancer

  5. Erlotinib Hydrochloride With or Without Carboplatin and Paclitaxel in Treating Patients With Stage III-IV Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-29

    Adenosquamous Lung Carcinoma; Bronchioloalveolar Carcinoma; Lung Adenocarcinoma; Malignant Pericardial Effusion; Malignant Pleural Effusion; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  6. Lung cancer - non-small cell

    MedlinePlus

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Smoking causes most cases (around 90%) of lung cancer. The risk depends on the number of cigarettes ...

  7. Pulmonary Rehabilitation in Improving Lung Function in Patients With Locally Advanced Non-Small Cell Lung Cancer Undergoing Chemoradiation

    ClinicalTrials.gov

    2015-03-17

    Cachexia; Fatigue; Pulmonary Complications; Radiation Toxicity; Recurrent Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  8. EGFR Mutation Positive Stage IV Non-Small-Cell Lung Cancer: Treatment Beyond Progression

    PubMed Central

    Van Assche, Katrijn; Ferdinande, Liesbeth; Lievens, Yolande; Vandecasteele, Katrien; Surmont, Veerle

    2014-01-01

    Non-small-cell lung cancer (NSCLC) is the leading cause of death from cancer for both men and women. Chemotherapy is the mainstay of treatment in advanced disease, but is only marginally effective. In about 30% of patients with advanced NSCLC in East Asia and in 10–15% in Western countries, epidermal growth factor receptor (EGFR) mutations are found. In this population, first-line treatment with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, or afatinib is recommended. The treatment beyond progression is less well-defined. In this paper, we present three patients, EGFR mutation positive, with local progression after an initial treatment with TKI. These patients were treated with local radiotherapy. TKI was temporarily stopped and restarted after radiotherapy. We give an overview of the literature and discuss the different treatment options in case of progression after TKI: TKI continuation with or without chemotherapy, TKI continuation with local therapy, alternative dosing or switch to next-generation TKI or combination therapy. There are different options for treatment beyond progression in EGFR mutation positive metastatic NSCLC, but the optimal strategy is still to be defined. Further research on this topic is ongoing. PMID:25538894

  9. Lung cancer - non-small cell

    MedlinePlus

    Cancer - lung - non-small cell; Non-small cell lung cancer; NSCLC; Adenocarcinoma - lung; Squamous cell carcinoma - lung ... Smoking causes most cases (around 90%) of lung cancer. The risk ... day and for how long you have smoked. Being around the smoke ...

  10. A Case of Stage IV Non-Small Cell Lung Cancer Treated with Korean Medicine Therapy Alone

    PubMed Central

    Lee, Dong-hyun; Seong, Shin; Kim, Sung-su; Han, Jae-bok

    2013-01-01

    This report presents a case that shows a significant anticancer effect of Korean medicine therapy (KMT). A 79-year-old man, who was diagnosed as stage IV non-small cell lung cancer (NSCLC) in December 2012, was treated with KMT including intravenous pharmacopunctures and oral herbal medicine from February 22, 2013, until September 2013 without any surgical intervention, chemotherapy or radiotherapy. The intravenous pharmacopunctures were the wild ginseng pharmacopuncture, Cordyceps sinensis pharmacopuncture and Trichosanthes kirilowii pharmacopuncture. The oral herbal medicine used was soramdan, made of cultivated wild ginseng. The effectiveness of this therapy was evaluated with computed tomography and the Eastern Cooperative Oncology Group (ECOG) performance scale. The size of the tumor mass was markedly decreased and the ECOG performance scale was also improved. These results suggest that KMT alone can be an effective method to treat NSCLC. PMID:24348396

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

    ClinicalTrials.gov

    2016-04-11

    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

  12. Comparison of outcomes in patients with stage III versus limited stage IV non-small cell lung cancer

    PubMed Central

    2011-01-01

    Background Standard therapy for metastatic non small cell lung cancer (NSCLC) includes palliative systemic chemotherapy and/or radiotherapy. Recent studies of patients with limited metastases treated with curative-intent stereotactic body radiation therapy (SBRT) have shown encouraging survival. We hypothesized that patients treated with SBRT for limited metastases have comparable outcomes with those treated with curative-intent radiation for Stage III NSCLC. Methods We retrospectively reviewed the records of NSCLC patients treated with curative-intent radiotherapy at the University of Rochester from 2000-2008. We identified 3 groups of patients with NSCLC: stage III, stage IV, and recurrent stage IV (initial stage I-II). All stage IV NSCLC patients treated with SBRT had ≤ 8 lesions. Results Of 146 patients, 88% had KPS ≥ 80%, 30% had > 5% weight loss, and 95% were smokers. The 5-year OS from date of NSCLC diagnosis for stage III, initial stage IV and recurrent stage IV was 7%, 14%, and 27% respectively. The 5-year OS from date of metastatic diagnosis was significantly (p < 0.00001) superior among those with limited metastases (≤ 8 lesions) versus stage III patients who developed extensive metastases not amenable to SBRT (14% vs. 0%). Conclusion Stage IV NSCLC is a heterogeneous patient population, with a selected cohort apparently faring better than Stage III patients. Though patients with limited metastases are favorably selected by virtue of more indolent disease and/or less bulky disease burden, perhaps staging these patients differently is appropriate for prognostic and treatment characterization. Aggressive local therapy may be indicated in these patients, though prospective clinical studies are needed. PMID:21718501

  13. Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer

    PubMed Central

    2010-01-01

    Background Immunohistochemistry (IHC) with mutation-specific antibodies may be an ancillary method of detecting EGFR mutations in lung cancer patients. Methods EGFR mutation status was analyzed by DNA assays, and compared with IHC results in five non-small-cell lung cancer (NSCLC) cell lines and tumor samples from 78 stage IV NSCLC patients. Results IHC correctly identified del 19 in the H1650 and PC9 cell lines, L858R in H1975, and wild-type EGFR in H460 and A549, as well as wild-type EGFR in tumor samples from 22 patients. IHC with the mAb against EGFR with del 19 was highly positive for the protein in all 17 patients with a 15-bp (ELREA) deletion in exon 19, whereas in patients with other deletions, IHC was weakly positive in 3 cases and negative in 9 cases. IHC with the mAb against the L858R mutation showed high positivity for the protein in 25/27 (93%) patients with exon 21 EGFR mutations (all with L858R) but did not identify the L861Q mutation in the remaining two patients. Conclusions IHC with mutation-specific mAbs against EGFR is a promising method for detecting EGFR mutations in NSCLC patients. However these mAbs should be validated with additional studies to clarify their possible role in routine clinical practice for screening EGFR mutations in NSCLC patients. PMID:21167064

  14. Measurement of mid-arm muscle circumference and prognosis in stage IV non-small cell lung cancer patients.

    PubMed

    Tartari, Rafaela Festugatto; Ulbrich-Kulczynski, Jane Maria; Filho, Antônio Fabiano Ferreira

    2013-03-01

    Overall survival (OS) varies widely in patients with stage IV non-small cell lung cancer (NSCLC). Strong prognostic factors are still needed to improve decision-making regarding standard treatment options, to stratify patients for inclusion in innovative therapeutic trials and to identify patients who would be best treated with palliative care rather than with systemic chemotherapy. Mid-arm muscle circumference (MAMC) is a bedside anthropometric measurement that estimates somatic protein reserve, an early indicator of nutritional depletion. This measurement is simple, non-invasive, objective and inexpensive to perform. We evaluated MAMC as a potential prognostic factor in patients with stage IV NSCLC. A total of 56 non-selected consecutive patients with stage IV NSCLC were evaluated. The MAMC measurement results for these patients were expressed as a percentage of the expected reference values, adjusted for gender and age. Patients were categorized as normal (MAMC ≥90%) or depleted (MAMC <90%). The mean age of patients was 63 years (range 47-80), and the mean MAMC was 89 (range 66-122), with 55% of patients classified as depleted. The median OS was 6.2 months (95% CI, 5.1-7.3). In the subgroup with normal MAMC, the median OS was 10.2 months (95% CI, 9.2-11.1). In patients classified as depleted, the median OS was 5.0 months (95% CI, 4.2-5.8). The difference in OS between these two subgroups was highly significant (p<0.001 by the log-rank test; HR=0.21; 95% CI, 0.09-0.5 for patients with normal MAMC). In a multivariate analysis with Karnofsky status, age and gender as covariates, the difference in OS between the MAMC groups remained statistically significant (p<0.001, according to the Cox proportional hazards model). MAMC is a strong independent prognostic factor in stage IV NSCLC patients. Patients with MAMC <90% of the expected value had poor OS. PMID:23426523

  15. Phase 3 Study of Bavituximab Plus Docetaxel Versus Docetaxel Alone in Patients With Late-stage Non-squamous Non-small-cell Lung Cancer

    ClinicalTrials.gov

    2016-02-01

    Non-Small-Cell Lung Cancer Stage IIIB; Non-Small-Cell Lung Cancer Stage IV; Non-Small-Cell Lung Cancer Metastatic; Carcinoma, Non-Small-Cell Lung; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Nonsmall Cell Lung Cancer

  16. Sirolimus and Gold Sodium Thiomalate in Treating Patients With Advanced Squamous Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2012-12-13

    Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  17. Stereotactic Body Radiation Therapy in Treating Patients With Metastatic Breast Cancer, Non-small Cell Lung Cancer, or Prostate Cancer

    ClinicalTrials.gov

    2016-06-17

    Male Breast Carcinoma; Prostate Adenocarcinoma; Recurrent Breast Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Prostate Carcinoma; Stage IV Breast Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Prostate Cancer

  18. Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2015-09-01

    Recurrent Large Cell Lung Carcinoma; Recurrent Lung Adenocarcinoma; Recurrent Squamous Cell Lung Carcinoma; Stage IV Large Cell Lung Carcinoma; Stage IV Lung Adenocarcinoma; Stage IV Squamous Cell Lung Carcinoma

  19. GTI-2040 and Docetaxel in Treating Patients With Recurrent, Metastatic, or Unresectable Locally Advanced Non-Small Cell Lung Cancer, Prostate Cancer, or Other Solid Tumors

    ClinicalTrials.gov

    2013-01-23

    Recurrent Non-small Cell Lung Cancer; Recurrent Prostate Cancer; Stage III Prostate Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  20. General Information about Non-Small Cell Lung Cancer

    MedlinePlus

    ... most patients with non-small cell lung cancer, current treatments do not cure the cancer. If lung ... professional versions have detailed information written in technical language. The patient versions are written in easy-to- ...

  1. Distinctive Patterns of Initially Presenting Metastases and Clinical Outcomes According to the Histological Subtypes in Stage IV Non-Small Cell Lung Cancer

    PubMed Central

    Lee, Dong Soo; Kim, Yeon S.; Kay, Chul S.; Kim, Sung H.; Yeo, Chang D.; Kim, Jin W.; Kim, Seung Joon; Kim, Young K.; Ko, Yoon H.; Kang, Jin H.; Lee, Kyo Y.

    2016-01-01

    Abstract This study was designed to compare the primary patterns of metastases and clinical outcomes between adenocarcinoma (Adenoca) and squamous cell carcinoma (SQ) in initially diagnosed stage IV non-small cell lung cancer (NSCLC). Between June 2007 and June 2013, a total of 427 eligible patients were analyzed. These patients were histologically confirmed as Adenoca or SQ and underwent systemic imaging studies, including 18F-fluorodeoxyglucose positron emission tomography/computed tomography and brain imaging. Synchronous metastatic sites were categorized into 7 areas, and whole-body metastatic scores were calculated from 1 to 7 by summation of each involved region. We compared the patient, tumor, and metastatic characteristics according to the histological subtypes, and examined clinical outcomes. The enrolled study cohort comprised 81% (n = 346) Adenoca patients and 19% (n = 81) SQ patients. The median age of the study population was 65 years (range, 30–94 years), and 263 (61.6%) patients were male. The most common metastatic sites were thoracic lymph nodes (LNs) (84.3%), followed by lung to lung/lymphangitic spread (59%) and bone (54.8%). The distribution of patient characteristics revealed that age ≥65 years (69.1% vs 50.6%; P = 0.003) and male sex (84% vs 56.4%; P < 0.001) were more frequently found in SQ patients. Regarding metastatic features, bone metastasis (60.4% vs 30.9%; P < 0.001), lung to lung/lymphangitic metastasis (63% vs 42%; P = 0.001), and brain metastasis (35% vs 16%; P = 0.001) were significantly and more frequently found in Adenoca patients. Patients with high metastatic scores (score 3–6) were more frequently found to have Adenoca (91.6% vs 73.4%; P < 0.001). In multivariate prognostic evaluation, sex (P = 0.001), age (P < 0.001), histology (P < 0.001), LN status (P = 0.032), pleural/pericardial metastasis (P = 0.003), abdomen/pelvis metastasis (P < 0.001), axilla

  2. Pilot study of a specific dietary supplement in tumor-bearing mice and in stage IIIB and IV non-small cell lung cancer patients.

    PubMed

    Sun, A S; Yeh, H C; Wang, L H; Huang, Y P; Maeda, H; Pivazyan, A; Hsu, C; Lewis, E R; Bruckner, H W; Fasy, T M

    2001-01-01

    Previously, a specific dietary supplement, selected vegetables (SV), was found to be associated with prolonged survival of stage III and IV non-small cell lung cancer (NSCLC) patients. In this study, several anticancer components in SV were measured; the anticancer activity of SV was assessed using a lung tumor model, line 1 in BALB/c mice. SV was also used in conjunction with conventional therapies by stage IIIB and IV NSCLC patients whose survival and clinical responses were evaluated. A daily portion (283 g) of SV was found to contain 63 mg of inositol hexaphosphate, 4.4 mg of daidzein, 2.6 mg of genistein, and 16 mg of coumestrol. Mouse food containing 5% SV (wt/wt) was associated with a 53-74% inhibition of tumor growth rate. Fourteen of the 18 patients who ingested SV daily for 2-46 months were included in the analyses; none showed evidence of toxicity. The first lead case remained tumor free for > 133 months; the second case showed complete regression of multiple brain lesions after using SV and radiotherapy. The median survival time of the remaining 12 patients was 33.5 months, and one-year survival was > 70%. The median survival time of the 16 "intent-to-treat" patients (including ineligible patients) was 20 months, and one-year survival was 55%. The Karnofsky performance status of eligible patients was 55 +/- 13 at entry but improved to 92 +/- 9 after use of SV for five months or longer (p < 0.01). Five patients had stable lesions for 30, 30, 20, 12, and 2 months; two of them, whose primary tumor was resected, used SV alone and demonstrated an objective response of their metastatic tumors. In addition to the two lead cases, eight patients had no new metastases after using SV. Three patients had complete regression of brain metastases after using radiotherapy and SV. In this study, daily ingestion of SV was associated with objective responses, prolonged survival, and attenuation of the normal pattern of progression of stage IIIB and IV NSCLC. A large

  3. Low-Dose Acetylsalicylic Acid in Treating Patients With Stage I-III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-28

    Adenocarcinoma of the Lung; Recurrent Non-small Cell Lung Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  4. Nintedanib Compared With Placebo in Treating Against Radiation-Induced Pneumonitis in Patients With Non-small Cell Lung Cancer That Cannot Be Removed by Surgery and Are Undergoing Chemoradiation Therapy

    ClinicalTrials.gov

    2016-04-27

    Radiation-Induced Pneumonitis; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  5. Survival outcome according to KRAS mutation status in newly diagnosed patients with stage IV non-small cell lung cancer treated with platinum doublet chemotherapy

    PubMed Central

    Brady, Anna K.; McNeill, Jonathan D.; Judy, Brendan; Bauml, Joshua; Evans, Tracey L.; Cohen, Roger B.; Langer, Corey; Vachani, Anil; Aggarwal, Charu

    2015-01-01

    Introduction Mutations (MT) of the KRAS gene are the most common mutation in non-small cell lung cancer (NSCLC), seen in about 20–25% of all adenocarcinomas. Effect of KRAS MT on response to cytotoxic chemotherapy is unclear. Methods We undertook a single-institution retrospective analysis of 93 consecutive patients with stage IV NSCLC adenocarcinoma with known KRAS and EGFR MT status to determine the association of KRAS MT with survival. All patients were treated between January 1, 2008 and December 31, 2011 with standard platinum based chemotherapy at the University of Pennsylvania. Overall and progression free survival were analyzed using Kaplan-Meier and Cox proportional hazard methods. Results All patients in this series received platinum doublet chemotherapy, and 42 (45%) received bevacizumab. Overall survival and progression free survival for patients with KRAS MT was no worse than for patients with wild type KRAS. Median overall survival for patients with KRAS MT was 19 months (mo) vs. 15.6 mo for KRAS WT, p = 0.34, and progression-free survival was 6.2 mo in patients with KRAS MT vs. 7mo in patients with KRAS WT, p = 0.51. In multivariable analysis including age, race, gender, and ECOG PS, KRAS MT was not associated with overall survival (HR 1.12, 95% CI 0.58–2.16, p = 0.74) or progression free survival (HR 0.80, 95% CI 0.48–1.34, p = 41). Of note, receipt of bevacizumab was associated with improved overall survival only in KRAS WT patients (HR 0.34, p = 0.01). Conclusions KRAS MT are not associated with inferior progression-free and overall survival in advanced NSCLC patients treated with standard first-line platinum-based chemotherapy. PMID:26471290

  6. Serum lactate dehydrogenase levels at presentation in stage IV non-small cell lung cancer: predictive value of metastases and relation to survival outcomes.

    PubMed

    Lee, Dong Soo; Park, Kyung Ran; Kim, Seung Joon; Chung, Mi Joo; Lee, Yun Hee; Chang, Ji Hyun; Kang, Jin Hyoung; Hong, Sook Hee; Kim, Myung Sin; Kim, Yeon Sil

    2016-01-01

    This study aimed to evaluate the clinical correlations between serum lactate dehydrogenase (LDH) levels and tumor characteristics and to investigate the prognostic impact of serum LDH levels in advanced non-small cell lung cancer (NSCLC). A total of 394 patients were included in the present study between June 2007 and January 2013. All eligible patients had serum LDH levels available before treatment, and whole-body metastatic extent was measured using whole-body metastatic scores, as determined by 18(F)-fludeoxyglucose positron emission tomography scans from 1 to 7 as the sum of each metastatic region. The diagnostic cutoff value for an abnormal serum LDH level was 450 IU/L. The median serum LDH level was 477 IU/L (range, 113-2850), and 224 (56.9 %) patients had abnormal serum LDH levels. The serum LDH levels showed no significant associations with age, gender, histology, tumor differentiation, and smoking history. However, the proportion of patients with abnormal serum LDH levels was statistically significantly higher in the high total metastatic score group (scores 3-7) than in the low total metastatic score group (scores 1-2) (65.3 vs 50.4 %, p = 0.001). In a multivariate survival analysis, age (p = 0.001), gender (p = 0.001), histology (p = 0.003), tumor differentiation (p = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.001), LDH levels (p = 0.046), and treatment factors (p = 0.001) proved to be independent prognostic factors for survival outcomes. The results of this study suggest that the serum LDH levels at presentation may be significantly correlated with whole-body tumor extent and might independently but modestly prognosticate OS in stage IV NSCLC. PMID:26240025

  7. Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-small Cell Lung Cancer, or Squamous Cell Head and Neck Cancer

    ClinicalTrials.gov

    2016-05-05

    Head and Neck Squamous Cell Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Skin Melanoma; Stage IIIB Non-Small Cell Lung Cancer; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Non-Small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma

  8. Serum Biomarkers Associated with Clinical Outcomes Fail to Predict Brain Metastases in Patients with Stage IV Non-Small Cell Lung Cancers

    PubMed Central

    Li, Bob T.; Lou, Emil; Hsu, Meier; Yu, Helena A.; Naidoo, Jarushka; Zauderer, Marjorie G.; Sima, Camelia; Johnson, Melissa L.; Daras, Mariza; DeAngelis, Lisa M.; Fleisher, Martin; Kris, Mark G.; Azzoli, Christopher G.

    2016-01-01

    Background Lung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown. Methods Serum NSE, CYFRA 21–1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC. Pre-treatment serum biomarker levels as well as age, histology, and epidermal growth factor receptor (EGFR) mutation status were evaluated for association with the baseline presence of brain metastases using logistic regression and multivariable analysis. For patients without brain metastases at baseline, the cumulative incidence of subsequent brain metastases were compared according to baseline biomarkers and clinical factors using Gray’s test. Results A total of 118 patients were enrolled, 31 (26%; 95% CI 0.19–0.35) had brain metastases at baseline and a further 26 (22%; 95% CI 0.15–0.30) developed brain metastases subsequently. Pre-treatment serum biomarker levels were available in 104 patients. There was no significant association between the six serum biomarkers and the baseline presence or subsequent development of brain metastases. Age younger than 65 years was the only clinical factor significantly associated with brain metastasis at baseline (OR 3.00; 95% CI 1.22–7.34, P = 0.02) by multivariable analysis. A trend toward increased cumulative incidence of subsequent brain metastases was observed in patients with EGFR mutation (p = 0.2), but this was not statistically significant possibly due to small sample size. Conclusions Serum NSE, CYFRA 21–1, Pro-GRP, SCC-Ag, TIMP1, and HE4 are not significantly associated with brain metastases. Our methods taking into account follow-up time

  9. Thoracoscopic Lobectomy for Non-small Cell Lung Cancer.

    PubMed

    Gaudet, Matthew A; D'Amico, Thomas A

    2016-07-01

    Lobectomy is the gold standard treatment in operable patients with surgically resectable non-small cell lung cancer. Thoracoscopic lobectomy has emerged as an option for surgeons facile with the technique. Video-assisted thoracoscopic surgery (VATS) is used for a variety of indications, but its efficacy as a reliable oncologic procedure makes it appealing in the treatment of non-small cell lung cancer. Fewer postoperative complications and decreased postoperative pain associated with VATS procedures can lead to shorter lengths of stay and lower overall costs. Thoracoscopic surgery continues to evolve, and uniportal, robot-assisted, and awake thoracoscopic procedures have all shown promising results. PMID:27261912

  10. The Impact of Local and Regional Disease Extent on Overall Survival in Patients With Advanced Stage IIIB/IV Non-Small Cell Lung Carcinoma

    SciTech Connect

    Higginson, Daniel S.; Chen, Ronald C.; Tracton, Gregg; Morris, David E.; Halle, Jan; Rosenman, Julian G.; Stefanescu, Mihaela; Pham, Erica; Socinski, Mark A.; Marks, Lawrence B.

    2012-11-01

    Purpose: Patients with advanced stage IIIB or stage IV non-small cell lung carcinoma are typically treated with initial platinum-based chemotherapy. A variety of factors (eg, performance status, gender, age, histology, weight loss, and smoking history) are generally accepted as predictors of overall survival. Because uncontrolled pulmonary disease constitutes a major cause of death in these patients, we hypothesized that clinical and radiographic factors related to intrathoracic disease at diagnosis may be prognostically significant in addition to conventional factors. The results have implications regarding the selection of patients for whom palliative thoracic radiation therapy may be of most benefit. Methods and Materials: We conducted a pooled analysis of 189 patients enrolled at a single institution into 9 prospective phase II and III clinical trials involving first-line, platinum-based chemotherapy. Baseline clinical and radiographic characteristics before trial enrollment were analyzed as possible predictors for subsequent overall survival. To assess the relationship between anatomic location and volume of disease within the thorax and its effect on survival, the pre-enrollment computed tomography images were also analyzed by contouring central and peripheral intrapulmonary disease. Results: On univariate survival analysis, multiple pulmonary-related factors were significantly associated with worse overall survival, including pulmonary symptoms at presentation (P=.0046), total volume of intrathoracic disease (P=.0006), and evidence of obstruction of major bronchi or vessels on prechemotherapy computed tomography (P<.0001). When partitioned into central and peripheral volumes, central (P<.0001) but not peripheral (P=.74) disease was associated with worse survival. On multivariate analysis with known factors, pulmonary symptoms (hazard ratio, 1.46; P=.042), central disease volume (hazard ratio, 1.47; P=.042), and bronchial/vascular compression (hazard ratio, 1

  11. Hyponatremia of non-small cell lung cancer: Indian experience

    PubMed Central

    Bose, Chinmoy K.; Dey, Subhashis; Mukhopadhyay, Ashis

    2011-01-01

    Background: Hyponatremia is a hazardous complication of lung cancer and its treatment. It is seen at presentation in approximately 15% of patients with small-cell lung cancer (SCLC) and 1% of patients with non-small cell lung cancer (NSCLC). Platinum compounds used as first-line agents along with taxols frequently cause hyponatremia. Till date there is no data on its prevalence in patients with advanced lung cancer in the Indian subcontinent. Aim: This study was undertaken to find out its incidence before and after institution of chemotherapy and to observe the results of treatment of hyponatremia in a group of lung cancer patient. Materials and Methods: Forty patients with advanced lung cancer (25 patients with stage III disease and 15 with stage IV disease) were included in the study. Variables looked at included, but were not limited to, serum sodium, serum albumin, serum alkaline phosphatase, serum lactate dehydrogenase, and hemoglobin. These variables were measured as per the standard clinical laboratory procedure. No ethics approval was required as these parameters are routinely measured in such patients. Results: In the chemo-naïve state, one out of five cases with SCLC (20%) had hyponatremia at presentation; among the 35 cases of NSCLC, 7 patients (20%) had hyponatremia at presentation, which is in sharp contrast to earlier reports of 1% prevalence of hyponatremia in this group. Among the 27 cases who died within 6 months, 11 had hyponatremia; this finding was statistically highly significant. Conclusion: In India, NSCLC patients are at high risk of having hyponatremia at presentation and this is significantly associated with a worse outcome. PMID:22557779

  12. EF5 in Measuring Tumor Hypoxia in Patients With Stage I-III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2015-04-10

    Stage IA Non-Small Cell Lung Carcinoma; Stage IB Non-Small Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer

  13. [Immune Checkpoint Therapy for Non-Small-Cell Lung Cancer].

    PubMed

    Miyauchi, Eisaku; Inoue, Akira

    2016-06-01

    Nivolumab is an anti-PD-1 antibody that has recently been approved in Japan, and has shown high response rates and more favorable safety profiles in 2 phase III clinical trials. Accordingly, immune checkpoint therapy has now been included as a new standard treatment for non-small-cell lung cancer. These immune checkpoints are receptors expressed on T cells that regulate the immune response. The PD-1/PD-L1 signal inhibits cytotoxic T lymphocyte proliferation and survival, induces apoptosis of infiltrative T cells, and increases the amount of regulatory T cells in the tumor microenvironment. Therefore, severe immune-related adverse event(irAE)have been observed, including enterocolitis, neuropathies, and endocrinopathies. There are different management approaches to irAEs with conventional cytotoxic drugs. This article reviews the available data regarding immune checkpoint therapy for patients with non-small-cell lung cancer. PMID:27306803

  14. Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-07-01

    Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Bladder Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Transitional Cell Carcinoma of the Bladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  15. Survivorship Care Planning in Patients With Colorectal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-12-16

    Stage I Colon Cancer; Stage I Rectal Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Colon Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIA Rectal Cancer; Stage IIB Colon Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIB Rectal Cancer; Stage IIC Colon Cancer; Stage IIC Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer

  16. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    PubMed Central

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2012-01-01

    Purpose Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of KrasG12D-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radio-sensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer. PMID:23182391

  17. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    SciTech Connect

    Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T.; Aftab, Blake T.; Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John; Rudin, Charles M.; Tran, Phuoc T.; Hales, Russell K.

    2013-05-01

    Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

  18. Neoadjuvant Therapy in Non-Small Cell Lung Cancer.

    PubMed

    Zheng, Yifan; Jaklitsch, Michael T; Bueno, Raphael

    2016-07-01

    Locally advanced (stage IIIA) non-small cell lung cancer (NSCLC) is confined to the chest, but requires more than surgery to maximize cure. Therapy given preoperatively is termed neoadjuvant, whereas postoperative therapy is termed adjuvant. Trimodality therapy (chemotherapy, radiation, and surgery) has become the standard treatment regimen for resectable, locally advanced NSCLC. During the past 2 decades, several prospective, randomized, and nonrandomized studies have explored various regimens for preoperative treatment of NSCLC. The evaluation of potential candidates with NSCLC for neoadjuvant therapy as well as the currently available therapeutic regimens are reviewed. PMID:27261916

  19. Cisplatin and Etoposide With or Without Veliparib in Treating Patients With Extensive Stage Small Cell Lung Cancer or Metastatic Large Cell Neuroendocrine Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-01

    Carcinoma of Unknown Primary Origin; Extensive Stage Small Cell Lung Carcinoma; Large Cell Lung Carcinoma; Neuroendocrine Carcinoma; Newly Diagnosed Carcinoma of Unknown Primary Origin; Stage IV Non-Small Cell Lung Cancer

  20. Application of proteomics in non-small-cell lung cancer.

    PubMed

    Cho, William C S

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is a heterogeneous disease with diverse pathological features. Clinical proteomics allows the discovery of molecular markers and new therapeutic targets for this most prevalent type of lung cancer. Some of them may be used to detect early lung cancer, while others may serve as predictive markers of resistance to different therapies. Therapeutic targets and prognostic markers in NSCLC have also been discovered. These proteomics biomarkers may help to pair the individual NSCLC patient with the best treatment option. Despite the fact that implementation of these biomarkers in the clinic appears to be scarce, the recently launched Precision Medicine Initiative may encourage their translation into clinical practice. PMID:26577456

  1. [Therapy of Metastatic Non-small Cell Lung Cancer].

    PubMed

    Reinmuth, N; Gröschel, A; Schumann, C; Sebastian, M; Wiewrodt, R; Reck, M

    2016-09-01

    Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors, anti angiogenic agents, and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decision-making. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC. PMID:27603945

  2. Bortezomib in Treating Patients With Stage IIIB or Stage IV Lung Cancer

    ClinicalTrials.gov

    2014-08-04

    Adenocarcinoma of the Lung; Bronchoalveolar Cell Lung Cancer; Non-small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer

  3. EF5 and Motexafin Lutetium in Detecting Tumor Cells in Patients With Abdominal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-15

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Fallopian Tube Cancer; Gastrointestinal Stromal Tumor; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Gastrointestinal Carcinoid Tumor; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Primary Peritoneal Cavity Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Adult Soft Tissue Sarcoma; Recurrent Colon Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Small Intestine Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage 0 Non-small Cell Lung Cancer; Stage I Adult Soft Tissue Sarcoma; Stage I Colon Cancer; Stage I Gastric Cancer; Stage I Non-small Cell Lung Cancer; Stage I Ovarian Epithelial Cancer; Stage I Ovarian Germ Cell Tumor; Stage I Pancreatic Cancer; Stage I Rectal Cancer; Stage I Uterine Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage II Colon Cancer; Stage II Gastric Cancer; Stage II Non-small Cell Lung Cancer; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; Stage II Pancreatic Cancer; Stage II Rectal Cancer; Stage II Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Colon Cancer; Stage III Gastric Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Uterine Sarcoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Colon Cancer; Stage

  4. Personalized Therapy of Non-small Cell Lung Cancer (NSCLC).

    PubMed

    Gadgeel, Shirish M

    2016-01-01

    Lung cancer remains the most common cause of cancer related deaths in both men and women in the United States and non-small cell lung cancer (NSCLC) accounts for over 85 % of all lung cancers. Survival of these patients has not significantly altered in over 30 years. This chapter initially discusses the clinical presentation of lung cancer patients. Most patients diagnosed with lung cancer due to symptoms have advanced stage cancer. Once diagnosed, lung cancer patients need imaging studies to assess the stage of the disease before decisions regarding therapy are finalized. The most important prognostic factors are stage of the disease and performance status and these factors also determine therapy. The chapter subsequently discusses management of each stage of the disease and the impact of several pathologic, clinical factors in personalizing therapy for each individual patient. Transition from chemotherapy for every patient to a more personalized approach based on histology and molecular markers has occurred in the management of advanced stage NSCLC. It is expected that such a personalized approach will extend to all stages of NSCLC and will likely improve the outcomes of all NSCLC patients. PMID:26703806

  5. Advances in immunotherapy for non-small cell lung cancer.

    PubMed

    Reckamp, Karen L

    2015-12-01

    In most patients, lung cancer presents as advanced disease with metastases to lymph nodes and/or distant organs, and survival is poor. Lung cancer is also a highly immune-suppressing malignancy with numerous methods to evade antitumor immune responses, including deficiencies in antigen processing and presentation, release of immunomodulatory cytokines, and inhibition of T-cell activation. Advances in understanding the complex interactions of the immune system and cancer have led to novel therapies that promote T-cell activation at the tumor site, resulting in prolonged clinical benefit. Immune checkpoint inhibitors, specifically programmed death receptor 1 pathway antibodies, have demonstrated impressively durable responses and improved survival in patients with non-small cell lung cancer. This article will review the recent progress made in immunotherapy for lung cancer with data from trials evaluating programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 monoclonal antibodies in addition to cancer vaccines. The review will focus on studies that have been published and the latest randomized trials exploring immune therapy in lung cancer. These results form the framework for a new direction in the treatment of lung cancer toward immunotherapy. PMID:27058851

  6. Cediranib Maleate and Whole Brain Radiation Therapy in Patients With Brain Metastases From Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-03-07

    Male Breast Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer; Tumors Metastatic to Brain

  7. Immunotherapy for non-small cell lung cancer

    PubMed Central

    Kelly, Ronan J.; Gulley, James L.; Giaccone, Giuseppe

    2012-01-01

    Developing effective immunotherapy for lung cancer is a daunting but hugely attractive challenge. Until recently, non-small cell lung cancer was thought of as a non-immunogenic tumor, but there is now evidence highlighting the integral role played by both inflammatory and immunological responses in lung carcinogenesis. Despite recent encouraging preclinical and phase I/II data, there is a paucity of phase III trials showing a clear clinical benefit for vaccines in lung cancer. There are many difficulties to overcome prior to the development of a successful therapy. Perhaps a measurable immune response may not translate into a clinically meaningful or radiological response. Patient selection may also be a problem for ongoing clinical studies. The majority of trials for lung cancer vaccines are focused on patients with advanced-stage disease, while the ideal candidates may be patients with a lower tumor burden stage I or II disease. Selecting the exact antigens to target is also difficult. It will likely require multiple epitopes of a diverse set of genes restricted to multiple haplotypes to generate a truly effective vaccine that is able to overcome the various immunologic escape mechanisms that tumors employ. This review discusses active immunotherapy employing protein/peptide vaccines, whole cell vaccines, and dendritic cell vaccines and examines the current data on some novel immunomodulating agents. PMID:20630824

  8. [Maintenance therapy for advanced non-small-cell lung cancer].

    PubMed

    Saruwatari, Koichi; Yoh, Kiyotaka

    2014-08-01

    Maintenance therapy is a new treatment strategy for advanced non-small-cell lung cancer(NSCLC), and it consists of switch maintenance and continuation maintenance.Switch maintenance is the introduction of a different drug, not included as part of the induction therapy, immediately after completion of 4 cycles of first-line platinum-based chemotherapy.Continuation maintenance is a continuation of at least one of the drugs used in the induction therapy in the absence of disease progression.Several phase III trials have reported survival benefits with continuation maintenance of pemetrexed and switch maintenance of pemetrexed or erlotinib.Therefore, maintenance therapy has become a part of the standard first-line treatment for advanced NSCLC.However, further research is needed to elucidate the selection criteria of patients who may benefit the most from maintenance therapy. PMID:25132023

  9. Telomerase activity in non-small cell lung cancer

    PubMed Central

    Dobija-Kubica, Katarzyna; Bruliński, Krzysztof; Rogoziński, Paweł; Wiczkowski, Andrzej; Gawrychowska, Agata; Gawrychowski, Jacek

    2016-01-01

    Introduction High telomerase activity has been detected in the majority of malignant neoplasms including lung cancer. The purpose of the study was to attempt to use telomerase activity as a prognostic factor in patients with non-small cell lung cancer (NSCLC). Material and methods Telomerase activity was analyzed in 47 tissue specimens taken from patients with NSCLC. The control group consisted of 30 specimens of non-cancerous lung parenchyma. Telomerase activity was measured by means of the telomeric repeat amplification protocol (TRAP). Results Telomerase activity in the neoplastic tissue was significantly higher than in the lung parenchyma that was free from neoplastic infiltration. There was no significant association between telomerase activity and age, gender, tobacco smoking, histological type of the tumor, or staging (pTNM). No association was found between the level of telomerase activity in NSCLC specimens and the two-year survival rate of patients (p = 0.326). A higher level of telomerase activity in poorly differentiated tumors (G3) as compared to moderately differentiated tumors (G2) was detected (p = 0.008). A positive association was identified between telomerase activity in pulmonary parenchyma free from tumor infiltration and the presence of leukocyte infiltration (p = 0.0001). Conclusions No association was found between the level of telomerase activity in NSCLC specimens and the two-year survival rate of patients. The study has revealed a positive association between telomerase activity and the grade of differentiation (G) in NSCLC. PMID:27212973

  10. Combination Chemotherapy, Radiation Therapy, and Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-06-04

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  11. Expression of a phosphorylated form of ATF4 in lung and non-small cell lung cancer tissues.

    PubMed

    Fan, Chui-Feng; Miao, Yuan; Lin, Xu-Yong; Zhang, Di; Wang, En-Hua

    2014-01-01

    ATF4 is a member of the cAMP-responsive element-binding protein family of basic zipper-containing proteins, a family of transcription factors phosphorylated at serines residues by protein kinase A. The family has been proved to be able to stimulate the transcription of the genes containing CRE elements. Elevated ATF4 expression was detected in some tumors including breast carcinoma compared to their corresponding nontumor tissues. p-ATF4 (ser 245), a phosphorylated form of ATF4 protein at serine 245 site, was believed to be an active type of this protein. However, its expression and clinical significance in malignant tumors including non-small cell lung cancer were not reported up to date. In the current study, we investigate the expression of p-ATF4 (ser 245) in non-small cell lung cancer using tissue microarray and immunohistochemistry. p-ATF4 (ser 245) immunostaining was detected in nucleus and cytoplasm in cancer cells and normal lung epithelial cells. Compared to bronchial epithelium and submucosal glands (total positive rate, 14.6% (12/82)), there was increased expression of p-ATF4 (ser 245) in non-small cell lung cancer cells (total positive rate, 42.7% (35/82)) (p < 0.05). In addition, increased expression of p-ATF4 (ser 245) was associated with lymph node metastasis and advanced TNM stages (III and IV) in non-small cell lung cancer (p < 0.05). Immunofluorescent staining confirmed nuclear and cytoplasmic expression of p-ATF4 (ser 245) in lung and cancer tissues, and also in non-small cell lung cancer cell lines including NCI-H157 and LTE cells. These results indicate that increased expression of p-ATF4 (ser 245) may contribute to cancer development of non-small cell lung cancer and may be a potential cancer marker. PMID:23975372

  12. Anthropometric measurements in non-small-cell lung cancer.

    PubMed

    Ferrigno, D; Buccheri, G

    2001-10-01

    There is evidence that malnutrition is an important cause of morbidity and mortality in lung cancer patients and may have an impact on the clinical course of disease. The simplest way to assess nutritional status at the patient's bedside remains recourse to anthropometric measurements. This study was carried out in order to assess the clinical and prognostic significance of triceps skinfold thickness (TST), arm circumference (AC), and wrist circumference (WC) in lung cancer. The patient population was a consecutive series of 388 patients seen for a newly diagnosed primary non-small-cell lung cancer during the last 4 years. A set of 22 anthropometric, clinical, physical, laboratory, radiological, and pathological variables was prospectively recorded for all patients. Patients were carefully followed up, and their subsequent clinical course was recorded. The median values of TST, WC and AC were 8 mm (range 2-25 mm), 18 cm (range 10-27 cm), and 25 cm (range 15-35 cm), respectively. In 107 patients (27.6% of the total) TST values were below the reference value, and 37 of these patients also had a pathologically low small circumference. In all, AC was below the normality range in 60 of the 388 subjects (15.5%). Among the three variables, the strongest relationships were those between AC and WC (r(s)=0.541), and between TST and AC (r(s)=0.521). Univariate analyses of survival showed that TST was strongly predictive of a better prognosis (P<0.001), while WC was unrelated to outcome (P=0.101). Patients with higher values of AC had significantly longer survival than patients with lower values (P<0.018). The multivariate model, in contrast, did not confirm the prognostic capability of any of the anthropometric measures. These data indicate that the anthropometric measures may be significant predictors of survival, although not independently of the other prognostic factors. PMID:11680832

  13. Targeting Angiogenesis in Squamous Non-small Cell Lung Cancer

    PubMed Central

    Merla, Amartej; Perez-Soler, Roman

    2014-01-01

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and can be further classified as nonsquamous carcinoma (including adenocarcinoma, which accounts for 50% of NSCLCs) and squamous NSCLC, which makes up 30% of NSCLC cases. The emergence of inhibitors of epidermal growth factor receptors, anaplastic lymphoma kinase, and vascular endothelial growth factors (VEGF) in the last decade has resulted in steady improvement in clinical outcome for patients with advanced lung adenocarcinoma. However, improvements in the survival of patients with squamous NSCLC have remained elusive, presenting an urgent need for understanding and investigating therapeutically relevant molecular targets specifically in squamous NSCLC. Although anti-VEGF therapy has been studied in squamous NSCLC, progress has been slow, in part due to issues related to pulmonary hemorrhage. In addition to these safety concerns, several phase III trials that initially included patients with squamous NSCLC failed to demonstrate improved overall survival (primary endpoint) with the addition of antiangiogenic therapy to chemotherapy compared with chemotherapy alone. Angiogenesis is an established hallmark of tumor progression and metastasis, and the role of VEGF signaling in angiogenesis is well established. However, some studies suggest that while inhibiting VEGF signaling may be beneficial, prolonged exposure to VEGF/VEGF receptor (VEGFR) inhibitors may allow tumor cells to utilize alternative angiogenic mechanisms and become resistant. As a result, agents that target multiple angiogenic pathways simultaneously are also under evaluation. This review focuses on current and investigational antiangiogenic targets in squamous NSCLC, including VEGF/VEGFRs, fibroblast growth factor receptors, platelet-derived growth factor receptors, and angiopoietin. Additionally, clinical trials investigating VEGF- and multi-targeted antiangiogenic therapies are discussed. PMID:24578213

  14. Autophagy in non-small cell lung carcinogenesis

    PubMed Central

    Rao, Shuan; Yang, Heng; Penninger, Josef M; Kroemer, Guido

    2014-01-01

    In a mouse model of non-small cell lung carcinogenesis, we recently found that the inactivation of the essential autophagy gene Atg5 causes an acceleration of the early phases of oncogenesis. Thus, hyperplastic lesions and adenomas are more frequent at early stages after adenoviral delivery of Cre recombinase via inhalation, when Cre—in addition to activating the KRasG12D oncogene—inactivates both alleles of the Atg5 gene. The accelerated oncogenesis of autophagy-deficient tumors developing in KRas;Atg5fl/fl mice (as compared with autophagy-competent KRas;Atg5fl/+ control tumors) correlates with an increased infiltration by FOXP3+ regulatory T cells (Tregs). Depletion of such Tregs by means of specific monoclonal antibodies inhibits the accelerated oncogenesis of autophagy-deficient tumors down to the level observed in autophagy-competent controls. Subsequent analyses revealed that the combination of KRas activation and Atg5 inactivation favors the expression of ENTPD1/CD39, an ecto-ATPase that initiates the conversion of extracellular ATP, which is immunostimulatory, into adenosine, which is immunosuppressive. Pharmacological inhibition of ENTPD1 or blockade of adenosinergic receptors reduces the infiltration of KRas;Atg5fl/fl tumors by Tregs and reverses accelerated oncogenesis. Altogether these data favor a model according to which autophagy deficiency favors oncogenesis via changes in the tumor microenvironment that ultimately entail the Treg-mediated inhibition of anticancer immunosurveillance. PMID:24413089

  15. Surgical Management of Oligometastatic Non-Small Cell Lung Cancer.

    PubMed

    Lanuti, Michael

    2016-08-01

    Patients harboring stage IV non-small cell lung cancer represent a heterogeneous population with limited life expectancy. Targeted chemotherapy and immunotherapy have improved median survival for a minority of patients. A subset of patients with solitary foci of metastatic disease appears to have improved survival compared to others with stage IV NSCLC. The role of aggressive local control with curative intent for all disease sites in synchronous oligometastatic disease lacks randomized data; however, published retrospective series from single institutions suggest improved survival in highly selected patients (11-30%, 5-year survival) with low morbidity and mortality < 2%. PMID:27427523

  16. Radiation Therapy, Chemotherapy, and Soy Isoflavones in Treating Patients With Stage IIIA-IIIB Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2016-02-08

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  17. Therapeutic vaccines in non-small cell lung cancer

    PubMed Central

    Socola, Francisco; Scherfenberg, Naomi; Raez, Luis E

    2013-01-01

    Non-small cell lung cancer (NSCLC) unfortunately carries a very poor prognosis. Patients usually do not become symptomatic, and therefore do not seek treatment, until the cancer is advanced and it is too late to employ curative treatment options. New therapeutic options are urgently needed for NSCLC, because even current targeted therapies cure very few patients. Active immunotherapy is an option that is gaining more attention. A delicate and complex interplay exists between the tumor and the immune system. Solid tumors utilize a variety of mechanisms to evade immune detection. However, if the immune system can be stimulated to recognize the tumor as foreign, tumor cells can be specifically eliminated with little systemic toxicity. A number of vaccines designed to boost immunity against NSCLC are currently undergoing investigation in phase III clinical trials. Belagenpumatucel-L, an allogeneic cell vaccine that decreases transforming growth factor (TGF-β) in the tumor microenvironment, releases the immune suppression caused by the tumor and it has shown efficacy in a wide array of patients with advanced NSCLC. Melanoma-associated antigen A3 (MAGE-A3), an antigen-based vaccine, has shown promising results in MAGE-A3+ NSCLC patients who have undergone complete surgical resection. L-BLP25 and TG4010 are both antigenic vaccines that target the Mucin-1 protein (MUC-1), a proto-oncogene that is commonly mutated in solid tumors. CIMAVax is a recombinant human epidermal growth factor (EGF) vaccine that induces anti-EGF antibody production and prevents EGF from binding to its receptor. These vaccines may significantly improve survival and quality of life for patients with an otherwise dismal NSCLC prognosis. This review is intended to give an overview of the current data and the most promising studies of active immunotherapy for NSCLC.

  18. Spotlight on gefitinib in non-small-cell lung cancer.

    PubMed

    Frampton, James E; Easthope, Stephanie E

    2005-01-01

    Gefitinib (Iressa), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both docetaxel and platinum-based chemotherapy regimens. Gefitinib represents a significant advance in the treatment of this population; a once-daily oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilization, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favorably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use program. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings. Preliminary data demonstrate the presence of activating mutations in EGFR-TK among patients whose disease was highly responsive to treatment with gefitinib, although such mutations have not been correlated to all patients who benefit from the drug. Further studies are needed to fully elucidate the clinical implications of EGFR mutations and to identify patients likely to benefit from EGFR-targeted therapy. PMID:15813676

  19. Wnt signaling pathway in non-small cell lung cancer.

    PubMed

    Stewart, David J

    2014-01-01

    Wnt/β-catenin alterations are prominent in human malignancies. In non-small cell lung cancer (NSCLC), β-catenin and APC mutations are uncommon, but Wnt signaling is important in NSCLC cell lines, and Wnt inhibition reduces proliferation. Overexpression of Wnt-1, -2, -3, and -5a and of Wnt-pathway components Frizzled-8, Dishevelled, Porcupine, and TCF-4 is common in resected NSCLC and is associated with poor prognosis. Conversely, noncanonical Wnt-7a suppresses NSCLC development and is often downregulated. Although β-catenin is often expressed in NSCLCs, it was paradoxically associated with improved prognosis in some series, possibly because of E-cadherin interactions. Downregulation of Wnt inhibitors (eg, by hypermethylation) is common in NSCLC tumor cell lines and resected samples; may be associated with high stage, dedifferentiation, and poor prognosis; and has been reported for AXIN, sFRPs 1-5, WIF-1, Dkk-1, Dkk-3, HDPR1, RUNX3, APC, CDX2, DACT2, TMEM88, Chibby, NKD1, EMX2, ING4, and miR-487b. AXIN is also destabilized by tankyrases, and GSK3β may be inactivated through phosphorylation by EGFR. Preclinically, restoration of Wnt inhibitor function is associated with reduced Wnt signaling, decreased cell proliferation, and increased apoptosis. Wnt signaling may also augment resistance to cisplatin, docetaxel, and radiotherapy, and Wnt inhibitors may restore sensitivity. Overall, available data indicate that Wnt signaling substantially impacts NSCLC tumorigenesis, prognosis, and resistance to therapy, with loss of Wnt signaling inhibitors by promoter hypermethylation or other mechanisms appearing to be particularly important. Wnt pathway antagonists warrant exploration clinically in NSCLC. Agents blocking selected specific β-catenin interactions and approaches to increase expression of downregulated Wnt inhibitors may be of particular interest. PMID:24309006

  20. Integrated molecular portrait of non-small cell lung cancers

    PubMed Central

    2013-01-01

    Background Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of ~800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions Integrated molecular characterization of AC and SCC helped identify clinically relevant markers

  1. Genetic polymorphisms and non-small-cell lung cancer: future paradigms

    PubMed Central

    de Mello, Ramon Andrade Bezerra

    2014-01-01

    This article addresses some current issues about genetic polymorphisms studied in the non-small-cell lung cancer translational field. Furthermore, it discusses about new potential biomarkers regarding lung cancer risk and prognosis. PMID:25628210

  2. PET/CT in the Staging of the Non-Small-Cell Lung Cancer

    PubMed Central

    Chao, Fangfang; Zhang, Hong

    2012-01-01

    Lung cancer is a common disease and the leading cause of cancer-related death in many countries. Precise staging of patients with non-small-cell lung cancer plays an important role in determining treatment strategy and prognosis. Positron emission tomography/computed tomography (PET/CT), combining anatomic information of CT and metabolic information of PET, is emerging as a potential diagnosis and staging test in patients with non-small-cell lung cancer (NSCLC). The purpose of this paper is to discuss the value of integrated PET/CT in the staging of the non-small-cell lung cancer and its health economics. PMID:22577296

  3. Population pharmacokinetic modeling of sepantronium bromide (YM155), a small molecule survivin suppressant, in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma.

    PubMed

    Aoyama, Yumiko; Kaibara, Atsunori; Takada, Akitsugu; Nishimura, Tetsuya; Katashima, Masataka; Sawamoto, Taiji

    2013-04-01

    Purpose Population pharmacokinetics (PK) of sepantronium bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m(2)/day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CLCR), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CLCR was the most influential covariate on sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CLCR = 40 mL/min) compared to patients with normal CLCR. Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for sepantronium in cancer therapy. PMID:22892872

  4. Immunotherapy for non-small cell lung cancer: current concepts and clinical trials.

    PubMed

    Mayor, Marissa; Yang, Neng; Sterman, Daniel; Jones, David R; Adusumilli, Prasad S

    2016-05-01

    Recent successes in immunotherapeutic strategies are being investigated to combat cancers that have less than ideal responses to standard of care treatment, such as non-small-cell lung cancer. In this paper, we summarize concepts and the current status of immunotherapy for non-small cell lung cancer, including salient features of the major categories of immunotherapy-monoclonal antibody therapy, immune checkpoint blockade, immunotoxins, anticancer vaccines, and adoptive cell therapy. PMID:26516195

  5. Comparison of Two Therapeutic Strategies in Patients With Non-squamous Non-small Cell Lung Cancer (NSCLC) With Asymptomatic Brain Metastases

    ClinicalTrials.gov

    2015-11-29

    Non-small Cell Lung Cancer Metastatic; Non Epidermoid; Non-small Cell Lung Cancer; Adenocarcinoma of Lung Metastatic to Brain; Cerebral Metastases; Cerebral Radiotherapy; Brain Radiotherapy; Bevacizumab

  6. Classification of Epidermal Growth Factor Receptor Gene Mutation Status Using Serum Proteomic Profiling Predicts Tumor Response in Patients with Stage IIIB or IV Non-Small-Cell Lung Cancer

    PubMed Central

    Yang, Lin; Tang, Chuanhao; Xu, Bin; Wang, Weixia; Li, Jianjie; Li, Xiaoyan; Qin, Haifeng; Gao, Hongjun; He, Kun; Song, Santai; Liu, Xiaoqing

    2015-01-01

    Objectives Epidermal growth factor receptor (EGFR) gene mutations in tumors predict tumor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). However, obtaining tumor tissue for mutation analysis is challenging. Here, we aimed to detect serum peptides/proteins associated with EGFR gene mutation status, and test whether a classification algorithm based on serum proteomic profiling could be developed to analyze EGFR gene mutation status to aid therapeutic decision-making. Patients and Methods Serum collected from 223 stage IIIB or IV NSCLC patients with known EGFR gene mutation status in their tumors prior to therapy was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software. Differences in serum peptides/proteins between patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes were detected in a training group of 100 patients; based on this analysis, a serum proteomic classification algorithm was developed to classify EGFR gene mutation status and tested in an independent validation group of 123 patients. The correlation between EGFR gene mutation status, as identified with the serum proteomic classifier and response to EGFR-TKIs was analyzed. Results Nine peptide/protein peaks were significantly different between NSCLC patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes in the training group. A genetic algorithm model consisting of five peptides/proteins (m/z 4092.4, 4585.05, 1365.1, 4643.49 and 4438.43) was developed from the training group to separate patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes. The classifier exhibited a sensitivity of 84.6% and a specificity of 77.5% in the validation group. In the 81 patients from the validation group treated with EGFR-TKIs, 28 (59.6%) of 47 patients whose matched samples were labeled as “mutant” by the classifier and 3 (8.8%) of 34 patients

  7. Treatment Option Overview (Non-Small Cell Lung Cancer)

    MedlinePlus

    ... lung cancer include a cough that doesn't go away and shortness of breath. Sometimes lung cancer ... discomfort or pain. A cough that doesn’t go away or gets worse over time. Trouble breathing. ...

  8. Treatment Options by Stage (Non-Small Cell Lung Cancer)

    MedlinePlus

    ... lung cancer include a cough that doesn't go away and shortness of breath. Sometimes lung cancer ... discomfort or pain. A cough that doesn’t go away or gets worse over time. Trouble breathing. ...

  9. Stages of Non-Small Cell Lung Cancer

    MedlinePlus

    ... lung cancer include a cough that doesn't go away and shortness of breath. Sometimes lung cancer ... discomfort or pain. A cough that doesn’t go away or gets worse over time. Trouble breathing. ...

  10. Non-small cell lung carcinoma metastasis to the anus.

    PubMed

    Dhandapani, Ramya Gowri; Anosike, Chinedum; Ganguly, Akash

    2016-01-01

    A 70-year-old man presenting with a lung mass was investigated and treated with pneumonectomy for adenocarcinoma of the lung. He re-presented 3 months later with a large perianal abscess and mass. Subsequent investigations and biopsies showed disseminated metastases from the lung primary. Immunohistochemical staining confirmed the nature of the anal metastasis from the lung adenocarcinoma. Lung cancer is notorious for metastases, hence it is important to be aware of the uncommon modes of spread, which will help obtain early diagnosis and optimise treatment. PMID:27130556

  11. Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer

    ClinicalTrials.gov

    2016-06-17

    Adenosquamous Lung Carcinoma; Bronchioloalveolar Carcinoma; Large Cell Lung Carcinoma; Lung Adenocarcinoma; Non-Small Cell Lung Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer

  12. Mediastinal Staging in Non-Small Cell Lung Cancer.

    PubMed

    Gamliel, Ziv

    2016-07-01

    In the absence of distant metastases, lung cancer treatment is determined by the results of mediastinal lymph node staging. Occult mediastinal lymph node metastases can be missed by radiologic and needle-based staging methods. Aggressive staging of mediastinal lymph nodes improves staging accuracy. Improved accuracy of mediastinal lymph node staging results in more appropriate lung cancer treatment. Improved accuracy of mediastinal lymph node staging can improve stage-specific survival from lung cancer. PMID:27261911

  13. Crizotinib for Advanced Non-Small Cell Lung Cancer

    Cancer.gov

    A summary of results from an international phase III clinical trial that compared crizotinib versus chemotherapy in previously treated patients with advanced lung cancer whose tumors have an EML4-ALK fusion gene.

  14. Vaccine therapy in non-small-cell lung cancer.

    PubMed

    Albright, Carol; Garst, Jennifer

    2007-07-01

    Lung cancer is the leading cause of death from cancer worldwide. First-line therapy is based on stage at diagnosis and can include chemotherapy, radiation, and surgery. Despite advances, the prognosis for advanced-stage lung cancer is very poor. Vaccines with the capability to activate the host immune system may have a role in second-line therapy. Advances in the understanding of cellular and molecular immunology are forming the basis for improving vaccine therapy. Most trials to date have demonstrated safety but inconsistent efficacy. Further research is needed to enhance this potential. PMID:17588347

  15. Intracardiac Metastasis From Non-Small Cell Lung Cancer

    PubMed Central

    Verma, Vivek; Talmon, Geoffrey A.; Zhen, Weining K.

    2015-01-01

    A 56-year-old female with history of stage IIA adenosquamous lung carcinoma treated 13 months prior to presentation with lobectomy, mediastinal lymph node dissection, and adjuvant chemotherapy, presented for several weeks of worsening dyspnea. Exam was non-focal aside from tachycardia. Computed tomography of the chest revealed a large 4 cm × 5 cm mass in the bilateral ventricular myocardium. There was also evidence of metastatic disease elsewhere in the body, including a supraclavicular lymph node that was positive for metastatic adenosquamous lung carcinoma. She started whole heart radiotherapy and was to commence chemotherapy but passed away. This report discusses important aspects of diagnosis of this not uncommon condition that many oncologists may come across. We also discuss differential diagnosis of an isolated intracardiac mass as first-diagnosis presentations, and discuss the great importance of multidisciplinary cardio-oncologic management and clinical prioritization. PMID:26258073

  16. Combination Chemotherapy, Radiation Therapy, and Bevacizumab in Treating Patients With Newly Diagnosed Stage III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-05-26

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Bronchoalveolar Cell Lung Cancer; Large Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  17. Protein signature for non-small cell lung cancer prognosis

    PubMed Central

    Liu, Wei; Wu, Yong; Wang, Libo; Gao, Ling; Wang, Yingping; Liu, Xiaoliang; Zhang, Kai; Song, Jena; Wang, Hongxia; Bayer, Thomas A; Glaser, Laurel; Sun, Yezhou; Zhang, Weijia; Cutaia, Michael; Zhang, David Y; Ye, Fei

    2014-01-01

    Background: Current histopathological classification and TNM staging have limited accuracy in predicting survival and stratifying patients for appropriate treatment. The goal of the study is to determine whether the expression pattern of functionally important regulatory proteins can add additional values for more accurate classification and prognostication of non-small lung cancer (NSCLC). Methods: The expression of 108 proteins and phosphoproteins in 30 paired NSCLC samples were assessed using Protein Pathway Array (PPA). The differentially expressed proteins were further confirmed using a tissue microarray (TMA) containing 94 NSCLC samples and were correlated with clinical data and survival. Results: Twelve of 108 proteins (p-CREB(Ser133), p-ERK1/2(Thr202/Tyr204), Cyclin B1, p-PDK1(Ser241), CDK4, CDK2, HSP90, CDC2p34, β-catenin, EGFR, XIAP and PCNA) were selected to build the predictor to classify normal and tumor samples with 97% accuracy. Five proteins (CDC2p34, HSP90, XIAP, CDK4 and CREB) were confirmed to be differentially expressed between NSCLC (n=94) and benign lung tumor (n=19). Over-expression of CDK4 and HSP90 in tumors correlated with a favorable overall survival in all NSCLC patients and the over-expression of p-CREB(Ser133) and CREB in NSCLC correlated with a favorable survival in smokers and those with squamous cell carcinoma, respectively. Finally, the four proteins (CDK4, HSP90, p-CREB and CREB) were used to calculate the risk score of each individual patient with NSCLC to predict survival. Conclusion: In summary, our data demonstrated a broad disturbance of functionally important regulatory proteins in NSCLC and some of these can be selected as clinically useful biomarkers for diagnosis, classification and prognosis. PMID:24959380

  18. Veliparib With or Without Radiation Therapy, Carboplatin, and Paclitaxel in Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-08-31

    Bronchioloalveolar Carcinoma; Large Cell Lung Carcinoma; Lung Adenocarcinoma; Lung Adenocarcinoma, Mixed Subtype; Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Non-Small Cell Lung Cancer

  19. Cost-effectiveness of paclitaxel plus cisplatin in advanced non-small-cell lung cancer

    PubMed Central

    Earle, C C; Evans, W K

    1999-01-01

    The aim of this study was to assess the cost-effectiveness of combination chemotherapy with paclitaxel/cisplatin, compared with standard etoposide/cisplatin in patients with advanced non-small cell lung cancer (NSCLC). We obtained the primary survival and resource utilization data from a large three-arm randomized trial comparing: paclitaxel 135 mg m−2 by 24-h intravenous (i.v.) infusion + cisplatin; paclitaxel 250 mg m−2 by 24-h i.v. infusion + cisplatin + granulocyte colony-stimulating factor (G-CSF); and standard etoposide/cisplatin in patients with stage IIIb or IV NSCLC. We also modelled the regimens with paclitaxel 135 mg m−2 + cisplatin administered as an outpatient by 3-h infusion, as clinical data suggest that this is equivalent to 24-h infusion. We collected costing data from the Ottawa Regional Cancer Centre and applied it to the resources consumed in the randomized trial. We integrated these data into the Statistics Canada POpulation HEalth Model (POHEM), which generated hypothetical cohorts of patients treated with each regimen. The POHEM model assigned diagnostic work-up, treatment, disease progression and survival characteristics to each individual in these cohorts and tabulated the costs associated with each. We did sensitivity analyses around the costs of chemotherapy and its administration, and the survival differences between the two regimens. All costs are in 1997 Canadian dollars ($1.00 Canadian ˜ £0.39 sterling). The perspective is that of the Canadian health care system. In the trial, the two paclitaxel-containing arms had almost identical survival curves with a median survival of 9.7 months compared with 7.4 months for etoposide/cisplatin. As administered in the trial, paclitaxel/cisplatin cost $76 370 per life-year gained (LYG) and paclitaxel/cisplatin/G-CSF $138 578 per LYG relative to etoposide/cisplatin. However, when modelled as an outpatient 3-h infusion, paclitaxel/cisplatin was moderately cost-effective at $30 619 per LYG

  20. Local Therapy Indications in the Management of Patients with Oligometastatic Non-Small Cell Lung Cancer.

    PubMed

    Miller, Douglas A; Krasna, Mark J

    2016-07-01

    Advances in surgical, radiation, and interventional radiology therapies carry a reduction in morbidity associated with therapy. Aggressive management of patients with oligometastatic non-small cell lung cancer offers the potential for improved disease-free survival and quality of life compared with traditional systemic therapy alone. PMID:27261919

  1. Curcumin-ER Prolonged Subcutaneous Delivery for the Treatment of Non-Small Cell Lung Cancer.

    PubMed

    Ranjan, Amalendu P; Mukerjee, Anindita; Gdowski, Andrew; Helson, Lawrence; Bouchard, Annie; Majeed, Muhammed; Vishwanatha, Jamboor K

    2016-04-01

    Non-small-cell lung cancer therapy is a challenge due to poor prognosis and low survival rate. There is an acute need for advanced therapies having higher drug efficacy, low immunogenicity and fewer side effects which will markedly improve patient compliance and quality of life of cancer patients. The purpose of this study was to develop a novel hybrid curcumin nanoformulation (Curcumin-ER) and evaluate the therapeutic efficacy of this formulation on a non-small cell lung cancer xenograft model. Use of curcumin, a natural anticancer agent, is majorly limited due to its poor aqueous solubility and hence it's low systemic bioavailability. In this paper, we carried out the nanoformulation of Curcumin-ER, optimized the formulation process and determined the anticancer effects of Curcumin-ER against human A549 non-small cell lung cancer using in vitro and in vivo studies. Xenograft tumors in nude mice were treated with 20 mg/kg subcutaneous injection of Curcumin-ER and liposomal curcumin (Lipocurc) twice a week for seven weeks. Results showed that tumor growth was suppressed by 52.1% by Curcumin-ER treatment and only 32.2% by Lipocurc compared to controls. Tumor sections were isolated from murine xenografts and histology and immunohistochemistry was performed. A decrease in expression of NFκB-p65 subunit and proliferation marker, Ki-67 was observed in treated tumors. In addition, a potent anti-angiogenic effect, characterized by reduced expression of annexin A2 protein, was observed in treated tumors. These results establish the effectiveness of Curcumin-ER in regressing human non-small cell lung cancer growth in the xenograft model using subcutaneous route of administration. The therapeutic efficacy of Curcumin-ER highlights the potential of this hybrid nanoformulation in treating patients with non-small cell lung cancer. PMID:27301194

  2. Thermal ablation of stage I non-small cell lung carcinoma.

    PubMed

    Ridge, Carol A; Solomon, Stephen B; Thornton, Raymond H

    2014-06-01

    Ablation options for the treatment of localized non-small cell lung carcinoma (NSCLC) include radiofrequency ablation, microwave ablation, and cryotherapy. Irreversible electroporation is a novel ablation method with the potential of application to lung tumors in risky locations. This review article describes the established and novel ablation techniques used in the treatment of localized NSCLC, including mechanism of action, indications, potential complications, clinical outcomes, postablation surveillance, and use in combination with other therapies. PMID:25053863

  3. Epidermal growth factor receptor in non-small cell lung cancer

    PubMed Central

    2015-01-01

    Following the identification of a group of patients in the initial tyrosine kinase inhibitor (TKI) trials for lung cancer, there has been detailed focus on which patients may benefit from inhibitor therapy. This article reviews the background, genetics and prevalence of epidermal growth factor mutations in non-small cell lung cancer (NSCLC). Additionally, the prevalence in unselected patients is compared against various other reviews. PMID:25870793

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

    ClinicalTrials.gov

    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

  5. Non small-cell lung cancer with metastasis to thigh muscle and mandible: two case reports

    PubMed Central

    2013-01-01

    Introduction Lung cancer is the leading cause of cancer-related death in Europe and the US. Isolated metastases to skeletal muscle and the mandible are very uncommon. Case presentation This report presents two cases. Case 1 concerns a 45-year-old Caucasian woman affected by muscle metastasis of the right thigh from non-small-cell lung cancer. Case 2 concerns a 61-year-old Caucasian man affected by mandible metastasis from non-small-cell lung cancer. Both metastases were detected by diagnostic imaging studies. Both patients were treated with radiation therapy with palliative and antalgic intent. Conclusion Radiation therapy was effective and well tolerated in both cases. Both our patients are alive, with follow-up of 18 months and five months, respectively. PMID:23566415

  6. Immunotherapy in locally-advanced non-small cell lung cancer: releasing the brakes on consolidation?

    PubMed Central

    2016-01-01

    Locally-advanced non-small cell lung cancer (LA-NSCLC) is optimally treated with definitive chemoradiation or surgery in combination with chemotherapy or chemoradiation. Prognosis, however, remains poor, and attempts to improve outcomes using consolidation or maintenance chemotherapy have not improved overall survival. Given the limited success of traditional cytotoxic chemotherapies as maintenance therapy for LA-NSCLC, recent studies have investigated the role of novel agents such as maintenance or consolidation, including antiangiogenic agents and molecular targeted therapy. With multiple newly reported trials demonstrating improved outcomes with immunotherapy over cytotoxic chemotherapy for stage IV NSCLC, integrating immunotherapy with definitive chemoradiation regimens or as consolidative therapy for LA-NSCLC is an attractive option. The recently published START trial is the first to test immunotherapy in LA-NSCLC in a randomized, phase III setting. In that trial, the administration of maintenance tecemotide (L-BLP25), which induces a T-cell response to the mucin 1 (MUC1) glycoprotein, was found to be well tolerated and improve overall survival compared with placebo among patients receiving concurrent, but not sequential, chemoradiation. Despite the promising findings of this trial, numerous questions regarding immunotherapy for LA-NSCLC remain, and several additional immunotherapy trials are underway or planned in this patient population. PMID:26958509

  7. Phase II study of lonidamine in non-small cell lung cancer: final report.

    PubMed

    Kokron, O; Maca, S; De Gregorio, M; Ciottoli, G B

    1990-02-01

    Lonidamine (LND) is a new anti-cancer drug which interferes with the energy-yielding processes of tumour cells without affecting DNA replication. A total of 69 previously untreated patients with non-small cell lung cancer (NSCLC) entered this study. LND was given orally as a single agent at doses ranging from 450 to 900 mg day-1 until tumour progression (2 to greater than or equal to 1,402 days). Partial responses (PR) occurred in 7/69 patients (10.1%); 4/25, 1/27 and 2/9 for epidermoid, adenocarcinoma and large cell cancer respectively. PR by stage was 4/10, 1/3, 1/20 and 1/28 for stages I, II, III and IV, respectively. The median duration of response was 303 days (greater than or equal to 61 to greater than or equal to 338 days). The median survival for the whole group was 261 days. Toxicity was assessed in all patients. No myelosuppression occurred. The main side-effects were myalgia (68%), loss of appetite (23%), asthenia (20%) and testicular pain (13%). Doses above 450 mg day-1 produced more severe side-effects without any improvement in therapeutic activity. PMID:2155644

  8. Safety and Palliative Efficacy of Single-Dose 8-Gy Reirradiation for Painful Local Failure in Patients With Stage IV Non-Small Cell Lung Cancer Previously Treated With Radical Chemoradiation Therapy

    SciTech Connect

    Topkan, Erkan; Yildirim, Berna Akkus; Guler, Ozan Cem; Parlak, Cem; Pehlivan, Berrin; Selek, Ugur

    2015-03-15

    Purpose: To investigate the safety and efficacy of single-dose 8-Gy palliative chest reirradiation (CRI) in metastatic non-small cell lung cancer (M-NSCLC) patients with painful thoracic failures (TF) within the previous radiation portal. Patients and Methods: We retrospectively analyzed the clinical data of 78 M-NSCLC patients who received single-dose 8-Gy CRI for painful TF after concurrent chemoradiation therapy to a total radiation dose of 52 to 66 Gy between 2007 and 2012. Primary endpoints included significant pain relief (SPR) defined as a ≥2 point decrement in the Visual Analogue Scale for Pain inventory (VAS-P), time to pain relief, and duration of pain control. Secondary objectives were survival and prognostic factors. Results: Treatment was well tolerated, with only 5.1% grade 3 pneumonitis and 1.3% grade 2 esophagitis. Pre-CRI median and post-CRI minimum VAS-P were 7 and 3 (P<.001), respectively. SPR was noted in 67 (85.9%) patients, and only 3 (3.9%) scored progressive pain. Median time to lowest VAS-P and duration of pain control were 27 days and 6.1 months, respectively. Median overall survival (OS) was 7.7 months, and the 1-year OS rate was 26.5%. On multivariate analyses, lower Eastern Cooperative Oncology group score (1-2; P<.001), absence of anemia (P=.001), and fewer metastatic sites (1-2; P<.001) were found to be associated with longer OS. Conclusions: Single-dose 8-Gy CRI provides safe, effective, and durable pain palliation for TF in radically irradiated M-NSCLC patients. Because of its convenience, lower cost, and higher comfort, the present protocol can be considered an appropriate option for patients with limited life spans.

  9. Prognostic Factors and Survival in Non-Small Cell Lung Cancer Patients Treated with Chemoradiotherapy

    PubMed Central

    Crvenkova, Simonida

    2015-01-01

    BACKGROUND: According to the literature, performance status, stage-tumor dimension and nodal status, weight loss, were the most important prognostic factors for survival in patients with locally advanced non-small cell lung cancer. AIM: To evaluate the treatment results and the prognostic variables in our patients treated with sequential and concurrent chemoradiotherapy. MATERIAL AND METHODS: In the study 85 patients were randomly assigned to one of the two treatment arms. In the sequential arm, 45 patients had previously received sequential chemotherapy with 4 cycles of and etoposide followed by conformal radiotherapy (RT). In the second concurrent group, 40 patients received concomitant chemotherapy of cisplatine and etoposide and conformal RT, followed by two cycles of consolidation chemotherapy of carboplatine and etoposide. We described all phases of the conformal three dimensional (3-D) RT. RESULTS: From October 2005 to March 2008, 93 patients were enrolled. Eight patients were not eligible, seven had stage IV and one patient had pleural effusion. They were all initially considered to have stage IIIB disease. The median survival was 13 months for the patients in the sequential arm and 19 months for those in the concurrent treatment arm. The differences were statistically significant (log-rank test p=0.0039). The disease-free survival was 9 months in the sequential arm and 16 months in the concurrent treatment group. The differences were statistically significant (log-rank test p=0.0023). We found that the following prognostic factors significantly influenced the survival in lung cancer patients treated with conservative method: - age, p<0.05; - performant status, p<0.001; - weight loss, p<0.001; tumor dimension, p<0.05; and - nodal involvement, p<0.05. CONCLUSION: In our study, the dose-limiting toxicity, esophagitis was reduced by performing conformal radiotherapy. Conformal thoracic radiotherapy and new radiotherapy technics, such as respiratory gated

  10. Secondary osteosarcoma developing 10 years after chemoradiotherapy for non-small-cell lung cancer.

    PubMed

    Yagishita, Shigehiro; Horinouchi, Hidehito; Yorozu, Takashi; Kitazono, Satoru; Mizugaki, Hidenori; Kanda, Shintaro; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Mori, Taisuke; Tsuta, Koji; Sumi, Minako; Tamura, Tomohide

    2014-02-01

    A 53-year-old female patient was admitted with pain and a progressively enlarging mass in the right upper chest. Chest computed tomography revealed a mass lesion in the region of the right upper ribs. Ten years prior to this admission, the patient had undergone right lobectomy for lung adenocarcinoma. One year after the surgery, follow-up computed tomography had revealed tumor recurrence in the mediastinal and supraclavicular lymph nodes, and the patient had been treated by chemoradiotherapy. Thereafter, regular follow-up had revealed no evidence of recurrence of the non-small-cell lung cancer. Histopathological findings revealed proliferation of spindle-shaped malignant tumor cells in a background of osteoid, consistent with the diagnosis of osteosarcoma. The location of the tumor was consistent with the radiation field. Based on the clinicopathological findings, the patient was diagnosed as having secondary osteosarcoma occurring as a result of the chemoradiotherapy administered previously for the recurrent non-small-cell lung cancer. Unfortunately, the patient died of rapid progression of the osteosarcoma within a week of admission to the hospital. The autopsy revealed contiguous invasion by the tumor of the heart, with massive thrombus formation. The peripheral pulmonary arteries were diffusely occluded by metastatic tumors. Our case serves to highlight the risk of development of secondary sarcoma as a life-threatening late complication after chemoradiotherapy for locally advanced non-small-cell lung cancer, even after complete cure of the primary tumor. PMID:24338556

  11. Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer

    PubMed Central

    Aftab, Blake T.; Dobromilskaya, Irina; Liu, Jun O.; Rudin, Charles M.

    2011-01-01

    The anti-angiogenic agent bevacizumab has been approved for the treatment of non-small cell lung cancer, although the survival benefit associated with this agent is marginal, and toxicities and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral anti-fungal drug itraconazole as a novel agent with potential anti-angiogenic activity. Here we define and characterize the anti-angiogenic and anti-cancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently demonstrated potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-mediated angiogenic stimulation. In vivo, using primary xenograft models of human non-small cell lung cancer, oral itraconazole showed single agent growth-inhibitory activity associated with induction of tumor HIF1α expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the anti-tumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic non-small cell lung cancer. PMID:21896639

  12. A rare case of non-small cell carcinoma of lung presenting as miliary mottling.

    PubMed

    Jayaram Subhashchandra, Ballaekere; Ismailkhan, Mohammed; Chikkaveeraiah Shashidhar, Kuppegala; Gopalakrishna Narahari, Moda

    2013-03-01

    Miliary mottling on chest radiography is seen in miliary tuberculosis, certain fungal infections, sarcoidosis, coal miner's pneumoconiosis, silicosis, hemosiderosis, fibrosing alveolitis, acute extrinsic allergic alveolitis, pulmonary eosinophilic syndrome, pulmonary alveolar proteinosis, and rarely in hematogenous metastases from the primary cancers of the thyroid, kidney, trophoblasts, and some sarcomas. Although very infrequent, miliary mottling can be seen in primary lung cancers. Herein, we report the case of a 28-year-old female with chest X-ray showing miliary mottling. Thoracic computed tomography (CT) features were suggestive of tuberculoma with miliary tuberculosis. CT-guided fine needle aspiration cytology confirmed the diagnosis as lower-lobe, left lung non-small cell carcinoma (adenocarcinoma). It is rare for the non-small cell carcinoma of the lung to present as miliary mottling. The rarity of our case lies in the fact that a young, non-smoking female with miliary mottling was diagnosed with non-small cell carcinoma of the lung. PMID:23645961

  13. Image-Guided Hypofractionated Radiation Therapy With Stereotactic Body Radiation Therapy Boost and Combination Chemotherapy in Treating Patients With Stage II-III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-09-07

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  14. Role of immunotherapy in the treatment of advanced non-small-cell lung cancer.

    PubMed

    Rijavec, Erika; Genova, Carlo; Alama, Angela; Barletta, Giulia; Sini, Claudio; Pronzato, Paolo; Coco, Simona; Dal Bello, Maria Giovanna; Savarino, Graziana; Truini, Anna; Boccardo, Francesco; Grossi, Francesco

    2014-01-01

    After several decades of modest results with nonspecific immune stimulants, immunotherapy has become an exciting approach in the treatment of cancer. Although non-small-cell lung cancer has not been considered an immunogenic disease for very long, a better understanding of tumor immunology and the identification of new targets have led to the development of many clinical trials of immune-based therapies for this neoplasm. Promising results from many clinical trials suggest that immunotherapy could be an effective strategy in the management of advanced non-small-cell lung cancer. Further studies are required to help clinicians in the selection of patients who are more likely to benefit from immunotherapy strategies by the identification of biomarkers and to understand when the combination of immunotherapy with other agents should be recommended. PMID:24328411

  15. [A case of non-small cell lung cancer with hemodialysis which responded to docetaxel monotherapy].

    PubMed

    Abe, Yumiko; Tanaka, Kentaro; Matsumoto, Koichiro; Takayama, Koichi; Inoue, Hiroyuki; Izumi, Miiru; Inoue, Hiromasa; Nakanishi, Yoichi

    2010-10-01

    A 56-year-old man receiving hemodialysis treatment was hospitalized for examination of a mass in the right middle lobe. Chest computed tomography showed a right hilar mass shadow accompanied by pleural effusion. Non-small cell lung cancer (NSCLC) was diagnosed by cytological examination of the pleural effusion. No epidermal growth factor receptor (EGFR) mutation was found. He was treated with 6 courses of docetaxel as first-line chemotherapy. Docetaxel was administered on the same day as hemodialysis. Adverse events, including hematotoxicity, were managed safely and no delay in administration occurred. This chemotherapy resulted in a partial response. Because docetaxel is metabolized in the liver and does not affect renal function, it can be administered as a standard regimen. This suggests that docetaxel monotherapy is an efficient therapy for non-small cell lung cancer patients receiving hemodialysis. PMID:21066867

  16. ROS1 rearranged non-small cell lung cancer brain metastases respond to low dose radiotherapy.

    PubMed

    Lukas, Rimas V; Hasan, Yasmin; Nicholas, Martin K; Salgia, Ravi

    2015-12-01

    We present a young woman with ROS1 gene rearranged non-small cell lung cancer (NSCLC) with brain metastases. ROS is a proto-oncogene tyrosine protein kinase. The patient received a partial course of whole brain radiation therapy and experienced a sustained partial response in the brain. We hypothesize that ROS1 rearranged NSCLC brain metastases may be particularly sensitive to radiation therapy. PMID:26159887

  17. Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer.

    PubMed

    Engel, Julian; Lategahn, Jonas; Rauh, Daniel

    2016-01-14

    In the last five years, the detailed understanding of how to overcome T790M drug resistance in non-small cell lung cancer (NSCLC) has culminated in the development of a third-generation of covalent EGFR inhibitors with excellent clinical outcomes. However, the emergence of a newly discovered acquired drug resistance challenges the concept of small molecule targeted cancer therapy in NSCLC. PMID:26819655

  18. Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer

    PubMed Central

    Dutt, Amit; Ramos, Alex H.; Hammerman, Peter S.; Mermel, Craig; Cho, Jeonghee; Sharifnia, Tanaz; Chande, Ajit; Tanaka, Kumiko Elisa; Stransky, Nicolas; Greulich, Heidi; Gray, Nathanael S.; Meyerson, Matthew

    2011-01-01

    Background Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma. Methodology/Principal Findings Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition. Conclusions/Significance These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer. PMID:21666749

  19. Selection of chemotherapy for non-small cell lung cancer is facilitated by new therapeutic strategies

    PubMed Central

    Wang, Zhehai

    2014-01-01

    Nowadays, advanced non-small cell lung cancer is still an incurable disease. Recent researches have led to considerable progress in the treatment of non-small cell lung cancer. This article reviews the main studies on chemotherapy on non-small cell lung cancer and discusses the new therapeutic strategies available to date. Stable disease (SD) is necessary in chemotherapy for tumor. The proportion of population with responders or SD basically maintained similar regardless of regimens. The overall survival after chemotherapy for patients with SD was lower than patients with responders, and higher than patients with progressive disease. Greater benefits could be achieved in patients with effective induction chemotherapy using chemotherapeutic agents for maintenance therapy, whereas the benefits were relatively small for patients with SD. It has been found that epidermal growth factor receptor (EGFR) mutation status had certain correlation with the efficacy of chemotherapy. First-line chemotherapy has shown advantages in effective rate and progression free survival on EGFR mutant. EGFR mutation produced significant effects on the efficacy of postoperative adjuvant chemotherapy. Patients with EGFR mutation had a higher effective rate than wild-type EGFR patients, and patients with responders had a greater benefit in progression free survival from maintenance therapy. However, it is still necessary to carry out more careful and deeper studies and analyses on traditional cytotoxic chemotherapy, to further optimize cytotoxic chemotherapy and to use molecular targeted agents with different mechanisms. PMID:25550891

  20. [Advances in Bevacizumab Therapy for Non-small Cell Lung Cancer 
with Brain Metastases].

    PubMed

    Qu, Liyan; Geng, Rui; Song, Xia

    2016-08-20

    Brain metastases are frequently encountered in patients with non-small cell lung cancer (NSCLC) and are a significant cause of morbidity and mortality. Antiangiogenesis therapy plays a major role in the management of brain metastases in lung cancer. Bevacizumab have become the novel method for the treatment of lung cancer with brain metastases beyond the whole brain radiation therapy, stereotactic radiosurgery and chemotherapy. Recently, more and more studies and trials laid emphasis on the bevacizumab for NSCLC with brain metastases treatment. The key point is the efficacy and safety. In this review, bevacizumab therapy of NSCLC with brain metastases were summarized. PMID:27561800

  1. Use of Palliative Radiotherapy Among Patients With Metastatic Non-Small-Cell Lung Cancer

    SciTech Connect

    Hayman, James A. Abrahamse, Paul H.; Lakhani, Indu; Earle, Craig C.; Katz, Steven J.

    2007-11-15

    Purpose: Radiotherapy (RT) is known to effectively palliate many symptoms of patients with metastatic non-small-cell lung cancer (NSCLC). Anecdotally, RT is believed to be commonly used in this setting, but limited population-based data are available. The objective of this study was to examine the utilization patterns of palliative RT among elderly patients with Stage IV NSCLC and, in particular, to identify factors associated with its use. Methods and Materials: A retrospective population-based cohort study was performed using linked Surveillance, Epidemiology and End Results (SEER)-Medicare data to identify 11,084 Medicare beneficiaries aged {>=}65 years who presented with Stage IV NSCLC in the 11 SEER regions between 1991 and 1996. The primary outcome was receipt of RT. Logistic regression analysis was used to identify factors associated with receipt of RT. Results: A total of 58% of these patients received RT, with its use decreasing over time (p = 0.01). Increasing age was negatively associated with receipt of treatment (p <0.001), as was increasing comorbidities (p <0.001). Factors positively associated with the receipt of RT included income (p = 0.001), hospitalization (p <0.001), and treatment with chemotherapy (p <0.001). Although the use varied across the SEER regions (p = 0.001), gender, race/ethnicity, and distance to the nearest RT facility were not associated with treatment. Conclusions: Elderly patients with metastatic NSCLC frequently receive palliative RT, but its use varies, especially with age and receipt of chemotherapy. Additional research is needed to determine whether this variability reflects good quality care.

  2. Definitive Primary Therapy in Patients Presenting With Oligometastatic Non-Small Cell Lung Cancer

    SciTech Connect

    Parikh, Ravi B.; Cronin, Angel M.; Kozono, David E.; Oxnard, Geoffrey R.; Mak, Raymond H.; Jackman, David M.; Lo, Peter C.; Baldini, Elizabeth H.; Johnson, Bruce E.; Chen, Aileen B.

    2014-07-15

    Purpose: Although palliative chemotherapy is the standard of care for patients with diagnoses of stage IV non-small cell lung cancer (NSCLC), patients with a small metastatic burden, “oligometastatic” disease, may benefit from more aggressive local therapy. Methods and Materials: We identified 186 patients (26% of stage IV patients) prospectively enrolled in our institutional database from 2002 to 2012 with oligometastatic disease, which we defined as 5 or fewer distant metastatic lesions at diagnosis. Univariate and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary tumor on overall survival. Results: Median age at diagnosis was 61 years of age; 51% of patients were female; 12% had squamous histology; and 33% had N0-1 disease. On multivariable analysis, Eastern Cooperate Oncology Group performance status ≥2 (hazard ratio [HR], 2.43), nodal status, N2-3 (HR, 2.16), squamous pathology, and metastases to multiple organs (HR, 2.11) were associated with a greater hazard of death (all P<.01). The number of metastatic lesions and radiologic size of the primary tumor were not significantly associated with overall survival. Definitive local therapy to the primary tumor was associated with prolonged survival (HR, 0.65, P=.043). Conclusions: Definitive local therapy to the primary tumor appears to be associated with improved survival in patients with oligometastatic NSCLC. Select patient and tumor characteristics, including good performance status, nonsquamous histology, and limited nodal disease, may predict for improved survival in these patients.

  3. Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer

    PubMed Central

    Le, Long P.; Zheng, Zongli; Muzikansky, Alona; Drilon, Alexander; Patel, Manish; Bauer, Todd M.; Liu, Stephen V.; Ou, Sai-Hong I.; Jackman, David; Costa, Daniel B.; Multani, Pratik S.; Li, Gary G.; Hornby, Zachary; Chow-Maneval, Edna; Luo, David; Lim, Jonathan E.; Iafrate, Anthony J.; Shaw, Alice T.

    2015-01-01

    Introduction: Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib. Methods: We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment. Results: We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3–4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR. Conclusions: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases. PMID:26565381

  4. For non-small cell lung cancer with T3 (central) disease, sleeve lobectomy or pneumonectomy?

    PubMed Central

    Ma, Qian-Li; Guo, Yong-Qing; Shi, Bin; Tian, Yan-Chu; Song, Zhi-Yi

    2016-01-01

    Background Pneumonectomy (PN) has traditionally been the treatment of choice for central lung tumors for which the alternative is sleeve lobectomy (SL). The aim of this study was to compare early and long-term results after SL and PN in focusing on T3 central non-small cell lung cancer (NSCLC). Methods Patients who underwent SL (n=58) or PN (n=42) were retrospectively analyzed. For bias reduction, these 100 patients had been selected according to the following criteria: (I) tumor located in the main bronchus less than 2 cm distal to the carina; (II) there were no N2 disease; (III) no induction therapy was applied; (IV) complete resection (R0) was achieved. Results SL and PN patients had comparable mean ages, gender distribution, mean forced expiratory volume in 1 second (FEV1), stage and tumor grade. Postoperative mortality (3.4% vs. 4.8%, P=1.0) and morbidity (41% vs. 38%, P=0.74) were similar between the two groups. Recurrences occurred in 48% of patients after SL and in 31% of those after PN (P=0.08). The 5-year survival after SL (64.8%) and PN (61.4%) was not significantly different (P=0.20). Multivariable survival analysis showed that there were no independent prognostic factors. Conclusions SL does not compromise survival for NSCLC with T3 central disease compared with PN. It is an adequate oncologic resection and should be treated as the first line intervention whenever complete resection can be achieved. PMID:27293841

  5. Cytoplasmic Kaiso is associated with poor prognosis in non-small cell lung cancer

    PubMed Central

    2009-01-01

    Background Kaiso has been identified as a new member of the POZ-zinc finger family of transcription factors that are implicated in development and cancer. Although controversy still exists, Kaiso is supposed to be involved in human cancer. However, there is limited information regarding the clinical significance of cytoplasmic/nuclear Kaiso in human lung cancer. Methods In this study, immunohistochemical studies were performed on 20 cases of normal lung tissues and 294 cases of non-small cell lung cancer (NSCLC), including 50 cases of paired lymph node metastases and 88 cases with complete follow-up records. Three lung cancer cell lines showing primarily nuclear localization of Kaiso were selected to examine whether roles of Kaiso in cytoplasm and in nucleus are identical. Nuclear Kaiso was down-regulated by shRNA technology or addition a specific Kaiso antibody in these cell lines. The proliferative and invasive abilities were evaluated by MTT and Matrigel invasive assay, transcription of Kaiso's target gene matrilysin was detected by RT-PCR. Results Kaiso was primarily expressed in the cytoplasm of lung cancer tissues. Overall positive cytoplasmic expression rate was 63.61% (187/294). The positive cytoplasmic expression of Kaiso was higher in advanced TNM stages (III+IV) of NSCLC, compared to lower stages (I+II) (p = 0.019). A correlation between cytoplasmic Kaiso expression and lymph node metastasis was found (p = 0.003). In 50 paired cases, cytoplasmic expression of Kaiso was 78.0% (41/50) in primary sites and 90.0% (45/50) in lymph node metastases (p = 0.001). The lung cancer-related 5-year survival rate was significantly lower in patients who were cytoplasmic Kaiso-positive (22.22%), compared to those with cytoplasmic Kaiso-negative tumors (64.00%) (p = 0.005). Nuclear Kaiso staining was seen in occasional cases with only a 5.10% (15/294) positive rate and was not associated with any clinicopathological features of NSCLC. Furthermore, after the down

  6. Surgical Intervention Improves Survival for Metastatic Non-Small Cell Lung Cancer Patients

    PubMed Central

    Shen, Hong; Cao, Ying; Li, Xiaofen; Tan, Yinuo; Chen, Jiaqi; Yang, Ziru; Kong, Yiyao; Yuan, Ying

    2016-01-01

    Abstract Surgical intervention for stage IV non-small cell lung cancer (NSCLC) is still controversial. This study sought to evaluate the clinical effects of surgical intervention on survival in patients with stage IV NSCLCs and to identify the cohort benefitting the most from surgery. A retrospective study from the Surveillance, Epidemiology, and End Results database was performed to compare the survival of stage IV NSCLC patients who had undergone surgery with those who did not undergo surgery. Overall survival (OS) was evaluated using the Kaplan–Meier method and the log-rank test. The Cox proportional hazards model was used for multivariate analysis. The total number of eligible patients was 43,538, including 16.8% in the M1a stage and 83.2% in the M1b stage. The percentages of patients with no surgery (NONE), only metastatic tumor resection (MTR), only primary tumor resection (PTR), and both primary and metastatic tumor resection (PMTR) were 89.0%, 6.7%, 3.5%, and 0.8%, respectively; the corresponding 5-year survival rates were 2.0%, 4.0%, 13.0%, and 20.0%, respectively (P < 0.001); and the corresponding OS rates were 11.1 months, 14.7 months, 29.4 months, and 34.9 months, respectively (P < 0.001). Notably, the pairwise comparisons of 5-year survival rate and OS among the subgroups were all statistically significant. The multivariate analysis showed that surgical intervention was correlated with longer survival in patients with stage IV NSCLC. The stratified analysis showed significant differences in the OS on strata of the M1a stage and strata of the M1b stage. In the M1a stage, patients with PTR had significantly better OS than those with NONE (P < 0.001) or MTR (P < 0.001) but showed no significant differences compared with those with PMTR (P = 0.174); patients with MTR did not have prolonged survival compared with patients with NONE (P = 0.185), and they also did not have prolonged survival compared with patients with PMTR (P

  7. Erlotinib in Treating Patients With Advanced Non-Small Cell Lung Cancer, Ovarian Cancer, or Squamous Cell Carcinoma of the Head and Neck

    ClinicalTrials.gov

    2013-01-08

    Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Ovarian Epithelial Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Ovarian Epithelial Cancer; Stage IIIC Ovarian Epithelial Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; 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 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 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

  8. [Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis].

    PubMed

    Song, Qi; Jiao, Shunchang; Li, Fang

    2016-08-20

    Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients' quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work. PMID:27561803

  9. New and emerging targeted treatments in advanced non-small-cell lung cancer.

    PubMed

    Hirsch, Fred R; Suda, Kenichi; Wiens, Jacinta; Bunn, Paul A

    2016-09-01

    Targeted therapies are substantially changing the management of lung cancers. These treatments include drugs that target driver mutations, those that target presumed important molecules in cancer cell proliferation and survival, and those that inhibit immune checkpoint molecules. This area of research progresses day by day, with novel target discoveries, novel drug development, and use of novel combination treatments. Researchers and clinicians have also extensively investigated the predictive biomarkers and the molecular mechanisms underlying inherent or acquired resistance to these targeted therapies. We review recent progress in the development of targeted treatments for patients with advanced non-small-cell lung cancer, especially focusing on data from published clinical trials. PMID:27598681

  10. [Stereotactic radiotherapy is established treatment in localized non-small cell lung cancer].

    PubMed

    Sailas, Liisa; Virsunen, Heli

    2016-01-01

    Surgery has been the standard treatment in localized non-small cell lung cancer. Some of the early stage lung cancer patients are not suitable for surgery owing to associated diseases or refusing surgery. Ninety percent of untreated patients die within five years. Stereotactic ablative radiotherapy is a technique in which highly focused radiation treatment is given at a couple of high single doses to the tumor region. The treatment results in an average of 90% local control of the cancer, and the adverse effects are minor. Treatment outcome is equivalent to those of surgical therapy and is better than obtained with conventional external radiation therapy. PMID:27132296

  11. Inoperable stage III non-small cell lung cancer: Current treatment and role of vinorelbine

    PubMed Central

    Provencio, Mariano; Isla, Dolores; Sánchez, Antonio; Cantos, Blanca

    2011-01-01

    Most lung cancer patients are diagnosed with a non-resectable disease; and around 40% in advanced stages. Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with great variations in its clinical extent which presents a major therapeutic challenge. Although chemo-radiotherapy treatment has become the most widely used, there is currently no consensus on the best standard treatment and the experience of the therapy team plays an important role in the decision taking. We review the treatment of inoperable stage III NSCLC and the role of concomitant vinorelbine in this clinical scenario. PMID:22263088

  12. MOLECULARLY TARGETED THERAPIES IN NON-SMALL CELL LUNG CANCER ANNUAL UPDATE 2014

    PubMed Central

    Morgensztern, Daniel; Campo, Meghan J.; Dahlberg, Suzanne E.; Doebele, Robert C.; Garon, Edward; Gerber, David E.; Goldberg, Sarah B.; Hammerman, Peter S.; Heist, Rebecca; Hensing, Thomas; Horn, Leora; Ramalingam, Suresh S.; Rudin, Charles M.; Salgia, Ravi; Sequist, Lecia; Shaw, Alice T.; Simon, George R.; Somaiah, Neeta; Spigel, David R.; Wrangle, John; Johnson, David; Herbst, Roy S.; Bunn, Paul; Govindan, Ramaswamy

    2015-01-01

    There have been significant advances in the understanding of the biology and treatment of non-small cell lung cancer (NSCLC) over the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC (Table 1). We are beginning to understand the mechanisms of acquired resistance following exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies and immunotherapy. PMID:25535693

  13. Genomic signatures in non-small-cell lung cancer: targeting the targeted therapies.

    PubMed

    Dressman, Holly K; Bild, Andrea; Garst, Jennifer; Harpole, David; Potti, Anil

    2006-07-01

    Despite major developments in targeted biologic agents, patients with advanced non-small-cell lung cancer have a poor prognosis. Recent development of targeted biologic agents have given us insight into possibilities of matching therapy with disease; however, the success of these agents has been marginal. In this article, we discuss the use of genomic signatures that have been developed to identify unique aspects of individual lung tumors and provide insight on how novel strategies can be used to identify populations susceptible to specific targeted agents. PMID:17254524

  14. Opsoclonus-myoclonus syndrome associated with non-small cell lung cancer.

    PubMed

    Karasaki, Takahiro; Tanaka, Makoto

    2015-11-01

    A 68-year-old man developed progressive vertigo, saccadic eye movements, and tremors. Computed tomography showed multiple lung nodules. Surgery was performed and the pathological diagnosis was large cell neuroendocrine carcinoma in the left upper lobe with ipsilobar metastases, and adenocarcinoma in the left lower lobe. The neurological symptoms resolved dramatically after complete resection of the tumors. Opsoclonus-myoclonus syndrome associated with non-small-cell lung carcinoma is extremely rare. Surgery should not be delayed if a complete resection is expected. PMID:26038602

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

    PubMed Central

    Berman, Abigail T.; St. James, Sara; 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. PMID:26147335

  16. Third CECOG consensus on the systemic treatment of non-small-cell lung cancer.

    PubMed

    Brodowicz, T; Ciuleanu, T; Crawford, J; Filipits, M; Fischer, J R; Georgoulias, V; Gridelli, C; Hirsch, F R; Jassem, J; Kosmidis, P; Krzakowski, M; Manegold, Ch; Pujol, J L; Stahel, R; Thatcher, N; Vansteenkiste, J; Minichsdorfer, C; Zöchbauer-Müller, S; Pirker, R; Zielinski, C C

    2012-05-01

    The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic options. PMID:21940784

  17. New insights in beta-tubulin sequence analysis in non-small cell lung cancer.

    PubMed

    de Castro, J; Belda-Iniesta, C; Cejas, P; Casado, E; Fresno Vara, J A; Hardisson, D; Sánchez, J J; Feliu, J; Ordóñez, A; Nistal, M; González-Barón, M

    2003-07-01

    Scarce data are available regarding the molecular mechanisms implicated in paclitaxel resistance. There is controversial data about beta-tubulin mutations role in paclitaxel resistance. We have conducted this trial to address the influence of beta-tubulin mutations in paclitaxel resistance in advanced non-small cell lung cancer (NSCLC). A group of 15 patients were biopsied and diagnosed of stages IIIB and IV NSCLC. Tumor specimens were used for DNA isolation and exon 4 of HM40 beta-tubulin isotype was amplified and automatically sequenced, using both intronic and exonic primers. Next, the chemotherapy schedule consisted of weekly paclitaxel (100 or 150 mg/m(2) x 6) followed 2 weeks later by cisplatin 100 mg/m(2) on day 1, gemcitabine 1000 mg/m(2) on days 1 and 14, and vinorelbine 25 mg/m(2) on days 1 and 14, every 28 days. Using exonic primers, gene sequence alterations were found in 13/15 (87%) patients, including transitions (codons 180 and 182) and one silent transversion (codon 195). Also, three transversions (codons 231, 234, and 235) were found in all patients and controls. All alterations disappeared when sequenced with intronic primers. Our results suggest that point mutations demonstrated with exonic primers but not with intronic ones are probably due to beta-tubulin pseudogenes present in advanced NSCLC specimens. Even so, when these beta-tubulin pseudogenes are found there is a clear relation with clinical response. Although these changes could be relevant in paclitaxel resistance, this observation must be proven in future clinical trials to resolve "the tubulin dilemma". PMID:12826311

  18. Wnt signaling pathway pharmacogenetics in non-small cell lung cancer.

    PubMed

    Stewart, D J; Chang, D W; Ye, Y; Spitz, M; Lu, C; Shu, X; Wampfler, J A; Marks, R S; Garces, Y I; Yang, P; Wu, X

    2014-12-01

    Wingless-type protein (Wnt)/β-catenin pathway alterations in non-small cell lung cancer (NSCLC) are associated with poor prognosis and resistance. In 598 stage III-IV NSCLC patients receiving platinum-based chemotherapy at the MD Anderson Cancer Center (MDACC), we correlated survival with 441 host single-nucleotide polymorphisms (SNPs) in 50 Wnt pathway genes. We then assessed the most significant SNPs in 240 Mayo Clinic patients receiving platinum-based chemotherapy for advanced NSCLC, 127 MDACC patients receiving platinum-based adjuvant chemotherapy and 340 early stage MDACC patients undergoing surgery alone (cohorts 2-4). In multivariate analysis, survival correlates with SNPs for AXIN2 (rs11868547 and rs4541111, of which rs11868547 was assessed in cohorts 2-4), Wnt-5B (rs12819505), CXXC4 (rs4413407) and WIF-1 (rs10878232). Median survival was 19.7, 15.6 and 10.7 months for patients with 1, 2 and 3-5 unfavorable genotypes, respectively (P=3.8 × 10(-9)). Survival tree analysis classified patients into two groups (median survival time 11.3 vs 17.3 months, P=4.7 × 10(-8)). None of the SNPs achieved significance in cohorts 2-4; however, there was a trend in the same direction as cohort 1 for 3 of the SNPs. Using online databases, we found rs10878232 displayed expression quantitative trait loci correlation with the expression of LEMD3, a neighboring gene previously associated with NSCLC survival. In conclusion, results from cohort 1 provide further evidence for an important role for Wnt in NSCLC. Investigation of Wnt inhibitors in advanced NSCLC would be reasonable. Lack of an SNP association with outcome in cohorts 2-4 could be due to low statistical power, impact of patient heterogeneity or false-positive observations in cohort 1. PMID:24980784

  19. Role of positron emission tomography-computed tomography in non-small cell lung cancer.

    PubMed

    Garg, Pankaj Kumar; Singh, Saurabh Kumar; Prakash, Gaurav; Jakhetiya, Ashish; Pandey, Durgatosh

    2016-03-26

    Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell carcinoma and small cell carcinoma are the main histological subtypes and constitutes around 85% and 15% of all lung cancer respectively. Multimodality treatment plays a key role in the successful management of lung cancer depending upon the histological subtype, stage of disease, and performance status. Imaging modalities play an important role in the diagnosis and accurate staging of the disease, in assessing the response to neoadjuvant therapy, and in the follow-up of the patients. Last decade has witnessed voluminous upsurge in the use of positron emission tomography-computed tomography (PET-CT); role of PET-CT has widened exponentially in the management of lung cancer. The present article reviews the role of 18-fluoro-deoxyglucose PET-CT in the management of non small cell lung cancer with emphasis on staging of the disease and the assessment of response to neoadjuvant therapy based on available literature. PMID:27018223

  20. Role of positron emission tomography-computed tomography in non-small cell lung cancer

    PubMed Central

    Garg, Pankaj Kumar; Singh, Saurabh Kumar; Prakash, Gaurav; Jakhetiya, Ashish; Pandey, Durgatosh

    2016-01-01

    Lung cancer is the leading cause of cancer-related mortality worldwide. Non-small cell carcinoma and small cell carcinoma are the main histological subtypes and constitutes around 85% and 15% of all lung cancer respectively. Multimodality treatment plays a key role in the successful management of lung cancer depending upon the histological subtype, stage of disease, and performance status. Imaging modalities play an important role in the diagnosis and accurate staging of the disease, in assessing the response to neoadjuvant therapy, and in the follow-up of the patients. Last decade has witnessed voluminous upsurge in the use of positron emission tomography-computed tomography (PET-CT); role of PET-CT has widened exponentially in the management of lung cancer. The present article reviews the role of 18-fluoro-deoxyglucose PET-CT in the management of non small cell lung cancer with emphasis on staging of the disease and the assessment of response to neoadjuvant therapy based on available literature. PMID:27018223

  1. CXCR4/CXCL12 in Non-Small-Cell Lung Cancer Metastasis to the Brain

    PubMed Central

    Cavallaro, Sebastiano

    2013-01-01

    Lung cancer represents the leading cause of cancer-related mortality throughout the world. Patients die of local progression, disseminated disease, or both. At least one third of the people with lung cancer develop brain metastases at some point during their disease, even often before the diagnosis of lung cancer is made. The high rate of brain metastasis makes lung cancer the most common type of tumor to spread to the brain. It is critical to understand the biologic basis of brain metastases to develop novel diagnostic and therapeutic approaches. This review will focus on the emerging data supporting the involvement of the chemokine CXCL12 and its receptor CXCR4 in the brain metastatic evolution of non-small-cell lung cancer (NSCLC) and the pharmacological tools that may be used to interfere with this signaling axis. PMID:23322021

  2. Targeted therapies and immunotherapy in non-small-cell lung cancer

    PubMed Central

    Cortinovis, D; Abbate, M; Bidoli, P; Capici, S; Canova, S

    2016-01-01

    Non-small-cell lung cancer is still considered a difficult disease to manage because of its aggressiveness and resistance to common therapies. Chemotherapy remains the gold standard in nearly 80% of lung cancers, but clinical outcomes are discouraging, and the impact on median overall survival (OS) barely reaches 12 months. At the end of the last century, the discovery of oncogene-driven tumours completely changed the therapeutic landscape in lung cancers, harbouring specific gene mutations/translocations. Epidermal growth factors receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later led new insights in lung cancer biology knowledge. The use of specific tyrosine kinases inhibitors overturned the biological behaviour of EGFR mutation positive tumours and became a preclinical model to understand the heterogeneity of lung cancers and the mechanisms of drug resistance. In this review, we summarise the employment of targeted agents against the most representative biomolecular alterations and provide some criticisms of the therapeutic strategies. PMID:27433281

  3. Non-small cell lung cancer: current treatment and future advances

    PubMed Central

    Zappa, Cecilia

    2016-01-01

    Lung cancer has a poor prognosis; over half of people diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is less than 18%. Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancer cases. Risk factors for developing NSCLC have been identified, with cigarette smoking being a major factor along with other environmental and genetic risk factors. Depending on the staging of lung cancer, patients are eligible for certain treatments ranging from surgery to radiation to chemotherapy as well as targeted therapy. With the advancement of genetics and biomarkers testing, specific mutations have been identified to better target treatment for individual patients. This review discusses current treatments including surgery, chemotherapy, radiotherapy, and immunotherapy as well as how biomarker testing has helped improve survival in patients with NSCLC. PMID:27413711

  4. Detection of Brk expression in non-small cell lung cancer: clinicopathological relevance.

    PubMed

    Fan, Chuifeng; Zhao, Yang; Liu, Di; Zhang, Xiupeng; Wang, Enhua

    2011-10-01

    Breast tumor kinase (Brk), also known as protein tyrosine kinase 6, is a nonreceptor tyrosine kinase containing SH3, SH2, and tyrosine kinase catalytic domains. Brk upregulation and oncogenic properties have been found in several malignant tumors, including breast, colon carcinomas, and melanomas, but the expression of Brk and its clinical significance in non-small cell lung cancer (NSCLC) remains unclear. In the current study, we examined the expression of Brk and its correlation with clinicopathological features involving p53, ki67, and E-cadherin status in NSCLC tissue using immunohistochemistry. We also used immunocytochemistry and immunofluorescent staining to examine the Brk expression and its subcellular localization in NSCLC cell lines, including LTE and H460. We further confirmed cytoplasmic and nucleus expression of Brk in LTE and H460 cells using Western blotting. The Brk expression in NSCLC cells was mainly found in cytoplasm (59/122, 48.4%) with some nucleus staining (17/122, 13.9%) with a total positive rate of 53.3% (65/122). Cytoplasmic Brk expression in NSCLC was higher than that in normal lung tissues (24/122, 19.7%) (P < 0.05). Increased cytoplasmic Brk expression in NSCLC was associated with large tumor size (≥ 3 cm), lymph node metastasis, and advanced tumor-node-metastasis (TNM) stages (III and IV) (P < 0.05). Moreover, increased cytoplasmic Brk expression was positively associated with Ki67 status in NSCLC (P < 0.05). Reduced E-cadherin expression was also found to be associated with lymph node metastasis and advanced TNM stages (III and IV) in NSCLC (P < 0.05). Brk expression was not associated with E-cadherin expression and P53 status in NSCLC (P > 0.05). The present findings indicate an increase of cytoplasmic Brk expression in NSCLC which may play a role in tumor development, including tumor expansion and lymph node metastasis in which Ki67, but not E-cadherin, and P53 status may be involved. PMID:21603980

  5. Epidermal growth factor receptors in non-small cell lung cancer.

    PubMed Central

    Veale, D.; Ashcroft, T.; Marsh, C.; Gibson, G. J.; Harris, A. L.

    1987-01-01

    The epidermal growth factor receptor is homologous to the oncogene erb-beta and is the receptor for a class of tumour growth factors (TGF-alpha). The clinical correlations with its expression were studied in 77 non-small cell lung cancers (NSCLC). They were stained for epidermal growth factor receptor (EGFr) by means of an indirect immunoperoxidase technique using a monoclonal antibody against the receptor. Normal lung tissue and normal bronchus were stained for comparison. Cancer tissue showed significantly increased staining compared to normal lung (P less than 0.05). Staining for EGFr in 40 squamous carcinomas was significantly stronger than in 37 specimens of other types of NSCLC (P less than 0.05), and staining in stage three NSCLC was stronger than in stage 1 and 2 (P less than 0.05). These results suggest that the presence of a high intensity of staining for EGF receptor is associated with spread of human non-small cell lung cancer and this receptor may be a suitable target for therapy. Images Figure 1 Figure 2 PMID:3038157

  6. Prognostic factors for long term survival in patients with advanced non-small cell lung cancer

    PubMed Central

    Moumtzi, Despoina; Lampaki, Sofia; Porpodis, Konstantinos; Lagoudi, Kalliopi; Hohenforst-Schmidt, Wolfgang; Pataka, Athanasia; Tsiouda, Theodora; Zissimopoulos, Athanasios; Lazaridis, George; Karavasilis, Vasilis; Timotheadou, Helen; Barbetakis, Nikolaos; Pavlidis, Pavlos; Kontakiotis, Theodoros; Zarogoulidis, Konstantinos

    2016-01-01

    Background Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. It is estimated that 60% of patients with NSCLC at time of diagnosis have advanced disease. The aim of this study was to investigate clinical and demographic prognostic factors of long term survival in patients with unresectable NSCLC. Methods We retrospectively reviewed data of 1,156 patients with NSCLC stage IIIB or IV who survived more than 60 days from the time of diagnosis and treated from August 1987 until March 2013 in the Oncology Department of Pulmonary Clinic of the General Hospital Papanikolaou. Initially univariate analysis using the log-rank test was conducted and then multivariate analysis using the proportional hazards model of Cox. Also Kaplan Meier curves were used to describe the distribution of survival times of patients. The level of significance was set at 0.05. Results The mean age at diagnosis was 62 years. About 11.9% of patients were women and 88.1% were male. The majority of cases were adenocarcinomas (42.2%), followed squamous (33%) and finally the large cell (6%). Unlike men, most common histological type among women was adenocarcinoma rather than squamous (63% vs. 10.9%). In univariate analysis statistically significant factors in the progression free survival (PFS) and overall survival (OS) were: weight loss ≥5%, histological type, line 1 drugs, line 1 combination, line 1 cycles and radio lung. Specifically radio lung gives clear survival benefit in the PFS and OS in stage IIIB (P=0.002) and IV (P<0.001). On the other hand, the number of distant metastases in stage IV patients did not affect OS, neither PFS. In addition patients who received platinum and taxane had better PFS (P=0.001) and OS (P<0.001) than those who received platinum without taxane. Also the third drug administration proved futile, since survival (682.06±34.9) (P=0.023) and PFS (434.93±26.93) (P=0.012) of patients who received less than three drugs was significantly larger. Finally

  7. Cyclophosphamide or Denileukin Diftitox Followed By Expanding a Patient's Own T Cells in the Laboratory in Treating Patients With HER-2/Neu Overexpressing Metastatic Breast Cancer, Ovarian Cancer, or Non-Small Cell Lung Cancer Previously Treated With HER-2/Neu Vaccine

    ClinicalTrials.gov

    2014-11-07

    HER2-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Stage IV Breast Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor

  8. Hyperoside induces both autophagy and apoptosis in non-small cell lung cancer cells in vitro

    PubMed Central

    Fu, Ting; Wang, Ling; Jin, Xiang-nan; Sui, Hai-juan; Liu, Zhou; Jin, Ying

    2016-01-01

    Aim: Hyperoside (quercetin-3-O-β-D-galactopyranoside) is a flavonol glycoside found in plants of the genera Hypericum and Crataegus, which exhibits anticancer, anti-oxidant, and anti-inflammatory activities. In this study we investigated whether autophagy was involved in the anticancer mechanisms of hyperoside in human non-small cell lung cancer cells in vitro. Methods: Human non-small cell lung cancer cell line A549 was tested, and human bronchial epithelial cell line BEAS-2B was used for comparison. The expression of LC3-II, apoptotic and signaling proteins was measured using Western blotting. Autophagosomes were observed with MDC staining, LC3 immunocytochemistry, and GFP-LC3 fusion protein techniques. Cell viability was assessed using MTT assay. Results: Hyperoside (0.5, 1, 2 mmol/L) dose-dependently increased the expression of LC3-II and autophagosome numbers in A549 cells, but had no such effects in BEAS-2B cells. Moreover, hyperoside dose-dependently inhibited the phosphorylation of Akt, mTOR, p70S6K and 4E-BP1, but increased the phosphorylation of ERK1/2 in A549 cells. Insulin (200 nmol/L) markedly enhanced the phosphorylation of Akt and decreased LC3-II expression in A549 cells, which were reversed by pretreatment with hyperoside, whereas the MEK1/2 inhibitor U0126 (20 μmol/L) did not blocked hyperoside-induced LC3-II expression. Finally, hyperoside dose-dependently suppressed the cell viability and induced apoptosis in A549 cells, which were significantly attenuated by pretreatment with the autophagy inhibitor 3-methyladenine (2.5 mmol/L). Conclusion: Hyperoside induces both autophagy and apoptosis in human non-small cell lung cancer cells in vitro. The autophagy is induced through inhibiting the Akt/mTOR/p70S6K signal pathways, which contributes to anticancer actions of hyperoside. PMID:26948085

  9. Proton Beam Therapy of Stage II and III Non-Small-Cell Lung Cancer

    SciTech Connect

    Nakayama, Hidetsugu; Satoh, Hiroaki; Sugahara, Shinji; Kurishima, Koichi; Tsuboi, Koji; Sakurai, Hideyuki; Ishikawa, Shigemi; Tokuuye, Koichi

    2011-11-15

    Purpose: The present retrospective study assessed the role of proton beam therapy (PBT) in the treatment of patients with Stage II or III non-small-cell lung cancer who were inoperable or ineligible for chemotherapy because of co-existing disease or refusal. Patients and Methods: Between November 2001 and July 2008, PBT was given to 35 patients (5 patients with Stage II, 12 with Stage IIIA, and 18 with Stage IIIB) whose median age was 70.3 years (range, 47.4-85.4). The median proton dose given was 78.3 Gy (range, 67.1-91.3) (relative biologic effectiveness). Results: Local progression-free survival for Stage II-III patients was 93.3% at 1 year and 65.9% at 2 years during a median observation period of 16.9 months. Four patients (11.4%) developed local recurrence, 13 (37.1%) developed regional recurrence, and 7 (20.0%) developed distant metastases. The progression-free survival rate for Stage II-III patients was 59.6% at 1 year and 29.2% at 2 years. The overall survival rate of Stage II-III patients was 81.8% at 1 year and 58.9% at 2 years. Grade 3 or greater toxicity was not observed. A total of 15 patients (42.9%) developed Grade 1 and 6 (17.1%) Grade 2 toxicity. Conclusion: PBT for Stage II-III non-small-cell lung cancer without chemotherapy resulted in good local control and low toxicity. PBT has a definite role in the treatment of patients with Stage II-III non-small-cell lung cancer who are unsuitable for surgery or chemotherapy.

  10. Preliminary results of proton-beam therapy for stage III non-small-cell lung cancer

    PubMed Central

    Hatayama, Y.; Nakamura, T.; Suzuki, M.; Azami, Y.; Ono, T.; Yamaguchi, H.; Hayashi, Y.; Tsukiyama, I.; Hareyama, M.; Kikuchi, Y.; Takai, Y.

    2015-01-01

    Background We conducted a preliminary retrospective evaluation of the efficacy and toxicity of proton-beam therapy (pbt) for stage iii non-small-cell lung cancer. Methods Between January 2009 and August 2013, 27 patients (26 men, 1 woman) with stage iii non-small-cell lung cancer underwent pbt. The relative biologic effectiveness value of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned such that the 90% isodose volume of the prescribed dose encompassed the planning target volume. Of the 27 patients, 11 underwent neoadjuvant chemotherapy. Cumulative survival curves were calculated using the Kaplan–Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events. Results Median age of the patients was 72 years (range: 57–91 years), and median follow-up was 15.4 months (range: 7.8–36.9 months). Clinical stage was iiia in 14 patients (52%) and iiib in 13 (48%). The median dose of pbt was 77 GyE (range: 66–86.4 GyE). The overall survival rate in the cohort was 92.3% at 1 year and 51.1% at 2 years. Locoregional failure occurred in 7 patients, and distant metastasis, in 10. In 2 patients, initial failure was both locoregional and distant. The 1-year and 2-year rates of local control were 68.1% and 36.4% respectively. The 1-year and 2-year rates of progression-free survival were 39.9% and 21.4% respectively. Two patients experienced grade 3 pneumonitis. Conclusions For patients with stage iii non-small-cell lung cancer, pbt can be an effective and safe treatment option. PMID:26628878

  11. Advances in the diagnosis and treatment of non-small cell lung cancer.

    PubMed

    Pillai, Rathi N; Ramalingam, Suresh S

    2014-03-01

    The diagnostic and therapeutic landscape of non-small cell lung cancer (NSCLC) has changed dramatically in the past 50 years since the Surgeon General's report on smoking and lung cancer. Early detection is now a reality for lung cancer. The use of low-dose computed tomography scans for early detection decreases mortality and is beginning to be used in routine clinical practice. Technological advances such as positron emission tomography and endobronchial ultrasound have improved the accuracy of NSCLC staging. The cure rate for early-stage NSCLC has improved as a result of multimodality treatment approaches. The role of systemic therapy has also expanded to earlier stages of the disease. In recent years, the initial steps toward personalized medicine by utilization of targeted treatments based on tumor genotype have been undertaken. Emerging technological advances and greater insights into tumor biology are poised to greatly reduce the burden of lung cancer in the years to come. PMID:24516099

  12. Selection of Patients With Non-Small-Cell Lung Carcinoma for Surgical Resection

    PubMed Central

    Rizk, Norman W.

    1985-01-01

    Cancer of the lung is rapidly increasing in incidence in both sexes and soon will overtake breast cancer as the most deadly cancer in women. Selection of patients with non-small-cell carcinoma for surgical resection is largely based on preoperative clinical staging, using the American Joint Committee on Cancer's TNM-based group staging protocol. Determining the presence or absence of mediastinal nodal metastasis is paramount and is currently best achieved by computed tomographic scanning of the chest and biopsy of enlarged nodes via mediastinoscopy. Certain types of stage III lesions, previously excluded from surgical treatment, are now recognized as operable. PMID:3909642

  13. Understanding the Rationale for Immunotherapy in Non-Small Cell Lung Cancer.

    PubMed

    Pennell, Nathan A

    2015-10-01

    Although immunotherapy has been used for decades in immunogenic tumor types, such as melanoma and renal cell carcinoma, historically immunotherapeutic approaches in other tumor types, including non-small cell lung cancer (NSCLC), have met with failure. Nonetheless, evidence exists supporting the role of the immune system in tumor suppression, even in tumor types believed to be non-immunogenic. In NSCLC, immune checkpoint molecules have recently proven to be successful targets, with nivolumab, the first immune checkpoint inhibitor indicated for NSCLC, approved by the US Food and Drug Administration in March 2015. Several other immune checkpoint inhibitors are currently in phase III development in NSCLC. PMID:26477472

  14. Advances in adjuvant systemic therapy for non-small-cell lung cancer.

    PubMed

    Leong, David; Rai, Rajat; Nguyen, Brandon; Lee, Andrew; Yip, Desmond

    2014-10-10

    Non-small-cell lung cancer remains a leading cause of death around the world. For most cases, the only chance of cure comes from resection for localised disease, however relapse rates remain high following surgery. Data has emerged over recent years regarding the utility of adjuvant chemotherapy for improving disease-free and overall survival of patients following curative resection. This paper reviews the clinical trials that have been conducted in this area along with the studies integrating radiation therapy in the adjuvant setting. The role of prognostic gene signatures are reviewed as well as ongoing clinical trials including those incorporating biological or targeted therapies. PMID:25302167

  15. Adjuvant Therapy for Stage I and II Non-Small Cell Lung Cancer.

    PubMed

    Naylor, Evan C

    2016-07-01

    Patients with stage I and stage II non-small cell lung cancer undergoing complete resection have a 40% to 70% 5-year overall survival despite optimal local therapy. Chemotherapy administered after complete resection has been shown to improve overall survival at 5 years by approximately 5%. This improvement in survival may be confined to patients with stage IB disease 4 cm or greater, and to those with hilar or mediastinal lymph node involvement. The optimal chemotherapy regimen appears to be cisplatin-based doublet or triplet chemotherapy for 3 to 4 cycles. The addition of biologic agents has failed to improve outcomes. PMID:27261917

  16. Cyclooxygenase-2 Expression in Non-Small Cell Lung Cancer Correlates With Hypertrophic Osteoarthropathy.

    PubMed

    Rotas, Ioannis; Cito, Giovanni; Letovanec, Igor; Christodoulou, Michel; Perentes, Jean Y

    2016-02-01

    Hypertrophic osteoarthrpathy (HO) is a rare paraneoplasic syndrome associated with non-small cell lung cancer (NSCLC). The pathophysiology of HO is unknown but was recently related to enhanced levels of urine prostaglandin E2 (PGE2). Here, we report the case of a patient that presented HO in association with a resectable left upper lobe NSCLC. Following surgery and adjuvant chemotherapy, HO resolved and did not recur with development of a brain metastasis 1 year later. Interestingly, tumor cyclooxygenase-2, an enzyme responsible the synthesis of PGE2, was expressed in the primary tumor but not in the resected metastasis. PMID:26777972

  17. Overcoming toxicity-challenges in chemoradiation for non-small cell lung cancer

    PubMed Central

    2016-01-01

    Concurrent chemoradiation (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (NSCLC) with a modest survival benefit over sequential chemoradiation or radiotherapy (SCRT) alone. However, this benefit is at the cost of increasing acute toxicity such as esophagitis. Previous analysis revealed several predictive parameters in dose-volume and patient characteristics which helped us to identify those patients at risk for severe esophagus toxicity. As a result, supportive care interventions including individualized patient information, dietary guidance, adequate medication, hydration and tubefeeding could be initiated. This paper discusses the challenges in overcoming chemoradiation induced acute esophageal toxicity (AET). PMID:27413701

  18. Bronchoscopy: Diagnostic and Therapeutic for Non-Small Cell Lung Cancer.

    PubMed

    Bauer, Thomas L; Berkheim, David B

    2016-07-01

    The bronchoscope has gone through much advancement from its origin as a thin metal tube. It has become a highly sophisticated tool for clinicians. Both rigid and the flexible bronchoscopes are invaluable in the diagnosis and treatment of non-small cell lung cancer. Treatment of this disease process hinges on accurate diagnosis and lymph node staging. Technologies, such as endobronchial ultrasound, navigational bronchoscopy, and autofluorescence, have improved efficacy of endobronchial diagnosis and sample collection. If a patient is not a candidate for surgery and has a complication from a centrally located mass, the bronchoscope has been used to deliver palliative therapies. PMID:27261910

  19. The relationship between weight loss and interleukin 6 in non-small-cell lung cancer.

    PubMed

    Scott, H R; McMillan, D C; Crilly, A; McArdle, C S; Milroy, R

    1996-06-01

    Markers of the inflammatory response, interleukin 6, C-reactive protein, albumin and full blood count, were measured in non-small-cell lung cancer (NSCLC) patients (n = 21) with and without weight loss ( > 5%). There were significant increases in circulating C-reactive protein (P < 0.001), interleukin 6 (P < 0.01) and platelets (P < 0.01) in the weight-losing group. Moreover, there was a statistically significant correlation (r = 0.785, P < 0.001) between interleukin 6 and C-reactive protein concentrations. These results are consistent with interleukin 6 and the acute phase response promoting weight loss in NSCLC. PMID:8664130

  20. Is surgery still the optimal treatment for stage I non-small cell lung cancer?

    PubMed Central

    Moghanaki, Drew

    2016-01-01

    There is debate about what is the optimal treatment for operable stage I non-small cell lung cancer (NSCLC). Although surgery has been the standard of care for centuries, recent retrospective and prospective randomized studies indicated that stereotactic ablative radiotherapy (SABR) could be an option for this group of patients with similar survival and less toxicities. However, to change the standard of care, more studies are needed and participating ongoing larger randomized studies is the best approach to resolve this controversy. PMID:27183993

  1. Pulmonary Artery Agenesis Associated With Emphysema and Multiple Invasive Non-Small Cell Lung Cancers.

    PubMed

    Makdisi, George; Edell, Eric S; Maleszewski, Joseph J; Molina, Julian R; Deschamps, Claude

    2015-06-01

    Pulmonary artery (PA) agenesis in the absence of associated cardiac abnormalities is a rare congenital abnormality. It may remain undiagnosed until adulthood when patients present with respiratory symptoms such as hemoptysis, dyspnea, repeated respiratory infections, or pulmonary hypertension. Herein we present a case of a 50-year-old woman who was found to have multiple, morphologically distinct non-small cell lung cancers in association with agenesis of the PA. This instance represents the fourth reported case of such association in the English literature. PMID:26046873

  2. Managing acquired resistance in EGFR-mutated non-small cell lung cancer.

    PubMed

    Forde, Patrick M; Ettinger, David S

    2015-08-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) deliver high response rates with relatively modest toxicity in patients with advanced EGFR-mutated non-small cell lung cancer. Despite this, nearly all tumors eventually develop resistance to first-line therapy. At present, the only standard treatment option for patients with acquired resistance is cytotoxic chemotherapy. In this article, we review the latest research into methods of targeting acquired resistance to EGFR TKI therapy, including third-generation EGFR TKIs that target the T790M resistance mutation and other novel agents in development. PMID:26351816

  3. Identification of Serum Peptidome Signatures of Non-Small Cell Lung Cancer

    PubMed Central

    Klupczynska, Agnieszka; Swiatly, Agata; Hajduk, Joanna; Matysiak, Jan; Dyszkiewicz, Wojciech; Pawlak, Krystian; Kokot, Zenon J.

    2016-01-01

    Due to high mortality rates of lung cancer, there is a need for identification of new, clinically useful markers, which improve detection of this tumor in early stage of disease. In the current study, serum peptide profiling was evaluated as a diagnostic tool for non-small cell lung cancer patients. The combination of the ZipTip technology with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for the analysis of peptide pattern of cancer patients (n = 153) and control subjects (n = 63) was presented for the first time. Based on the observed significant differences between cancer patients and control subjects, the classification model was created, which allowed for accurate group discrimination. The model turned out to be robust enough to discriminate a new validation set of samples with satisfactory sensitivity and specificity. Two peptides from the diagnostic pattern for non-small cell lung cancer (NSCLC) were identified as fragments of C3 and fibrinogen α chain. Since ELISA test did not confirm significant differences in the expression of complement component C3, further study will involve a quantitative approach to prove clinical utility of the other proteins from the proposed multi-peptide cancer signature. PMID:27043541

  4. Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer

    PubMed Central

    Ang, Yvonne LE; Lim, Joline SJ; Soo, Ross A

    2016-01-01

    Until recently, the prognosis and treatment of patients with advanced-stage squamous cell lung cancers have been limited. An improvement in the understanding of the role of the immune system in tumor immunosurveillance has led to the development of the programmed death-1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo). Nivolumab is the first PD-1 inhibitor approved for the treatment of advanced-stage squamous cell non-small-cell lung cancer following platinum-based chemotherapy. In the key Phase III trial CHECKMATE 017, a better overall survival and progression-free survival were seen in patients treated with second-line nivolumab compared with docetaxel. Programmed death ligand-1 (PD-L1) expression did not predict for outcome. In addition, nivolumab had better safety and tolerability, and led to better patient reported outcomes. Further research on the role of PD-L1 expression as a predictive biomarker should be performed, and other biomarkers that can predict the efficacy of PD-1/PD-L1 inhibitors should also be pursued. Further studies on the combination treatment are ongoing to determine the optimal role of nivolumab as monotherapy or nivolumab with other agents in non-small-cell lung cancer. PMID:27313464

  5. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment.

    PubMed

    El-Osta, Hazem; Shahid, Kamran; Mills, Glenn M; Peddi, Prakash

    2016-01-01

    Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. PMID:27574451

  6. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer treatment

    PubMed Central

    El-Osta, Hazem; Shahid, Kamran; Mills, Glenn M; Peddi, Prakash

    2016-01-01

    Lung cancer is the major cause for cancer-related death in the US. Although advances in chemotherapy and targeted therapy have improved the outcome of metastatic non-small-cell lung cancer, its prognosis remains dismal. A deeper understanding of the complex interaction between the immune system and tumor microenvironment has identified immune checkpoint inhibitors as new avenue of immunotherapy. Rather than acting directly on the tumor, these therapies work by removing the inhibition exerted by tumor cell or other immune cells on the immune system, promoting antitumoral immune response. To date, two programmed death-1 inhibitors, namely nivolumab and pembrolizumab, have received the US Food and Drug Administration approval for the treatment of advanced non-small-cell lung cancer that failed platinum-based chemotherapy. This manuscript provides a brief overview of the pathophysiology of cancer immune evasion, summarizes pertinent data on completed and ongoing clinical trials involving checkpoint inhibitors, discusses the different strategies to optimize their function, and outlines various challenges that are faced in this promising yet evolving field. PMID:27574451

  7. [Stereotactic body radiation radiotherapy for oligometastatic non-small cell lung cancer (NSCLC): A case report].

    PubMed

    Leduc, C; Antoni, D; Quoix, É; Noël, G

    2015-05-01

    Metastatic non-small cell lung cancer is associated with a poor prognosis, and palliative chemotherapy is the mainstay of treatment. However, long-time survival has been observed in oligometastatic patients treated with locally ablative therapies to all sites of metastatic disease. An 80-year-old man was diagnosed with an adenocarcinoma of the lung. The right upper lobe lesion was classified cT2aN0M0 and was treated with stereotactic body radiation therapy at the dose of 60Gy in eight fractions. A few months after, he successively presented with two brain metastases and one left adrenal metastasis, with a complete response on the primary tumor. The three secondary lesions were treated with stereotactic body radiation therapy alone. Thirty months after the diagnosis and 12months after metastases' apparition, primary and brain lesion kept controlled (complete response). Oligometastatic non-small cell lung cancer management is not clear. Locally ablative therapies such as stereotactic body radiation therapy, surgery and radiofrequency are efficient and should be considered. A phase III study should evaluate radical treatment strategies in such patients. PMID:25841992

  8. Identification of Serum Peptidome Signatures of Non-Small Cell Lung Cancer.

    PubMed

    Klupczynska, Agnieszka; Swiatly, Agata; Hajduk, Joanna; Matysiak, Jan; Dyszkiewicz, Wojciech; Pawlak, Krystian; Kokot, Zenon J

    2016-01-01

    Due to high mortality rates of lung cancer, there is a need for identification of new, clinically useful markers, which improve detection of this tumor in early stage of disease. In the current study, serum peptide profiling was evaluated as a diagnostic tool for non-small cell lung cancer patients. The combination of the ZipTip technology with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) for the analysis of peptide pattern of cancer patients (n = 153) and control subjects (n = 63) was presented for the first time. Based on the observed significant differences between cancer patients and control subjects, the classification model was created, which allowed for accurate group discrimination. The model turned out to be robust enough to discriminate a new validation set of samples with satisfactory sensitivity and specificity. Two peptides from the diagnostic pattern for non-small cell lung cancer (NSCLC) were identified as fragments of C3 and fibrinogen α chain. Since ELISA test did not confirm significant differences in the expression of complement component C3, further study will involve a quantitative approach to prove clinical utility of the other proteins from the proposed multi-peptide cancer signature. PMID:27043541

  9. Chemotherapy in elderly patients with advanced non-small cell lung cancer.

    PubMed

    Quoix, Elisabeth; Westeel, Virginie; Zalcman, Gérard; Milleron, Bernard

    2011-12-01

    Because of increasing life expectancy and of higher risk of cancer with ageing, lung cancer in elderly is a frequent disease. For a long time nihilism influenced treatment decisions in elderly patients with advanced non-small cell lung cancer. Since the beginning of the last decade single agent chemotherapy has been accepted as standard of care, vinorelbine and gemcitabine being the most frequently used drugs in Europe and US, docetaxel in Japan. Platinum-based doublets have been shown to be superior to monotherapy in young and fit patients with advanced non-small cell lung cancer. Although there were some indications from subgroup analyses of clinical trials not specifically dedicated to elderly patients that a platinum-based doublet might also benefit to older patients, there was no definitive proof of concept until ASCO meeting 2010. At this meeting results of a phase 3 trial showed that PS 0-2 patients, aged 70-89 years drove a significant benefit from a treatment with carboplatin associated to weekly paclitaxel compared to a monotherapy. Thus, the paradigm of treatment in elderly patients should perhaps be modified from a single agent to doublet chemotherapy. Whether other platinum-based doublets would provide the same benefit as the specific one studied remains to be evaluated. PMID:21893363

  10. Genetic Testing in Screening Patients With Stage IB-IIIA Non-Small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)

    ClinicalTrials.gov

    2016-08-30

    Large Cell Lung Carcinoma; Lung Adenocarcinoma; Stage IB Non-Small Cell Lung Carcinoma; Stage IB Squamous Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIA Squamous Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIB Squamous Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Squamous Cell Lung Carcinoma

  11. Current Concepts on the Molecular Pathology of Non-small Cell Lung Carcinoma

    PubMed Central

    Fujimoto, Junya; Wistuba, Ignacio I.

    2014-01-01

    Recent advances in the understanding of the complex biology of non-small cell lung carcinoma (NSCLC), particularly activation of oncogenes by mutation, translocation and amplification, have provided new treatment targets for this disease, and allowed the identification of subsets of NSCLC tumors, mostly with adenocarcinoma histology, having unique molecular profiles that can predict response to targeted therapy. The identification of a specific genetic and molecular targetable abnormalities using tumor tissue and cytology specimens followed by the administration of a specific inhibitor to the target, are the basis of personalized lung cancer treatment. In this new paradigm, the role of a precise pathology diagnosis of lung cancer and the proper handling of tissue and cytology samples for molecular testing is becoming increasingly important. These changes have posed multiple new challenges for pathologists to adequately integrate routine histopathology analysis and molecular testing into the clinical pathology practice for tumor diagnosis and subsequent selection of the most appropriate therapy. PMID:25239274

  12. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease.

    PubMed

    Hiley, Crispin T; Le Quesne, John; Santis, George; Sharpe, Rowena; de Castro, David Gonzalez; Middleton, Gary; Swanton, Charles

    2016-09-01

    Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial. PMID:27598680

  13. The role of videomediastinoscopy in staging of non-small cell lung cancer.

    PubMed

    Bacić, Ivan; Skarica, Rade; Sulen, Nina; Zadro, Zvonko; Lisica-Sikić, Natasa; Karlo, Robert; Petani, Barbara

    2012-12-01

    Lung cancer is the most frequent malignant disease and the leading cause of death from malignant diseases in the world and its incidence is increasing. At the time when diagnosis is established most patients have advanced disease and are not candidates for radical surgical treatment. Patients without distant metastases are subjected to various diagnostic methods to detect metastases in mediastinal lymph nodes that make up the path of lymph drainage from the lungs. The most reliable invasive diagnostic procedures for detecting metastases in mediastinal lymph nodes are videomediastinoscopy and endobronchial ultrasound with transtracheal puncture. In the absence of mediastinal lymph node metastases surgery is the treatment of choice. If mediastinal lymph nodes are positive for metastases multimodal treatment is implemented. At the Department of Thoracic Surgery, Zadar General Hospital, videomediastinoscopy for the staging of primary non-small cell lung cancer has been performed routinely since September 2009. PMID:23390847

  14. [Postoperative radiotherapy for non-small cell lung cancer: Efficacy, target volume, dose].

    PubMed

    Dupic, G; Bellière-Calandry, A

    2016-04-01

    The rate of local failure of stage IIIA-N2 non-small cell lung cancer is 20 to 40%, even if they are managed with surgery and adjuvant chemotherapy. Postoperative radiotherapy improves local control, but its benefit on global survival remains to be demonstrated. Considered for many years as an adjuvant treatment option for pN2 cancers, it continues nevertheless to be deemed too toxic. What is the current status of postoperative radiotherapy? The Lung Adjuvant Radiotherapy Trial (Lung ART) phase III trial should give us a definitive, objective response on global survival, but inclusion of patients is difficult. The results are consequently delayed. The aim of this review is to show all the results about efficacy and tolerance of postoperative radiotherapy and to define the target volume and dose to prescribe. PMID:26996789

  15. Pemetrexed for advanced non-small cell lung cancer patients with interstitial lung disease

    PubMed Central

    2014-01-01

    Background Non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC patients with ILD have yet to be established. Method We investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed. Results Twenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group) were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12 patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CT) (UIP group) and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3 patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk factor for PEM-related pulmonary toxicity. Conclusion We found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to treat NSCLC patients with IIPs. PMID:25012241

  16. Blood-based biomarkers for monitoring antiangiogenic therapy in non-small cell lung cancer.

    PubMed

    Rodríguez Garzotto, Analia; Díaz-García, C Vanesa; Agudo-López, Alba; Prieto García, Elena; Ponce, Santiago; López-Martín, José A; Paz-Ares, Luis; Iglesias, Lara; Agulló-Ortuño, M Teresa

    2016-10-01

    Tumor angiogenesis pathways have been identified as important therapeutic targets in non-small cell lung cancer. However, no biomarkers have been described as predictors of response to antiangiogenic therapy in these patients. In this study, plasma levels of VEGF, bFGF, E-selectin, and S-ICAM and gene expression profiles of peripheral blood mononuclear cells from non-small cell lung cancer patients treated with chemotherapy plus bevacizumab were analyzed before and after treatment. Values were correlated with clinicopathological characteristics and treatment response. Plasma factor levels were measured using commercially available ELISA kits. The TaqMan(®) human angiogenesis array was used to investigate the effect of treatment on gene expression profiles. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis was performed for differentially expressed genes using WEB-based GEne SeT AnaLysis Toolkit. Our results suggest a benefit for patients with increased plasma levels of VEGF, E-selectin, and S-ICAM in the course of bevacizumab treatment. Also, we identified differentially expressed genes between paired blood samples from patients before and after treatment, and significantly perturbed pathways were predicted. These changes in gene expression and levels of plasma factors could be used to assess the effectiveness of antiangiogenic therapy, in addition to standard clinical and radiological evaluations. PMID:27568331

  17. MicroRNA-455 suppresses non-small cell lung cancer through targeting ZEB1.

    PubMed

    Li, Ying-Jie; Ping, Chen; Tang, Jian; Zhang, Wen

    2016-06-01

    MicroRNA-455 (miRNA-455), which is downregulated in human cancer, potently mediates the multiple steps of carcinogenesis. However, the role of miR-455 in non-small cell lung cancer (NSCLC) carcinogenesis remains unclear. In present study, we determined the mature miRNA-455 expression in NSCLC tissues and cells by real-time PCR. Follow-up studies examined the effects of a miR-455 mimic (gain of function) on cell proliferation, migration, and invasion. Our data indicate that miR-455 was significantly down-regulated in NSCLC cell lines and tissues. In functional assays, overexpression of miR-455 suppressed the proliferation, migration, and invasion of NSCLC cell lines. Data from reporter assays showed that miR-455 directly binds to 3'UTR of ZEB1 and suppresses the endogenous level of ZEB1 protein expression. Furthermore, overexpression of ZEB1 reverses miR-455-suppressed malignant phenotype of NSCLC cells. Moreover, we found that upregulation of ZEB1 expression is inversely associated with miR-455 expression in NSCLC tissues. Taken together, miR-455 as an anti-oncogene in non-small cell lung cancer through up-regulation of ZEB1 and serve as a potential therapeutic target in NSCLC. PMID:26801503

  18. SKA1 regulates the metastasis and cisplatin resistance of non-small cell lung cancer

    PubMed Central

    SHEN, LIHUA; YANG, MIN; LIN, QIONGHUA; ZHANG, ZHONGWEI; MIAO, CHANGHONG; ZHU, BIAO

    2016-01-01

    Currently, chemotherapy with platinum-based drugs including cisplatin is the most effective therapy for the treatment of non-small cell lung carcinoma (NSCLC). However, the efficacy of chemotherapy is limited due to commonly developed drug resistance. Spindle and kinetochore-associated complex subunit 1 (SKA1) is part of a complex essential for stabilizing the attachment of spindle microtubules to kinetochores and for maintaining the metaphase plate during mitosis. In the present study, we aimed to investigate the role of SKA1 in the process of metastasis and drug resistance of NSCLC. We completed a series of experiments to investigate the function of SKA1 in NSCLC metastasis and drug resistance including qRT-PCR, immunohistochemistry and western blotting, as well as MTT, BrdU, wounded healing, Transwell and gelatin zymography assays. We demonstrated that the expression levels of SKA1 were elevated in NSCLC and were correlated with cancer progression and malignancy. We also reported that SKA1 positively regulated the proliferation and metastatic ability of NSCLC cells. In addition, we determined that SKA1 contributed to cisplatin resistance in NSCLC cells by protecting these cells from cisplatin-induced cell apoptosis. SKA1 also appeared to regulate the ERK1/2 and the Akt-mediated signaling pathways in NSCLC cells. SKA1 is required for metastasis and cisplatin resistance of non-small cell lung cancer. PMID:26985856

  19. Natural History of Non-Small-Cell Lung Cancer with Bone Metastases

    PubMed Central

    Daniele, Santini; Sandro, Barni; Salvatore, Intagliata; Alfredo, Falcone; Francesco, Ferraù; Domenico, Galetta; Luca, Moscetti; Nicla, La Verde; Toni, Ibrahim; Fausto, Petrelli; Enrico, Vasile; Laura, Ginocchi; Davide, Ottaviani; Flavia, Longo; Cinzia, Ortega; Antonio, Russo; Giuseppe, Badalamenti; Elena, Collovà; Gaetano, Lanzetta; Giovanni, Mansueto; Vincenzo, Adamo; Filippo, De Marinis; Satolli, Maria Antonietta; Flavia, Cantile; Andrea, Mancuso; Tanca, Francesca Maria; Raffaele, Addeo; Marco, Russano; Sterpi, M; Francesco, Pantano; Bruno, Vincenzi; Giuseppe, Tonini

    2015-01-01

    We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival. PMID:26690845

  20. The plasma lncRNA acting as fingerprint in non-small-cell lung cancer.

    PubMed

    Hu, Xiaodong; Bao, Jitao; Wang, Zhen; Zhang, Zigang; Gu, Peijie; Tao, Feng; Cui, Di; Jiang, Weilong

    2016-03-01

    Recent studies have indicated that long non-coding RNAs (lncRNAs) could act as non-invasive tumor markers in both diagnosis and predicting the prognosis. In this study, we focused to determine the expression of circulating lncRNAs in patients suffering from non-small-cell lung cancer (NSCLC), aiming to found the potential lncRNA as predictor. Twenty-one lncRNAs which previously identified were selected as candidate targets for subsequent circulating lncRNA assay. The candidate lncRNAs were validated by qRT-PCR arranged in the training and validation sets. Circulating SPRY4-IT1, ANRIL, and NEAT1 were significantly increased in plasma samples of NSCLC patients during training set and validation set. Receiver operating characteristic curve (ROC) analysis revealed that plasma ANRIL provided the highest diagnostic performance with an area under ROC curve value (AUC) of 0.798. Further combination with the three factors indicated a higher power (AUC, 0.876; sensitivity, 82.8 %; specificity, 92.3 %). The stableness detection of the three factors indicated that circulating SPRY4-IT1, ANRIL, and NEAT might serve as a predictor for the early warning of non-small-cell lung cancer. PMID:26453113

  1. Natural History of Non-Small-Cell Lung Cancer with Bone Metastases.

    PubMed

    Daniele, Santini; Sandro, Barni; Salvatore, Intagliata; Alfredo, Falcone; Francesco, Ferraù; Domenico, Galetta; Luca, Moscetti; Nicla, La Verde; Toni, Ibrahim; Fausto, Petrelli; Enrico, Vasile; Laura, Ginocchi; Davide, Ottaviani; Flavia, Longo; Cinzia, Ortega; Antonio, Russo; Giuseppe, Badalamenti; Elena, Collovà; Gaetano, Lanzetta; Giovanni, Mansueto; Vincenzo, Adamo; Filippo, De Marinis; Satolli, Maria Antonietta; Flavia, Cantile; Andrea, Mancuso; Tanca, Francesca Maria; Raffaele, Addeo; Marco, Russano; Sterpi, M; Francesco, Pantano; Bruno, Vincenzi; Giuseppe, Tonini

    2015-01-01

    We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival. PMID:26690845

  2. Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

    SciTech Connect

    Ma, Qing; Yu, Tao; Ren, Yao-Yao; Gong, Ting; Zhong, Dian-Sheng

    2014-11-07

    Highlights: • SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). • Knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro. • Overexpression of SAMD9 suppressed proliferation and invasion in A549 cells in vitro. • Depletion of SAMD9 increases tumor formation in vivo. - Abstract: The Sterile Alpha Motif Domain-containing 9 (SAMD9) gene has been recently emphasized during the discovery that it is expressed at a lower level in aggressive fibromatosis and some cases of breast and colon cancer, however, the underlying mechanisms are poorly understood. Here, we found that SAMD9 is down-regulated in human non-small cell lung cancer (NSCLC). Furthermore, knockdown of SAMD9 expression is increased the invasion, migration and proliferation in H1299 cells in vitro and overexpression of SAMD9 suppressed proliferation and invasion in A549 cells. Finally, depletion of SAMD9 increases tumor formation in vivo. Our results may provide a strategy for blocking NSCLC tumorigenesis and progression.

  3. Reduced Expression of FADS1 Predicts Worse Prognosis in Non-Small-Cell Lung Cancer

    PubMed Central

    Wang, Dong; Lin, Yan; Gao, Bei; Yan, Shumei; Wu, Huini; Li, Yong; Wu, Qiuliang; Wei, Yucheng

    2016-01-01

    Objective: Fatty acid desaturase 1 is a member of the fatty acid desaturase, which is related to a number of diseases. However, its role in cancers remains unclear. This study was to explore the clinical importance of FADS1 expression in non-small-cell lung cancer (NSCLC). Materials and Methods: Immunochemistry was used to evaluate FADS1 expressions in 216 paraffin-embedded specimens. The expression of FADS1 was divided into high and low groups. The clinical and prognostic significance of FADS1 expression was analyzed statistically by Kaplan-Meier estimate and Cox regression model. Results: FADS1 overexpressed in normal bronchial mucosa compared with non-small-cell lung cancer. Reduced FADS1 expression was associated with tumor size (P=0.023) and histological grade (P<0.0001). Patients with lower expression of FADS1 had shorter overall survival and disease free survival (P=0.001 and P=0.002). Multivariate analysis showed FADS1 expression was an independent prognostic factor in NSCLC (P=0.011). Conclusion: Reduced expression of FADS1 suggests pessimistic prognosis for NSCLC patients. Further studies are warranted. PMID:27390597

  4. Significance and evaluation of anaplastic lymphoma kinase by immunohistochemistry in non-small cell lung cancer.

    PubMed

    Ding, Shuting; Liu, Nan; Zhao, Huanyu; Jiang, Guiyang; Zhang, Xiupeng; Wang, Enhua

    2016-08-01

    We used immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) to evaluate anaplastic lymphoma kinase (ALK) protein expression and gene rearrangements, respectively, in 283 cases of wild-type epidermal growth factor receptor (EGFR) non-small cell lung cancer biopsy specimens. Immunohistochemistry was positive for ALK in 52 cases (18.4 %), and there was no significant difference in staining between various monoclonal antibodies (Roche ALK test kit, D5F3, p-ALK, and EML4-ALK). On RT-PCR, 36 cases (12.7 %) were positive for ALK. Immunohistochemistry and RT-PCR were both positive in 35 cases and both negative in 230 cases, and both have a high consistency (265/283, 93.6 %). Including 17 cases, immunohistochemistry was positive but RT-PCR was negative, and in one case, immunohistochemistry was negative but RT-PCR was positive. On fluorescence in situ hybridization (FISH) testing of these 18 cases, only three cases were positive (one RT-PCR was positive; two immunohistochemistry were positive). There is a high prevalence of ALK positivity in wild-type EGFR non-small cell lung cancer. Immunohistochemistry for the detection of ALK gene rearrangements was highly consistent with RT-PCR, and thus, it is a good screening tool but produces false positive results that necessitate further screening by RT-PCR or FISH. PMID:26886284

  5. SKA1 regulates the metastasis and cisplatin resistance of non-small cell lung cancer.

    PubMed

    Shen, Lihua; Yang, Min; Lin, Qionghua; Zhang, Zhongwei; Miao, Changhong; Zhu, Biao

    2016-05-01

    Currently, chemotherapy with platinum-based drugs including cisplatin is the most effective therapy for the treatment of non-small cell lung carcinoma (NSCLC). However, the efficacy of chemotherapy is limited due to commonly developed drug resistance. Spindle and kinetochore-associated complex subunit 1 (SKA1) is part of a complex essential for stabilizing the attachment of spindle microtubules to kinetochores and for maintaining the metaphase plate during mitosis. In the present study, we aimed to investigate the role of SKA1 in the process of metastasis and drug resistance of NSCLC. We completed a series of experiments to investigate the function of SKA1 in NSCLC metastasis and drug resistance including qRT-PCR, immunohistochemistry and western blotting, as well as MTT, BrdU, wounded healing, Transwell and gelatin zymography assays. We demonstrated that the expression levels of SKA1 were elevated in NSCLC and were correlated with cancer progression and malignancy. We also reported that SKA1 positively regulated the proliferation and metastatic ability of NSCLC cells. In addition, we determined that SKA1 contributed to cisplatin resistance in NSCLC cells by protecting these cells from cisplatin-induced cell apoptosis. SKA1 also appeared to regulate the ERK1/2 and the Akt-mediated signaling pathways in NSCLC cells. SKA1 is required for metastasis and cisplatin resistance of non-small cell lung cancer. PMID:26985856

  6. [Successful Treatment of Non-Small Cell Lung Cancer with Afatinib after Gefitinib-Induced Hepatotoxicity].

    PubMed

    Imai, Aya; Hachiya, Tsutomu; Ikuyama, Yuichi; Sonehara, Kei; Fujimori, Aiko; Shiba, Hiroko; Atobe, Osamu

    2016-01-01

    A 71-year-old man was referred to our hospital for treatment of non-small-cell lung cancer (adenocarcinoma of the lungs, with multiple bone metastases, cT1bN0M1b, harboring an EGFR mutation [exon 19 deletion]). Gefitinib was administered as daily oral doses of 250 mg. After 18 days, gefitinib was discontinued because of hepatotoxicity (Grade 3). Forty days later, afatinib was administered as daily oral doses of 40 mg. Within 1 year, the primary tumor and bone metastases achieved a partial response without hepatotoxicity. We suggest that afatinib is an effective and well-tolerated treatment option for patients with hepatotoxicity under gefitinib treatment. PMID:26809532

  7. Pazopanib diminishes non-small cell lung cancer (NSCLC) growth and metastases in vivo

    PubMed Central

    Zhao, Honglin; Yang, Fan; Shen, Wang; Wang, Yuli; Li, Xuebing; You, Jiacong; Zhou, Qinghua

    2015-01-01

    Background Anti-angiogenesis has been demonstrated to have a critical role in lung cancer pathogenesis. Here, we characterized the effect of the small-molecule angiogenesis inhibitor pazopanib on non-small cell lung cancer (NSCLC) cells. Methods NSCLC cells were tested for viability and migration after incubation with varying concentrations of pazopanib. Further, the phosphorylation status of extracellular signal-regulated kinase, protein kinase B, and MEK were assessed in vitro. For in vivo testing, mice grafted with NSCLC cell lines L9981 and A549 were treated orally with pazopanib. Results Pazopanib inhibits signaling pathways in tumor cells, thus blocking NSCLC cell growth and migration in vitro and inducing tumor cell arrest at G0/G1 phase. We show that pazopanib could inhibit tumor cell growth, decrease metastases, and prolong survival in two mouse xenograft models of human NSCLC. Conclusion These preclinical studies of pazopanib show the possibility of clinical application and, ultimately, improvement in patient outcome. PMID:26273349

  8. Prognostic and predictive value of MET deregulation in non-small cell lung cancer

    PubMed Central

    Toschi, Luca; Gianoncelli, Letizia; Baretti, Marina; Santoro, Armando

    2015-01-01

    Recent progress in cancer biology has led to the discovery of increasing number of oncogene alterations that have dramatically changed the paradigm of lung cancer treatment. MET is a tyrosine kinase receptor for the hepatocyte growth factor (HGF) that is deregulated in several malignancies, including non-small cell lung cancer (NSCLC). Abnormal MET-HGF signaling pathway activation can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. MET protein overexpression and increased MET gene number have been identified as poor prognostic factors in several series of surgically resected NSCLC making this receptor an attractive target for cancer treatment. Several clinical trials have recently evaluated the activity of a variety of anti-MET strategies in NSCLC patients with or without molecular selection with a variable degree of success, underscoring the need of establishing the best predictive biomarker for the identification of responding patients. PMID:25992382

  9. GENOMIC LANDSCAPE OF NON-SMALL CELL LUNG CANCER IN SMOKERS AND NEVER SMOKERS

    PubMed Central

    Govindan, Ramaswamy; Ding, Li; Griffith, Malachi; Subramanian, Janakiraman; Dees, Nathan D.; Kanchi, Krishna L.; Maher, Christopher A.; Fulton, Robert; Fulton, Lucinda; Wallis, John; Chen, Ken; Walker, Jason; McDonald, Sandra; Bose, Ron; Ornitz, David; Xiong, Donghai; You, Ming; Dooling, David J.; Watson, Mark; Mardis, Elaine R.

    2013-01-01

    Summary We report the results of whole genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and over 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatic modification and DNA repair pathways were identified along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions including ROS1 and ALK as well as novel metabolic enzymes. Cell cycle and JAK-STAT pathways are significantly altered in lung cancer along with perturbations in 54 genes that are potentially targetable with currently available drugs. PMID:22980976

  10. Immune Checkpoint Blockade: A New Era for Non-Small Cell Lung Cancer.

    PubMed

    Califano, Raffaele; Kerr, Keith; Morgan, Robert David; Russo, Giuseppe Lo; Garassino, Marina; Morgillo, Floriana; Rossi, Antonio

    2016-09-01

    Despite better understanding of it's molecular biology, non-small cell lung cancer (NSCLC) remains a challenging disease to treat. Unfortunately, treatment options are still very limited and prognosis for advanced disease is poor. Immune surveillance plays a crucial role in a host's defence against tumour cells, and this is particular relevant for lung cancer due to it's high somatic mutational load, which increases the chances for the immune system to recognize cancer cells as 'non-self'. Novel immunotherapies are emerging as an effective treatment for this disease. In this review, we present the data on immune checkpoint inhibitors for NSCLC, describing their mechanism of action, data efficacy from recent clinical trials, and strategies to select patients more likely to benefit from these agents. PMID:27484062

  11. Gender-related disparities in non-small cell lung cancer.

    PubMed

    Paggi, Marco G; Vona, Rosa; Abbruzzese, Claudia; Malorni, Walter

    2010-12-01

    Epidemiological studies clearly outline some disparities in cancer onset, progression as well as prognosis and therapeutic response between sexes. In particular, in lung cancer, the leading cause of cancer death, at least in Western countries, a gender disparity appears now to emerge, especially for non-small cell lung cancer (NSCLC). Such a disparity is apparently due to a variety of mechanisms, ranging from genetic and epigenetic differences to gender-specific lifestyle as well as to behavioral causes and, clearly, to sex hormones activity. Here we briefly recapitulate gender differences in terms of risk factors, histopathological features and pathogenetic mechanisms in NSCLC, and hypothesize that a gender-oriented pharmacology could beneficially impact on innovative therapeutic strategies. PMID:20826048

  12. New molecular targeted therapies for advanced non-small-cell lung cancer

    PubMed Central

    Méndez, Míriam; Custodio, Ana; Provencio, Mariano

    2011-01-01

    Non-small-cell lung cancer (NSCLC) is a uniformly fatal disease and most patients will present with advanced stage. Treatment outcomes remain unsatisfactory, with low long-term survival rates. Standard treatment, such as palliative chemotherapy and radiotherapy, offers a median survival not exceeding 1 year. Hence, considerable efforts have started to be made in order to identify new biological agents which may safely and effectively be administered to advanced NSCLC patients. Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. However, novel targeted therapies that interfere with other dysregulated pathways in lung cancer are already in the clinic. This review outlines the most promising research approaches to the treatment of NSCLC, discussed according to the specific molecular pathway targeted. PMID:22263060

  13. Current and future targeted therapies for non-small-cell lung cancers with aberrant EGF receptors

    PubMed Central

    Kanthala, Shanthi; Pallerla, Sandeep; Jois, Seetharama

    2015-01-01

    Expression of the EGF receptors (EGFRs) is abnormally high in many types of cancer, including 25% of lung cancers. Successful treatments target mutations in the EGFR tyrosine kinase domain with EGFR tyrosine kinase inhibitors (TKIs). However, almost all patients develop resistance to this treatment, and acquired resistance to first-generation TKI has prompted the clinical development of a second generation of EGFR TKI. Because of the development of resistance to treatment of TKIs, there is a need to collect genomic information about EGFR levels in non-small-cell lung cancer patients. Herein, we focus on current molecular targets that have therapies available as well as other targets for which therapies will be available in the near future. PMID:25757687

  14. Targeting PD-L1 for non-small-cell lung cancer.

    PubMed

    Feld, Emily; Horn, Leora

    2016-06-01

    Lung cancer is the leading cause of cancer-related death worldwide. For decades, cytotoxic chemotherapy has been the mainstay of treatment for the majority of patients, yet median survival remains poor and side effects from chemotherapy are not trivial. Immune checkpoint inhibitors, which exert antitumor effects by inhibiting negative T-cell regulators, are changing the landscape of treatment options for patients with non-small-cell lung cancer (NSCLC). The anti-PD-1 antibodies nivolumab and pembrolizumab are approved by the US FDA for treatment of patients with NSCLC and other tumor types. Additional agents are in clinical development. This review provides an update on the PD-1 and PD-L1 immune checkpoint inhibitors currently being evaluated in NSCLC patients. PMID:27197542

  15. Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts

    PubMed Central

    Vizoso, Miguel; Puig, Marta; Carmona, F.Javier; Maqueda, María; Velásquez, Adriana; Gómez, Antonio; Labernadie, Anna; Lugo, Roberto; Gabasa, Marta; Rigat-Brugarolas, Luis G.; Trepat, Xavier; Ramírez, Josep; Moran, Sebastian; Vidal, Enrique; Reguart, Noemí; Perera, Alexandre; Esteller, Manel; Alcaraz, Jordi

    2015-01-01

    Epigenetic changes through altered DNA methylation have been implicated in critical aspects of tumor progression, and have been extensively studied in a variety of cancer types. In contrast, our current knowledge of the aberrant genomic DNA methylation in tumor-associated fibroblasts (TAFs) or other stromal cells that act as critical coconspirators of tumor progression is very scarce. To address this gap of knowledge, we conducted genome-wide DNA methylation profiling on lung TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer patients using the HumanMethylation450 microarray. We found widespread DNA hypomethylation concomitant with focal gain of DNA methylation in TAFs compared to CFs. The aberrant DNA methylation landscape of TAFs had a global impact on gene expression and a selective impact on the TGF-β pathway. The latter included promoter hypermethylation-associated SMAD3 silencing, which was associated with hyperresponsiveness to exogenous TGF-β1 in terms of contractility and extracellular matrix deposition. In turn, activation of CFs with exogenous TGF-β1 partially mimicked the epigenetic alterations observed in TAFs, suggesting that TGF-β1 may be necessary but not sufficient to elicit such alterations. Moreover, integrated pathway-enrichment analyses of the DNA methylation alterations revealed that a fraction of TAFs may be bone marrow-derived fibrocytes. Finally, survival analyses using DNA methylation and gene expression datasets identified aberrant DNA methylation on the EDARADD promoter sequence as a prognostic factor in non-small cell lung cancer patients. Our findings shed light on the unique origin and molecular alterations underlying the aberrant phenotype of lung TAFs, and identify a stromal biomarker with potential clinical relevance. PMID:26449251

  16. Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts.

    PubMed

    Vizoso, Miguel; Puig, Marta; Carmona, F Javier; Maqueda, María; Velásquez, Adriana; Gómez, Antonio; Labernadie, Anna; Lugo, Roberto; Gabasa, Marta; Rigat-Brugarolas, Luis G; Trepat, Xavier; Ramírez, Josep; Moran, Sebastian; Vidal, Enrique; Reguart, Noemí; Perera, Alexandre; Esteller, Manel; Alcaraz, Jordi

    2015-12-01

    Epigenetic changes through altered DNA methylation have been implicated in critical aspects of tumor progression, and have been extensively studied in a variety of cancer types. In contrast, our current knowledge of the aberrant genomic DNA methylation in tumor-associated fibroblasts (TAFs) or other stromal cells that act as critical coconspirators of tumor progression is very scarce. To address this gap of knowledge, we conducted genome-wide DNA methylation profiling on lung TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer patients using the HumanMethylation450 microarray. We found widespread DNA hypomethylation concomitant with focal gain of DNA methylation in TAFs compared to CFs. The aberrant DNA methylation landscape of TAFs had a global impact on gene expression and a selective impact on the TGF-β pathway. The latter included promoter hypermethylation-associated SMAD3 silencing, which was associated with hyperresponsiveness to exogenous TGF-β1 in terms of contractility and extracellular matrix deposition. In turn, activation of CFs with exogenous TGF-β1 partially mimicked the epigenetic alterations observed in TAFs, suggesting that TGF-β1 may be necessary but not sufficient to elicit such alterations. Moreover, integrated pathway-enrichment analyses of the DNA methylation alterations revealed that a fraction of TAFs may be bone marrow-derived fibrocytes. Finally, survival analyses using DNA methylation and gene expression datasets identified aberrant DNA methylation on the EDARADD promoter sequence as a prognostic factor in non-small cell lung cancer patients. Our findings shed light on the unique origin and molecular alterations underlying the aberrant phenotype of lung TAFs, and identify a stromal biomarker with potential clinical relevance. PMID:26449251

  17. AKAP4 is a circulating biomarker for non-small cell lung cancer

    PubMed Central

    Gumireddy, Kiranmai; Li, Anping; Chang, David H.; Liu, Qin; Kossenkov, Andrew V.; Yan, Jinchun; Korst, Robert J.; Nam, Brian T.; Xu, Hua; Zhang, Lin; Ganepola, Ganepola A.P.; Showe, Louise C.; Huang, Qihong

    2015-01-01

    Cancer testis antigens (CTAs) are widely expressed in tumor tissues, circulating tumor cells (CTCs) and in cancer derived exosomes that are frequently engulfed by lymphoid cells. To determine whether tumor derived CTA mRNAs could be detected in RNA from purified peripheral blood mononuclear cells (PBMC) of non-small cell lung cancer (NSCLC) patients, we assayed for the expression of 116 CTAs in PBMC RNA in a discovery set and identified AKAP4 as a potential NSCLC biomarker. We validated AKAP4 as a highly accurate biomarker in a cohort of 264 NSCLCs and 135 controls from 2 different sites including a subset of controls with high risk lung nodules. When all (264) lung cancers were compared with all (135) controls the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers are compared with all controls the AUC is 0.9795 and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules, a comparison of significant clinical importance, the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage, but independent of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer. PMID:26160834

  18. Loss of expression of BAP1 is very rare in non-small cell lung carcinoma.

    PubMed

    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. PMID:27114369

  19. Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing.

    PubMed

    Liu, Pengyuan; Morrison, Carl; Wang, Liang; Xiong, Donghai; Vedell, Peter; Cui, Peng; Hua, Xing; Ding, Feng; Lu, Yan; James, Michael; Ebben, John D; Xu, Haiming; Adjei, Alex A; Head, Karen; Andrae, Jaime W; Tschannen, Michael R; Jacob, Howard; Pan, Jing; Zhang, Qi; Van den Bergh, Francoise; Xiao, Haijie; Lo, Ken C; Patel, Jigar; Richmond, Todd; Watt, Mary-Anne; Albert, Thomas; Selzer, Rebecca; Anderson, Marshall; Wang, Jiang; Wang, Yian; Starnes, Sandra; Yang, Ping; You, Ming

    2012-07-01

    Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2. PMID:22510280

  20. Radiofrequency ablation in primary non-small cell lung cancer: What a radiologist needs to know

    PubMed Central

    Bhatia, Shivank; Pereira, Keith; Mohan, Prasoon; Narayanan, Govindarajan; Wangpaichitr, Medhi; Savaraj, Niramol

    2016-01-01

    Lung cancer continues to be one of the leading causes of death worldwide. In advanced cases of lung cancer, a multimodality approach is often applied, however with poor local control rates. In early non-small cell lung cancer (NSCLC), surgery is the standard of care. Only 15-30% of patients are eligible for surgical resection. Improvements in imaging and treatment delivery systems have provided new tools to better target these tumors. Stereotactic body radiation therapy (SBRT) has evolved as the next best option. The role of radiofrequency ablation (RFA) is also growing. Currently, it is a third-line option in stage 1 NSCLC, when SBRT cannot be performed. More recent studies have demonstrated usefulness in recurrent tumors and some authors have also suggested combination of RFA with other modalities in larger tumors. Following the National Lung Screening Trial (NLST), screening by low-dose computed tomography (CT) has demonstrated high rates of early-stage lung cancer detection in high-risk populations. Hence, even considering the current role of RFA as a third-line option, in view of increasing numbers of occurrences detected, the number of potential RFA candidates may see a steep uptrend. In view of all this, it is imperative that interventional radiologists be familiar with the techniques of lung ablation. The aim of this article is to discuss the procedural technique of RFA in the lung and review the current evidence regarding RFA for NSCLC. PMID:27081229

  1. Targeting Aromatase and Estrogen Signaling in Human Non-Small Cell Lung Cancer

    PubMed Central

    Márquez-Garbán, Diana C.; Chen, Hsiao-Wang; Goodglick, Lee; Fishbein, Michael C.; Pietras, Richard J.

    2009-01-01

    Lung cancer has become increasingly common in women, and gender differences in the physiology and pathogenesis of the disease have suggested a role for estrogens. In the lung recent data have shown local production of estrogens from androgens via the action of aromatase enzyme and higher levels of estrogen in tumor tissue as compared with surrounding normal lung tissue. High levels of aromatase expression are also maintained in metastases as compared with primary tumors. Consistent with these findings, clinical studies suggest that aromatase expression may be a useful predictive biomarker for prognosis in the management of non-small cell lung cancer (NSCLC), the most common form of lung malignancy. Low levels of aromatase associate with a higher probability of long-term survival in older women with early stage NSCLC. Treatment of lung NSCLC xenografts in vivo with an aromatase inhibitor (exemestane) alone or combined with standard cisplatin chemotherapy elicits a significant reduction in tumor progression as compared to paired controls. Further, lung cancer progression is also governed by complex interactions between estrogen and growth factor signaling pathways to stimulate the growth of NSCLC as well as tumor-associated angiogenesis. We find that combination therapy with the multitargeted growth factor receptor inhibitor vandetanib and the estrogen receptor antagonist fulvestrant inhibit tumor growth more effectively than either treatment administered alone. Thus, incorporation of antiestrogen treatment strategies in standard antitumor therapies for NSCLC may contribute to improved patient outcome, an approach that deserves to be tested in clinical trials. PMID:19250205

  2. 76 FR 35450 - Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-17

    .... This guidance does not address endpoints for drugs to prevent or decrease the incidence of lung cancer... the Approval of Non-Small Cell Lung Cancer Drugs and Biologics; Availability AGENCY: Food and Drug... Cell Lung Cancer Drugs and Biologics.'' This draft guidance provides recommendations to applicants...

  3. Targeting the KRAS variant for treatment of non-small cell lung cancer: potential therapeutic applications.

    PubMed

    Ricciuti, Biagio; Leonardi, Giulia Costanza; Metro, Giulio; Grignani, Francesco; Paglialunga, Luca; Bellezza, Guido; Baglivo, Sara; Mencaroni, Clelia; Baldi, Alice; Zicari, Daniela; Crinò, Lucio

    2016-01-01

    Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the deadliest cancer-related proteins and plays a pivotal role in the most aggressive and lethal human cancers, including lung adenocarcinoma where it represents one of the most frequently mutated oncogene. Although therapeutic progresses have made an impact over the last decade, median survival for patients with advanced lung cancer remains disappointing, with a 5-year worldwide survival rate of <15%. For more than 20 years it has been recognized that constitutively active signaling downstream of KRAS is a fundamental driver of lung tumorigenesis. However, years of pursuit have failed to yield a drug that can safely curb KRAS activity; up to now no approved therapies exist for KRAS-mutant NSCLC. The aim of this review is to discuss the current knowledge of KRAS-mutated NSCLC, touching upon KRAS clinical relevance as a prognostic and predictive biomarker, with an emphasis on novel therapeutic approaches for the treatment of KRAS-variant NSCLC. PMID:26714748

  4. TASK-1 Regulates Apoptosis and Proliferation in a Subset of Non-Small Cell Lung Cancers.

    PubMed

    Leithner, Katharina; Hirschmugl, Birgit; Li, Yingji; Tang, Bi; Papp, Rita; Nagaraj, Chandran; Stacher, Elvira; Stiegler, Philipp; Lindenmann, Jörg; Olschewski, Andrea; Olschewski, Horst; Hrzenjak, Andelko

    2016-01-01

    Lung cancer is the leading cause of cancer deaths worldwide; survival times are poor despite therapy. The role of the two-pore domain K+ (K2P) channel TASK-1 (KCNK3) in lung cancer is at present unknown. We found that TASK-1 is expressed in non-small cell lung cancer (NSCLC) cell lines at variable levels. In a highly TASK-1 expressing NSCLC cell line, A549, a characteristic pH- and hypoxia-sensitive non-inactivating K+ current was measured, indicating the presence of functional TASK-1 channels. Inhibition of TASK-1 led to significant depolarization in these cells. Knockdown of TASK-1 by siRNA significantly enhanced apoptosis and reduced proliferation in A549 cells, but not in weakly TASK-1 expressing NCI-H358 cells. Na+-coupled nutrient transport across the cell membrane is functionally coupled to the efflux of K+ via K+ channels, thus TASK-1 may potentially influence Na+-coupled nutrient transport. In contrast to TASK-1, which was not differentially expressed in lung cancer vs. normal lung tissue, we found the Na+-coupled nutrient transporters, SLC5A3, SLC5A6, and SLC38A1, transporters for myo-inositol, biotin and glutamine, respectively, to be significantly overexpressed in lung adenocarcinomas. In summary, we show for the first time that the TASK-1 channel regulates apoptosis and proliferation in a subset of NSCLC. PMID:27294516

  5. TASK-1 Regulates Apoptosis and Proliferation in a Subset of Non-Small Cell Lung Cancers

    PubMed Central

    Leithner, Katharina; Hirschmugl, Birgit; Li, Yingji; Tang, Bi; Papp, Rita; Nagaraj, Chandran; Stacher, Elvira; Stiegler, Philipp; Lindenmann, Jörg; Olschewski, Andrea; Olschewski, Horst; Hrzenjak, Andelko

    2016-01-01

    Lung cancer is the leading cause of cancer deaths worldwide; survival times are poor despite therapy. The role of the two-pore domain K+ (K2P) channel TASK-1 (KCNK3) in lung cancer is at present unknown. We found that TASK-1 is expressed in non-small cell lung cancer (NSCLC) cell lines at variable levels. In a highly TASK-1 expressing NSCLC cell line, A549, a characteristic pH- and hypoxia-sensitive non-inactivating K+ current was measured, indicating the presence of functional TASK-1 channels. Inhibition of TASK-1 led to significant depolarization in these cells. Knockdown of TASK-1 by siRNA significantly enhanced apoptosis and reduced proliferation in A549 cells, but not in weakly TASK-1 expressing NCI-H358 cells. Na+-coupled nutrient transport across the cell membrane is functionally coupled to the efflux of K+ via K+ channels, thus TASK-1 may potentially influence Na+-coupled nutrient transport. In contrast to TASK-1, which was not differentially expressed in lung cancer vs. normal lung tissue, we found the Na+-coupled nutrient transporters, SLC5A3, SLC5A6, and SLC38A1, transporters for myo-inositol, biotin and glutamine, respectively, to be significantly overexpressed in lung adenocarcinomas. In summary, we show for the first time that the TASK-1 channel regulates apoptosis and proliferation in a subset of NSCLC. PMID:27294516

  6. Whole genome microarray analysis in non-small cell lung cancer

    PubMed Central

    AL Zeyadi, Mohammad; Dimova, Ivanka; Ranchich, Vladislav; Rukova, Blaga; Nesheva, Desislava; Hamude, Zora; Georgiev, Sevdalin; Petrov, Danail; Toncheva, Draga

    2015-01-01

    Lung cancer is a serious health problem, since it is one of the leading causes for death worldwide. Molecular–cytogenetic studies could provide reliable data about genetic alterations which could be related to disease pathogenesis and be used for better prognosis and treatment strategies. We performed whole genome oligonucleotide microarray-based comparative genomic hybridization in 10 samples of non-small cell lung cancer. Trisomies were discovered for chromosomes 1, 13, 18 and 20. Chromosome arms 5p, 7p, 11q, 20q and Хq were affected by genetic gains, and 1p, 5q, 10q and 15q, by genetic losses. Microstructural (<5 Mbp) genomic aberrations were revealed: gains in regions 7p (containing the epidermal growth factor receptor gene) and 12p (containing KRAS) and losses in 3p26 and 4q34. Based on high amplitude of alterations and small overlapping regions, new potential oncogenes may be suggested: NBPF4 (1p13.3); ETV1, AGR3 and TSPAN13 (7p21.3-7p21.1); SOX5 and FGFR1OP2 (12p12.1-12p11.22); GPC6 (13q32.1). Significant genetic losses were assumed to contain potential tumour-suppressor genes: DPYD (1p21.3); CLDN22, CLDN24, ING2, CASP3, SORBS2 (4q34.2-q35.1); DEFB (8p23.1). Our results complement the picture of genomic characterization of non-small cell lung cancer. PMID:26019623

  7. Curative radiotherapy in non-small cell carcinoma of the lung

    SciTech Connect

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

    1990-07-01

    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.

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

    PubMed

    Reveliotis, Konstantinos; Kalavrouziotis, George; Skevis, Konstantinos; Charpidou, Andriani; Trigidou, Rodoula; Syrigos, Kostas

    2014-09-23

    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 investigate the efficacy

  9. [Treatment of advanced non-small-cell lung cancer with driver mutations].

    PubMed

    Tessmer, Antje; Kollmeier, Jens

    2015-03-01

    Advanced non-small-cell lung cancer is no longer one disease but the collective name for different diseases defined by clinical, histological, immunohistochemical and, to an increasing extent, molecular biomarkers. This article deals with the treatment options we gained by identifying so called driver mutations in a growing subset of these cancers. For patients whose tumors are characterized by a targetable molecular alteration such as an activating EGFR-Mutation, an ALK-translocation or a ROS1-rearrangement, we see prolonged survival and oral treatments with tyrosine kinase inhibitors demonstrate superiority to chemotherapy in terms of response (remission rate), progression free survival and quality of life. We provide a review of the literature and discuss the status quo of the diagnostic need and the therapeutic options in Germany and Europe. PMID:25734673

  10. Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer: Theory and Practice.

    PubMed

    Rusthoven, Chad G; Yeh, Norman; Gaspar, Laurie E

    2015-01-01

    Management paradigms for metastatic non-small cell lung cancer (mNSCLC) are evolving. Locally ablative therapies are now being increasingly integrated into combined-modality treatment strategies for mNSCLC patients with limited burdens of metastatic foci, termed oligometastases. Concurrently, techniques allowing for precise high-dose radiotherapy delivered over 1 to 5 total treatments, termed stereotactic body radiation therapy (SBRT) or stereotactic ablative radiation therapy (SABR), have emerged as a powerful means of noninvasive tumor ablation with broad patient candidacy. Strong rationale exists for ablative therapy in the setting of oligometastatic NSCLC, including patterns-of-failure analyses and data supporting local ablation of oligoprogressive disease for patients with oncogene-addicted mNSCLC treated with tyrosine kinase inhibitors. In this article, we examine the theoretical basis for ablation of oligometastatic NSCLC and review the growing clinical literature of mNSCLC patients treated with ablative radiation therapy. PMID:26389766

  11. The Role of Anti-angiogenesis in Non-small-cell Lung Cancer: an Update

    PubMed Central

    Socinski, Mark A.

    2016-01-01

    Recognition of the vascular endothelial growth factor (VEGF) pathway as a key mediator of angiogenesis has led to the clinical study of several VEGF and VEGF receptor (VEGFR) targeted therapies in non-small-cell lung cancer (NSCLC). These targeted therapies include neutralizing antibodies to VEGF (bevacizumab and aflibercept) and VEGFR-2 (ramucirumab) and tyrosine kinase inhibitors (TKIs) with selectivity for the VEGFRs. Bevacizumab and ramucirumab are associated with survival advantages in the treatment of advanced NSCLC: bevacizumab in the first-line setting in combination with carboplatin/paclitaxel and ramucirumab in combination with docetaxel in the second-line setting. The VEGFR-2 TKIs have been associated with responses and improved progression-free survival in selected NSCLC settings; however, this level of activity has thus far been insufficient to confer significant survival advantages. This review will focus on the current state of VEGF targeted therapies in NSCLC. PMID:25947099

  12. Understanding immunotherapy for the treatment of non-small cell lung cancer.

    PubMed

    Thomas, Rachel

    2016-09-01

    Patients diagnosed with advanced non-small-cell lung cancer (NSCLC) (either squamous or non-squamous) have previously had limited treatment options after progression on chemotherapy. With the emergence of new drugs, particularly in the immuno-oncology setting, this is now changing. Recent clinical trial evidence demonstrates that compared with docetaxel, patients who received nivolumab had better overall survival and also significantly fewer grade 3-4 adverse events. This article reviews the clinical trial data for nivolumab and provides an overview of how this drug works. The adverse event profile of nivolumab is assessed and compared to that of docetaxel. The important role that nurses can play in supporting patients on nivolumab is also discussed. PMID:27615536

  13. The emerging role of pemetrexed (Alimta) and gemcitabine in non-small cell lung cancer.

    PubMed

    Le Chevalier, Thierry

    2003-08-01

    In recent years, several new cytotoxic agents have been investigated for the management of non-small cell lung cancer (NSCLC), including the antimetabolic gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and the new multitargeted antifolate pemetrexed (Alimta, Eli Lilly and Company), which are both among the most active agents in advanced NSCLC. Gemcitabine has become one of the key drugs in the management of NSCLC, alone or in association with platin compounds. Promising results have also been reported with pemetrexed used as a single-agent or in combination with cisplatin or gemcitabine. These results indicate that pemetrexed may also play a vital role in the treatment of NSCLC, malignant mesothelioma, and other solid tumors. Ongoing (and planned) trials are investigating the use of single-agent pemetrexed, or combinations with cisplatin, gemcitabine, and other cytotoxic agents in various malignancies. PMID:12947960

  14. Prognostic significance of FoxM1 expression in non-small cell lung cancer

    PubMed Central

    Dong, Min; Chen, Yujuan; Zhang, Jiawei; Qiao, Jinpeng; Guo, Xuedan

    2016-01-01

    Background Various studies examined the relationship between FoxM1 overexpression with the clinical outcome in patients with non-small cell lung cancer (NSCLC), but yielded conflicting results. Methods Electronic databases updated to Jan 01, 2015 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between FoxM1 overexpression and survival of patients with NSCLC Survival data were aggregated and quantitatively analyzed. Results We performed a meta-analysis of seven studies (n=860 patients) that evaluated the correlation between FoxM1 overexpression and survival in patients with NSCLC. Combined hazard ratios suggested that FoxM1 overexpression was associated with poor prognosis of overall survival (OS) (HR =1.73, 95% CI: 1.32–2.14) in patients with NSCLC. Conclusions FoxM1 overexpression indicates a poor prognosis for patients with NSCLC. PMID:27293846

  15. Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

    PubMed Central

    Asami, Kazuhiro; Atagi, Shinji

    2014-01-01

    First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs. PMID:25302168

  16. Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts

    NASA Astrophysics Data System (ADS)

    Harder, Samantha J.; Isabelle, Martin; Devorkin, Lindsay; Smazynski, Julian; Beckham, Wayne; Brolo, Alexandre G.; Lum, Julian J.; Jirasek, Andrew

    2016-02-01

    External beam radiation therapy is a standard form of treatment for numerous cancers. Despite this, there are no approved methods to account for patient specific radiation sensitivity. In this report, Raman spectroscopy (RS) was used to identify radiation-induced biochemical changes in human non-small cell lung cancer xenografts. Chemometric analysis revealed unique radiation-related Raman signatures that were specific to nucleic acid, lipid, protein and carbohydrate spectral features. Among these changes was a dramatic shift in the accumulation of glycogen spectral bands for doses of 5 or 15 Gy when compared to unirradiated tumours. When spatial mapping was applied in this analysis there was considerable variability as we found substantial intra- and inter-tumour heterogeneity in the distribution of glycogen and other RS spectral features. Collectively, these data provide unique insight into the biochemical response of tumours, irradiated in vivo, and demonstrate the utility of RS for detecting distinct radiobiological responses in human tumour xenografts.

  17. True Video-Assisted Thoracic Surgery for Early–Stage Non-Small Cell Lung Cancer

    PubMed Central

    Cao, Christopher Q.; Stine, Munkholm-Larsen; Yan, Tristan D.

    2009-01-01

    Since its inception, minimally invasive surgery has made a dramatic impact on all branches of surgery. Video-assisted thoracic surgery (VATS) lobectomy for early-stage non-small cell lung cancer (NSCLC) was first described in the early 1990s and has since become popular in a number of tertiary referral centers. Proponents of this relatively new procedure cite a number of potentially favorable perioperative outcomes, possibly due to reduced surgical trauma and stress. However, a significant proportion of the cardiothoracic community remains skeptical, as there is still a paucity of robust clinical data on long-term survival and recurrence rates. The definition of ‘true’ VATS has also been under scrutiny, with a number of previous studies being considered ‘mini-thoracotomy lobectomy’ rather than VATS lobectomy. We hereby examine the literature on true VATS lobectomy, with a particular focus on comparative studies that directly compared VATS lobectomy with conventional open lobectomy. PMID:22263000

  18. Role of Chemokines in Non-Small Cell Lung Cancer: Angiogenesis and Inflammation

    PubMed Central

    Rivas-Fuentes, Selma; Salgado-Aguayo, Alfonso; Pertuz Belloso, Silvana; Gorocica Rosete, Patricia; Alvarado-Vásquez, Noé; Aquino-Jarquin, Guillermo

    2015-01-01

    Non-small cell lung cancer (NSCLC) is one of the most common types of aggressive cancer. The tumor tissue, which shows an active angiogenesis, is composed of neoplastic and stromal cells, and an abundant inflammatory infiltrate. Angiogenesis is important to support tumor growth, while infiltrating cells contribute to the tumor microenvironment through the secretion of growth factors, cytokines and chemokines, important molecules in the progression of the disease. Chemokines are important in development, activation of the immune response, and physiological angiogenesis. Chemokines have emerged as important regulators in the pathophysiology of cancer. These molecules are involved in the angiogenesis/angiostasis balance and in the recruitment of tumor infiltrating hematopoietic cells. In addition, chemokines promote tumor cell survival, as well as the directing and establishment of tumor cells to metastasis sites. The findings summarized here emphasize the central role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in the inflammatory process of NSCLC angiogenesis. PMID:26316890

  19. Recent advances in squamous non-small cell lung cancer: evidence beyond predictive biomarkers.

    PubMed

    Genova, Carlo; Rijavec, Erika; Grossi, Francesco

    2016-01-01

    Squamous non-small cell lung cancer (NSCLC) has always been characterized by a limited number of therapeutic options and by the lack of actionable biomarkers compared to its non-squamous counterpart. Recent clinical trials have led to the approval of new anti-neoplastic drugs available to both non-squamous and squamous NSCLC, consisting in a vascular-disrupting agent and two immune check-point inhibitors; additionally, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) is currently under evaluation by the Food and Drug Administration (FDA). While predictive molecular biomarkers have not been identified with consistency and are still highly demanded, these agents proved themselves noteworthy and can be considered a powerful addition to the available treatments for squamous NSCLC. PMID:26567561

  20. RACK1 Promotes Non-small-cell Lung Cancer Tumorigenicity through Activating Sonic Hedgehog Signaling Pathway*

    PubMed Central

    Shi, Shuo; Deng, Yue-Zhen; Zhao, Jiang-Sha; Ji, Xiao-Dan; Shi, Jun; Feng, Yu-Xiong; Li, Guo; Li, Jing-Jing; Zhu, Di; Koeffler, H. Phillip; Zhao, Yun; Xie, Dong

    2012-01-01

    Non-small-cell lung cancer (NSCLC) is a deadly disease due to lack of effective diagnosis biomarker and therapeutic target. Much effort has been made in defining gene defects in NSCLC, but its full molecular pathogenesis remains unexplored. Here, we found RACK1 (receptor of activated kinase 1) was elevated in most NSCLC, and its expression level correlated with key pathological characteristics including tumor differentiation, stage, and metastasis. In addition, RACK1 activated sonic hedgehog signaling pathway by interacting with and activating Smoothened to mediate Gli1-dependent transcription in NSCLC cells. And silencing RACK1 dramatically inhibited in vivo tumor growth and metastasis by blocking the sonic hedgehog signaling pathway. These results suggest that RACK1 represents a new promising diagnosis biomarker and therapeutic target for NSCLC. PMID:22262830

  1. Isolated brain metastasis as a late recurrence of completely resected non-small cell lung cancer

    PubMed Central

    JU, LIXIA; HAN, MINGQUAN

    2016-01-01

    The brain is one of the most common sites for non-small cell lung cancer (NSCLC) metastasis; however, late isolated brain metastasis as a recurrence of NSCLC is rare. The present study describes a case of isolated solitary brain metastasis as a late recurrence of NSCLC, which occurred >2 years following the successful resection of the primary tumor, and was identified by magnetic resonance imaging. To the best of our knowledge, this is the first report of isolated brain metastasis as a postoperative recurrence of NSCLC. The aim of the present study was to highlight that, despite its rarity, such recurrence should be considered possible, and particular attention to the treatment of such patients should be paid. PMID:27347208

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

    PubMed Central

    Ma, Debin; Jia, Hui; Qin, Mengmeng; Dai, Wenjie; Wang, Tao; Liang, Erguang; Dong, Guofu; Wang, Zuojun; Zhang, Zhiyuan; Feng, Fan

    2015-01-01

    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. PMID:26389880

  3. Review of the current targeted therapies for non-small-cell lung cancer.

    PubMed

    Nguyen, Kim-Son H; Neal, Joel W; Wakelee, Heather

    2014-10-10

    The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come. PMID:25302162

  4. ALK-rearrangements and testing methods in non-small cell lung cancer: a review

    PubMed Central

    Shackelford, Rodney E.; Vora, Moiz; Mayhall, Kim; Cotelingam, James

    2014-01-01

    The anaplastic lymphoma tyrosine kinase (ALK) gene was first described as a driver mutation in anaplastic non-Hodgkin's lymphoma. Dysregulated ALK expression is now an identified driver mutation in nearly twenty different human malignancies, including 4-9% of non-small cell lung cancers (NSCLC). The tyrosine kinase inhibitor crizotinib is more effective than standard chemotherapeutic agents in treating ALK positive NSCLC, making molecular diagnostic testing for dysregulated ALK expression a necessary step in identifying optimal treatment modalities. Here we review ALKmediated signal transduction pathways and compare the molecular protocols used to identify dysregulated ALK expression in NSCLC. We also discuss the use of crizotinib and second generation ALK tyrosine kinase inhibitors in the treatment of ALK positive NSCLC, and the known mechanisms of crizotinib resistance in NSCLC. PMID:24955213

  5. The potential diagnostic power of circulating tumor cell analysis for non-small-cell lung cancer.

    PubMed

    Ross, Kirsty; Pailler, Emma; Faugeroux, Vincent; Taylor, Melissa; Oulhen, Marianne; Auger, Nathalie; Planchard, David; Soria, Jean-Charles; Lindsay, Colin R; Besse, Benjamin; Vielh, Philippe; Farace, Françoise

    2015-01-01

    In non-small-cell lung cancer (NSCLC), genotyping tumor biopsies for targetable somatic alterations has become routine practice. However, serial biopsies have limitations: they may be technically difficult or impossible and could incur serious risks to patients. Circulating tumor cells (CTCs) offer an alternative source for tumor analysis that is easily accessible and presents the potential to identify predictive biomarkers to tailor therapies on a personalized basis. Examined here is our current knowledge of CTC detection and characterization in NSCLC and their potential role in EGFR-mutant, ALK-rearranged and ROS1-rearranged patients. This is followed by discussion of the ongoing issues such as the question of CTC partnership as diagnostic tools in NSCLC. PMID:26564313

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

    PubMed

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

    2015-10-01

    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. PMID:26341266

  7. Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

    PubMed Central

    Bayraktar, Soley; Rocha-Lima, Caio M

    2013-01-01

    Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death in both men and women in the United States. Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease. Improvements in overall survival and quality of life have been modest. Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics, thus changing the treatment paradigm for many NSCLC patients. In this review, we present a summary of many of the currently investigated biologic targets in NSCLC, discuss their current clinical trial status, and also discuss the potential for development of other targeted agents. PMID:23696960

  8. Review of the Treatment of Non-Small Cell Lung Cancer with Gefitinib

    PubMed Central

    Araki, Takuya; Yashima, Hideaki; Shimizu, Kimihiro; Aomori, Tohru; Hashita, Tadahiro; Kaira, Kyoichi; Nakamura, Tomonori; Yamamoto, Koujirou

    2012-01-01

    In the past decade, molecular-targeted drugs have been focused upon for the treatment of cancer. In 2002, gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor became available in Japan for the treatment of non-small cell lung cancer (NSCLC). Over 80% of selected patients, such as EGFR mutation-positive patients, respond to gefitinib treatment; however, most patients develop acquired resistance to gefitinib within a few years. Recently, many studies have been performed to determine precisely how to select patients who will respond to gefitinib, the best timing for its administration, and how to avoid the development of acquired resistance as well as adverse drug effects. This article reviews the use of gefitinib for the treatment of NSCLC from a pharmaceutical viewpoint. PMID:23239933

  9. BRAF mutations in non-small cell lung cancer: has finally Janus opened the door?

    PubMed

    Caparica, Rafael; de Castro, Gilberto; Gil-Bazo, Ignacio; Caglevic, Christian; Calogero, Raffaele; Giallombardo, Marco; Santos, Edgardo S; Raez, Luis E; Rolfo, Christian

    2016-05-01

    B-Raf mutations occur in about 1-2% of non-small cell lung cancers (NSCLC). These mutations generate a permanent activation of the mitogen activated protein kinase (MAPK) pathway, which promotes tumor growth and proliferation. In the present review, we discuss B-Raf mutation epidemiology, diagnostic methods to detect B-Raf mutations, the role of B-Raf as a driver mutation and a potential therapeutic target in NSCLC. The results of clinical trials involving B-Raf or MAPK pathway inhibitors for the treatment of NSCLC are also discussed. Clinical trials evaluating B-Raf inhibitors in BRAF mutated NSCLC patients have shown promising results, and larger prospective studies are warranted to validate these findings. Enrollment of these patients in clinical trials is an interesting strategy to offer a potentially more effective and less toxic targeted therapy. PMID:26960735

  10. [Tumor vasculature as a therapeutic target in non-small cell lung cancer].

    PubMed

    Döme, Balázs; Magyar, Melinda

    2008-09-01

    Despite developments in conventional (chemo)radiotherapy and surgery, survival of non-small cell lung cancer (NSCLC) patients remains poor. Treatments with targeted molecular drugs offer novel therapeutic strategies. Bevacizumab, a recombinant anti-vascular endothelial growth factor (VEGF) antibody, is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC. However, a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain. Furthermore, novel agents targeting the pre-existing NSCLC vasculature (i.e. vascular disrupting agents, VDAs) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies. Herein, we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC. PMID:18845495

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

    PubMed

    Ma, Debin; Jia, Hui; Qin, Mengmeng; Dai, Wenjie; Wang, Tao; Liang, Erguang; Dong, Guofu; Wang, Zuojun; Zhang, Zhiyuan; Feng, Fan

    2015-01-01

    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. PMID:26389880

  12. Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer

    PubMed Central

    Cooper, Maryann R; Binkowski, Chelsea; Hartung, Jessica; Towle, Jennifer

    2016-01-01

    The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC. PMID:27110124

  13. High level of BRD4 promotes non-small cell lung cancer progression

    PubMed Central

    Zhu, Shu-Qiang; Jin, Chun; Xu, Jian-Jun; Ding, Jian-Yong

    2016-01-01

    Bromodomain containing protein 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) protein family, has been shown to play important roles in tumor progression. However, its role in non-small cell lung cancer (NSCLC) is still largely unknown. Here, we found that BRD4 expression was significantly upregulated in NSCLC tissues and NSCLC cell lines with higher invasion and metastasis potentials. Suppression of BRD4 expression in NSCLC cell lines impaired cell invasion, inhibited cell proliferation, and accelerated cell apoptosis. Clinically, we observed that the BRD4 level was significantly related to histological type, lymph node metastasis, tumor stage and differentiation. More importantly, high level of BRD4 was closely correlated with the poor prognosis of NSCLC patients. Therefore, our study suggests that BRD4 is one of the major contributors to the invasion-prone phenotype of NSCLC, and a potential therapeutic target of NSCLC. PMID:26840017

  14. Overexpression of WDR79 in non-small cell lung cancer is linked to tumour progression.

    PubMed

    Sun, Yang; Yang, Chao; Chen, Jieying; Song, Xin; Li, Zhen; Duan, Minlan; Li, Jianglin; Hu, Xiaoxiao; Wu, Kuangpei; Yan, Guobei; Yang, Cai; Liu, Jing; Tan, Weihong; Ye, Mao

    2016-04-01

    WD-repeat protein 79 (WDR79), a member of the WD-repeat protein family, acts as a scaffold protein, participating in telomerase assembly, Cajal body formation and DNA double-strand break repair. Here, we first report that WDR79 is frequently overexpressed in cell lines and tissues derived from non-small cell lung cancer (NSCLC). Knockdown of WDR79 significantly inhibited the proliferation of NSCLC cells in vitro and in vivo by inducing cell cycle arrest and apoptosis. WD-repeat protein 79 -induced cell cycle arrest at the G0/G1 phase was associated with the expression of G0/G1-related cyclins and cyclin-dependent kinase complexes. We also provide evidence that WDR79 knockdown induces apoptosis via a mitochondrial pathway. Collectively, these results suggest that WDR79 is involved in the tumorigenesis of NSCLC and is a potential novel diagnostic marker and therapeutic target for NSCLC. PMID:26849396

  15. New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib

    PubMed Central

    Rothschild, Sacha I

    2016-01-01

    Rearrangements in ALK gene and EML4 gene were first described in 2007. This genomic aberration is found in about 2%–8% of non-small-cell lung cancer (NSCLC) patients. Crizotinib was the first ALK tyrosine kinase inhibitor licensed for the treatment of metastatic ALK-positive NSCLC based on a randomized Phase III trial. Despite the initial treatment response of crizotinib, disease progression inevitably develops after approximately 10 months of therapy. Different resistance mechanisms have recently been described. One relevant mechanism of resistance is the development of mutations in ALK. Novel ALK tyrosine kinase inhibitors have been developed to overcome these mutations. Ceritinib is an oral second-generation ALK inhibitor showing clinical activity not only in crizotinib-resistant ALK-positive NSCLC but also in treatment-naïve ALK-positive disease. In this paper, preclinical and clinical data of ceritinib are reviewed, and its role in the clinical setting is put into perspective. PMID:27217763

  16. The Role of STAT3 in Non-Small Cell Lung Cancer

    PubMed Central

    Harada, Daijiro; Takigawa, Nagio; Kiura, Katsuyuki

    2014-01-01

    Persistent phosphorylation of signal transducer and activator of transcription 3 (STAT3) has been demonstrated in 22%~65% of non-small cell lung cancers (NSCLC). STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET, cytokine receptors, such as IL-6, and non-receptor kinases, such as Src. Overexpression of total or phosphorylated STAT3 in resected NSCLC leads to poor prognosis. In a preclinical study, overexpression of STAT3 was correlated with chemoresistance and radioresistance in NSCLC cells. Here, we review the role of STAT3 and the mechanisms of treatment resistance in malignant diseases, especially NSCLC. As STAT3 is a critical mediator of the oncogenic effects of EGFR mutations, we discuss STAT3 pathways in EGFR-mutated NSCLC, referring to mechanisms of EGFR tyrosine kinase inhibitor resistance. PMID:24675568

  17. The Role of STAT3 in Non-Small Cell Lung Cancer.

    PubMed

    Harada, Daijiro; Takigawa, Nagio; Kiura, Katsuyuki

    2014-01-01

    Persistent phosphorylation of signal transducer and activator of transcription 3 (STAT3) has been demonstrated in 22%~65% of non-small cell lung cancers (NSCLC). STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET, cytokine receptors, such as IL-6, and non-receptor kinases, such as Src. Overexpression of total or phosphorylated STAT3 in resected NSCLC leads to poor prognosis. In a preclinical study, overexpression of STAT3 was correlated with chemoresistance and radioresistance in NSCLC cells. Here, we review the role of STAT3 and the mechanisms of treatment resistance in malignant diseases, especially NSCLC. As STAT3 is a critical mediator of the oncogenic effects of EGFR mutations, we discuss STAT3 pathways in EGFR-mutated NSCLC, referring to mechanisms of EGFR tyrosine kinase inhibitor resistance. PMID:24675568

  18. Induction and concurrent chemotherapy with concomitant boost radiotherapy in non-small cell lung cancer.

    PubMed

    Oral, Ethem Nezih; Aydiner, Adnan; Eralp, Yesim; Topuz, Erkan

    2005-01-01

    This study was designed to evaluate the tolerability and therapeutic activity of paclitaxel and carboplatin combination therapy followed by radical thoracic radiotherapy with a concomitant boost technique with concurrent weekly paclitaxel in good performance status of patients with stage IIIA and IIIB non-small cell lung cancer. Patients with newly diagnosed inoperable non-small cell lung cancer received paclitaxel (100 mg/m(2)) as a 1-h infusion on d 1,8,15,28,35, and 42. Carboplatin (area under the curve of 6) was given as a 30-min infusion on d 1 and 28. Radiotherapy commenced on d 49 and was delivered with accelerated fractionation with concomitant boost at 1.8 Gy/fraction/d, 5 d/week and 1.5 Gy/fraction/d to a boost field as a second daily treatment for the last 10 treatment days to 60 Gy/35 fractions/5 wk. During radiation treatment, paclitaxel (60 mg/m(2)) was given as a 1-h infusion once weekly for 5 wk. Twenty-four patients were enrolled in the study. Hematologic toxicities and alopecia were the major acute toxicities during induction chemotherapy; 8.7% of the patients experienced grade 3-4 neutropenia and alopecia. The main acute toxicity of concurrent chemoradiotherapy was esophagitis; grade 3 esophagitis was documented in 23.5% of the patients. No major late toxicity was seen. Overall response rate to the treatment was 65.2%. The median and 1-yr overall-survival rates were 24.9 mo and 63.8%, respectively. The median and 1-yr progression-free survival rates were 9.0 mo and 27.8%, respectively. The main acute toxicities were hematologic toxicity, esophagitis, and alopecia. The response rate and the survival rates achieved with this treatment regimen are particularly noteworthy, especially considering the advanced stage of the patients treated. PMID:16260854

  19. Prognostic markers in resectable non-small cell lung cancer: a multivariate analysis

    PubMed Central

    Pelletier, Marc P.; deB. Edwardes, Michael D.; Michel, René P.; Halwani, Fawaz; Morin, Jean E.

    2001-01-01

    Objective To identify the prognostic significance of certain clinical, cellular and immunologic markers in resectable non-small cell lung cancer (NSCLC). Design A cohort of patients with resectable NSCLC was prospectively followed up for 8 years (100% follow-up). Setting A university hospital in a large Canadian city. Patients One hundred and thirteen consecutive patients who underwent surgical resection of primary NSCLC. Main outcome measures Presence of peritumoral B lymphocytes (identified with antibody to CD20) and T lymphocytes (antibody to CD43), along with tumour markers (carcinoembryonic antigen [CEA], keratin, cytokeratin, S-100 protein, vimentin, chromogranin) and other factors such as age, sex, cell type, American Joint Committee on Cancer (AJCC) stage, histologic grade, DNA ploidy and S-phase fraction were correlated with survival. Results The mean age of patients in the study was 66.0 years; 60% were male. Histologic types of the tumours were: adenocarcinoma 57 (50.4%), squamous cell 47 (41.6%), adenosquamous 6 (5.3%) and large cell 3 (2.6%). AJCC stages were: I 66 (58.4%), II 20 (17.7%) and III 27 (23.9%). Histologic grades were: I (well differentiated) 31 (27.4%), II 50 (44.2%), III 29 (25.7%) and IV 3 (2.6%). Survival was 85% at 1 year (95% confidence interval [CI] 76%–90%), 44% at 5 years (95% CI 34%–53%) and 34% at 10 years (95% CI 22%–46%). Multivariate analyses using the Cox proportional hazards model for survival confirmed AJCC stage (p < 0.001) in all histologic subtypes to be the strongest factor of independent prognostic significance. It also revealed the presence of CD20-stained B lymphocytes (p = 0.04) in the peritumoral region of all tumours to be a positive prognostic factor. This relation was especially strong for nonsquamous cell carcinomas (p < 0.001). For squamous cell carcinomas, the immunohistochemical presence of CEA was of marginally negative prognostic value (p = 0.04). DNA ploidy and a high S-phase fraction showed no

  20. Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group

    PubMed Central

    Dietel, Manfred; Bubendorf, Lukas; Dingemans, Anne-Marie C; Dooms, Christophe; Elmberger, Göran; García, Rosa Calero; Kerr, Keith M; Lim, Eric; López-Ríos, Fernando; Thunnissen, Erik; Van Schil, Paul E; von Laffert, Maximilian

    2016-01-01

    Background There is currently no Europe-wide consensus on the appropriate preanalytical measures and workflow to optimise procedures for tissue-based molecular testing of non-small-cell lung cancer (NSCLC). To address this, a group of lung cancer experts (see list of authors) convened to discuss and propose standard operating procedures (SOPs) for NSCLC. Methods Based on earlier meetings and scientific expertise on lung cancer, a multidisciplinary group meeting was aligned. The aim was to include all relevant aspects concerning NSCLC diagnosis. After careful consideration, the following topics were selected and each was reviewed by the experts: surgical resection and sampling; biopsy procedures for analysis; preanalytical and other variables affecting quality of tissue; tissue conservation; testing procedures for epidermal growth factor receptor, anaplastic lymphoma kinase and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) in lung tissue and cytological specimens; as well as standardised reporting and quality control (QC). Finally, an optimal workflow was described. Results Suggested optimal procedures and workflows are discussed in detail. The broad consensus was that the complex workflow presented can only be executed effectively by an interdisciplinary approach using a well-trained team. Conclusions To optimise diagnosis and treatment of patients with NSCLC, it is essential to establish SOPs that are adaptable to the local situation. In addition, a continuous QC system and a local multidisciplinary tumour-type-oriented board are essential. PMID:26530085

  1. Cross-talk between AMPK and EGFR dependent Signaling in Non-Small Cell Lung Cancer

    PubMed Central

    Praveen, Paurush; Hülsmann, Helen; Sültmann, Holger; Kuner, Ruprecht; Fröhlich, Holger

    2016-01-01

    Lung cancers globally account for 12% of new cancer cases, 85% of these being Non Small Cell Lung Cancer (NSCLC). Therapies like erlotinib target the key player EGFR, which is mutated in about 10% of lung adenocarcinoma. However, drug insensitivity and resistance caused by second mutations in the EGFR or aberrant bypass signaling have evolved as a major challenge in controlling these tumors. Recently, AMPK activation was proposed to sensitize NSCLC cells against erlotinib treatment. However, the underlying mechanism is largely unknown. In this work we aim to unravel the interplay between 20 proteins that were previously associated with EGFR signaling and erlotinib drug sensitivity. The inferred network shows a high level of agreement with protein-protein interactions reported in STRING and HIPPIE databases. It is further experimentally validated with protein measurements. Moreover, predictions derived from our network model fairly agree with somatic mutations and gene expression data from primary lung adenocarcinoma. Altogether our results support the role of AMPK in EGFR signaling and drug sensitivity. PMID:27279498

  2. Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers.

    PubMed

    Momcilovic, Milica; McMickle, Robert; Abt, Evan; Seki, Atsuko; Simko, Sarah A; Magyar, Clara; Stout, David B; Fishbein, Michael C; Walser, Tonya C; Dubinett, Steven M; Shackelford, David B

    2015-11-15

    Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mTOR complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing comutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas and squamous cell carcinomas (SCC). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1-mutant human cell lines and genetically engineered mouse models of NSCLC that develop both adenocarcinomas and SCCs. Specifically, we found that KRAS/LKB1-mutant lung adenocarcinomas responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors, thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1-mutant adenocarcinomas and squamous cell tumors. PMID:26574479

  3. Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53

    SciTech Connect

    Wang, Jing-Ping; Lin, Kai-Han; Liu, Chun-Yen; Yu, Ya-Chu; Wu, Pei-Tsun; Chiu, Chien-Chih; Su, Chun-Li; Chen, Kwun-Min; Fang, Kang

    2013-11-15

    In this work, we demonstrated that the growth of human non-small-cell-lung-cancer cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells. - Highlights: • Teroxirone repressed tumor cell growth in nude mice of human lung cancer cells. • The apoptotic cell death reverted by caspase-3 inhibitor is related to p53 status. • Teroxirone provides a good candidate for lung cancer treatment.

  4. Cross-talk between AMPK and EGFR dependent Signaling in Non-Small Cell Lung Cancer

    NASA Astrophysics Data System (ADS)

    Praveen, Paurush; Hülsmann, Helen; Sültmann, Holger; Kuner, Ruprecht; Fröhlich, Holger

    2016-06-01

    Lung cancers globally account for 12% of new cancer cases, 85% of these being Non Small Cell Lung Cancer (NSCLC). Therapies like erlotinib target the key player EGFR, which is mutated in about 10% of lung adenocarcinoma. However, drug insensitivity and resistance caused by second mutations in the EGFR or aberrant bypass signaling have evolved as a major challenge in controlling these tumors. Recently, AMPK activation was proposed to sensitize NSCLC cells against erlotinib treatment. However, the underlying mechanism is largely unknown. In this work we aim to unravel the interplay between 20 proteins that were previously associated with EGFR signaling and erlotinib drug sensitivity. The inferred network shows a high level of agreement with protein-protein interactions reported in STRING and HIPPIE databases. It is further experimentally validated with protein measurements. Moreover, predictions derived from our network model fairly agree with somatic mutations and gene expression data from primary lung adenocarcinoma. Altogether our results support the role of AMPK in EGFR signaling and drug sensitivity.

  5. CD24+/CD38- as new prognostic marker for non-small cell lung cancer

    PubMed Central

    2013-01-01

    Background Lung cancer is the leading cause of death among cancers in the world. The annual death toll due to this disease exceeds the combined deaths caused by colon, breast, prostate, and pancreatic cancers. As a result, there has been a tremendous effort to identify new biomarkers for early detection and diagnosis of lung cancer. Methods In this study we report the results of screening a panel of eight non-small cell lung cancer (NSCLC) cell lines originating from different subtypes of lung cancer in an attempt to identify potential biomarkers unique to this disease. We used real-time polymerase chain reaction and flow cytometry techniques to analyze the expression of ALDHA1, EpCAM, CD133, CD24, and CD38 in this panel. Results We demonstrate for the first time that the majority of NSCLC cells do not express levels of CD38 that would qualify it as a new biomarker for the disease. In contrast, we found that CD24 is over-expressed in 6 out of 8 of the cell lines. The combined CD24+/CD38-/low phenotype was detected in 50% of the cell lines that are also positive for CD133 and EpCAM. Conclusions We report that CD24+/CD38-/low signature could potentially be used as a new biomarker for the early detection of NSCLC. PMID:24094028

  6. Overexpression of Cathepsin L is associated with gefitinib resistance in non-small cell lung cancer.

    PubMed

    Cui, F; Wang, W; Wu, D; He, X; Wu, J; Wang, M

    2016-07-01

    Lung cancer, the most common malignancy, is still the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) accounts for 80 % of all lung cancers. Recent studies showed Cathepsin L (CTSL) is overexpressed in various cancerous tissues; however, the association between CTSL expression and EGFR-TKI resistance remains unknown. In this study, we investigated the expression of CTSL in lung cancer specimens and matched normal tissues by quantitative real-time PCR and IHC. The functional role of CTSL in resistant PC-9/GR cell line was investigated by proliferation and apoptosis analysis compared with control PC-9 cells. Our results found that the level of CTSL expression was higher in NSCLC tissues compared with matched normal adjacent tissue samples, and CTSL was more highly expressed in PC-9/GR cells compared to PC-9 cells. Knocking-down of CTSL in PC-9/GR cells could decrease cell proliferation and potentiate apoptosis induced by gefitinib, suggesting CTSL may contribute to gefitinib resistance in NSCLC. CTSL might be explored as a candidate of therapeutic target for modulating EGFR-TKI sensitivity in NSCLC. PMID:26474873

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

    PubMed Central

    Richer, Amanda L; Friel, Jacqueline M; Carson, Vashti M; Inge, Landon J; Whitsett, Timothy G

    2015-01-01

    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. PMID:25897257

  8. Epigenetics in non-small cell lung cancer: from basics to therapeutics

    PubMed Central

    Ansari, Junaid; El-Osta, Hazem

    2016-01-01

    Lung cancer remains the number one cause of cancer-related deaths worldwide with 221,200 estimated new cases and 158,040 estimated deaths in 2015. Approximately 80% of cases are non-small cell lung cancer (NSCLC). The diagnosis is usually made at an advanced stage where the prognosis is poor and therapeutic options are limited. The evolution of lung cancer is a multistep process involving genetic, epigenetic, and environmental factor interactions that result in the dysregulation of key oncogenes and tumor suppressor genes, culminating in activation of cancer-related signaling pathways. The past decade has witnessed the discovery of multiple molecular aberrations that drive lung cancer growth, among which are epidermal growth factor receptor (EGFR) mutations and translocations involving the anaplastic lymphoma kinase (ALK) gene. This has translated into therapeutic agent developments that target these molecular alterations. The absence of targetable mutations in 50% of NSCLC cases and targeted therapy resistance development underscores the importance for developing alternative therapeutic strategies for treating lung cancer. Among these strategies, pharmacologic modulation of the epigenome has been used to treat lung cancer. Epigenetics approaches may circumvent the problem of tumor heterogeneity by affecting the expression of multiple tumor suppression genes (TSGs), halting tumor growth and survival. Moreover, it may be effective for tumors that are not driven by currently recognized druggable mutations. This review summarizes the molecular pathology of lung cancer epigenetic aberrations and discusses current efforts to target the epigenome with different pharmacological approaches. Our main focus will be on hypomethylating agents, histone deacetylase (HDAC) inhibitors, microRNA modulations, and the role of novel epigenetic biomarkers. Last, we will address the challenges that face this old-new strategy in treating lung cancer. PMID:27186511

  9. Epigenetics in non-small cell lung cancer: from basics to therapeutics.

    PubMed

    Ansari, Junaid; Shackelford, Rodney E; El-Osta, Hazem

    2016-04-01

    Lung cancer remains the number one cause of cancer-related deaths worldwide with 221,200 estimated new cases and 158,040 estimated deaths in 2015. Approximately 80% of cases are non-small cell lung cancer (NSCLC). The diagnosis is usually made at an advanced stage where the prognosis is poor and therapeutic options are limited. The evolution of lung cancer is a multistep process involving genetic, epigenetic, and environmental factor interactions that result in the dysregulation of key oncogenes and tumor suppressor genes, culminating in activation of cancer-related signaling pathways. The past decade has witnessed the discovery of multiple molecular aberrations that drive lung cancer growth, among which are epidermal growth factor receptor (EGFR) mutations and translocations involving the anaplastic lymphoma kinase (ALK) gene. This has translated into therapeutic agent developments that target these molecular alterations. The absence of targetable mutations in 50% of NSCLC cases and targeted therapy resistance development underscores the importance for developing alternative therapeutic strategies for treating lung cancer. Among these strategies, pharmacologic modulation of the epigenome has been used to treat lung cancer. Epigenetics approaches may circumvent the problem of tumor heterogeneity by affecting the expression of multiple tumor suppression genes (TSGs), halting tumor growth and survival. Moreover, it may be effective for tumors that are not driven by currently recognized druggable mutations. This review summarizes the molecular pathology of lung cancer epigenetic aberrations and discusses current efforts to target the epigenome with different pharmacological approaches. Our main focus will be on hypomethylating agents, histone deacetylase (HDAC) inhibitors, microRNA modulations, and the role of novel epigenetic biomarkers. Last, we will address the challenges that face this old-new strategy in treating lung cancer. PMID:27186511

  10. Mast cells and histamine enhance the proliferation of non-small cell lung cancer cells.

    PubMed

    Stoyanov, Evgeniy; Uddin, Mohib; Mankuta, David; Dubinett, Steven M; Levi-Schaffer, Francesca

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the most common form of lung cancer with an extremely low survival rate. It is characterized by a chronic inflammatory process with intense mast cell infiltrate that is associated with reduced survival. The aim of this study was to test the hypothesis that mast cells have an enhancing effect on NSCLC proliferation. To assess the tumor-promoting potential of mast cells, we used the human alveolar basal adenocarcinoma (A549) and the mouse Lewis lung carcinoma (LLC) cell lines, umbilical cord blood-derived mast cells (CBMC) and the mast cell-deficient mouse Sash model. The proliferation rate of A549/LLC cells was markedly increased by mast cells and histamine. Histamine proliferating activity was mediated via H(1), H(2) and H(4) receptors and caused ERK phosphorylation. LLC induced in Sash mice or in wild-type mice treated with the mast cell stabilizer nedocromil sodium displayed an accelerated growth (number of metastic colonies in the lungs, total lung area and lung/total mice weight ratio). In summary, we have shown a significant effect of mast cells and histamine in enhancing NSCLC/LLCX growth in vitro, while in a mouse LLC model in vivo we have found that mast cells are important negative regulators of cancer development. Therefore our results would indicate a pro-tumorogenic effect of the mast cells in vitro on established lung tumor cell lines, and anti-tumorogenic effect in mice at lung cancer induction. In conclusion, mast cell/anti-histamine targeted therapies should carefully consider this dual effect. PMID:21733595

  11. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer

    SciTech Connect

    Jang, Sang-Min; An, Joo-Hee; Kim, Chul-Hong; Kim, Jung-Woong Choi, Kyung-Hee

    2015-08-07

    Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. - Highlights: • Identification of new target genes of FOXA2. • Identifications of novel interaction proteins of FOXA2. • Construction of FOXA2-centered transcriptional regulatory network in non-small cell lung cancer.

  12. Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer.

    PubMed

    Li, Xiaolei; Zhang, Qianhui; Fan, Kai; Li, Baiyan; Li, Huifeng; Qi, Hanping; Guo, Jing; Cao, Yonggang; Sun, Hongli

    2016-01-01

    (1) BACKGROUND: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca(2+)-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance and biological functions of TRPV3 in non-small cell lung cancer (NSCLC); (2) METHODS: Immunohistochemistry was used to detect the expression of TRPV3 in NSCLC tissues and adjacent noncancerous lung tissues. Western blot was used to detect the protein expressions of TRPV3, CaMKII, p-CaMKII, CyclinA, CyclinD, CyclinE1, CDK2, CDK4, and P27. Small interfering RNA was used to deplete TRPV3 expression. A laser scanning confocal microscope was used to measure intracellular calcium concentration ([Ca(2+)]i). Flow cytometry was used to analyze cell cycle; (3) RESULTS: TRPV3 was overexpressed in 65 of 96 (67.7%) human lung cancer cases and correlated with differentiation (p = 0.001) and TNM stage (p = 0.004). Importantly, TRPV3 expression was associated with short overall survival. In addition, blocking or knockdown of TRPV3 could inhibit lung cancer cell proliferation. Moreover, TRPV3 inhibition could decrease [Ca(2+)]i of lung cancer cells and arrest cell cycle at the G1/S boundary. Further results revealed that TRPV3 inhibition decreased expressions of p-CaMKII, CyclinA, CyclinD1, CyclinE, and increased P27 level; (4) CONCLUSIONS: Our findings demonstrate that TRPV3 was overexpressed in NSCLC and correlated with lung cancer progression. TRPV3 activation could promote proliferation of lung cancer cells. TRPV3 might serve as a potential companion drug target in NSCLC. PMID:27023518

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

    PubMed Central

    Zhao, Xiaoting; Guo, Yinan; Yue, Wentao; Zhang, Lina; Gu, Meng; Wang, Yue

    2014-01-01

    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. PMID:24591841

  14. Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer

    PubMed Central

    Li, Xiaolei; Zhang, Qianhui; Fan, Kai; Li, Baiyan; Li, Huifeng; Qi, Hanping; Guo, Jing; Cao, Yonggang; Sun, Hongli

    2016-01-01

    (1) Background: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca2+-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance and biological functions of TRPV3 in non-small cell lung cancer (NSCLC); (2) Methods: Immunohistochemistry was used to detect the expression of TRPV3 in NSCLC tissues and adjacent noncancerous lung tissues. Western blot was used to detect the protein expressions of TRPV3, CaMKII, p-CaMKII, CyclinA, CyclinD, CyclinE1, CDK2, CDK4, and P27. Small interfering RNA was used to deplete TRPV3 expression. A laser scanning confocal microscope was used to measure intracellular calcium concentration ([Ca2+]i). Flow cytometry was used to analyze cell cycle; (3) Results: TRPV3 was overexpressed in 65 of 96 (67.7%) human lung cancer cases and correlated with differentiation (p = 0.001) and TNM stage (p = 0.004). Importantly, TRPV3 expression was associated with short overall survival. In addition, blocking or knockdown of TRPV3 could inhibit lung cancer cell proliferation. Moreover, TRPV3 inhibition could decrease [Ca2+]i of lung cancer cells and arrest cell cycle at the G1/S boundary. Further results revealed that TRPV3 inhibition decreased expressions of p-CaMKII, CyclinA, CyclinD1, CyclinE, and increased P27 level; (4) Conclusions: Our findings demonstrate that TRPV3 was overexpressed in NSCLC and correlated with lung cancer progression. TRPV3 activation could promote proliferation of lung cancer cells. TRPV3 might serve as a potential companion drug target in NSCLC. PMID:27023518

  15. [Whole Brain Irradiation and Hypo-fractionation Radiotherapy for the Metastases in Non-small Cell Lung Cancer].

    PubMed

    Gu, Xingting; Zhao, Yaqin; Xu, Feng

    2016-04-20

    Up to 40% non-small cell lung cancer patients developed brain metastasis during progression. Multiple brain metastases are common in non-small cell lung cancer. The prognosis of brain metastasis is poor with median survival of less than 1 year. Radio therapy for brain metastases has gradually developed from whole brain radiotherapy (WBRT) to various radiation strategies. WBRT, surgery+WBRT, stereotactic radiotherapy+WBRT or WBRT with simultaneous integrated boost (SIB), etc. have better overall survival than those untreated patients. The damage of the cognitive function from WBRT has been realized recently, however, options of radiation strategies for long expected survival patients remain controversial. This paper will discuss different WBRT strategies and treatment side effects of non-small cell lung cancer with brain metastases. PMID:27118651

  16. Adherence to Survivorship Care Guidelines in Health Care Providers for Non-Small Cell Lung Cancer and Colorectal Cancer Survivor Care

    ClinicalTrials.gov

    2016-03-01

    Adenocarcinoma of the Lung; Mucinous Adenocarcinoma of the Colon; Mucinous Adenocarcinoma of the Rectum; Signet Ring Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Rectum; Squamous Cell Lung Cancer; Stage I Colon Cancer; Stage I Rectal Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Colon Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIA Rectal Cancer; Stage IIB Colon Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIB Rectal Cancer; Stage IIC Colon Cancer; Stage IIC Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Rectal Cancer

  17. Non-small cell lung cancer is characterized by dramatic changes in phospholipid profiles

    PubMed Central

    Marien, Eyra; Meister, Michael; Muley, Thomas; Fieuws, Steffen; Bordel, Sergio; Derua, Rita; Spraggins, Jeffrey; Van de Plas, Raf; Dehairs, Jonas; Wouters, Jens; Bagadi, Muralidhararao; Dienemann, Hendrik; Thomas, Michael; Schnabel, Philipp A; Caprioli, Richard M; Waelkens, Etienne; Swinnen, Johannes V

    2015-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development. What’s new? Cellular membranes are subject to extensive modification in cancer, often with marked alterations in phospholipid metabolism. The extent and nature of those changes are not fully known, however, particularly for non-small cell lung cancer (NSCLC). In this study, lipidomics analysis

  18. CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation.

    PubMed Central

    Ganju, R K; Sunday, M; Tsarwhas, D G; Card, A; Shipp, M A

    1994-01-01

    The cell surface metalloproteinase CD10/neutral endopeptidase 24.11 (NEP) hydrolyzes a variety of peptide substrates and reduces cellular responses to specific peptide hormones. Because CD10/NEP modulates peptide-mediated proliferation of small cell carcinomas of the lung (SCLC) and normal fetal bronchial epithelium, we evaluated the enzyme's expression in non-small cell lung carcinomas (NSCLC). Bronchoalveolar and large cell carcinoma cell lines had low levels of CD10/NEP expression whereas squamous, adenosquamous, and adenocarcinoma cell lines had higher and more variable levels of the cell surface enzyme. Regional variations in CD10/NEP immunostaining in primary NSCLC specimens prompted us to correlate CD10/NEP expression with cell growth. In primary carcinomas of the lung, clonal NSCLC cell lines and SV40-transformed fetal airway epithelium, subsets of cells expressed primarily CD10/NEP or the proliferating cell nuclear antigen (PCNA). Cultured airway epithelial cells had the lowest levels of CD10/NEP expression when the highest percentage of cells were actively dividing; in addition, these cells grew more rapidly when cell surface CD10/NEP was inhibited. NSCLC cell lines had receptors for a variety of mitogenic peptides known to be CD10/NEP substrates, underscoring the functional significance of growth-related variability in CD10/NEP expression. Images PMID:7962523

  19. The practice of cardiothoracic surgeons in the perioperative staging of non-small cell lung cancer.

    PubMed Central

    Tsang, G M; Watson, D C

    1992-01-01

    BACKGROUND: The treatment and prognosis of non-small cell lung cancer, and assessment of the results of treatment, depend on accurate perioperative staging. The extent to which this is carried out in the United Kingdom is unknown. METHODS: A postal questionnaire survey was undertaken in 1990 to determine the perioperative staging practices of cardiothoracic surgeons in the United Kingdom. RESULTS: Replies from 77 surgeons, who between them performed about 4833 pulmonary resections a year for lung cancer, were analysed. Forty four per cent of surgeons, operating on 43% of the patients, do not perform computed tomography of the thorax or mediastinal exploration before surgery. They may therefore embark on a thoracotomy for stage III disease. At thoracotomy 45% of surgeons, operating on 40% of patients, do not sample macroscopically normal lymph nodes. They may therefore understage cases as N0/N1 when there is at least microscopic disease in mediastinal lymph nodes. CONCLUSIONS: The staging of lung cancer in the United Kingdom in 1990 appears in many instances to be inadequate. There should be a more organised approach to perioperative staging so that prognosis may be assessed and comparisons between groups of patients can be made. PMID:1311463

  20. Predicting Diagnostic Gene Biomarkers for Non-Small-Cell Lung Cancer

    PubMed Central

    Liang, Bin; Shao, Yang; Long, Fei

    2016-01-01

    Lung cancer is the primary reason for death due to cancer worldwide, and non-small-cell lung cancer (NSCLC) is the most common subtype of lung cancer. Most patients die from complications of NSCLC due to poor diagnosis. In this paper, we aimed to predict gene biomarkers that may be of use for diagnosis of NSCLC by integrating differential gene expression analysis with functional association network analysis. We first constructed an NSCLC-specific functional association network by combining gene expression correlation with functional association. Then, we applied a network partition algorithm to divide the network into gene modules and identify the most NSCLC-specific gene modules based on their differential expression pattern in between normal and NSCLC samples. Finally, from these modules, we identified genes that exhibited the most impact on the expression of their functionally associated genes in between normal and NSCLC samples and predicted them as NSCLC biomarkers. Literature review of the top predicted gene biomarkers suggested that most of them were already considered critical for development of NSCLC.

  1. [Photodynamic therapy in combined treatment of stage III non-small cell lung carcinoma].

    PubMed

    Akopov, A L; Rusanov, A A; Molodtsova, V P; Chistiakov, I V; Kazakov, N V; Urtenova, M A; Rait, Makhmud; Papaian, G V

    2013-01-01

    The aim of the study was to evaluate the effectiveness of combined treatment of locally advanced lung cancer with the use of neoadjuvant chemotherapy and surgery with the use of pre- and intraoperative photodynamic therapy. 20 patients with IIIa (n=7) and IIIb (n=13) stage of non-small cell lung carcinoma were included. At the time of diagnosis the surgical treatment was decided to abstain because of the trachea invasion in 9 patients, wide mediastinal invasion in 2 patients and contralateral mediastinal lymph nodes metastases in 2 patients; pneumonectomy was not possible due to the poor respiratory function in 7 patients. Neoadjuvant therapy included 3 courses of chemotherapy and endobronchial photodynamic therapy. During the operation, along with the lung resection (pneumonectomy - 15, lobectomy - 5), photodynamic therapy of the resection margins were carried out. No adjuvant treatment was done. Preoperative treatment led to partial regress of the disease in all cases; the goal of surgery was the complete tumor removal. No complications of the photodynamic therapy were observed. 18 surgical interventions were radical and two non-complete microscopically (R1). Postoperative morbidity was 20%, one patient died due to massive gastrointestinal bleeding. The average follow-up period was 18 months: 19 patients were alive, of them 18 with no signs of the disease recurrence. The first experience of the combined use of neoadjuvant chemotherapy and surgery with pre- and intraoperative photodynamic therapy demonstrates safety and efficacy of the suggested treatment tactics. PMID:23612332

  2. Association of smoking with tumor size at diagnosis in non-small cell lung cancer.

    PubMed

    Chen, Xing; Gorlov, Ivan P; Merriman, Kelly W; Weng, Shih-Feng; Foy, Millennia; Keener, Gwendolyn; Amos, Christopher I; Spitz, Margaret R; Kimmel, Marek; Gorlova, Olga Y

    2011-12-01

    Tumor size at diagnosis (TSD) indirectly reflects tumor growth rate. The relationship between TSD and smoking is poorly understood. The aim of the study was to determine the relationship between smoking and TSD. We reviewed 1712 newly diagnosed and previously untreated non-small cell lung cancer (NSCLC) patients' electronic medical records and collected tumor characteristics. Demographic and epidemiologic characteristics were derived from questionnaires administered during personal interviews. Univariate and multivariate linear regression models were used to evaluate the relationship between TSD and smoking controlling for demographic and clinical factors. We also investigated the relationship between the rs1051730 SNP in an intron of the CHRNA3 gene (the polymorphism most significantly associated with lung cancer risk and smoking behavior) and TSD. We found a strong dose dependent relationship between TSD and smoking. Current smokers had largest and never smokers smallest TSD with former smokers having intermediate TSD. In the multivariate linear regression model, smoking status (never, former, and current), histological type (adenocarcinoma versus SqCC), and gender were significant predictors of TSD. Smoking duration and intensity may explain the gender effect in predicting TSD. We found that the variant allele of rs1051730 in CHRNA3 gene was associated with larger TSD of squamous cell carcinoma. In the multivariate linear regression model, both rs1051730 and smoking were significant predictors for the size of squamous carcinomas. We conclude that smoking is positively associated with lung tumor size at the moment of diagnosis. PMID:21645942

  3. The role of pembrolizumab in the treatment of advanced non-small cell lung cancer

    PubMed Central

    Santabarbara, Giuseppe; Maione, Paolo; Rossi, Antonio; Palazzolo, Giovanni

    2016-01-01

    Lung cancer is the leading cause of death cancer related worldwide. The standard therapies have unmet medical needs both due to the limited activity and relevant toxicity of platinum-based chemotherapy and to the low frequency of specific alterations required to use targeted therapies. Immune checkpoint inhibition due to restoring the immune system’s capacity to eradicate tumors is undergoing in extensive investigation in non-small cell lung cancer (NSCLC) as a new treatment approach. Programmed cell death protein-1 (PD-1) and its ligand, programmed cell death-ligand 1 (PD-L1) have recently led to significantly and durable improvements in the clinical outcome of several kind of tumors including lung cancer. Pembrolizumab, approved by the U.S. FDA for the treatment of advanced NSCLC progressed after other therapies and with expression of PD-L1, has demonstrated durable response and prolonged overall survival (OS) especially in patients with high PD-L1 expression. Further investigation are needed to improve treatment outcomes through combination of immunotherapy or combined with other targeted therapies. PMID:27386489

  4. Therapeutic options in older patients with metastatic non-small cell lung cancer

    PubMed Central

    2012-01-01

    The increase in life expectancy, with its concomitant increase in the risk of cancer, has led to an increased incidence of lung cancer in older people. The median age at diagnosis of lung cancer is between 63 and 70 years. For a long time, there has been a pessimistic attitude by doctors, patients and their relatives and thus an undertreatment of older patients. Older patients have some specific differences compared with younger patients: more comorbidities with concomitant medications that may interfere with chemotherapy, geriatric syndromes, frailty and so on. The first trial devoted to older patients with advanced non-small cell lung cancer (NSCLC) was a comparison between vinorelbine and best supportive care. There was a significant benefit of survival in the chemotherapy arm. Doublet therapy with gemcitabine plus vinorelbine did not give better results than either of these drugs alone. Thus, the recommendations for the treatment of older patients with advanced NSCLC were to give monotherapy. In some clinical trials not dedicated to older patients it appeared that patients might benefit from platinum-based doublet therapy like their younger counterparts. A randomized trial conducted by the French intergroup, IFCT, in patients aged at least 70 years comparing vinorelbine or gemcitabine alone with monthly carboplatin combined with weekly paclitaxel demonstrated that there was a highly significant benefit of survival in the doublet arm. This study resulted in a modification of the recommendations on the treatment of older patients with advanced NSCLC. PMID:22942907

  5. Stereotactic Ablative Body Radiation Therapy for Octogenarians With Non-Small Cell Lung Cancer

    SciTech Connect

    Takeda, Atsuya; Sanuki, Naoko; Eriguchi, Takahisa; Kaneko, Takeshi; Morita, Satoshi; Handa, Hiroshi; Aoki, Yousuke; Oku, Yohei; Kunieda, Etsuo

    2013-06-01

    Purpose: To retrospectively investigate treatment outcomes of stereotactic ablative body radiation therapy (SABR) for octogenarians with non-small cell lung cancer (NSCLC). Methods and Materials: Between 2005 and 2012, 109 patients aged ≥80 years with T1-2N0M0 NSCLC were treated with SABR: 47 patients had histology-unproven lung cancer; 62 patients had pathologically proven NSCLC. The prescribed doses were either 50 Gy/5 fractions for peripheral tumors or 40 Gy/5 fractions for centrally located tumors. The treatment outcomes, toxicities, and the correlating factors for overall survival (OS) were evaluated. Results: The median follow-up duration after SABR was 24.2 (range, 3.0-64.6) months. Only limited toxicities were observed, except for 1 grade 5 radiation pneumonitis. The 3-year local, regional, and distant metastasis-free survival rates were 82.3%, 90.1%, and 76.8%, respectively. The OS and lung cancer-specific survival rates were 53.7% and 70.8%, respectively. Multivariate analysis revealed that medically inoperable, low body mass index, high T stage, and high C-reactive protein were the predictors for short OS. The OS for the operable octogenarians was significantly better than that for inoperable (P<.01). Conclusions: Stereotactic ablative body radiation therapy for octogenarians was feasible, with excellent OS. Multivariate analysis revealed that operability was one of the predictors for OS. For medically operable octogenarians with early-stage NSCLC, SABR should be prospectively compared with resection.

  6. Pharmacogenomics and targeted therapy of cancer: Focusing on non-small cell lung cancer.

    PubMed

    Haghgoo, Seyyed Mortaza; Allameh, Abdolamir; Mortaz, Esmaeil; Garssen, Johan; Folkerts, Gert; Barnes, Peter J; Adcock, Ian M

    2015-05-01

    Recent studies have been established high degree of genetic diversity in solid organ tumors among individuals and even between individual tumor cells. This intratumor and intertumor genetic diversity results in a heterogeneous tumor with unique characteristics which potentially allows effective drug therapy. The goal of pharmacogenomics is to elucidate the genetic network(s) that underlie drug efficacy and drug resistance. Advances in targeted and personalized therapy play an increasingly important role in many common cancers, notably lung cancer, due to the high incidence, prevalence, mortality and the greater tendency towards drug resistance seen in these patients. Non-small cell lung cancer (NSCLC) is characterized by mutations in the epidermal growth factor receptor (EGFR) and or downstream kinase pathways. This has led to the development of highly selective monoclonal antibodies and EGFR tyrosine kinase inhibitors (EGFR-TKIs) to prevent cancer initiation, proliferation, differentiation, angiogenesis, survival, and invasion. However, resistance to many of these new treatments is induced and further pharmacogenomic analysis has revealed mutations associated with increased or reduced drug efficacy. Combinations of kinase inhibitors or potentially the targeting of cancer stem cells may further increase the success of pharmacogenomics in treating patients with lung cancer. PMID:25725115

  7. Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype

    PubMed Central

    Larrayoz, Marta; Pio, Ruben; Pajares, María J; Zudaire, Isabel; Ajona, Daniel; Casanovas, Oriol; Montuenga, Luis M; Agorreta, Jackeline

    2014-01-01

    The vascular endothelial growth factor (VEGF) pathway is a clinically validated antiangiogenic target for non-small cell lung cancer (NSCLC). However, some contradictory results have been reported on the biological effects of antiangiogenic drugs. In order to evaluate the efficacy of these drugs in NSCLC histological subtypes, we analyzed the anticancer effect of two anti-VEGFR2 therapies (sunitinib and DC101) in chemically induced mouse models and tumorgrafts of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Antiangiogenic treatments induced vascular trimming in both histological subtypes. In ADC tumors, vascular trimming was accompanied by tumor stabilization. In contrast, in SCC tumors, antiangiogenic therapy was associated with disease progression and induction of tumor proliferation. Moreover, in SCC, anti-VEGFR2 therapies increased the expression of stem cell markers such as aldehyde dehydrogenase 1A1, CD133, and CD15, independently of intratumoral hypoxia. In vitro studies with ADC cell lines revealed that antiangiogenic treatments reduced pAKT and pERK signaling and inhibited proliferation, while in SCC-derived cell lines the same treatments increased pAKT and pERK, and induced survival. In conclusion, this study evaluates for the first time the effect of antiangiogenic drugs in lung SCC murine models in vivo and sheds light on the contradictory results of antiangiogenic therapies in NSCLC. PMID:24500694

  8. A multi-analyte serum test for the detection of non-small cell lung cancer

    PubMed Central

    Farlow, E C; Vercillo, M S; Coon, J S; Basu, S; Kim, A W; Faber, L P; Warren, W H; Bonomi, P; Liptay, M J; Borgia, J A

    2010-01-01

    Background: In this study, we appraised a wide assortment of biomarkers previously shown to have diagnostic or prognostic value for non-small cell lung cancer (NSCLC) with the intent of establishing a multi-analyte serum test capable of identifying patients with lung cancer. Methods: Circulating levels of 47 biomarkers were evaluated against patient cohorts consisting of 90 NSCLC and 43 non-cancer controls using commercial immunoassays. Multivariate statistical methods were used on all biomarkers achieving statistical relevance to define an optimised panel of diagnostic biomarkers for NSCLC. The resulting biomarkers were fashioned into a classification algorithm and validated against serum from a second patient cohort. Results: A total of 14 analytes achieved statistical relevance upon evaluation. Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-α, CYFRA 21-1, interleukin-1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. When tested against a second patient cohort, the panel successfully classified 75 of 88 patients. Conclusions: Here, we report the development of a serum algorithm with high specificity for classifying patients with NSCLC against cohorts of various ‘high-risk' individuals. A high rate of false positives was observed within the cohort in which patients had non-neoplastic lung nodules, possibly as a consequence of the inflammatory nature of these conditions. PMID:20859284

  9. Prognostic implication of PTPRH hypomethylation in non-small cell lung cancer

    PubMed Central

    SATO, TAKASHI; SOEJIMA, KENZO; ARAI, ERI; HAMAMOTO, JUNKO; YASUDA, HIROYUKI; ARAI, DAISUKE; ISHIOKA, KOTA; OHGINO, KEIKO; NAOKI, KATSUHIKO; KOHNO, TAKASHI; TSUTA, KOJI; WATANABE, SHUN-ICHI; KANAI, YAE; BETSUYAKU, TOMOKO

    2015-01-01

    PTPRH is a receptor-type protein tyrosine phosphatase thought to be a potential regulator of tumorigenesis. The aim of the present study was to clarify the significance of PTPRH expression and its regulation by DNA methylation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LADC). PTPRH mRNA expression was examined in 89 NSCLC and corresponding non-cancerous tissues. The correlation between DNA methylation and PTPRH gene expression was investigated in another cohort that consisted of 145 patients with LADC, a major NSCLC subtype. Gene regulation by DNA methylation was assessed using a DNA methylation inhibitor. PTPRH mRNA expression was significantly upregulated in NSCLC. PTPRH DNA methylation was reduced in LADC samples and inversely correlated with mRNA expression. 5-Aza-2′-deoxycytidine treatment of lung cancer cell lines with low PTPRH expression, restored mRNA PTPRH expression levels. Furthermore, low PTPRH methylation was associated with shorter recurrence-free survival (P=1.64×10−4) and overall survival (P=5.54×10−5). Multivariate analysis revealed that PTPRH DNA methylation was an independent prognostic factor (P=6.88×10−3). It was confirmed that PTPRH is overexpressed in NSCLC. Furthermore, we determined that PTPRH is epigenetically regulated by DNA hypomethylation, with prognostic implications for LADC. PMID:26134684

  10. Prognostic implication of PTPRH hypomethylation in non-small cell lung cancer.

    PubMed

    Sato, Takashi; Soejima, Kenzo; Arai, Eri; Hamamoto, Junko; Yasuda, Hiroyuki; Arai, Daisuke; Ishioka, Kota; Ohgino, Keiko; Naoki, Katsuhiko; Kohno, Takashi; Tsuta, Koji; Watanabe, Shun-Ichi; Kanai, Yae; Betsuyaku, Tomoko

    2015-09-01

    PTPRH is a receptor-type protein tyrosine phosphatase thought to be a potential regulator of tumorigenesis. The aim of the present study was to clarify the significance of PTPRH expression and its regulation by DNA methylation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LADC). PTPRH mRNA expression was examined in 89 NSCLC and corresponding non-cancerous tissues. The correlation between DNA methylation and PTPRH gene expression was investigated in another cohort that consisted of 145 patients with LADC, a major NSCLC subtype. Gene regulation by DNA methylation was assessed using a DNA methylation inhibitor. PTPRH mRNA expression was significantly upregulated in NSCLC. PTPRH DNA methylation was reduced in LADC samples and inversely correlated with mRNA expression. 5-Aza-2'-deoxycytidine treatment of lung cancer cell lines with low PTPRH expression, restored mRNA PTPRH expression levels. Furthermore, low PTPRH methylation was associated with shorter recurrence-free survival (P=1.64x10(-4)) and overall survival (P=5.54x10(-5)). Multivariate analysis revealed that PTPRH DNA methylation was an independent prognostic factor (P=6.88x10(-3)). It was confirmed that PTPRH is overexpressed in NSCLC. Furthermore, we determined that PTPRH is epigenetically regulated by DNA hypomethylation, with prognostic implications for LADC. PMID:26134684

  11. Targeting the MET gene for the treatment of non-small-cell lung cancer.

    PubMed

    Gelsomino, F; Facchinetti, F; Haspinger, E R; Garassino, M C; Trusolino, L; De Braud, F; Tiseo, M

    2014-02-01

    Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era. In non-small-cell lung cancer (NSCLC), molecular research has allowed the discrimination of different aberrant RTKs in lung cancer tumorigenesis and progression, and thus the identification of several targetable oncogenic drivers. Following the development of small molecules (gefitinib/erlotinib and crizotinib) able to reversibly inhibit the epidermal growth factor receptor (EGFR) and signaling pathways mediated by anaplastic lymphoma kinase (ALK), respectively, the MET signaling pathway has also been recognized as a potential target. Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance. PMID:24355409

  12. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer

    PubMed Central

    Young, Jonathan H.; Peyton, Michael; Seok Kim, Hyun; McMillan, Elizabeth; Minna, John D.; White, Michael A.; Marcotte, Edward M.

    2016-01-01

    Motivation: Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Results: Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel. Availability and implementation: The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc_paper. Contact: marcotte@icmb.utexas.edu or jon.young@utexas.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26755624

  13. Predicting Diagnostic Gene Biomarkers for Non-Small-Cell Lung Cancer.

    PubMed

    Liang, Bin; Shao, Yang; Long, Fei; Jiang, Shu-Juan

    2016-01-01

    Lung cancer is the primary reason for death due to cancer worldwide, and non-small-cell lung cancer (NSCLC) is the most common subtype of lung cancer. Most patients die from complications of NSCLC due to poor diagnosis. In this paper, we aimed to predict gene biomarkers that may be of use for diagnosis of NSCLC by integrating differential gene expression analysis with functional association network analysis. We first constructed an NSCLC-specific functional association network by combining gene expression correlation with functional association. Then, we applied a network partition algorithm to divide the network into gene modules and identify the most NSCLC-specific gene modules based on their differential expression pattern in between normal and NSCLC samples. Finally, from these modules, we identified genes that exhibited the most impact on the expression of their functionally associated genes in between normal and NSCLC samples and predicted them as NSCLC biomarkers. Literature review of the top predicted gene biomarkers suggested that most of them were already considered critical for development of NSCLC. PMID:27579312

  14. K-Ras Mutations in Non-Small-Cell Lung Cancer: Prognostic and Predictive Value

    PubMed Central

    D'Arcangelo, Manolo; Cappuzzo, Federico

    2012-01-01

    Non-small-cell lung cancer (NSCLC) is a heterogeneous disease due to the presence of different clinically relevant molecular subtypes. Until today, several biological events have been identified in lung adenocarcinoma, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, offering new hopes to patients with metastatic disease. Unfortunately, in approximately 50% of adenocarcinoma and for those harbouring K-RAS mutations, the most frequent mutation in Caucasian lung adenocarcinoma, so far no specific drug demonstrated efficacy. The rat sarcoma (RAS) genes, including H-RAS, K-RAS, and N-RAS, encode a family of proteins regulating cell growth, differentiation, and apoptosis. K-RAS mutations are present in 20–30% of NSCLC and occur most commonly, but not exclusively, in adenocarcinoma histology and life-long smokers. Although in colorectal cancer patients K-RAS mutations represent a validated negative predictive biomarker for treatment with anti-EGFR monoclonal antibodies, their role in selecting specific treatment for NSCLC patients remains undefined. Aim of the present paper is to critically analyze the prognostic and predictive value of K-RAS mutations in NSCLC.

  15. [Metastatic non-small cell lung cancer: Systemic treatment of patients aged 70 and over].

    PubMed

    Quoix, Elisabeth; Ducoloné, Alain; Mennecier, Bertrand; Fraisse, Philippe

    2011-04-01

    Patients aged 70 and over represent the third of the population of patients with lung cancer. There has been for a long time a certain nihilism regarding the treatment of elderly patients with advanced lung cancer as well from medical doctors but also from families and patients themselves with the false belief of an indolent course of the disease in elderly patients. As a result, clinical trials devoted to elderly patients were quite scarce until the end of the last decade. Nevertheless, an important trial was published in 1999 with the comparison of vinorelbine as a single agent versus best supportive care only in patients aged 70 and over with an advanced non-small cell lung cancer. The survival benefit with vinorelbine was important. Then two trials were published comparing monotherapy with either vinorelbine or gemcitabine to the doublet vinorelbine and gemcitabine without convincing results. As a consequence, the ASCO 2004 recommendations were to treat elderly patients with a monotherapy (gemcitabine or vinorelbine). Recently an IFCT trial was presented at the plenary session of the ASCO 2010. A carboplatin (every 4weeks)+weekly paclitaxel doublet was compared to a vinorelbine or gemcitabine (choice of the center). The survival benefit was of such magnitude that the paradigm of treatment of elderly patients PS 0-2 with advanced NSCLC should be modified in favor of the tested doublet. There should be a reappraisal of the geriatric indexes recommended by the oncogeriatricians regarding their exact prognostic or predictive role. PMID:21388776

  16. Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer

    PubMed Central

    Cihoric, N; Savic, S; Schneider, S; Ackermann, I; Bichsel-Naef, M; Schmid, R A; Lardinois, D; Gugger, M; Bubendorf, L; Zlobec, I; Tapia, C

    2014-01-01

    Background: Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC. Methods: FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I–II. The FISH results were correlated with clinico-pathological features and overall survival (OS). Results: The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC. Conclusions: FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation. PMID:24853178

  17. Racial diversity of actionable mutations in non-small cell lung cancer

    PubMed Central

    Bollig-Fischer, Aliccia; Chen, Wei; Gadgeel, Shirish M.; Wenzlaff, Angela S.; Cote, Michele L.; Schwartz, Ann G.; Bepler, Gerold

    2014-01-01

    Introduction Lung cancer is the leading cause of cancer-related deaths in the United States. The reasons for higher incidence and poorer survival rates among black compared to white lung cancer patients have not been defined. We hypothesized that differential incidence of somatic cancer gene mutations may be a contributing factor. Previous genomic studies of non-small cell lung cancer (NSCLC) have not adequately represented black patients. Methods A MALDI-TOF mass-spectrometry approach was used to analyze tumor DNA for 214 coding mutations in 26 cancer genes previously identified in NSCLC. The samples included NSCLC from 335 white patients and 137 black patients. For 299 of these, normal matched DNA was available and analyzed. Results EGFR exon 19 deletions were only detected in female cases, with increased odds for black women compared to white women (odds ratio=3.914, 95% CI: 1.014–15.099, p=0.048). Beyond race, variations in mutation frequencies were seen by histology. DDR2 alterations, previously described as somatic mutations, were identified as constitutional variants. Conclusions This study is among the largest comparing somatic mutations in black and white patients. The results point to the molecular diversity of NSCLC and raise new questions as to the importance of inherited alleles. Genomic tumor testing will benefit both populations, although the mutation spectrum appears to vary by sex, race, and histology. PMID:25376516

  18. Role of survivin re-expression in the development and progression of non-small cell lung cancer.

    PubMed

    Javid, Jamsheed; Mir, Rashid; Julka, P K; Ray, P C; Saxena, Alpana

    2015-07-01

    Survivin is highly expressed in fetal tissue and is completely absent in terminally differentiated cells, but its re-expression has been observed in most human tumors. Presently, we aimed to analyze the possible impact of the survivin gene (-31G > C, rs 9904341) promoter polymorphism on the expression profile of survivin gene and ultimately the role of survivin re-expression in the development and progression of non-small cell lung cancer. A case-control study of 100 non-small cell lung cancer patients and 100 cancer-free healthy controls was conducted. Survivin gene promoter polymorphism was analyzed by PCR-restriction fragment length polymorphisms (RFLP) technique, and the survivin expression profile was evaluated using quantitative real-time PCR assay. Compared to the survivin GG genotype, odd ratio of 3.2 (95 % CI 4.8-25.9, p = 0.004) was found to be associated to homozygous CC genotype with 15-fold increase of survivin gene expression in non-small cell lung cancer patients. Significant trend of increase in survivin expression was observed with the increase in severity of the disease. Patients with survivin (-31CC) genotype had significantly shorter overall survival compared to survivin (-31GG) genotype carriers. In addition, advanced disease status and significant poor overall survival were also reflected by patients with higher-fold increase in survivin gene expression. In conclusion, present study demonstrated that survivin (-31G > C) polymorphism may contribute to the risk of developing non-small cell lung cancer in Indian population. Survivin (-31CC) genotype was associated with significantly increased survivin gene expression and ultimately may contribute in the poor clinical outcome of non-small cell lung cancer patients, suggesting its possible significance in the development and progression of non-small cell lung cancer. PMID:25677909

  19. Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells

    SciTech Connect

    Duan, Lincan; Shen, Hongmei; Zhao, Guangqiang; Yang, Runxiang; Cai, Xinyi; Zhang, Lijuan; Jin, Congguo; Huang, Yunchao

    2014-04-18

    Highlights: • Disulfiram and copper synergistically inhibit lung cancer cell proliferation. • Lung cancer cell colony formation ability is inhibited by Disulfiram/copper. • Disulfiram/copper increases the sensitivity of cisplatin to lung cancer cells. • Lung cancer stem cells are specifically targeted by Disulfiram/copper complex. - Abstract: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death in both men and women worldwide. Recently, Disulfiram has been reported to be able to inhibit glioblastoma, prostate, or breast cancer cell proliferation. In this study, the synergistic effect of Disulfiram and copper on NSCLC cell growth was investigated. Inhibition of cancer cell proliferation was detected by 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) assay and cell cycle analysis. Liquid colony formation and tumor spheroid formation assays were used to evaluate their effect on cancer cell clonogenicity. Real-time PCR was performed to test the mRNA level of cancer stem cell related genes. We found that Disulfiram or copper alone did not potently inhibit NSCLC cell proliferation in vitro. However, the presence of copper significantly enhanced inhibitory effect of Disulfiram on NSCLC cell growth, indicating a synergistic effect between Disulfiram and copper. Cell cycle analysis showed that Disulfiram/copper complex caused NSCLC cell cycle arrest in G2/M phase. Furthermore, Disulfiram/copper significantly increased the sensitivity of cisplatin in NSCLC cells tested by MTT assay. Liquid colony formation assay revealed that copper dramatically increased the inhibitory effect of Disulfiram on NSCLC cell colony forming ability. Disulfiram combined with copper significantly attenuated NSCLC cell spheroid formation and recuded the mRNA expression of lung cancer stem cell related genes. Our data suggest that Disulfiram/copper complex alone or combined with other chemotherapy is a potential therapeutic strategy for NSCLC patients.

  20. Non-small cell lung cancer cell survival crucially depends on functional insulin receptors.

    PubMed

    Frisch, Carolin Maria; Zimmermann, Katrin; Zilleßen, Pia; Pfeifer, Alexander; Racké, Kurt; Mayer, Peter

    2015-08-01

    Insulin plays an important role as a growth factor and its contribution to tumor proliferation is intensely discussed. It acts via the cognate insulin receptor (IR) but can also activate the IGF1 receptor (IGF1R). Apart from increasing proliferation, insulin might have additional effects in lung cancer. Therefore, we investigated insulin action and effects of IR knockdown (KD) in three (NCI-H292, NCI-H226 and NCI-H460) independent non-small cell lung cancer (NSCLC) cell lines. All lung cancer lines studied were found to express IR, albeit with marked differences in the ratio of the two variants IR-A and IR-B. Insulin activated the classical signaling pathway with IR autophosphorylation and Akt phosphorylation. Moreover, activation of MAPK was observed in H292 cells, accompanied by enhanced proliferation. Lentiviral shRNA IR KD caused strong decrease in survival of all three lines, indicating that the effects of insulin in lung cancer go beyond enhancing proliferation. Unspecific effects were ruled out by employing further shRNAs and different insulin-responsive cells (human pre-adipocytes) for comparison. Caspase assays demonstrated that IR KD strongly induced apoptosis in these lung cancer cells, providing the physiological basis of the rapid cell loss. In search for the underlying mechanism, we analyzed alterations in the gene expression profile in response to IR KD. A strong induction of certain cytokines (e.g. IL20 and tumour necrosis factor) became obvious and it turned out that these cytokines trigger apoptosis in the NSCLC cells tested. This indicates a novel role of IR in tumor cell survival via suppression of pro-apoptotic cytokines. PMID:26113601

  1. Role of ATG10 expression quantitative trait loci in non-small cell lung cancer survival.

    PubMed

    Xie, Kaipeng; Liang, Cheng; Li, Qin; Yan, Caiwang; Wang, Cheng; Gu, Yayun; Zhu, Meng; Du, Fangzhi; Wang, Hui; Dai, Juncheng; Liu, Xiao'an; Jin, Guangfu; Shen, Hongbing; Ma, Hongxia; Hu, Zhibin

    2016-10-01

    The aim of this article was to evaluate whether genetic variants in autophagy-related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07-1.65; HR = 1.43, 95% CI = 1.13-1.81; HR = 1.38, 95% CI = 1.14-1.68, respectively) and positively correlated with ATG10 expression (all p < 0.05) from GTEx and TCGA datasets. The elevated expression of ATG10 may predict shorter survival time in lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33-3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression. PMID:27225307

  2. REV3L modulates cisplatin sensitivity of non-small cell lung cancer H1299 cells.

    PubMed

    Wang, Wenjie; Sheng, Wenjiong; Yu, Chenxiao; Cao, Jianping; Zhou, Jundong; Wu, Jinchang; Zhang, Huojun; Zhang, Shuyu

    2015-09-01

    Lung cancer remains the leading cause of cancer-related mortality worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer. Cisplatin plays a significant role in the management of human lung cancer. Translesion DNA synthesis (TLS) is involved in DNA damage repair. DNA polymerase ζ (Pol ζ) is able to mediate the DNA replication bypass of DNA damage, which is suggested to be involved in chemoresistance. REV3L is the catalytic subunit of Pol ζ. Due to its critical role in translesion DNA synthesis, whether REV3L modulates cisplatin response in NSCLC cells remains unknown. In this study, REV3L overexpression and silencing H1299 cell lines were established. The reports showed that cisplatin induced the expression of REV3L by recruiting Sp1 to its promoter. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. Co-transfection of the reporter with the REV3L overexpression vector or REV3L plus REV7L significantly enhanced the reporter activity. Nuclear condensation and fragmentation of shRNA-REV3L H1299 cells were more pronounced than shRNA-NC H1299 cells after cisplatin exposure, indicating that REV3L overexpression abolished cisplatin-induced DNA damage. Moreover, a forced expression of REV3L conferred the resistance of H1299 cells to cisplatin, whereas the knockdown of REV3L sensitized cisplatin efficacy in H1299 cells. Taken together, we demonstrated that inhibition of REV3L sensitized lung cancer H1299 cells to cisplatin treatment. Thus, REV3L may be a novel target for the chemotherapy of NSCLC. PMID:26165320

  3. Exploring Boron Neutron Capture Therapy for non-small cell lung cancer.

    PubMed

    Farías, Rubén O; Bortolussi, Silva; Menéndez, Pablo R; González, Sara J

    2014-12-01

    Boron Neutron Capture Therapy (BNCT) is a radiotherapy that combines biological targeting and high LET radiation. It consists in the enrichment of tumour with (10)B and in the successive irradiation of the target with low energy neutrons producing charged particles that mainly cause non-repairable damages to the cells. The feasibility to treat Non Small Cells Lung Cancer (NSCLC) with BNCT was explored. This paper proposes a new approach to determine treatment plans, introducing the possibility to choose the irradiation start and duration to maximize the tumour dose. A Tumour Control Probability (TCP) suited for lung BNCT as well as other high dose radiotherapy schemes was also introduced. Treatment plans were evaluated in localized and disseminated lung tumours. Semi-ideal and real energy spectra beams were employed to assess the best energy range and the performance of non-tailored neutron sources for lung tumour treatments. The optimal neutron energy is within [500 eV-3 keV], lower than the 10 keV suggested for the treatment of deep-seated tumours in the brain. TCPs higher than 0.6 and up to 0.95 are obtained for all cases. Conclusions drawn from [Suzuki et al., Int Canc Conf J 1 (4) (2012) 235-238] supporting the feasibility of BNCT for shallow lung tumours are confirmed, however discussions favouring the treatment of deeper lesions and disseminated disease are also opened. Since BNCT gives the possibility to deliver a safe and potentially effective treatment for NSCLC, it can be considered a suitable alternative for patients with few or no treatment options. PMID:25176019

  4. MicroRNA-dependent regulation of transcription in non-small cell lung cancer.

    PubMed

    Molina-Pinelo, Sonia; Gutiérrez, Gabriel; Pastor, Maria Dolores; Hergueta, Marta; Moreno-Bueno, Gema; García-Carbonero, Rocío; Nogal, Ana; Suárez, Rocío; Salinas, Ana; Pozo-Rodríguez, Francisco; Lopez-Rios, Fernando; Agulló-Ortuño, Maria Teresa; Ferrer, Irene; Perpiñá, Asunción; Palacios, José; Carnero, Amancio; Paz-Ares, Luis

    2014-01-01

    Squamous cell lung cancer (SCC) and adenocarcinoma are the most common histological subtypes of non-small cell lung cancer (NSCLC), and have been traditionally managed in the clinic as a single entity. Increasing evidence, however, illustrates the biological diversity of these two histological subgroups of lung cancer, and supports the need to improve our understanding of the molecular basis beyond the different phenotypes if we aim to develop more specific and individualized targeted therapy. The purpose of this study was to identify microRNA (miRNA)-dependent transcriptional regulation differences between SCC and adenocarcinoma histological lung cancer subtypes. In this work, paired miRNA (667 miRNAs by TaqMan Low Density Arrays (TLDA)) and mRNA profiling (Whole Genome 44 K array G112A, Agilent) was performed in tumor samples of 44 NSCLC patients. Nine miRNAs and 56 mRNAs were found to be differentially expressed in SCC versus adenocarcinoma samples. Eleven of these 56 mRNA were predicted as targets of the miRNAs identified to be differently expressed in these two histological conditions. Of them, 6 miRNAs (miR-149, miR-205, miR-375, miR-378, miR-422a and miR-708) and 9 target genes (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) were validated by quantitative PCR in an independent cohort of 41 lung cancer patients. Furthermore, the inverse correlation between mRNAs and microRNAs expression was also validated. These results suggest miRNA-dependent transcriptional regulation differences play an important role in determining key hallmarks of NSCLC, and may provide new biomarkers for personalized treatment strategies. PMID:24625834

  5. Genome-wide DNA methylation profiling of non-small cell lung carcinomas

    PubMed Central

    2012-01-01

    Background Non-small cell lung carcinoma (NSCLC) is a complex malignancy that owing to its heterogeneity and poor prognosis poses many challenges to diagnosis, prognosis and patient treatment. DNA methylation is an important mechanism of epigenetic regulation involved in normal development and cancer. It is a very stable and specific modification and therefore in principle a very suitable marker for epigenetic phenotyping of tumors. Here we present a genome-wide DNA methylation analysis of NSCLC samples and paired lung tissues, where we combine MethylCap and next generation sequencing (MethylCap-seq) to provide comprehensive DNA methylation maps of the tumor and paired lung samples. The MethylCap-seq data were validated by bisulfite sequencing and methyl-specific polymerase chain reaction of selected regions. Results Analysis of the MethylCap-seq data revealed a strong positive correlation between replicate experiments and between paired tumor/lung samples. We identified 57 differentially methylated regions (DMRs) present in all NSCLC tumors analyzed by MethylCap-seq. While hypomethylated DMRs did not correlate to any particular functional category of genes, the hypermethylated DMRs were strongly associated with genes encoding transcriptional regulators. Furthermore, subtelomeric regions and satellite repeats were hypomethylated in the NSCLC samples. We also identified DMRs that were specific to two of the major subtypes of NSCLC, adenocarcinomas and squamous cell carcinomas. Conclusions Collectively, we provide a resource containing genome-wide DNA methylation maps of NSCLC and their paired lung tissues, and comprehensive lists of known and novel DMRs and associated genes in NSCLC. PMID:22726460

  6. Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer

    PubMed Central

    Marquez-Garban, Diana C.; Mah, Vei; Alavi, Mohammad; Maresh, Erin L.; Chen, Hsiao-Wang; Bagryanova, Lora; Horvath, Steve; Chia, David; Garon, Edward; Goodglick, Lee; Pietras, Richard J.

    2011-01-01

    Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Although it is clear that tobacco smoking is a major cause of lung cancer, about half of all women with lung cancer worldwide are never-smokers. Despite a declining smoking population, the incidence of non-small cell lung cancer (NSCLC), the predominant form of lung cancer, has reached epidemic proportions particularly in women. Emerging data suggest that factors other than tobacco, namely endogenous and exogenous female sex hormones, have a role in stimulating NSCLC progression. Aromatase, a key enzyme for estrogen biosynthesis, is expressed in NSCLC. Clinical data show that women with high levels of tumor aromatase (and high intratumoral estrogen) have worse survival than those with low aromatase. The present and previous studies also reveal significant expression and activity of estrogen receptors (ERα, ERβ) in both extranuclear and nuclear sites in most NSCLC. We now report further on the expression of progesterone receptor (PR) transcripts and protein in NSCLC. PR transcripts were significantly lower in cancerous as compared to non-malignant tissue. Using immunohistochemistry, expression of PR was observed in the nucleus and/or extranuclear compartments in the majority of human tumor specimens examined. Combinations of estrogen and progestins administered in vitro cooperate in promoting tumor secretion of vascular endothelial growth factor and, consequently, support tumor-associated angiogenesis. Further, dual treatment with estradiol and progestin increased the numbers of putative tumor stem/progenitor cells. Thus, ER- and/or PR-targeted therapies may offer new approaches to manage NSCLC. PMID:21600232

  7. Minnelide: A Novel Therapeutic That Promotes Apoptosis in Non-Small Cell Lung Carcinoma In Vivo

    PubMed Central

    Rousalova, Ilona; Banerjee, Sulagna; Sangwan, Veena; Evenson, Kristen; McCauley, Joel A.; Kratzke, Robert; Vickers, Selwyn M.; Saluja, Ashok; D’Cunha, Jonathan

    2013-01-01

    Background Minnelide, a pro-drug of triptolide, has recently emerged as a potent anticancer agent. The precise mechanisms of its cytotoxic effects remain unclear. Methods Cell viability was studied using CCK8 assay. Cell proliferation was measured real-time on cultured cells using Electric Cell Substrate Impedence Sensing (ECIS). Apoptosis was assayed by Caspase activity on cultured lung cancer cells and TUNEL staining on tissue sections. Expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA, APAF-1) was estimated by qRTPCR. Effect of Minnelide on proliferative cells in the tissue was estimated by Ki-67 staining of animal tissue sections. Results In this study, we investigated in vitro and in vivo antitumor effects of triptolide/Minnelide in non-small cell lung carcinoma (NSCLC). Triptolide/Minnelide exhibited anti-proliferative effects and induced apoptosis in NSCLC cell lines and NSCLC mouse models. Triptolide/Minnelide significantly down-regulated the expression of pro-survival and anti-apoptotic genes (HSP70, BIRC5, BIRC4, BIRC2, UACA) and up-regulated pro-apoptotic APAF-1 gene, in part, via attenuating the NF-κB signaling activity. Conclusion In conclusion, our results provide supporting mechanistic evidence for Minnelide as a potential in NSCLC. PMID:24143232

  8. Surgical treatment of 125 patients with non-small cell lung cancer and chest wall involvement.

    PubMed Central

    Pitz, C. C.; Brutel de la Rivière, A.; Elbers, H. R.; Westermann, C. J.; van den Bosch, J. M.

    1996-01-01

    BACKGROUND: The optimum operative procedure for lung cancer with chest wall invasion (T3) remains controversial. In this study results of en bloc resection and extrapleural dissection are reviewed to determine survival characteristics. METHODS: Between 1977 and 1993 125 patients underwent surgery for primary non-small cell lung cancer with chest wall invasion. Patients with superior sulcus tumours, metastatic carcinomas, synchronous tumours, or recurrences were excluded. Extrapleural dissection was performed in 73 patients and en bloc resection (range 1-4 ribs) in 52. Resection was regarded as complete in 86 and incomplete in 39 patients. Actuarial survival time was estimated and risk factors for late death were identified. RESULTS: Hospital mortality was 3.2%. (n = 4). Estimated mean five year survival was 24% for all hospital survivors (n = 121), 11% for patients with incomplete resection, and 29% for patients having a complete resection. In patients who underwent complete resection mediastinal lymph node involvement and intrapleural tumour spill worsened the prognosis. Patients with adenocarcinoma had a better chance of long term survival. No relationship was found between survival and age, type of operative procedure, depth of chest wall invasion, and postoperative radiotherapy. CONCLUSIONS: Both operative procedures show reasonable survival results. Incomplete resection, mediastinal lymph node involvement, and intrapleural tumour spill adversely influence survival. PMID:8795676

  9. Mitochondrial Variations in Non-Small Cell Lung Cancer (NSCLC) Survival

    PubMed Central

    Wang, Zhaoxi; Choi, Sojung; Lee, Jinseon; Huang, Yen-Tsung; Chen, Feng; Zhao, Yang; Lin, Xihong; Neuberg, Donna; Kim, Jhingook; Christiani, David C

    2015-01-01

    Mutations in the mtDNA genome have long been suspected to play an important role in cancer. Although most cancer cells harbor mtDNA mutations, the question of whether such mutations are associated with clinical prognosis of lung cancer remains unclear. We resequenced the entire mitochondrial genomes of tumor tissue from a population of 250 Korean patients with non-small cell lung cancer (NSCLC). Our analysis revealed that the haplogroup (D/D4) was associated with worse overall survival (OS) of early-stage NSCLC [adjusted hazard ratio (AHR), 1.95; 95% CI, 1.14–3.33; Ptrend = 0.03]. By comparing the mtDNA variations between NSCLC tissues and matched blood samples, we found that haplogroups M/N and/or D/D4 were hotspots for somatic mutations, suggesting a more complicated mechanism of mtDNA somatic mutations other than the commonly accepted mechanism of sequential accumulation of mtDNA mutations. PMID:25657573

  10. New targeted treatments for non-small-cell lung cancer – role of nivolumab

    PubMed Central

    Zago, Giulia; Muller, Mirte; van den Heuvel, Michel; Baas, Paul

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage of disease, where it is no longer amenable to curative treatment. During the last decades, the survival has only improved significantly for lung cancer patients who have tumors harboring a driver mutation. Therefore, there is a clear unmet need for effective therapies for patients with no mutation. Immunotherapy has emerged as an effective treatment for different cancer types. Nivolumab, a monoclonal inhibitory antibody against PD-1 receptor, can prolong survival of NSCLC patients, with a manageable toxicity profile. In two Phase III trials, nivolumab was compared to docetaxel in patients with, respectively, squamous (CheckMate 017) and non-squamous NSCLC (CheckMate 057). In both trials, nivolumab significantly reduced the risk of death compared to docetaxel (41% and 27% lower risk of death for squamous and non-squamous NSCLC, respectively). Therefore, nivolumab has been approved in the US and in Europe as second-line treatment for advanced NSCLC. Unfortunately, accurate predictive factors for patient selection are lacking, making it difficult to decide who will benefit and who will not. Currently, there are many ongoing trials that evaluate the efficacy of nivolumab in different settings and in combination with other agents. This paper reviews the present literature about the role of nivolumab in the treatment of NSCLC. Particular attention has been given to efficacy studies, toxicity profile, and current and emerging predictive factors. PMID:27536062

  11. New targeted treatments for non-small-cell lung cancer - role of nivolumab.

    PubMed

    Zago, Giulia; Muller, Mirte; van den Heuvel, Michel; Baas, Paul

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage of disease, where it is no longer amenable to curative treatment. During the last decades, the survival has only improved significantly for lung cancer patients who have tumors harboring a driver mutation. Therefore, there is a clear unmet need for effective therapies for patients with no mutation. Immunotherapy has emerged as an effective treatment for different cancer types. Nivolumab, a monoclonal inhibitory antibody against PD-1 receptor, can prolong survival of NSCLC patients, with a manageable toxicity profile. In two Phase III trials, nivolumab was compared to docetaxel in patients with, respectively, squamous (CheckMate 017) and non-squamous NSCLC (CheckMate 057). In both trials, nivolumab significantly reduced the risk of death compared to docetaxel (41% and 27% lower risk of death for squamous and non-squamous NSCLC, respectively). Therefore, nivolumab has been approved in the US and in Europe as second-line treatment for advanced NSCLC. Unfortunately, accurate predictive factors for patient selection are lacking, making it difficult to decide who will benefit and who will not. Currently, there are many ongoing trials that evaluate the efficacy of nivolumab in different settings and in combination with other agents. This paper reviews the present literature about the role of nivolumab in the treatment of NSCLC. Particular attention has been given to efficacy studies, toxicity profile, and current and emerging predictive factors. PMID:27536062

  12. Dyspnea as a Prognostic Factor in Patients with Non-Small Cell Lung Cancer

    PubMed Central

    Ban, Wooho; Lee, Jong Min; Ha, Jick Hwan; Yeo, Chang Dong; Kang, Hyeon Hui; Rhee, Chin Kook; Moon, Hwa Sik

    2016-01-01

    Purpose To investigate associations between dyspnea and clinical outcomes in patients with non-small cell lung cancer (NSCLC). Materials and Methods From 2001 to 2014, we retrospectively reviewed the prospective lung cancer database of St. Paul's Hospital at the Catholic University of Korea. We enrolled patients with NSCLC and evaluated symptoms of dyspnea using modified Medical Research Council (mMRC) scores. Also, we estimated pulmonary functions and analyzed survival data. Results In total, 457 NSCLC patients were enrolled, and 259 (56.7%) had dyspnea. Among those with dyspnea and whose mMRC scores were available (109 patients had no mMRC score), 85 (56.6%) patients had an mMRC score <2, while 65 (43.3%) had an mMRC score ≥2. Significant decreased pulmonary functions were observed in patients with dyspnea. In multivariate analysis, aging, poor performance status, advanced stage, low forced expiratory volume in 1 second (%), and an mMRC score ≥2 were found to be significant prognostic factors for patient survival. Conclusion Dyspnea could be a significant prognostic factor in patients with NSCLC. PMID:27401635

  13. Molecular analysis of human papillomavirus in never-smokers with non-small cell lung cancer

    PubMed Central

    ISA, SHUN-ICHI; KURAHARA, YU; YAMAMOTO, SATOMI; TAMIYA, AKIHIRO; OMACHI, NAOKI; ASAMI, KAZUHIRO; OKISHIO, KYOICHI; UTSUMI, TOMOKI; ITO, NORIMASA; YOON, HYUNG-EUN; MATSUMURA, AKIHIDE; ATAGI, SHINJI; KAWAGUCHI, TOMOYA

    2015-01-01

    The causes of lung cancer in never-smokers remain unclear. The potential contribution of human papillomavirus (HPV) to the carcinogenesis of non-small cell lung cancer (NSCLC) has been reported. In 2008, a prospective registry of never-smokers with NSCLC was established at the Kinki-Chuo Chest Medical Center, Sakai, Osaka, Japan. Never-smokers with NSCLC were consecutively enrolled onto the registry. Of these patients, 114 with large tumor specimens, the majority of which were surgical tissues, were selected. In total, 23 of the most clinically relevant HPV types were assayed using polymerase chain reaction amplification of the viral genome. Following exclusion of samples with suboptimal quality, DNA was extracted from 96 formalin-fixed paraffin-embedded samples. These 96 cases consisted of 82 females (85.4%) and 14 males (14.6%), with a median age of 67 years (range, 29–83). Almost all cases (93.8%) were of the adenocarcinoma histological subtype. Despite confirmation of the quality and amount of DNA, HPV type 6 was detected in only one case (1.1%). Furthermore, no other samples examined were positive for any other HPV types. The results therefore suggest that HPV does not play a major role as the driving oncogenic event in never-smokers with NSCLC. PMID:25621070

  14. Overexpression of GOLPH3 is associated with poor survival in Non-small-cell lung cancer

    PubMed Central

    Tang, Wanfen; Han, Mengjiao; Ruan, Beihong; Jin, Wei; Lou, Jun; Yuan, Xiamei; Chen, Dingwei; Chen, Yangchao; Shin, Vivian Y; Jin, Hongchuan; Wang, Xian

    2016-01-01

    As a highly conserved protein of the Golgi apparatus, Golgi phosphoprotein 3 (GOLPH3) has been shown to be involved in tumorigenesis. This study aims to explore the expression and significance of GOLPH3 in non-small-cell lung cancer (NSCLC). We found that GOLPH3 expression was significantly elevated in NSCLC tissues when compared with adjacent lung tissues (p<0.01). Moreover, GOLPH3 expression was significantly associated with histological type (p<0.01), differentiation (p<0.01), and lymph node metastasis (p<0.05). Kaplan-Meier survival analysis showed that overall survival of patients with high expression of GOLPH3 was significantly shorter (n=100, p<0.05). In addition, GOLPH3 knock-down in two independent NSCLC cell lines inhibited cell viability through the induction of cell cycle arrest and apoptosis. In conclusion, GOLPH3 is closely related to the progression in NSCLC and could be served as a potential prognostic biomarker and therapeutic target for NSCLC. PMID:27186299

  15. Chimeric ubiquitin ligases inhibit non-small cell lung cancer via negative modulation of EGFR signaling.

    PubMed

    Zhong, Daixing; Ru, Yi; Wang, Qinhao; Zhang, Jing; Zhang, Jian; Wei, Junxia; Wu, Jin; Yao, Libo; Li, Xiaofei; Li, Xia

    2015-04-01

    Targeting epidermal growth factor receptor (EGFR) represents a promising therapeutic strategy for non-small cell lung cancers (NSCLC). The ubiquitin-proteasome system (UPS) is a major pathway that mediates protein degradation. To target the degradation of EGFR, we generated two artificial ubiquitin ligases, which are composed of an EGFR-binding domain, i.e., the SH2 domain from growth factor receptor binding protein 2 (Grb2), and an ubiquitin ligase catalytic domain, i.e., the RING domain from Cbl or the U-box domain from CHIP. When the chimeric ubiquitin ligases were introduced into lung cancer SPC-A1 cells, they effectively associated with EGFR, promoted its ubiquitination and degradation, and as a result, blocked the downstream PI3K-Akt signal pathway. Moreover, cell proliferation and invasion were inhibited, the sensitivity to docetaxel-induced apoptosis was enhanced and the tumorigenicity was suppressed. In conclusion, negative modulation of EGFR signaling by the chimeric ubiquitin ligases can inhibit malignancy of SPC-A1 cells and sensitize these cells to chemotherapy, thus it may be applied to targeted therapy for NSCLC. PMID:25573345

  16. PD-L1 expression is associated with advanced non-small cell lung cancer

    PubMed Central

    Chen, Zhiquan; Mei, Jiandong; Liu, Lunxu; Wang, Guochen; Li, Zuosheng; Hou, Jingpu; Zhang, Qiuyang; You, Zongbing; Zhang, Liu

    2016-01-01

    Lung cancer is the most common cause of cancer-associated mortalities worldwide. Novel immunotherapies have been developed to improve the clinical outcomes of non-small cell lung cancer (NSCLC). Antibodies against programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand 1 (PD-L1) have been tested in clinical trials, and anti-PD-1 antibody has been approved for the treatment of NSCLC. The aim of the present study was to assess expression of PD-1, PD-L1 and programmed cell death protein 1 ligand 2 (PD-L2) in 48 patients with NSCLC, using immunohistochemical staining. The results found that 35.4% (17/48) of patients were positive for PD-1 expression, 64.6% (31/48) were positive for PD-L1 expression and 45.8% (22/48) were positive for PD-L2 expression. Neither PD-1 nor PD-L2 expression was associated with gender, histology, differentiation status, tumor stage or lymph node metastasis. PD-L1 expression was not associated with gender, histology, differentiation status or lymph node metastasis; however, PD-L1 expression was significantly increased in stage III NSCLC (85.7% PD-L1+) compared with stage I/II NSCLC (55.9% PD-L1+) (P=0.049). PMID:27446371

  17. Targeted therapy of advanced non-small cell lung cancer: the role of bevacizumab

    PubMed Central

    Stinchcombe, Thomas E

    2007-01-01

    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. PMID:19707329

  18. Combined tamoxifen and gefitinib in non-small cell lung cancer shows antiproliferative effects.

    PubMed

    Shen, Hua; Yuan, Yuan; Sun, Jing; Gao, Wen; Shu, Yong-Qian

    2010-02-01

    Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC). According to statistics, NSCLC patients who are female, have adenocarcinoma, or never smoked have a higher response rate to gefitinib treatment. This phenomenon could be due to the interaction between the estrogen receptor (ER) and EGFR. To test whether inhibition of the EGFR signaling pathway affects the antitumour effect of gefitinib, NSCLC cell lines were treated with gefitinib and tamoxifen, an ER antagonist. Cotreatment with gefitinib plus tamoxifen decreased the proliferation and increased the apoptosis of A549 and H1650 adencarcinoma cell lines, when compared with either drug alone. However, there was no effect on H520 cells (squamous cell carcinoma). Rapid activation of the EGFR pathway by both EGF and beta-E2 was observed in A549 cells. Additionally, EGFR and ERbeta expression was down-regulated in response to estrogen and EGF, respectively, but up-regulated in response to tamoxifen and genfitib, respectively. These results suggest that there is a functional cross-signaling between the EGFR and the ER pathways in NSCLC, possibly providing a rationale to combine gefitinib with anti-estrogen therapy for lung cancer treatment. PMID:20005069

  19. P42 Ebp1 functions as a tumor suppressor in non-small cell lung cancer

    PubMed Central

    Ko, Hyo Rim; Nguyen, Truong LX; Kim, Chung Kwon; Park, Youngbin; Lee, Kyung-Hoon; Ahn, Jee-Yin

    2015-01-01

    Although the short isoform of ErbB3-binding protein 1 (Ebp1), p42 has been considered to be a potent tumor suppressor in a number of human cancers, whether p42 suppresses tumorigenesis of lung cancer cells has never been clarified. In the current study we investigated the tumor suppressor role of p42 in non-small cell lung cancer cells. Our data suggest that the expression level of p42 is inversely correlated with the cancerous properties of NSCLC cells and that ectopic expression of p42 is sufficient to inhibit cell proliferation, anchorage-independent growth, and invasion as well as tumor growth in vivo. Interestingly, p42 suppresses Akt activation and overexpression of a constitutively active form of Akt restores the tumorigenic activity of A549 cells that is ablated by exogenous p42 expression. Thus, we propose that p42 Ebp1 functions as a potent tumor suppressor of NSCLC through interruption of Akt signaling. [BMB Reports 2015; 48(3): 159-165] PMID:24998263

  20. CXCR6 expression in non-small cell lung carcinoma supports metastatic process via modulating metalloproteinases

    PubMed Central

    Mir, Hina; Singh, Rajesh; Kloecker, Goetz H.; Lillard, James W.; Singh, Shailesh

    2015-01-01

    Lung cancer (LuCa) is the leading cause of cancer-related deaths worldwide regardless of the gender. High mortality associated with LuCa is due to metastasis, molecular mechanisms of which are yet to be defined. Here, we present evidence that chemokine receptor CXCR6 and its only natural ligand, CXCL16, are significantly expressed by non-small cell lung cancer (NSCLC) and are involved in the pathobiology of LuCa. CXCR6 expression was significantly higher in two subtypes of NSCLC (adenocarcinomas-ACs and squamous cell carcinoma-SCCs) as compared to non-neoplastic tissue. Additionally, serum CXCL16 was significantly elevated in LuCa cases as compared to healthy controls. Similar to CXCR6 tissue expression, serum level of CXCL16 in AC patients was significantly higher than SCC patients. Biological significance of this axis was validated using SCC and AC cell lines. Expression of CXCR6 was higher in AC cells, which also showed higher migratory and invasive potential than SCC. Differences in migratory and invasive potential between AC and SCC were due to differential expression of metalloproteinases following CXCL16 stimulation. Hence, our findings suggest clinical and biological significance of CXCR6/CXCL16 axis in LuCa, which could be used as potential prognostic marker and therapeutic target. PMID:25888629

  1. Lymphatic drainage, CTV and molecular imaging in non-small cell lung cancer.

    PubMed

    Trodella, Lucio; Ciresa, Marzia; D'Angelillo, Rolando; Ramella, Sara

    2003-01-01

    Prognosis for non-small cell lung cancer (NSCLC) patients who have locally advanced unresectable disease is poor for persistent thoracic disease and development of distant metastasis. In view of the poor rate of local control following conventional radiation therapy, there is a great need for methods to improve its efficacy. Three-dimensional conformal radiation therapy (3DCRT) is a high precision radiotherapy able to deliver higher doses with smaller doses to the surrounding normal tissues. However, the real problem is: "what do I want to treat?" This question is addressed based on the clinical and biological target volume definition. Selection of the CTV is therefore basically the clinical compromise between the most radical possible CTV and the critical normal tissue tolerance. The clinical target volume includes the GTV plus a margin to encompass subclinical or microscopic malignant disease immediately adjacent to it. Standard radiation therapy consists of a dose of 40 Gy to the entire mediastinum, supraclavicular fossa, and ipsilateral hilum, even if there is no evidence of disease in these areas. Despite the high risk of nodal spread in lung cancer, the benefit of additional elective nodal irradiation (ENI) is not proven while it seems to significantly increase the rate of radiation morbidity. Several studies have been published where ENI was systematically omitted. The main arguments for omitting ENI and the principal clinical experiences, are discussed. PMID:15018317

  2. Recent advances in immunotherapy for non-small-cell lung cancer.

    PubMed

    Suzuki, Hiroyuki; Owada, Yuki; Watanabe, Yuzuru; Inoue, Takuya; Fukuharav, Mitsuro; Yamaura, Takumi; Mutoh, Satoshi; Okabe, Naoyuki; Yaginuma, Hiroshi; Hasegawa, Takeo; Yonechi, Atsushi; Ohsugi, Jun; Hoshino, Mika; Higuchi, Mitsunori; Shio, Yutaka; Gotoh, Mitsukazu

    2014-01-01

    Despite of recent development in the field of molecular targeted therapies, lung cancer is a leading cause of cancer death in the world. Remarkable progress has been made recently in immunotherapy for patients with non-small-cell lung cancer (NSCLC), with several modalities, concepts, and treatment settings being investigated. In vaccine development, large-scale clinical trials such as those with L-BLP25, belagenpumatucel-L, TG4010, and talactoferrin are already ongoing and some results have been reported. A trial of a vaccine as adjuvant therapy for patients with completely resected NSCLC is also ongoing with one of the major cancer-testis antigens, melanoma-associated antigen (MAGE)-A3. More recently, the effectiveness of multiple peptide vaccines has also been shown. Recently developed unique treatment modalities are the immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, which also show promise. However, although therapeutic cancer vaccines are generally thought to be safe, severe adverse events should be monitored carefully when using immune checkpoint inhibitors. Here, we discuss recent advances and future perspectives of immunotherapy for patients with NSCLC. PMID:24196313

  3. Prospective study on stereotactic radiotherapy of limited-stage non-small-cell lung cancer

    SciTech Connect

    Hoyer, Morten . E-mail: hoyer@as.aaa.dk; Roed, Henrik D.; Hansen, Anders Traberg; Ohlhuis, Lars; Petersen, Jorgen; Nellemann, Hanne; Berthelsen, Anne Kiil; Grau, Cai D.; Engelholm, Svend Aage D.; Maase, Hans D. von der

    2006-11-15

    Purpose: To test the effect of stereotactic body radiotherapy (SBRT) in the treatment of medically inoperable patients with limited-stage non-small-cell lung cancer (NSCLC) in a Phase II trial. Methods and Materials: Forty patients with Stage I NSCLC were treated with SBRT with a central dose of 15 Gy x 3 within 5-8 days. Results: Eight patients (20%) obtained a complete response, 15 (38%) had a partial response, and 12 (30%) had no change or could not be evaluated. Only 3 patients had a local recurrence, and the local control rate 2 years after SBRT was 85%. At 2 years, 54% were without local or distant progression, and overall survival was 47%. Within 6 months after treatment, one or more Grade {>=}2 reactions were observed in 48% of the patients. Conclusions: Stereotactic body radiotherapy in patients with limited-stage NSCLC resulted in a high probability of local control and a promising survival rate. The toxicity after SBRT of lung tumors was moderate. However, deterioration in performance status, respiratory insufficiency, and other side effects were observed.

  4. Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer.

    PubMed

    Aranda, F; Bloy, N; Pesquet, J; Petit, B; Chaba, K; Sauvat, A; Kepp, O; Khadra, N; Enot, D; Pfirschke, C; Pittet, M; Zitvogel, L; Kroemer, G; Senovilla, L

    2015-06-01

    cis-Diamminedichloroplatinum(II) (CDDP), which is mostly referred to as cisplatin, is a widely used antineoplastic. The efficacy of cisplatin can be improved by combining it with the vitamin B6 precursor pyridoxine. Here, we evaluated the putative synergistic interaction of CDDP with pyridoxine in the treatment of an orthotopic mouse model of non-small-cell lung cancer (NSCLC). CDDP and pyridoxine exhibited hyperadditive therapeutic effects. However, this synergy was only observed in the context of an intact immune system and disappeared when the otherwise successful drug combination was applied to the same NSCLC cancer implanted in the lungs of athymic mice (which lack T lymphocytes). Immunocompetent mice that had been cured from NSCLC by the combined regimen of CDDP plus pyridoxine became resistant against subcutaneous rechallenge with the same (but not with an unrelated) cancer cell line. In vitro, CDDP and pyridoxine did not only cause synergistic killing of NSCLC cells but also elicited signs of immunogenic cell death including an endoplasmic reticulum stress response and exposure of calreticulin at the surface of the NSCLC cells. NSCLC cells treated with CDDP plus pyridoxine in vitro elicited a protective anticancer immune response upon their injection into immunocompetent mice. Altogether, these results suggest that the combined regimen of cisplatin plus pyridoxine mediates immune-dependent antineoplastic effects against NSCLC. PMID:25065595

  5. Low level of 5-Hydroxymethylcytosine predicts poor prognosis in non-small cell lung cancer

    PubMed Central

    LIAO, YUNFEI; GU, JIE; WU, YONGBING; LONG, XIANG; GE, DI; XU, JIANJUN; DING, JIANYONG

    2016-01-01

    The loss of 5-hydroxymethylcytosine (5-hmC) has previously been demonstrated to be implicated in the initiation and progression of various tumors. However, its role in non-small cell lung cancer (NSCLC) remains unknown. The present study aimed to determine the level of 5-hmC in NSCLC and their adjacent normal lung tissues by immunohistochemistry and dot-blot analysis; then the relationship between 5-hmC level and the clinicopathological features of NSCLC and the prognostic significance of 5-hmC level in NSCLC patients were analyzed. By employing the dot-blot analysis, a significant reduction of 5-hmC level in NSCLC tissues compared with the adjacent normal tissues was detected, which were further verified by the immunohistochemistry results on tissue microarrays. Further analyses demonstrated that 65.38% (136/208) presented with low 5-hmC level, and low 5-hmC level was significantly associated with lymph node metastasis (P<0.001), histological type (P<0.001) and large tumor size (P=0.031). Notably, the 5-year overall survival rate of patients with low 5-hmC levels were significantly lower than patients with high 5-hmC levels (P<0.001). In addition, it was demonstrated that 5-hmC level was identified as independent prognostic factor in patients' overall survival. In conclusion, downregulation of 5-hmC may serve as a useful biomarker for NSCLC prognosis evaluation. PMID:27313688

  6. Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: Recent Progress and Future Directions.

    PubMed

    Cameron, Laird; Solomon, Benjamin

    2015-07-01

    Rearrangements of the anaplastic lymphoma kinase (ALK) gene originally discovered nearly 20 years ago in the context of anaplastic large cell lymphoma were identified as oncogenic drivers in a subset of non-small cell lung cancers (NSCLCs) in 2007. These ALK gene rearrangements are present in 3-5 % of NSCLC patients, typically younger, never or light smokers with adenocarcinomas. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor with significant activity in ALK-positive NSCLC that received accelerated US Food and Drug Administration approval for treatment of ALK-positive NSCLC in 2011, just 4 years after identification of ALK rearrangements in this setting. Subsequently, two phase III trials have shown crizotinib to have a tolerable toxicity profile and to be superior to standard chemotherapy for the first- or second-line treatment of advanced ALK-positive lung cancer and numerous countries have approved its use. Despite initial responses, acquired resistance to crizotinib invariably leads to disease progression. Mechanisms of resistance have been described to include ALK tyrosine kinase mutations, activation of bypass signalling pathways and pharmacokinetic failure of crizotinib. Several next-generation ALK inhibitors, including ceritinib and alectinib, are in clinical development and show efficacy in both the crizotinib naïve and crizotinib refractory settings. Ongoing clinical trials will identify the optimal strategy to incorporate these novel agents in the treatment of patients with ALK-positive NSCLC. PMID:26076736

  7. A Predictive Model for Personalized Therapeutic Interventions in Non-small Cell Lung Cancer.

    PubMed

    Kureshi, Nelofar; Abidi, Syed Sibte Raza; Blouin, Christian

    2016-01-01

    Non-small cell lung cancer (NSCLC) constitutes the most common type of lung cancer and is frequently diagnosed at advanced stages. Clinical studies have shown that molecular targeted therapies increase survival and improve quality of life in patients. Nevertheless, the realization of personalized therapies for NSCLC faces a number of challenges including the integration of clinical and genetic data and a lack of clinical decision support tools to assist physicians with patient selection. To address this problem, we used frequent pattern mining to establish the relationships of patient characteristics and tumor response in advanced NSCLC. Univariate analysis determined that smoking status, histology, epidermal growth factor receptor (EGFR) mutation, and targeted drug were significantly associated with response to targeted therapy. We applied four classifiers to predict treatment outcome from EGFR tyrosine kinase inhibitors. Overall, the highest classification accuracy was 76.56% and the area under the curve was 0.76. The decision tree used a combination of EGFR mutations, histology, and smoking status to predict tumor response and the output was both easily understandable and in keeping with current knowledge. Our findings suggest that support vector machines and decision trees are a promising approach for clinical decision support in the patient selection for targeted therapy in advanced NSCLC. PMID:25494516

  8. Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer.

    PubMed

    Hu, Jiangting; Bianchi, Fabrizio; Ferguson, Mary; Cesario, Alfredo; Margaritora, Stefano; Granone, Pierluigi; Goldstraw, Peter; Tetlow, Michelle; Ratcliffe, Cathy; Nicholson, Andrew G; Harris, Adrian; Gatter, Kevin; Pezzella, Francesco

    2005-02-10

    Angiogenesis is regarded as essential for tumour growth. However, we have demonstrated that some other aggressive non-small-cell lung carcinomas (n-SCLC) do not have angiogenesis. In this study, using cDNA microarray analysis, we demonstrate that angiogenic and nonangiogenic tumour types can be distinguished by their gene expression profiles. Tissue samples from 42 n-SCLC patients were obtained with consent. In all, 12 tumours were nonangiogenic and 30 angiogenic. The two groups were matched by age, sex, smoking and tumour stage. Total RNAs were extracted followed by microarray hybridization and image scan procedure. Data were analysed using GeneSpring 5.1 software. A total of 62 genes were found to be able to separate angiogenic from nonangiogenic tumours. Nonangiogenic tumours have higher levels of genes concerned with mitochondrial metabolism, mRNA transcription, protein synthesis and the cell cycle. Angiogenic tumours have higher levels of genes coding for membrane vesicles, integrins, remodelling, angiogenesis and apoptosis. These results further support our first finding that nonangiogenic lung tumours are fast-growing tumours filling the alveoli in the absence of vascular remodelling. We raise the hypothesis that in nonangiogenic tumours, hypoxia leads to a higher activation of the mitochondrial respiratory chain, which allows tumour growth without triggering angiogenesis. PMID:15592519

  9. Expression of Id-1 and VEGF in non-small cell lung cancer

    PubMed Central

    Kim, Mee-Seon; Park, Tae-In; Lee, Yu-Mi; Jo, Young-Min; Kim, Sunzoo

    2013-01-01

    Angiogenesis is essential for invasive tumor growth and metastasis. Bevacizumab has been widely used for the treatment of non-small cell lung cancer (NSCLC). Various studies clearly demonstrate the relevance of Id-1 and VEGF in angiogenesis. The aim of this study was to establish the role of Id-1 expression in tumor progression and angiogenesis in relation to VEGF in NSCLC. Seventy five patients underwent surgery for lung cancers. The expressions of Id-1 and VEGF in NSCLC samples were determined by immunohistochemistry. Expression of Id-1 and VEGF showed a close correlation in NSCLC (p < 0.001). In addition, Id-1 strong expression group showed high incidence of metastasis in multivariate analysis (p = 0.028). Id-1 strong expression group had short metastasis-free survival (p = 0.008) and short recurrence-free survival (p = 0.027). Strong Id-1 expression in NSCLC had a poor prognosis in association with VEGF expression. Id-1 may function in tumor growth and progression via angiogenesis. Therefore, Id-1 is considered to be a candidate for new therapeutic target and a prognostic factor in NSCLC. PMID:24133588

  10. KIAA1522 is a novel prognostic biomarker in patients with non-small cell lung cancer

    PubMed Central

    Liu, Yi-Zhen; Yang, Hai; Cao, Jian; Jiang, Yan-Yi; Hao, Jia-Jie; Xu, Xin; Cai, Yan; Wang, Ming-Rong

    2016-01-01

    Nowadays, no robust biomarkers have been applied to clinical practice to provide prognostic evaluation of non-small cell lung cancer (NSCLC). This study aims to identify new potential prognostic biomarkers for NSCLC. In the present work, KIAA1522 is screened out from two independent GEO datasets as aberrantly up-regulated gene in NSCLC tissues. We evaluate KIAA1522 expression immunohistochemically in 583 NSCLC tissue samples and paired non-tumor tissues. KIAA1522 displays stronger staining in NSCLC cases than in adjacent normal lung tissues. Importantly, patients with KIAA1522 overexpression had a significantly shorter overall survival compared to those with low expression (P < 0.00001). Multivariate Cox regression analyses show that KIAA1522 is an independent prognostic indicator, even for early-stage NSCLCs (P = 0.00025, HR = 2.317, 95%CI: 1.477–3.635). We also found that high expression of KIAA1522 is a significant risk factor for decreased overall survival of the patients who received platinum-based chemotherapy. Gene set enrichment analysis (GSEA) and functional studies reveal that KIAA1522 is associated with oncogenic KRAS pathways. Taken together, high expression of KIAA1522 can be used as an independent biomarker for predication of poor survival and platinum-resistance of NSCLC patients, and aberrant KIAA1522 might be a new target for the therapy of the disease. PMID:27098511

  11. Genetic modifiers of EGFR dependence in non-small cell lung cancer

    PubMed Central

    Sharifnia, Tanaz; Rusu, Victor; Piccioni, Federica; Bagul, Mukta; Imielinski, Marcin; Cherniack, Andrew D.; Pedamallu, Chandra Sekhar; Wong, Bang; Wilson, Frederick H.; Garraway, Levi A.; Altshuler, David; Golub, Todd R.; Root, David E.; Subramanian, Aravind; Meyerson, Matthew

    2014-01-01

    Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival. PMID:25512530

  12. Prognostic value of genomic damage in non-small-cell lung cancer.

    PubMed Central

    de Juan, C.; Iniesta, P.; Vega, F. J.; Peinado, M. A.; Fernandez, C.; Caldés, T.; Massa, M. J.; López, J. A.; Sánchez, A.; Torres, A. J.; Balibrea, J. L.; Benito, M.

    1998-01-01

    Genomic alterations have been analysed in 65 non-small-cell lung cancer (NSCLC) tissue samples by using the arbitrarily primed polymerase chain reaction (AP-PCR), which is a PCR-based genomic fingerprinting. We have shown that AP-PCR may be applied as a useful and feasible practical method for detection of the genomic alterations that accompany malignancy in NSCLC. Genomic changes detected by us consisted of: allelic losses or gains in anonymous DNA sequences, homozygously deleted DNA sequences and polymorphic DNA sequences. According to these genomic changes, lung tumours evaluated in the present study have been scored into three groups: low, moderate and high genomic damage tumours. The aim of this study was to investigate the effect of genomic damage on patient survival. Survival analysis was carried out in 51 NSCLC patients. Our results revealed that high genomic damage patients showed a poorer prognosis than those with low or moderate genomic damage (P = 0.038). Multivariate Cox regression analysis showed that patients with higher genomic alterations displayed an adjusted-by-stage risk ratio 4.26 times higher than the remaining patients (95% CI = 1.03-17.54). We can conclude that genomic damage has an independent prognostic value of poor clinical evolution in NSCLC. Images Figure 1 Figure 2 PMID:9667677

  13. Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer.

    PubMed

    Ochi, Nobuaki; Takigawa, Nagio; Harada, Daijiro; Yasugi, Masayuki; Ichihara, Eiki; Hotta, Katsuyuki; Tabata, Masahiro; Tanimoto, Mitsune; Kiura, Katsuyuki

    2014-03-10

    To study epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance mechanisms, we established a novel gefitinib-resistant lung cancer cell line derived from an EGFR-mutant non-small cell lung cancer cell line (PC-9) pretreated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (designated PC9-GR). We found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated after several hours in PC9-GR but not in PC-9. The combination of gefitinib with ERK inhibition (by U0126) restored gefitinib susceptibility in PC9-GR, but PI3K-Akt inhibition with LY294002 did not. Although the levels of phosphorylated Src were up-regulated simultaneously with ERK reactivation, neither ERK suppression using U0126 nor an ERK-specific siRNA induced Src phosphorylation. Furthermore, dual inhibition of EGFR and Src restored gefitinib sensitivity in PC9-GR in vitro and in vivo. In conclusion, our results indicate that Src-mediated ERK reactivation may play a role in a novel gefitinib resistance mechanism, and that the combined use of gefitinib with a Src inhibitor may be a potent strategy to overcome this resistance. PMID:24440771

  14. KIAA1522 is a novel prognostic biomarker in patients with non-small cell lung cancer.

    PubMed

    Liu, Yi-Zhen; Yang, Hai; Cao, Jian; Jiang, Yan-Yi; Hao, Jia-Jie; Xu, Xin; Cai, Yan; Wang, Ming-Rong

    2016-01-01

    Nowadays, no robust biomarkers have been applied to clinical practice to provide prognostic evaluation of non-small cell lung cancer (NSCLC). This study aims to identify new potential prognostic biomarkers for NSCLC. In the present work, KIAA1522 is screened out from two independent GEO datasets as aberrantly up-regulated gene in NSCLC tissues. We evaluate KIAA1522 expression immunohistochemically in 583 NSCLC tissue samples and paired non-tumor tissues. KIAA1522 displays stronger staining in NSCLC cases than in adjacent normal lung tissues. Importantly, patients with KIAA1522 overexpression had a significantly shorter overall survival compared to those with low expression (P < 0.00001). Multivariate Cox regression analyses show that KIAA1522 is an independent prognostic indicator, even for early-stage NSCLCs (P = 0.00025, HR = 2.317, 95%CI: 1.477-3.635). We also found that high expression of KIAA1522 is a significant risk factor for decreased overall survival of the patients who received platinum-based chemotherapy. Gene set enrichment analysis (GSEA) and functional studies reveal that KIAA1522 is associated with oncogenic KRAS pathways. Taken together, high expression of KIAA1522 can be used as an independent biomarker for predication of poor survival and platinum-resistance of NSCLC patients, and aberrant KIAA1522 might be a new target for the therapy of the disease. PMID:27098511

  15. Non-small cell lung cancer is characterized by dramatic changes in phospholipid profiles.

    PubMed

    Marien, Eyra; Meister, Michael; Muley, Thomas; Fieuws, Steffen; Bordel, Sergio; Derua, Rita; Spraggins, Jeffrey; Van de Plas, Raf; Dehairs, Jonas; Wouters, Jens; Bagadi, Muralidhararao; Dienemann, Hendrik; Thomas, Michael; Schnabel, Philipp A; Caprioli, Richard M; Waelkens, Etienne; Swinnen, Johannes V

    2015-10-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)-based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non-malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non-malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D-imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D-imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development. PMID:25784292

  16. HOXA11 hypermethylation is associated with progression of non-small cell lung cancer.

    PubMed

    Hwang, Jung-Ah; Lee, Bo Bin; Kim, Yujin; Park, Seong-Eun; Heo, Kyun; Hong, Seung-Hyun; Kim, Young-Ho; Han, Joungho; Shim, Young Mog; Lee, Yeon-Su; Kim, Duk-Hwan

    2013-12-01

    This study was aimed at understanding the functional significance of HOXA11 hypermethylation in non-small cell lung cancer (NSCLC). HOXA11 hypermethylation was characterized in six lung cancer cell lines, and its clinical significance was analyzed using formalin-fixed paraffin-embedded tissues from 317 NSCLC patients, and Ki-67 expression was analyzed using immunohistochemistry. The promoter region of HOXA11 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 HOXA11 into H23 lung cancer cells resulted in the inhibition of cell migration and proliferation. HOXA11 hypermethylation was found in 218 (69%) of 317 primary NSCLCs. HOXA11 hypermethylation was found at a higher prevalence in squamous cell carcinoma than in adenocarcinoma (74% vs. 63%, respectively). HOXA11 hypermethylation was associated with Ki-67 proliferation index (P = 0.03) and pT stage (P = 0.002), but not with patient survival. Patients with pT2 and pT3 stages were 1.85 times (95% confidence interval [CI] = 1.04-3.29; P = 0.04) and 5.47 times (95% CI = 1.18-25.50; P = 0.01), respectively, more likely to show HOXA11 hypermethylation than those with pT1 stage, after adjusting for age, sex, and histology. In conclusion, the present study suggests that HOXA11 hypermethylation may contribute to the progression of NSCLC by promoting cell proliferation or migration. PMID:24259349

  17. Antiproliferative effect of Toona sinensis leaf extract on non-small-cell lung cancer.

    PubMed

    Yang, Chih-Jen; Huang, Yu-Jung; Wang, Cheng-Yuan; Wang, Pei-Hui; Hsu, Hseng-Kuang; Tsai, May-Jywan; Chen, Yu-Chu; Bharath Kumar, V; Huang, Ming-Shyan; Weng, Ching-Feng

    2010-06-01

    Toona sinensis (TS), which is also known as Cedrela sinensis, belongs to Meliaceae family, the compounds identified from this TS leaves possess a wide range of biologic functions, such as hypoglycemic effects, anti-LDL glycative activity, antioxidant activities, and inhibition of sudden acute respiratory syndrome (SARS) coronavirus replication. However, their effect against cancer cells is not well explored. In this study, to understand the cytotoxic effect and molecular mechanism stimulated by TSL-1 (TS leaf extract fraction) we employed three different non-small-cell lung cancer (NSCLC) cell lines: H441 cells (lung adenocarcinoma), H661 cells (lung large cell carcinoma) and H520 cells (lung squamous cell carcinoma). IC50 value was varied between these three cell lines, the least IC(50) value was observed in TSL-1-treated H661cells. Exposure of NSCLC cells to TSL-1 caused cell-cycle arrest in subG1 phase and caused apoptosis. Moreover, TSL-1 treatment decreased the cell-cycle regulators; cyclin D1 and CDK4 proteins by up regulating p27 expression in a dose-dependent manner. Thus, the TSL-1-induced apoptosis was further confirmed by cell morphology, subG1 peak accumulation, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) cleavage, propidium iodide (PI)-Annexin-V double staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The decreased Bcl2 protein level was concurrent with an increased Bax protein level in all 3 cell lines. Additionally, the tumoricidal effect of TSL-1 was measured using a xenograft model, after 5 weeks of TSL-1 treatment by various regimen caused regression of tumor. Taken together both these in vitro and in vivo studies revealed that TSL-1 is a potent inhibitor against NSCLC growth and our provoking result suggest that TSL-1 can be a better nutriceutical as a singlet or along with doublet agents (taxane, vinorelbine, and gemcitabine) for treating NSCLC. PMID:20478545

  18. Circulating Tumor Microemboli Diagnostics for Patients with Non-Small Cell Lung Cancer

    PubMed Central

    Carlsson, Anders; Nair, Viswam S.; Luttgen, Madelyn S.; Keu, Khun Visith; Horng, George; Vasanawala, Minal; Kolatkar, Anand; Jamali, Mehran; Iagaru, Andrei H.; Kuschner, Ware; Loo, Billy W.; Shrager, Joseph B.; Bethel, Kelly; Hoh, Carl K.; Bazhenova, Lyudmila; Nieva, Jorge; Kuhn, Peter; Gambhir, Sanjiv S.

    2014-01-01

    Introduction Circulating Tumor Microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I Non-Small Cell Lung Cancer (NSCLC) patients undergoing imaging evaluation. Methods First, we prospectively enrolled patients during [18F] FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking and cancer history) and imaging (tumor diameter, location in lung and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group. Results We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area Under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p-value = 0.001) and for stage I patients alone (AUC = 0.87, p-value = 0.002). Conclusion CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform. PMID:25157764

  19. Metagenes Associated with Survival in Non-Small Cell Lung Cancer

    PubMed Central

    Urgard, Egon; Vooder, Tõnu; Võsa, Urmo; Välk, Kristjan; Liu, Mingming; Luo, Cheng; Hoti, Fabian; Roosipuu, Retlav; Annilo, Tarmo; Laine, Jukka; Frenz, Christopher M.; Zhang, Liqing; Metspalu, Andres

    2011-01-01

    NSCLC (non-small cell lung cancer) comprises about 80% of all lung cancer cases worldwide. Surgery is most effective treatment for patients with early-stage disease. However, 30%–55% of these patients develop recurrence within 5 years. Therefore, markers that can be used to accurately classify early-stage NSCLC patients into different prognostic groups may be helpful in selecting patients who should receive specific therapies. A previously published dataset was used to evaluate gene expression profiles of different NSCLC subtypes. A moderated two-sample t-test was used to identify differentially expressed genes between all tumor samples and cancer-free control tissue, between SCC samples and AC/BC samples and between stage I tumor samples and all other tumor samples. Gene expression microarray measurements were validated using qRT-PCR. Bayesian regression analysis and Kaplan-Meier survival analysis were performed to determine metagenes associated with survival. We identified 599 genes which were down-regulated and 402 genes which were up-regulated in NSCLC compared to the normal lung tissue and 112 genes which were up-regulated and 101 genes which were down-regulated in AC/BC compared to the SCC. Further, for stage Ib patients the metagenes potentially associated with survival were identified. Genes that expressed differently between normal lung tissue and cancer showed enrichment in gene ontology terms which were associated with mitosis and proliferation. Bayesian regression and Kaplan-Meier analysis showed that gene-expression patterns and metagene profiles can be applied to predict the probability of different survival outcomes in NSCLC patients. PMID:21695068

  20. miRNAs, a potential target in the treatment of Non-Small-Cell Lung Carcinomas.

    PubMed

    Malleter, Marine; Jacquot, Catherine; Rousseau, Bénédicte; Tomasoni, Christophe; Juge, Marcel; Pineau, Alain; Sakanian, Vehary; Roussakis, Christos

    2012-09-15

    Lung cancer is a serious public health problem and Non Small Cell Lung Carcinoma, NSCLC, is particularly resistant to current treatments. So it is important to find new strategies that are active against NSCLC. miRNA is implicated in cancer and may be implicated in NSCLC. Our team has been working on two genes HEF1, a gene implicated in different functions of cell cycle and B2, a large non-coding RNA (nc RNA). These two genes have the same localisation: chromosome 6 and locus p24-25. nc RNA B2 may be involved in the regulation of HEF1. Firstly, we examine a bank of different human miRNAs known to interact with exons of HEF1. HEF1 and B2 were overexpressed in vitro by treating NSCLC-N6 with the cytostatic molecule A190, and carried out qRT-PCR for the expression of miRNA. Secondly, using specific software, we sought for structures originating from the B2 RNA sequence which might interact with HEF1 and assessed their expression. This strategy enabled us to confirm firstly that known miRNAs that can interact with exons of HEF1 are expressed in NSCLC-N6 cells. More precisely this strategy highlighted overexpression of one miRNA, hsa-miR-146b, listed in miRbase. The second step of the studies highlighted the expression of miRNA, potentially sequences originating from B2 in the NSCLC-N6. This miRNA overexpressed might be one of the regulators of the gene HEF1 and consequently implies on the carcinogenesis of lung cancer. So in the future it could be a potential and an innovative way to find a new strategy for the treatment of lung cancer. PMID:22732573

  1. Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers.

    PubMed

    Saito, Ken; Takigawa, Nagio; Ohtani, Naoko; Iioka, Hidekazu; Tomita, Yuki; Ueda, Ryuzo; Fukuoka, Junya; Kuwahara, Kazuhiko; Ichihara, Eiki; Kiura, Katsuyuki; Kondo, Eisaku

    2013-08-01

    Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates the proliferation of tumors. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as a molecular-targeting agent for the inactivation of EGFR signaling and show considerable therapeutic effect in non-small cell lung cancers harboring activating EGFR mutations. However, prolonged treatment inevitably produces tumors with additional gefitinib-resistant mutations in EGFR, which is a critical issue for current therapeutics. We aimed to characterize the distinct molecular response to gefitinib between the drug-resistant and drug-sensitive lung adenocarcinoma cells in order to learn about therapeutics based on the molecular information. From the quantitative PCR analysis, we found a specific increase in p14(ARF) expression in gefitinib-sensitive lung adenocarcinoma clones, which was absent in gefitinib-resistant clones. Moreover, mitochondria-targeted p14(ARF) triggered the most augmented apoptosis in both clones. We identified the amino acid residues spanning from 38 to 65 as a functional core of mitochondrial p14(ARF) (p14 38-65 a.a.), which reduced the mitochondrial membrane potential and caused caspase-9 activation. The synthesized peptide covering the p14 38-65 a.a. induced growth suppression of the gefitinib-resistant clones without affecting nonneoplastic cells. Notably, transduction of the minimized dose of the p14 38-65 peptide restored the response to gefitinib like that in the sensitive clones. These findings suggest that the region of p14(ARF) 38-65 a.a. is critical in the pharmacologic action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics of gefitinib-resistant cancers. PMID:23761220

  2. Lentivirus-mediated gene silencing of NOB1 suppresses non-small cell lung cancer cell proliferation.

    PubMed

    Huang, Weiyi; Zhong, Weiqing; Xu, Jun; Su, Benhua; Huang, Guanghui; Du, Jiajun; Liu, Qi

    2015-09-01

    NIN/RPN12 binding protein 1 (NOB1p) encoded by NOB1 has been found to be an essential factor in 26S proteasome biogenesis which participates in protein degradation. However, the functions of NOB1 in non-small cell lung cancer cells are largely unknown. In the present study, lentivirus-mediated NOB1 shRNA transfection in two non-small cell lung cancer cell lines (A549 and H1299) was accomplished, as determined by fluorescence imaging. Downregulation of NOB1 expression was confirmed by real-time PCR and western blotting. NOB1 silencing resulted in a significant decline in the proliferation and colony formation capability of non-small cell lung cancer cells. Moreover, flow cytometry showed that A549 cells were arrested in the G0/G1 phase of the cell cycle after NOB1 suppression. Furthermore, depletion of NOB1 resulted in a significant decrease in CDK4 and cyclin D1 expression. These results suggest that NOB1 may act as an important regulator in non-small cell lung cancer growth and could be a therapeutic target of non‑small cell lung cancer. PMID:26178254

  3. Efficacy and safety of chemotherapy for newly diagnosed advanced non-small cell lung cancer with venous thromboembolism

    PubMed Central

    Zhang, Xueli; Li, Huiqiao; Chen, Wenhui; Yang, Yuanhua; Wang, Chen; Zhang, Yuhui

    2015-01-01

    Background Venous thromboembolism (VTE) is a serious complication in patients with lung cancer. The benefit of chemotherapy for lung cancer patients with VTE remains unknown. This study was conducted to elucidate the efficacy and safety of chemotherapy for advanced non-small cell lung cancer (NSCLC) in patients with VTE. Methods Newly diagnosed patients with advanced (i.e. stage IIIB and IV) NSCLC with VTE who received systemic chemotherapy were studied. Response rates, progression-free survival (PFS), overall survival (OS), and toxicity were retrospectively analyzed. Results In this study, 21 patients who received chemotherapy plus anticoagulation therapy between December 2009 and February 2011 were included. The objective response and disease control rates within the first regimen were 14.29% (3/21) and 76.19 %(16/21), respectively. The median PFS, one-year survival rate, and median OS were 5.50 months, 33.30%, and 8.70 months, respectively. The main grade 3/4 toxicities observed included neutropenia (28.57%), nausea 4 (19.05%), and anemia 2 (9.52%). Major bleeding was not observed. Conclusion Chemotherapy for newly diagnosed patients with advanced NSCLC and VTE was feasible and had acceptable toxicity; however, the survival of these patients remained inferior to that of patients without VTE. PMID:26557917

  4. Down-regulation of miR-133a as a poor prognosticator in non-small cell lung cancer.

    PubMed

    Wang, Yuzhou; Li, Jinmei; Chen, Hongming; Mo, Yanli; Ye, Haiyin; Luo, Yiping; Guo, Kangwen; Mai, Zongjiong; Zhang, Ying; Chen, Baoying; Zhou, Yijin; Yang, Zhixiong

    2016-10-15

    miR-133a has been demonstrated to play an important role in tumor progression. The aim of present study was to analyze the correlation between miR-133a expression level and clinicopathologic features and its prognostic significance in non-small cell lung cancer (NSCLC). The expression of miR-133a in 104 pairs of human lung cancer tissues and adjacent normal lung tissues were analyzed by qRT-PCR. Here we show that miR-133a was down-regulated in NSCLC. The levels of miR-133a were negatively correlated with the status of N classification (N0-N1 vs. N2-N3, P=0.000), clinical stage (I-II vs. III-IV, P=0.010) and MMP-14 expression (High vs. Low, P=0.012). The patients with low miR-133a expression had shorter survival time than those with high miR-133a expression. Multivariate analysis indicated that the level of miR-133a expression was an independent prognostic indicator (P=0.012) for the survival of patients with NSCLC. In conclusion, decreased expression of miR-133a might be a potential unfavorable prognostic factor for patients with NSCLC, and further studies would be needed to prove our findings. PMID:27282282

  5. Gefitinib in Treating Patients With Metastatic or Unresectable Head and Neck Cancer or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-11

    Anaplastic Thyroid Cancer; Insular Thyroid Cancer; Metastatic Parathyroid Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Parathyroid Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Thyroid Cancer; Recurrent Verrucous Carcinoma of the Larynx; Stage III Follicular Thyroid Cancer; Stage III Papillary Thyroid Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Larynx; Stage IIIB Non-small Cell Lung Cancer; Stage IV Lymphoepithelioma of the Nasopharynx; 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 Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVA Basal Cell Carcinoma of the Lip; Stage IVA Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Follicular Thyroid Cancer; Stage IVA Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IVA Lymphoepithelioma of the Oropharynx; Stage IVA Midline Lethal Granuloma of the Paranasal Sinus

  6. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer | Office of Cancer Genomics

    Cancer.gov

    Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding.

  7. Alectinib in RET-rearranged non-small cell lung cancer—Another progress in precision medicine?

    PubMed Central

    Filipits, Martin

    2015-01-01

    RET fusions have been recognized as potential therapeutic targets in advanced non-small cell lung cancer. RET fusion proteins are detected in about 2% of lung adenocarcinomas. Alectinib, a second generation ALK inhibitor, was shown to block growth of cells with RET fusions. Thus alectinib should be further evaluated within clinical trials in patients with RET fusion-positive adenocarcinomas of the lung. PMID:26798590

  8. Nintedanib, a novel triple angiokinase inhibitor for the treatment of non-small cell lung cancer.

    PubMed

    Noonan, S; Man Wong, K; Jimeno, A

    2015-06-01

    Lung cancer is the leading cause of cancer-related deaths worldwide. Recent advances involving targeted therapies are promising, but most patients do not have an "oncogene addicted" disease. A platinum doublet chemotherapy regimen has been the mainstay of therapy since 1997. The addition of antiangiogenic agents to traditional chemotherapy has improved survival in patients with non-small cell lung cancer. However, these agents are limited by serious adverse events such as thromboembolism, bowel perforation and hemorrhage and by the development of resistance. Nintedanib is a novel, orally available triple angiokinase inhibitor that targets three important pathways involved in the initiation and propagation of angiogenesis in tumors, the VEGF, FGF and PDGFR pathways. Phase I and II trials have identified the maximum tolerated dose in monotherapy and in combination with traditional chemotherapy. The toxicity profile is tolerable and reversible, dominated by transaminitis and gastrointestinal side effects. The phase III LUME-lung 1 study (NCT00805194) compared docetaxel, a standard treatment in the second line, with docetaxel in combination with nintedanib. Progression-free survival was 3.4 months in the combination group compared to 2.7 months in the docetaxel group, (HR 0.79, 95% CI 0.68-0.92, P = 0.0019). There was a significant improvement in overall survival in adenocarcinoma patients, 12.6 vs. 10.3 months (HR 0.83, 95% CI 0.7-0.99, P = 0.036). Based on the results of this study, nintedanib has been approved by the EMA in Europe, as a second-line treatment in patients with adenocarcinoma. It is a promising, well-tolerated therapy that is currently being investigated in multiple different tumor types. PMID:26261849

  9. Identification of serum proteome components associated with progression of non-small cell lung cancer.

    PubMed

    Pietrowska, Monika; Jelonek, Karol; Michalak, Malwina; Roś, Małgorzata; Rodziewicz, Paweł; Chmielewska, Klaudia; Polański, Krzysztof; Polańska, Joanna; Gdowicz-Kłosok, Agnieszka; Giglok, Monika; Suwiński, Rafał; Tarnawski, Rafał; Dziadziuszko, Rafał; Rzyman, Witold; Widłak, Piotr

    2014-01-01

    The aim of the present study was to perform comparative analysis of serum from patients with different stages of non-small cell lung cancer (NSCLC) using the three complementary proteomic approaches to identify proteome components associated with the progression of cancer. Serum samples were collected before any treatment from 200 patients with NSCLC, including 103 early stage, 64 locally advanced and 33 metastatic cancer samples, and from 200 donors without malignancy. The low-molecular-weight fraction of serum proteome was MALDI-profiled in all samples. Serum proteins were characterized using 2D-PAGE and LC-MS/MS approaches in a representative group of 30 donors. Several significant differences were detected between serum samples collected from patients with early stage cancer and patients with locally advanced cancer, as well as between patients with metastatic cancer and patients with local disease. Of note, serum components discriminating samples from early stage cancer and healthy persons were also detected. In general, about 70 differentiating serum proteins were identified, including inflammatory and acute phase proteins already reported to be associated with the progression of lung cancer (serum amyloid A or haptoglobin). Several differentiating proteins, including apolipoprotein H or apolipoprotein A1, were not previously associated with NSCLC. No significant differences in patterns of serum proteome components were detected between patients with adenocarcinoma and squamous cell carcinoma. In conclusion, we identified the biomarker candidates with potential importance for molecular proteomic staging of NSCLC. Additionally, several serum proteome components revealed their potential applicability in early detection of the lung cancer. PMID:24872961

  10. Stereotactic radiosurgery for brain metastasis in non-small cell lung cancer

    PubMed Central

    Won, Yong Kyun; Lee, Ja Young; Kang, Young Nam; Jang, Ji Sun; Kang, Jin-Hyoung; Jung, So-Lyoung; Sung, Soo Yoon; Jo, In Young; Park, Hee Hyun; Lee, Dong-Soo; Chang, Ji Hyun; Lee, Yun Hee

    2015-01-01

    Purpose Stereotactic radiosurgery (SRS) has been introduced for small-sized single and oligo-metastases in the brain. The aim of this study is to assess treatment outcome, efficacy, and prognostic variables associated with survival and intracranial recurrence. Materials and Methods This study retrospectively reviewed 123 targets in 64 patients with non-small cell lung cancer (NSCLC) treated with SRS between January 2006 and December 2012. Treatment responses were evaluated using magnetic resonance imaging. Overall survival (OS) and intracranial progression-free survival (IPFS) were determined. Results The median follow-up was 13.9 months. The median OS and IPFS were 14.1 and 8.9 months, respectively. Fifty-seven patients died during the follow-up period. The 5-year local control rate was achieved in 85% of 108 evaluated targets. The 1- and 2-year OS rates were 55% and 28%, respectively. On univariate analysis, primary disease control (p < 0.001), the Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2; p = 0.002), recursive partitioning analysis class (1 vs. 2; p = 0.001), and age (<65 vs. ≥65 years; p = 0.036) were significant predictive factors for OS. Primary disease control (p = 0.041) and ECOG status (p = 0.017) were the significant prognostic factors for IPFS. Four patients experienced radiation necrosis. Conclusion SRS is a safe and effective local treatment for brain metastases in patients with NSCLC. Uncontrolled primary lung disease and ECOG status were significant predictors of OS and intracranial failure. SRS might be a tailored treatment option along with careful follow-up of the intracranial and primary lung disease status. PMID:26484304

  11. Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer

    PubMed Central

    Phillips, Joseph D.; Blatner, Nichole R.; Haghi, Leila; DeCamp, Malcolm M.; Meyerson, Shari L.; Heiferman, Michael J.; Heiferman, Jeffrey R.; Gounari, Fotini; Bentrem, David J.; Khazaie, Khashayarsha

    2016-01-01

    Objectives Lung cancer is the leading cause of cancer-related death in the USA. Regulatory T cells (Tregs) normally function to temper immune responses and decrease inflammation. Previous research has demonstrated different subsets of Tregs with contrasting anti- or pro-inflammatory properties. This study aimed to determine Treg subset distributions and characteristics present in non-small cell lung cancer (NSCLC) patients. Methods Peripheral blood was collected from healthy controls (HC) and NSCLC patients preceding surgical resection, and mononuclear cells were isolated, stained, and analyzed by flow cytometry. Tregs were defined by expression of CD4 and CD25 and classified into CD45RA+Foxp3int (naïve, Fr. I) or CD45RA−Foxp3hi (activated Fr. II). Activated conventional T cells were CD4+CD45RA−Foxp3int (Fr. III). Results Samples from 23 HC and 26 NSCLC patients were collected. Tregs isolated from patients with NSCLC were found to have enhanced suppressive function on naive T cells. Cancer patients had significantly increased frequencies of activated Tregs (fraction II: FrII), 17.5 versus 3.2 % (P < 0.001). FrII Tregs demonstrated increased RORγt and IL17 expression and decreased IL10 expression compared to Tregs from HC, indicating pro-inflammatory characteristics. Conclusions This study demonstrates that a novel subset of Tregs with pro-inflammatory characteristics preferentially expand in NSCLC patients. This Treg subset appears identical to previously reported pro-inflammatory Tregs in human colon cancer patients and in mouse models of polyposis. We expect the pro-inflammatory Tregs in lung cancer to contribute to the immune pathogenesis of disease and propose that targeting this Treg subset may have protective benefits in NSCLC. PMID:26047578

  12. Quality of Life After Stereotactic Radiotherapy for Stage I Non-Small-Cell Lung Cancer

    SciTech Connect

    Voort van Zyp, Noelle C. van der; Prevost, Jean-Briac; Holt, Bronno van der; Braat, Cora; Klaveren, Robertus J. van; Pattynama, Peter M.; Levendag, Peter C.; Nuyttens, Joost J.

    2010-05-01

    Purpose: To determine the impact of stereotactic radiotherapy on the quality of life of patients with inoperable early-stage non-small-cell lung cancer (NSCLC). Overall survival, local tumor control, and toxicity were also evaluated in this prospective study. Methods and Materials: From January 2006 to February 2008, quality of life, overall survival, and local tumor control were assessed in 39 patients with pathologically confirmed T1 to 2N0M0 NSCLC. These patients were treated with stereotactic radiotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 and the QLQ LC13 lung cancer-specific questionnaire were used to investigate changes in quality of life. Assessments were done before treatment, at 3 weeks, and at 2, 4, 6, 9, and 12 months after treatment, until death or progressive disease. Toxicity was evaluated using common terminology criteria for adverse events version 3.0. Results: Emotional functioning improved significantly after treatment. Other function scores and QLQ C30 and QLQ LC13 lung symptoms (such as dyspnea and coughing) showed no significant changes. The overall 2-year survival rate was 62%. After a median follow-up of 17 months, 1 patient had a local recurrence (3%). No grade 4 or 5 treatment-related toxicity occurred. Grade 3 toxicity consisted of thoracic pain, which occurred in 1 patient within 4 months of treatment, while it occurred thereafter in 2 patients. Conclusions: Quality of life was maintained, and emotional functioning improved significantly after stereotactic radiotherapy for stage I NSCLC, while survival was acceptable, local tumor control was high, and toxicity was low.

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

    PubMed

    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. PMID:25580271

  14. Predictive Factors of Late Radiation Fibrosis: A Prospective Study in Non-Small Cell Lung Cancer

    SciTech Connect

    Mazeron, Renaud; Etienne-Mastroianni, Benedicte; Perol, David; Arpin, Dominique; Vincent, Michel; Falchero, Lionel; Martel-Lafay, Isabelle; Carrie, Christian; Claude, Line

    2010-05-01

    Purpose: To determine predictive factors of late radiation fibrosis (RF) after conformal radiotherapy (3D-RT) in non-small cell lung cancer (NSCLC). Methods and Materials: Ninety-six patients with Stage IA-IIIB NSCLC were included in a prospective trial. Clinical evaluation, chest X-ray, and pulmonary functional tests including diffusion parameters were performed before and 6 months after radiotherapy. An independent panel of experts prospectively analyzed RF, using Late Effects in Normal Tissues-Subjective, Objective, Management and Analytic scales classification. Logistic regression analysis was performed to identify relationships between clinical, functional, or treatment parameters and incidence of RF. Variations of circulating serum levels of pro-inflammatory (interleukin-6, tumor necrosis factor alpha, tumor growth factor beta1) and anti-inflammatory (interleukin-10) cytokines during 3D-RT were examined to identify correlations with RF. Results: Of the 96 patients included, 72 were evaluable for RF at 6 months. Thirty-seven (51.4%) developed RF (Grade >=1), including six severe RF (Grades 2-3; 8.3%). In univariate analysis, only poor Karnofsky Performance Status and previous acute radiation pneumonitis were associated with RF (p < 0.05). Dosimetric factors (mean lung dose, percentage of lung volume receiving more than 10, 20, 30, 40, and 50 Gy) were highly correlated with RF (p < 0.001). In multivariate analysis, previous acute radiation pneumonitis and dosimetric parameters were significantly correlated with RF occurrence. It was not significantly correlated either with cytokines at baseline or with their variation during 3D-RT. Conclusions: This study confirms the importance of dosimetric parameters to limit the risk of RF. Contrary to acute radiation pneumonitis, RF was not correlated to cytokine variations during 3D-RT.

  15. Management and future directions in non-small cell lung cancer with known activating mutations.

    PubMed

    Gerber, David E; Gandhi, Leena; Costa, Daniel B

    2014-01-01

    Lung cancer accounts for a quarter of all cancer deaths. Non-small cell lung cancer (NSCLC) is currently segregated by the presence of actionable driver oncogenes. This review will provide an overview of molecular subsets of lung cancer, including descriptions of the defining oncogenes (EGFR, ALK, KRAS, ROS1, RET, BRAF, ERBB2, NTRK1, FGFR, among others) and how these predict for response to small molecule tyrosine kinase inhibitors (TKIs) that are either clinically available or in clinical trial development for advanced NSCLC. Particular focus will be placed on subsets with EGFR mutated and ALK rearranged NSCLC. Somatic TKI-sensitizing EGFR mutations (such as exon 19 deletions and L858R substitutions) are the most robust predictive biomarker for symptom improvement, radiographic response, and increment in progression-free survival (PFS) when EGFR TKIs (gefitinib, erlotinib, and afatinib) are used for patients with advanced NSCLC. However, the palliative benefits that EGFR TKIs afford are limited by multiple biologic mechanisms of tumor adaptation/resistance (such as the EGFR-T790M mutation and oncogene bypass tracks), and future efforts toward delaying, preventing, and treating resistance are underway. Similar to EGFR mutations, ALK rearrangements exemplify an oncogene-driven NSCLC that can be effectively palliated with a precision TKI therapy (the multitargeted ALK/MET/ROS1 TKI crizotinib). When resistance to first-line crizotinib therapy occurs, multiple second generation ALK TKIs have demonstrated impressive rates of disease control in clinical trials, and these may modify long-term outcomes for patients with ALK-positive NSCLC. The development of TKIs for other oncogene-driven NSCLCs may expand the portfolio of precision therapies for this recalcitrant cancer. PMID:24857124

  16. The Comparative Effectiveness of Surgery and Radiosurgery for Stage I Non-Small Cell Lung Cancer

    PubMed Central

    Yu, James B.; Soulos, Pamela R.; Cramer, Laura D.; Decker, Roy H.; Kim, Anthony W.; Gross, Cary P.

    2015-01-01

    Background Although surgery is the standard treatment for early stage non-small cell lung cancer (NSCLC), stereotactic body radiotherapy (SBRT) has disseminated as an alternative therapy. The comparative mortality and toxicity of these treatments for patients of different life expectancies (LE) are unknown. Methods Using the Surveillance, Epidemiology, and End Results–Medicare linked database, we identified patients age ≥67 who underwent SBRT or surgery for stage I NSCLC from 2007–2009. Matched patients were stratified into short (<5 years) and long (≥5 years) LE. Mortality and complication rates were compared using Poisson regression. Findings Overall, 367 SBRT and 711 surgery patients were matched. Acute toxicity (0–1-month) from SBRT was lower than surgery (7.9% vs. 54.9%, p<.001). At 24-months post-treatment, there was no difference (69.7% vs. 73.9%, p=.31). The incidence rate ratio (IRR) for toxicity for SBRT vs. surgery was 0.74 [95%CI 0.64–0.87]. Overall mortality was lower for SBRT than surgery at 3-months (2.2% vs. 6.1%; p=.005), but by 24-months, overall mortality was higher for SBRT (40.1% vs. 22.3% p<.001). For patients with short LE there was no difference in lung cancer mortality (IRR 1.01 [95% CI 0.40–2.56]). However for patients with long LE, there was greater overall mortality (IRR 1.49 [95% CI 1.11–2.01]) and a trend towards greater lung cancer mortality (IRR 1.63 [95% CI 0.95–2.79]) for SBRT vs. surgery. Conclusions SBRT was associated with lower immediate mortality and toxicity compared to surgery. However, for patients with long LE, there appears to be a relative benefit for surgery compared to SBRT. PMID:25847699

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

    SciTech Connect

    Hemstroem, Therese H.; Joseph, Bertrand; Schulte, Gunnar; Lewensohn, Rolf; Zhivotovsky, Boris . E-mail: Boris.Zhivotovsky@imm.ki.se

    2005-04-15

    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.

  18. Inequalities in non-small cell lung cancer treatment and mortality

    PubMed Central

    Nur, Ula; Quaresma, Manuela; De Stavola, Bianca; Peake, Michael; Rachet, Bernard

    2015-01-01

    Background Non-small cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, and surgery is the preferred treatment for patients. The National Health Service established Primary Care Trusts (PCTs) in 2002 to manage local health needs. We investigate whether PCTs with a lower uptake of surgical treatment are those with above-average mortality 1 year after diagnosis. The applied methods can be used to monitor the performance of any administrative bodies responsible for the management of patients with cancer. Methods All adults diagnosed with NSCLC lung cancer during 1998–2006 in England were identified. We fitted mixed effect logistic models to predict surgical treatment within 6 months after diagnosis, and mortality within 1 year of diagnosis. Results Around 10% of the NCSLC patients received curative surgery. Older deprived patients and those who did not receive surgery had much higher odds of death 1 year after being diagnosed with cancer. In total, 69% of the PCTs were below the lower control limit of surgery and have predicted random intercepts above the mean value of zero of the random effect for mortality, whereas 40% were above the upper control limit of mortality within 1 year. Conclusions Our main results suggest the presence of clear geographical variation in the use of surgical treatment of NSCLC and mortality. Mixed-effects models combined with the funnel plot approach were useful for assessing the performance of PCTs that were above average in mortality and below average in surgery. PMID:26047831

  19. Neoadjuvant intratumoral immuno-gene therapy for non-small cell lung cancer.

    PubMed

    Predina, Jarrod D; Keating, Jane; Venegas, Ollin; Nims, Sarah; Singhal, Sunil

    2016-04-01

    Non-small Cell Lung Cancer (NSCLC) remains a deadly disease despite aggressive treatment protocols which incorporate chemotherapy, radiation and surgery. These traditional approaches have reached a plateau in therapeutic benefit. There is emerging evidence suggesting that immunotherapy can serve as an alternative treatment modality for NSCLC. Our group has nearly two decades of experience involving immuno-gene therapy with Ad.hIFN-α and Ad.hIFN-β in human mesothelioma trials, and has observed both safety and efficacy in treatment of Thoracic malignancies. We have expanded the scope of our work and have obtained encouraging pre-clinical evidence suggesting a role for immunotherapy as a surgical adjuvant for NSCLC cancers. By combining immunotherapy with surgery, synergistic results have been observed. Based on these observations, we have prepared a Phase I Clinical Trial that pairs Ad.hIFN-α with surgery for patients with resectable NSCLC. Patient enrollment is likely to begin in the Summer of 2016. We hope that this trial will serve as a platform for future trials aimed at pairing immunotherapy with surgery for patients diagnosed with NSCLC. PMID:27232513

  20. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments

    PubMed Central

    Sullivan, Ivana; Planchard, David

    2016-01-01

    The treatment of patients with advanced non-small cell lung cancer (NSCLC) harbouring chromosomal rearrangements of ALK (anaplastic lymphoma kinase) was revolutionized by crizotinib, a small molecule inhibitor of ALK, ROS1 and MET. Unfortunately, the disease progressed within the first 12 months in most of the patients because of the development of crizotinib resistance in the majority of patients and the emergence of acquired resistance mutations in most of them. Many of them had been reported even before its approval leading to the rapid development of second-generation ALK inhibitors for crizotinib-resistant NSCLC. In the last few years, novel potent ALK inhibitors with promising results and a good toxicity profile have become available: ceritinib (LDK378), alectinib (RG7853/AF-802/RO5424802/CH5424802), brigatinib (AP26113), entrectinib (RXDX-101, NMS-E628), PF-06463922, ASP3026, TSR-011, X-376/X-396 and CEP-28122/CEP-37440. Moreover, HSP90 (90 kDa heat shock protein) inhibitors have demonstrated clinical activity in patients with ALK+ NSCLC. This review focuses on the molecular and clinical properties of this new generation of ALK inhibitors under development in the clinic. PMID:26753004

  1. CD47 Promotes Tumor Invasion and Metastasis in Non-small Cell Lung Cancer

    PubMed Central

    Zhao, Hui; Wang, Jianxin; Kong, Xiaodan; Li, Encheng; Liu, Yuanbin; Du, Xiaohui; Kang, Zhijie; Tang, Ying; Kuang, Yanbin; Yang, Zhihui; Zhou, Youwen; Wang, Qi

    2016-01-01

    CD47 is overexpressed in many human cancers, its level positively correlates with tumor invasion and metastasis. However, it is largely unknown whether CD47 overexpression drives metastasis and how CD47 lead to tumor metastasis in non-small cell lung cancer (NSCLC). In this study, we analyzed NSCLC specimens and cell lines, and revealed that CD47 is expressed at a higher level than in tumor-free control samples. Furthermore, increased CD47 expression correlated with clinical staging, lymph node metastasis and distant metastasis. In order to understand the molecular mechanisms underlying CD47 functions, we applied both gain-of-function and loss-of-function approaches in cell lines. The siRNA-mediated downregulation of CD47 inhibited cell invasion and metastasis in vitro, while the overexpression of CD47 by plasmid transfection generated opposite effects. In vivo, CD47-specific shRNA significantly reduced tumor growth and metastasis. On the molecular level, the expression of CD47 correlated with that of Cdc42, both in cell lines and NSCLC specimens. The inhibition of Cdc42 attenuates the invasion and metastasis of CD47-overexpressing cells. These results indicate that Cdc42 is a downstream mediator of CD47-promoted metastasis. Our findings provide first evidence that CD47 is an adverse prognostic factor for disease progression and metastasis, and a promising therapeutic target for NSCLC. PMID:27411490

  2. Quantitative Phosphoproteomic Profiling of Human Non-Small Cell Lung Cancer Tumors

    PubMed Central

    Schweppe, Devin K.; Rigas, James R.; Gerber, Scott A.

    2013-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Within the molecular scope of NCSLC, a complex landscape of dysregulated cellular signaling has emerged, defined largely by mutations in select mediators of signal transduction, including the epidermal growth factor receptor (EGFR) and anaplastic lymphoma (ALK) kinases. Consequently, these mutant kinases become constitutively activated and targets for chemotherapeutic intervention. Encouragingly, small molecule inhibitors of these pathways have shown promise in clinical trials or are approved for clinical use. However, many protein kinases are dysregulated in NSCLC without genetic mutations. To quantify differences in tumor cell signaling that are transparent to genomic methods, we established a super-SILAC internal standard derived from NSCLC cell lines grown in vitro and labeled with heavy lysine and arginine, and deployed them in a phosphoproteomics workflow. We identified 9019 and 8753 phosphorylation sites in two separate tumors. Relative quantification of phosphopeptide abundance between tumor samples allowed for the determination of specific hubs and pathways differing between each tumor. Sites downstream of Ras showed decreased inhibitory phosphorylation (Raf/Mek) and increased activating phosphorylation (Erk1/2) in one tumor versus another. In this way, we were able to quantitatively access oncogenic kinase signaling in primary human tumors. PMID:23911959

  3. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC)

    PubMed Central

    Hall, Richard D.; Le, Tri M.; Haggstrom, Daniel E.

    2015-01-01

    In many cancers, including non-small cell lung cancer (NSCLC), tumor angiogenesis pathways have been identified as important therapeutic targets. Angiogenesis is essential in the process of primary tumor growth, proliferation and metastasis. One of the best characterized group of protein factors for angiogenesis include the members of the vascular endothelial growth factor (VEGF) family, consisting of VEGF-(A-D), and placenta growth factor (PIGF). Targeting tumor angiogenesis has been approached through two primary methods, monoclonal antibodies that block VEGF-vascular endothelial growth factor receptor (VEGFR) binding or small molecule tyrosine kinase inhibitors (TKIs) that inhibit the downstream VEGFR mediated signaling. Many TKIs inhibit multiple pro-angiogenic and pro-proliferative pathways such as the mitogen activated protein (MAP) kinase pathway. Bevacizumab and ramucirumab, monoclonal antibodies targeting VEGF and the VEGFR, respectively, have each led to improvements in overall survival (OS) for NSCLC when added to standard first and second line chemotherapy, respectively. Small incremental gains seen with both bevacizumab and ramucirumab may be further improved upon by incorporating novel agents and treatment strategies, and many additional trials are ongoing. PMID:26629420

  4. Trends in the use of postoperative radiotherapy for resected non-small-cell lung cancer

    SciTech Connect

    Bekelman, Justin E. . E-mail: bekelmaj@mskcc.org; Rosenzweig, Kenneth E.; Bach, Peter B.; Schrag, Deborah

    2006-10-01

    Purpose: A 1998 meta-analysis of postoperative radiotherapy (PORT) for non-small-cell lung cancer (NSCLC) found that PORT did not improve outcomes. Yet practice guidelines differ in their recommendations with regard to PORT use. We examine temporal trends in PORT use before and after the 1998 meta-analysis. Methods and Materials: Using data from the Surveillance, Epidemiology, and End Results (SEER) Program, we identified 22,953 patients with Stage I, II, or IIIA NSCLC who had resection between 1992 and 2002 in the United States and characterized each patient according to nodal status (N0, N1, or N2 disease). We measured use of PORT by calendar year. We examined the association between clinical and demographic characteristics and receipt of PORT using logistic regression. Results: For N0, N1, and N2 NSCLC, PORT use has declined. The proportion of patients with N0 disease receiving PORT declined from 8% in 1992 to 4% in 2002. For patients with N1 disease, PORT use declined from 51% in 1992 to 19% in 2002; and for patients with N2 disease, PORT use declined from 65% in 1992 to 37% in 2002. Conclusion: In the context of uncertainty about what constitutes optimal adjuvant treatment for resected NSCLC, PORT use has substantially declined.

  5. Gemcitabine and carboplatin for patients with advanced non-small cell lung cancer.

    PubMed

    Dómine, M; Casado, V; Estévez, L G; León, A; Martin, J I; Castillo, M; Rubio, G; Lobo, F

    2001-06-01

    The survival of patients with advanced non-small cell lung cancer remains poor. Cisplatin-based chemotherapy produces a modest benefit in survival compared with that observed with best supportive care. Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN), a novel nucleoside antimetabolite, is active and well tolerated. The combination of gemcitabine/cisplatin has shown a significant improvement in response rate and survival over cisplatin alone. Phase III trials comparing gemcitabine/cisplatin with older combinations such as cisplatin/etoposide or mitomycin/ifosfamide/cisplatin have shown a higher activity for gemcitabine/cisplatin; however, the best way to combine these drugs remains unclear. In addition, the 3-week schedule has obtained a higher dose intensity with less toxicity and similar efficacy as the 4-week schedule. The role of carboplatin in combination with new drugs is still under evaluation. Gemcitabine/carboplatin seems to be a good alternative, with the advantage of ambulatory administration and lower nonhematologic toxicity. The 4-week schedule has produced frequent grade 3/4 neutropenia and thrombocytopenia in some studies. The 3-week schedule, using gemcitabine on days 1 and 8 and carboplatin on day 1, is a convenient and well-tolerated regimen. The toxicity profile is acceptable without serious symptoms. This schedule could be considered a good option as a standard regimen. Semin Oncol 28 (suppl 10):4-9. PMID:11510027

  6. Tumor Volume Is a Prognostic Factor in Non-Small-Cell Lung Cancer Treated With Chemoradiotherapy

    SciTech Connect

    Alexander, Brian M.; Othus, Megan; Caglar, Hale B.

    2011-04-01

    Purpose: To investigate whether primary tumor and nodal volumes defined on radiotherapy planning scans are correlated with outcome (survival and recurrence) after combined-modality treatment. Methods and Materials: A retrospective review of patients with Stage III non-small-cell lung cancer treated with chemoradiation at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2000 to 2006 was performed. Tumor and nodal volume measurements, as computed by Eclipse (Varian, Palo Alto, CA), were used as independent variables, along with existing clinical factors, in univariate and multivariate analyses for association with outcomes. Results: For patients treated with definitive chemoradiotherapy, both nodal volume (hazard ratio [HR], 1.09; p < 0.01) and tumor volume (HR, 1.03; p < 0.01) were associated with overall survival on multivariate analysis. Both nodal volume (HR, 1.10; p < 0.01) and tumor volume (HR, 1.04; p < 0.01) were also associated with local control but not distant metastases. Conclusions: In addition to traditional surgical staging variables, disease burden, measured by primary tumor and nodal metastases volume, provides information that may be helpful in determining prognosis and identifying groups of patients for which more aggressive local therapy is warranted.

  7. [RAdio-chemo-surgical combined treatment of non-small cell lung carcinoma N2].

    PubMed

    Rovea, P; Sola, B; Boidi Trotti, A; Gabriele, A M; Fracchia, F; Casadio, C; Bretti, S

    1993-06-01

    As yet, no optimal treatment for stage-IIIA non-small-cell lung cancer (NSCLC) has been established. Particularly, in the patients with stage-IIIA N2 disease, surgical resection for cure is limited to few selected patients. Of late, a number of studies have suggested that such treatment modalities as chemotherapy, radiotherapy and surgery might be combined to improve treatment efficacy. Based on these conclusions, a cooperative study for N2 NSCLC patients was performed. Treatment included continuous CDDP infusion (6 mg/m2/day) and concomitant irradiation. Fifteen patients were examined. After neoadjuvant treatment, 4 patients were found to have unresectable lesions for local disease progression or metastasis. Eleven patients underwent complete resection (73% resectability). Follow-up ranged 6 to 32 months: 6 patients are now free from relapse (respectively at 31, 28, 23, 14, 12 and 3 months) and 1 is alive with adrenal gland metastasis. Overall and disease-free survival rates are 40.6% and 31.5%, respectively. Our preliminary results indicated that this protocol is well tolerated. Resectability was good and tumor sterilization rate was satisfying (complete T and N sterilization in 6 cases, sterilization of either T or N in 3 cases). The patients with non-adenocarcinoma histology exhibited better local control and prognosis than those with histologic diagnosis of adenocarcinoma. PMID:8393206

  8. Nintedanib in non-small cell lung cancer: from preclinical to approval.

    PubMed

    Caglevic, Christian; Grassi, Massimiliano; Raez, Luis; Listi, Angela; Giallombardo, Marco; Bustamante, Eva; Gil-Bazo, Ignacio; Rolfo, Christian

    2015-08-01

    Angiogenesis is a driving force of a tumor's development. Targeting this process is an attractive option, as this is a feature shared by most of the solid tumors. A lot of antiangiogenic drugs have been developed following this path, including bevacizumab, sorafenib, sunitinib, vandetanib, ramucirumab, motesanib and many others. The latest drug of this class to be approved for patients with non-small cell lung cancer (NSCLC) was nintedanib, a triple angiokinase inhibitor. This molecule targets vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways, avoiding the tumor's switch to normal escape mechanisms. The pharmacokinetic, pharmacodynamic and toxicity profiles of nintedanib have been tested in several studies. These trials revealed it to be very interesting, as this agent did not lead to the classical adverse events of other tyrosine kinase inhibitors. A phase III clinical trial that recently concluded provided us with relevant information in patients with NSCLC of adenocarcinoma histology. Here we present a short overview of the tumor angiogenesis pathways and antiangiogenic drugs. In particular, we will focus on nintedanib, from the preclinical studies to the latest phase III clinical trial that allowed this new agent to be approved by the European Medicines Agency as a second-line treatment option in association with docetaxel for NSCLC patients with adenocarcinoma histology. PMID:25855060

  9. Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts

    PubMed Central

    Harder, Samantha J.; Isabelle, Martin; DeVorkin, Lindsay; Smazynski, Julian; Beckham, Wayne; Brolo, Alexandre G.; Lum, Julian J.; Jirasek, Andrew

    2016-01-01

    External beam radiation therapy is a standard form of treatment for numerous cancers. Despite this, there are no approved methods to account for patient specific radiation sensitivity. In this report, Raman spectroscopy (RS) was used to identify radiation-induced biochemical changes in human non-small cell lung cancer xenografts. Chemometric analysis revealed unique radiation-related Raman signatures that were specific to nucleic acid, lipid, protein and carbohydrate spectral features. Among these changes was a dramatic shift in the accumulation of glycogen spectral bands for doses of 5 or 15 Gy when compared to unirradiated tumours. When spatial mapping was applied in this analysis there was considerable variability as we found substantial intra- and inter-tumour heterogeneity in the distribution of glycogen and other RS spectral features. Collectively, these data provide unique insight into the biochemical response of tumours, irradiated in vivo, and demonstrate the utility of RS for detecting distinct radiobiological responses in human tumour xenografts. PMID:26883914

  10. Molecular targeted therapy to improve radiotherapeutic outcomes for non-small cell lung carcinoma

    PubMed Central

    Bhardwaj, Bhaskar; Bhardwaj, Himanshu; Balusu, Sree; Shwaiki, Ali

    2016-01-01

    Effective treatments for non-small cell lung carcinoma (NSCLC) remain elusive. The use of concurrent chemotherapy with radiotherapy (RT) has improved outcomes, but a significant proportion of NSCLC patients are too frail to be able to tolerate an intense course of concurrent chemoradiotherapy. The development of targeted therapies ignited new hope in enhancing radiotherapeutic outcomes. The use of targeted therapies against the epidermal growth factor receptor (EGFR) has offered slight but significant benefits in concurrent use with RT for certain patients in certain situations. However, despite theoretical promise, the use of anti-angiogenics, such as bevacizumab and endostatin, has not proven clinically safe or useful in combination with RT. However, many new targeted agents against new targets are being experimented for combined use with RT. It is hoped that these agents may provide a significant breakthrough in the radiotherapeutic management of NSCLC. The current review provides a brief discussion about the targets, the targeted therapies, the rationale for the use of targeted therapies in combination with RT, and a brief review of the existing data on the subject. PMID:26904572

  11. Time to Treatment in Patients With Stage III Non-Small Cell Lung Cancer

    SciTech Connect

    Wang Li; Correa, Candace R.; Hayman, James A.; Zhao Lujun; Cease, Kemp; Brenner, Dean; Arenberg, Doug; Curtis, Jeffery; Kalemkerian, Gregory P.; Kong, F.-M.

    2009-07-01

    Purpose: To determine whether time to treatment (TTT) has an effect on overall survival (OS) in patients with unresectable or medically inoperable Stage III non-small cell lung cancer (NSCLC) and whether patient or treatment factors are associated with TTT. Methods and Materials: Included in the study were 237 consecutive patients with Stage III NSCLC treated at University of Michigan Hospital (UM) or the Veterans Affairs Ann Arbor Healthcare System (VA). Patients were treated with either palliative or definitive radiotherapy and radiotherapy alone (n = 106) or either sequential (n = 69) or concurrent chemoradiation (n = 62). The primary endpoint was OS. Results: Median follow-up was 69 months, and median TTT was 57 days. On univariate analysis, the risk of death did not increase significantly with longer TTT (p = 0.093). However, subset analysis showed that there was a higher risk of death with longer TTT in patients who survived {>=} 5 years (p = 0.029). Younger age (p = 0.027), male sex (p = 0.013), lower Karnofsky Performance Score (KPS) (p = 0.002), and treatment at the VA (p = 0.001) were significantly associated with longer TTT. However, on multivariate analysis, only lower KPS remained significantly associated with longer TTT (p = 0.003). Conclusion: Time to treatment is significantly associated with OS in patients with Stage III NSCLC who lived longer than 5 years, although it is not a significant factor in Stage III patients as a whole. Lower KPS is associated with longer TTT.

  12. Proteasome Inhibitors Block DNA Repair and Radiosensitize Non-Small Cell Lung Cancer

    PubMed Central

    Kushwaha, Deepa S.; Hsieh, Grace; Merzon, Dmitry; Rameseder, Jonathan; Chen, Clark C.; D’Andrea, Alan D.; Kozono, David

    2013-01-01

    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. PMID:24040035

  13. Sp1 transcriptionally regulates BRK1 expression in non-small cell lung cancer cells.

    PubMed

    Li, Meng; Ling, Bing; Xiao, Ting; Tan, Jinjing; An, Ning; Han, Naijun; Guo, Suping; Cheng, Shujun; Zhang, Kaitai

    2014-06-01

    Following a previous study reporting that BRK1 is upregulated in non-small cell lung cancer (NSCLC), the present study sought to clarify the role of specificity protein 1 (Sp1) in the transcriptional regulation of the BRK1 gene. Therefore, a construct, named F8, consisting of the -1341 to -1 nt sequence upstream of the start codon of the BRK1 gene inserted into pGL4.26 was made. A series of truncated fragments was then constructed based on F8. Segment S831, which contained the -84 to -1 nt region, displayed the highest transcriptional activity in the A549, H1299 and H520 NSCLC cell lines. Bioinformatic analysis showed a potential Sp1-binding element at -73 to -64 nt, and a mutation in this region suppressed the transcriptional activity of S831. Then the RNAi assays of Sp1 and its coworkers Sp3 and Sp4 were performed, and suppression of Sp1 by siRNA inhibited the mRNA expression of BRK1. Both an electrophoretic mobility shift assay (EMSA) and a chromatin immunoprecipitation (ChIP) assay demonstrated that Sp1 bound to the promoter area of the BRK1 gene. Our data identified a functional and positive Sp1 regulatory element from -73 to -64 nt in the BRK1 promoter, which may likely explain the overexpression of BRK1 in NSCLC. PMID:24680773

  14. The prognostic significance of fibroblast growth factor receptor 4 in non-small-cell lung cancer

    PubMed Central

    Huang, Hong-ping; Feng, Hui; Qiao, Hong-bo; Ren, Ze-xiang; Zhu, Ge-dong

    2015-01-01

    Background Fibroblast growth factor receptor 4 (FGFR4) has been proved to be correlated with progression and prognosis in many cancers. However, the significance of FGFR4 in non-small-cell lung cancer (NSCLC) is still not well elucidated. Methods In our experiment, we detected FGFR4 expression in 237 samples of NSCLC with immunohistochemistry, and further analyzed the correlation between FGFR4 and clinicopathologic features of NSCLC with chi-square test. Moreover, we evaluated the prognostic value of FGFR4 by Kaplan–Meier survival curve and Cox regression model. By regulating the expression of FGFR4 by overexpression or knockdown, we assessed the role of FGFR4 on NSCLC cell proliferation. Results FGFR4 expression was high in NSCLC (46.8%, 111/237). FGFR4 expression was significantly associated with tumor diameter (P=0.039). With univariate (P=0.009) and multivariate (P=0.002) analysis, FGFR4 was identified as an independent prognostic factor in NSCLC (P=0.009). Moreover, FGFR4 can promote the proliferation of NSCLC cell lines. Conclusion FGFR4 is an independent prognostic biomarker in NSCLC. FGFR4 can accelerate the proliferation of NSCLC cell lines, indicating FGFR4 could be a potential drug target of NSCLC. PMID:26045670

  15. Magnolol induces apoptosis via caspase-independent pathways in non-small cell lung cancer cells.

    PubMed

    Tsai, Jong-Rung; Chong, Inn-Wen; Chen, Yung-Hsiang; Hwang, Jhi-Jhu; Yin, Wei-Hsian; Chen, Hsiu-Lin; Chou, Shah-Hwa; Chiu, Chien-Chih; Liu, Po-Len

    2014-04-01

    Magnolol, a hydroxylated biphenyl agent isolated from herbal planet Magnolia officinalis, is a component of traditional Asian herbal teas. It has been reported to have anti-microbial, anti-inflammatory, and anti-cancer activity. Non-small cell lung cancer (NSCLC) cell lines (A549, H441 and H520) and normal human bronchial epithelial cells (HBECs) were used to evaluate the cytotoxic effect of magnolol. We show that magnolol inhibited cellular proliferation, increased DNA fragmentation, and decreased mitochondrial membrane potential in all NSCLC cells, but had no cytotoxic effect on HBECs. Magnolol triggered the release of pro-apoptotic proteins: Bid, Bax and cytochrome c from mitochondria, but did not activate the caspase-3, -8, and -9, suggesting that magnolol induces apoptosis of NSCLC cell lines via a caspase-independent pathway. The caspase-independent pathway is mediated through the activation of nuclear translocation of apoptosis-inducing factor, endonuclease G and cleaved poly(ADP-ribose) polymerase, which played important roles in mediating cell death. Furthermore, magnolol inhibited PI3K/AKT and ERK1/2 activity, but up-regulated p38 and JNK activity in A549 cell lines. The results of this study provided a basis for understanding and developing magnolol as a novel treatment of NSCLC. PMID:23943503

  16. IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer.

    PubMed

    Ibanez de Caceres, I; Cortes-Sempere, M; Moratilla, C; Machado-Pinilla, R; Rodriguez-Fanjul, V; Manguán-García, C; Cejas, P; López-Ríos, F; Paz-Ares, L; de CastroCarpeño, J; Nistal, M; Belda-Iniesta, C; Perona, R

    2010-03-18

    Cisplatin-based chemotherapy is the paradigm of non-small-cell lung cancer (NSCLC) treatment; however, it also induces de novo DNA-hypermethylation, a process that may be involved in the development of drug-resistant phenotypes by inactivating genes required for drug-cytotoxicity. By using an expression microarray analysis, we aimed to identify those genes reactivated in a set of two cisplatin (CDDP) resistant and sensitive NSCLC cell lines after epigenetic treatment. Gene expression, promoter methylation and CDDP-chemoresponse were further analyzed in three matched sets of sensitive/resistant cell lines, 23 human cancer cell lines and 36 NSCLC specimens. Results revealed specific silencing by promoter hypermethylation of IGFBP-3 in CDDP resistant cells, whereas IGFBP-3 siRNA interference, induced resistance to CDDP in sensitive cells (P<0.001). In addition, we found a strong correlation between methylation status and CDDP response in tumor specimens (P<0.001). Thus, stage I patients, whose tumors harbor an unmethylated promoter, had a trend towards increased disease-free survival (DFS). We report that a loss of IGFBP-3 expression, mediated by promoter-hypermethylation, results in a reduction of tumor cell sensitivity to cisplatin in NSCLC. Basal methylation status of IGFBP-3 before treatment may be a clinical biomarker and a predictor of the chemotherapy outcome, helping to identify patients who are most likely to benefit from CDDP therapy alone or in combination with epigenetic treatment. PMID:20023704

  17. Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

    PubMed Central

    Melosky, B.; Agulnik, J.; Albadine, R.; Banerji, S.; Bebb, D.G.; Bethune, D.; Blais, N.; Butts, C.; Cheema, P.; Cheung, P.; Cohen, V.; Deschenes, J.; Ionescu, D.N.; Juergens, R.; Kamel-Reid, S.; Laurie, S.A.; Liu, G.; Morzycki, W.; Tsao, M.S.; Xu, Z.; Hirsh, V.

    2016-01-01

    Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered. PMID:27330348

  18. Targeted therapy using novel agents in the treatment of non-small-cell lung cancer.

    PubMed

    Herbst, Roy S

    2002-03-01

    Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and high mortality. The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau. The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC. The anti-epidermal growth factor receptor (EGFR) group contains trastuzumab and IMC-C225, monoclonal antibodies against EGFRs that are overexpressed in many cancers. OSI-774 and ZD1839 are inhibitors of EGFR tyrosine kinase, a key enzyme of the signaling pathway. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumor activity. Antiangiogenesis agents that have shown promise include TNP-470, recombinant endostatin, and angiostatin. Antibodies to vascular endothelial growth factor (VEGF) also seem to control tumor progression and may prolong survival. LY317615, an inhibitor of protein kinase Cb, augmented the tumor growth delay produced by cytotoxic drugs. All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs. These new agents are more target specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC. PMID:14720353

  19. Clinical potential of necitumumab in non-small cell lung carcinoma

    PubMed Central

    Genova, Carlo; Hirsch, Fred R

    2016-01-01

    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. PMID:27621656

  20. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer

    PubMed Central

    Lee, Christian C.; Gainor, Justin F.; Crystal, Adam S.; Michellys, Pierre-Yves; Awad, Mark M.; Yanagitani, Noriko; Kim, Sungjoon; Pferdekamper, AnneMarie C.; Li, Jie; Kasibhatla, Shailaja; Sun, Frank; Sun, Xiuying; Hua, Su; McNamara, Peter; Mahmood, Sidra; Lockerman, Elizabeth L.; Fujita, Naoya; Nishio, Makoto; Harris, Jennifer L.; Shaw, Alice T.; Engelman, Jeffrey A.

    2014-01-01

    Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378) in the setting of crizotinib resistance. Interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of crizotinib-resistant NSCLC patients revealed that ceritinib potently overcomes crizotinib resistance mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations were identified in 5 out of 11 biopsies from patients with acquired resistance to ceritinib. Altogether our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease. PMID:24675041

  1. Current status of immunotherapy for non-small-cell lung cancer.

    PubMed

    Imbimbo, Martina; Lo Russo, Giuseppe; Blackhall, Fiona

    2016-08-01

    In the last few years, the introduction of novel immunotherapeutic agents has represented a treatment shift for a subset of patients with non-small-cell lung cancer (NSCLC). Checkpoint inhibitors have been demonstrated to improve survival in advanced stage disease with very good tolerability. This success follows many years of scientific effort to manipulate the human immune system to attack cancer cells. With a variety of approaches ranging from vaccines to administration of interleukin or interferon-γ, the results in NSCLC were unsuccessful, with the view that it is a scarcely immunogenic cancer, unlike melanoma or renal cell carcinoma. The step change has come from understanding of immune checkpoints-cell surface molecules that regulate immune system activation and mediate coinhibitory signaling pathways that physiologically protect the body from autoimmunity. These pathways play an important role in tumors, including NSCLC, and are a mechanism of escape from immune surveillance. Several monoclonal antibodies have been developed in order to inhibit these molecules and unleash the brakes of the immune system. Currently in NSCLC, 7 different checkpoint inhibitors are under investigation: 2 anti-cytotoxic T-lymphocyte-associated antigen 4, 2 anti-programmed death (PD)-1, and 3 anti-PD-ligand 1 antibodies. Here we review the progress to date in developing immunotherapy for NSCLC, summarize results from published trials, highlight ongoing trials, and discuss progress in the question of how best to select patients for this treatment. PMID:27443896

  2. Targeted Therapies in Non-Small Cell Lung Cancer—Beyond EGFR and ALK

    PubMed Central

    Rothschild, Sacha I.

    2015-01-01

    Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called “driver mutations”) for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed. PMID:26018876

  3. Stereotactic radiotherapy for early stage non-small cell lung cancer

    PubMed Central

    Badellino, Serena; Filippi, Andrea Riccardo

    2015-01-01

    Stereotactic body radiotherapy (SBRT) represents a consolidated treatment option for patients with medically inoperable early stage non-small cell lung cancer (NSCLC). The clinical evidence accumulated in the past decade supports its use as an alternative to surgery with comparable survival outcomes. Due to its limited toxicity, SBRT is also applicable to elderly patients with very poor baseline pulmonary function or other severe comorbidities. Recent comparative studies in operable patients raised the issue of the possible use of SBRT also for this subgroup, with quite promising results that still should be fully confirmed by prospective trials with long-term follow-up. Aim of this review is to summarize and discuss the major studies conducted over the years on SBRT and to provide data on the efficacy and toxicity of this radiotherapy technique for stage I NSCLC. Technical aspects and quality of life related issues are also discussed, with the goal to provide information on the current role and limitations of SBRT in clinical practice. PMID:26157674

  4. AZD9291 in EGFR-mutant advanced non-small-cell lung cancer patients.

    PubMed

    Remon, Jordi; Planchard, David

    2015-11-01

    Non-small-cell lung cancer (NSCLC) patients whose tumors have an EGFR-activating mutation develop acquired resistance after a median of 9-11 months from the beginning of treatment with erlotinib, gefitinib and afatinib. T790M mutation is the cause of this resistance in approximately 60% of cases. AZD9291 is an oral, irreversible, mutant-selective EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) developed to have potency against EGFR mutations, including T790M mutation, while sparing wild-type EGFR. A Phase I trial of AZD9291 in EGFR-mutant NSCLC patients, demonstrated high activity, essentially among T790M-mutant tumors, with a manageable tolerability profile. Ongoing Phase III trials are evaluating AZD9291 in EGFR-mutant patients as first-line treatment compared with erlotinib and gefitinib; and as second-line treatment compared with chemotherapy after progression on EGFR TKI in T790M-mutant tumors. Better identification of T790M-mutant tumors post EGFR TKI relapse and mechanisms of resistance to AZD9291 are the future challenges. This article reviews the emerging data regarding AZD9291 in the treatment of patients with advanced NSCLC. PMID:26450446

  5. Curcumin lowers erlotinib resistance in non-small cell lung carcinoma cells with mutated EGF receptor.

    PubMed

    Li, Shanqun; Liu, Zilong; Zhu, Fen; Fan, Xiaohong; Wu, Xiaodan; Zhao, Heng; Jiang, Liyan

    2013-01-01

    Non-small cell lung cancer (NSCLC) patients with activating mutations in the epidermal growth factor receptor (EGFR) are responsive to erlotinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of curcumin on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation was determined by MTT assay. Apoptosis was examined using TUNEL staining. Protein expression of genes was determined by Western blot. Tumor growth was assessed in a xenograft mouse model. Results showed that erlotinib had a stronger effect on the induction of apoptosis in erlotinib-sensitive PC-9 cells but showed a weaker effect on erlotinib-resistant H1975 and H1650 cells than cisplatin and curcumin. Furthermore, curcumin significantly increased the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, enhanced erlotinib-induced apoptosis, downregulated the expressions of EGFR, p-EGFR, and survivin, and inhibited the NF-κB activation in erlotinib-resistant NSCLC cells. The combination of curcumin and erlotinib exhibited the same effects on apoptosis as the combination of curcumin and cisplatin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of curcumin and erlotinib significantly inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that curcumin is a potential adjuvant for NSCLC patients during erlotinib treatment. PMID:24512728

  6. Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer

    PubMed Central

    Xie, Caifeng; Jin, Jiangbo; Bao, Xujie; Zhan, Wei-Hua; Han, Tian-Yu; Gan, Mingxi; Zhang, Chengfu; Wang, Jianbin

    2016-01-01

    The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has been approved based on the clinical benefit in non-small cell lung cancer (NSCLC) patients over the past decade. Unfortunately, cancer cells become resistant to this agent via various mechanisms, and this limits the improvement in patient outcomes. Thus, it is urgent to develop novel agents to overcome erlotinib resistance. Here, we propose a novel strategy to overcome acquired erlotinib resistance in NSCLC by inhibiting glutaminase activity. Compound 968, an inhibitor of the glutaminase C (GAC), when combined with erlotinib potently inhibited the cell proliferation of erlotinib-resistant NSCLC cells HCC827ER and NCI-H1975. The combination of compound 968 and erlotinib not only decreased GAC and EGFR protein expression but also inhibited GAC activity in HCC827ER cells. The growth of erlotinib-resistant cells was glutamine-dependent as proved by GAC gene knocked down and rescue experiment. More importantly, compound 968 combined with erlotinib down-regulated the glutamine and glycolysis metabolism in erlotinib-resistant cells. Taken together, our study provides a valuable approach to overcome acquired erlotinib resistance by blocking glutamine metabolism and suggests that combination of EGFR-TKI and GAC inhibitor maybe a potential treatment strategy for acquired erlotinib-resistant NSCLC. PMID:26575584

  7. EGFR fluorescence in situ hybridisation assay: guidelines for application to non-small-cell lung cancer.

    PubMed

    Varella-Garcia, M; Diebold, J; Eberhard, D A; Geenen, K; Hirschmann, A; Kockx, M; Nagelmeier, I; Rüschoff, J; Schmitt, M; Arbogast, S; Cappuzzo, F

    2009-11-01

    There is a need for predictive biomarkers that identify non-small-cell lung cancer (NSCLC) patients most likely to respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. There are numerous potential candidates, although none has been proven in prospective clinical trials. The EGFR gene copy number evaluated by fluorescence in situ hybridisation (FISH) has been highlighted as one of the most effective markers for sensitivity to EGFR TKIs in large phase III, randomised placebo-controlled trials and has been used in clinical settings to assist physicians in defining the therapeutic regimen. The EGFR FISH assay has technical challenges and it is critical that detailed guidelines are provided to help clinical laboratories in performing and interpreting the test. Excellent assay reproducibility and portability rates among laboratories are crucial to guarantee that accurate clinical decisions can be made for patients with NSCLC. This article discusses the consensus outcomes of a global workshop convened to discuss key technical issues and standardise reading strategies for the EGFR FISH assay of NSCLC tumour tissue. PMID:19861557

  8. Selenium-containing thioredoxin reductase inhibitor ethaselen sensitizes non-small cell lung cancer to radiotherapy.

    PubMed

    Wang, Lei; Fu, Jia-Ning; Wang, Jing-Yu; Jin, Cun-Jing; Ren, Xiao-Yuan; Tan, Qiang; Li, Jing; Yin, Han-Wei; Xiong, Kun; Wang, Tian-Yu; Liu, Xin-Min; Zeng, Hui-Hui

    2011-09-01

    It has been proposed that thioredoxin reductase (TR) is a mediator that allows non-small cell lung cancer (NSCLC) to develop resistance to irradiation; however, little is known regarding the detailed mechanisms of action. Thus, ethaselen {1, 2-[bis (1,2-benzisoselenazolone-3 (2H)-ketone)] ethane, BBSKE}, a novel organoselenium TR inhibitor, is currently being investigated in a phase I clinical trial in China. However, its radiosensitizing effect remains unexplored. In this study, we found that the activity of TR increased dramatically in both A549 and H1299 cells after radiation, and moreover, could be inhibited by pretreatment with BBSKE (5 μmol/l). As a TR inhibitor, BBSKE enhanced the efficacy of radiation therapy both in vivo and in vitro without observable toxicity. BBSKE was found to suppress irradiation-induced NF-κB activation dramatically when using A549 cells stably transfected with NF-κB luciferase reporter. These results show the critical role of TR in the radioresistance of NSCLC and suggest that BBSKE is a potentially promising agent for the treatment of patients with NSCLC clinically. PMID:21562407

  9. Immunotherapy in non-small cell lung cancer: the clinical impact of immune response and targeting

    PubMed Central

    Linardou, Helena; Kosmidis, Paris

    2016-01-01

    Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. In recent years, through a better understanding of the interactions between the immune system and tumor cells (TC), immunotherapy has emerged as a promising therapeutic strategy. Chemotherapy has long been reported to interfere with the immune response to the tumor and conversely, anti-tumor immunity may add to those effects. Anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, tumor cell vaccines and dendritic cell (DC) vaccines emerged as potent inducers of the immune response against the tumor. More recently the approval of the anti-programmed cell death 1 (anti-PD-1) monoclonal antibodies nivolumab and pembrolizumab for previously treated advanced squamous and non-squamous NSCLC, as well as other immune checkpoint inhibitors delivering promising results, has radically transformed the therapeutic landscape of NSCLC. Combination strategies now appear as the next step. Notwithstanding these successes, immunotherapy still holds significant drawbacks and currently several improvements are needed before routine use in clinical practice, including identification of robust biomarkers for optimal patient selection, as well as defining the best way to evaluate response. PMID:27563655

  10. Estimation of prognosis by circulating biomarkers in patients with non-small cell lung cancer.

    PubMed

    Holdenrieder, Stefan; Nagel, Dorothea; Stieber, Petra

    2010-01-01

    Prognostic information on the course of cancer disease is highly relevant for the accurate decision of the most effective treatment strategy for an individual patient. In early stage disease, the application of adjuvant chemo- or radiotherapy after surgery depends on the risk of the patient to early suffer from tumor recurrence. In advanced stage disease, risk stratification of the patients influences the choice of more aggressive or mild therapy alternatives. Besides tumor related parameters like tumor stage and individual factors, additional information by biomarkers is needed to better characterize patients prognosis in both situations. Although there are plenty of studies dealing on the prognostic relevance of diverse biomarkers in non-small cell lung cancer (NSCLC), the results are quite heterogeneous and sometimes conflicting. Reasons for this situation may be found in the design, the performance, the evaluation and the quality of result reporting of the studies. In this review, we focus on the prerequisites of informative prognostic trials, spot on the general shortcomings of studies published so far, and summarize the results of the prognostic studies available for early and advanced stages of NSCLC. PMID:20660963

  11. Immune modulation as a therapeutic strategy for non-small-cell lung cancer.

    PubMed

    Holt, Gregory E; Disis, Mary L

    2008-02-01

    Active tumor immunotherapy may provide hope for patients with non-small-cell lung cancer (NSCLC) because, in more than 20 years, current therapies have yet to change mortality statistics. Creating an efficacious vaccine involves selection of important tumor antigens and formulation of their immunogenic epitopes into a construct for delivery to antigen-presenting cells. The method of immunization will confer significant properties to the potency of the vaccine and might require augmentation with certain adjuvant agents like interleukin-12 and granulocyte-macrophage colony-stimulating factor. So far, clinical trials in NSCLC immunotherapy have shown promise with the Induction of Immune responses and the presence of clinical responses compared with historical controls treated with standard therapy. Immunotherapy could merge seamlessly into the current standard of care for NSCLC with the emergence of data supporting a beneficial role of chemotherapy and radiation in the production of antitumor immune responses. With continued work in this field, active immunotherapy may provide the necessary therapy for the successful treatment of this common disease. PMID:18540530

  12. Biopsy and Mutation Detection Strategies in Non-Small Cell Lung Cancer

    PubMed Central

    2013-01-01

    The emergence of new therapeutic agents for non-small cell lung cancer (NSCLC) implies that histologic subtyping and molecular predictive testing are now essential for therapeutic decisions. Histologic subtype predicts the efficacy and toxicity of some treatment agents, as do genetic alterations, which can be important predictive factors in treatment selection. Molecular markers, such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement, are the best predictors of response to specific tyrosine kinase inhibitor treatment agents. As the majority of patients with NSCLC present with unresectable disease, it is therefore crucial to optimize the use of tissue samples for diagnostic and predictive examinations, particularly for small biopsy and cytology specimens. Therefore, each institution needs to develop a diagnostic approach requiring close communication between the pulmonologist, radiologist, pathologist, and oncologist in order to preserve sufficient biopsy materials for molecular analysis as well as to ensure rapid diagnosis. Currently, personalized medicine in NSCLC is based on the histologic subtype and molecular status. This review summarizes strategies for tissue acquisition, histologic subtyping and molecular analysis for predictive testing in NSCLC. PMID:24348665

  13. Clinical Utility of Circulating Tumor Cells in ALK-Positive Non-Small-Cell Lung Cancer

    PubMed Central

    Faugeroux, Vincent; Pailler, Emma; Auger, Nathalie; Taylor, Melissa; Farace, Françoise

    2014-01-01

    The advent of rationally targeted therapies such as small-molecule tyrosine kinase inhibitors (TKIs) has considerably transformed the therapeutic management of a subset of patients with non-small-cell lung cancer (NSCLC) harboring defined molecular abnormalities. When such genetic molecular alterations are detected the use of specific TKI has demonstrated better results (overall response rate, progression free survival) compared to systemic therapy. However, the detection of such molecular abnormalities is complicated by the difficulty in obtaining sufficient tumor material, in terms of quantity and quality, from a biopsy. Here, we described how circulating tumor cells (CTCs) can have a clinical utility in anaplastic lymphoma kinase (ALK) positive NSCLC patients to diagnose ALK-EML4 gene rearrangement and to guide therapeutic management of these patients. The ability to detect genetic abnormalities such ALK rearrangement in CTCs shows that these cells could offer new perspectives both for the diagnosis and the monitoring of ALK-positive patients eligible for treatment with ALK inhibitors. PMID:25414829

  14. Clinical Utility of Circulating Tumor Cells in ALK-Positive Non-Small-Cell Lung Cancer.

    PubMed

    Faugeroux, Vincent; Pailler, Emma; Auger, Nathalie; Taylor, Melissa; Farace, Françoise

    2014-01-01

    The advent of rationally targeted therapies such as small-molecule tyrosine kinase inhibitors (TKIs) has considerably transformed the therapeutic management of a subset of patients with non-small-cell lung cancer (NSCLC) harboring defined molecular abnormalities. When such genetic molecular alterations are detected the use of specific TKI has demonstrated better results (overall response rate, progression free survival) compared to systemic therapy. However, the detection of such molecular abnormalities is complicated by the difficulty in obtaining sufficient tumor material, in terms of quantity and quality, from a biopsy. Here, we described how circulating tumor cells (CTCs) can have a clinical utility in anaplastic lymphoma kinase (ALK) positive NSCLC patients to diagnose ALK-EML4 gene rearrangement and to guide therapeutic management of these patients. The ability to detect genetic abnormalities such ALK rearrangement in CTCs shows that these cells could offer new perspectives both for the diagnosis and the monitoring of ALK-positive patients eligible for treatment with ALK inhibitors. PMID:25414829

  15. Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer.

    PubMed

    Melosky, B; Agulnik, J; Albadine, R; Banerji, S; Bebb, D G; Bethune, D; Blais, N; Butts, C; Cheema, P; Cheung, P; Cohen, V; Deschenes, J; Ionescu, D N; Juergens, R; Kamel-Reid, S; Laurie, S A; Liu, G; Morzycki, W; Tsao, M S; Xu, Z; Hirsh, V

    2016-06-01

    Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered. PMID:27330348

  16. Targeted therapy for localized non-small-cell lung cancer: a review

    PubMed Central

    Paleiron, Nicolas; Bylicki, Olivier; André, Michel; Rivière, Emilie; Grassin, Frederic; Robinet, Gilles; Chouaïd, Christos

    2016-01-01

    Targeted therapies have markedly improved the management of patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy in localized NSCLC is less well established. The aim of this review is to analyze trials of targeted therapies in localized NSCLC. In patients with wild-type EGFR, tyrosine kinase inhibitors have shown no efficacy in Phase III trials. Few data are available for EGFR-mutated localized NSCLC, as routine biological profiling is not recommended. Available studies are small, often retrospectives, and/or conducted in a single-center making it difficult to draw firm conclusions. Ongoing prospective Phase III trials are comparing adjuvant tyrosine kinase inhibitor administration versus adjuvant chemotherapy. By analogy with the indication of bevacizumab in advanced NSCLC, use of antiangiogenic agents in the perioperative setting is currently restricted to nonsquamous NSCLC. Several trials of adjuvant or neoadjuvant bevacizumab are planned or ongoing, but for the moment there is no evidence of efficacy. Data on perioperative use of biomarkers in early-stage NSCLC come mainly from small, retrospective, uncontrolled studies. Assessment of customized adjuvant or neoadjuvant therapy in localized NSCLC (with or without oncogenic driver mutations) is a major challenge. PMID:27462164

  17. Monitoring drug induced apoptosis and treatment sensitivity in non-small cell lung carcinoma using dielectrophoresis.

    PubMed

    Taruvai Kalyana Kumar, Rajeshwari; Liu, Shanshan; Minna, John D; Prasad, Shalini

    2016-09-01

    Non-invasive real time methods for characterizing biomolecular events that contribute towards apoptotic kinetics would be of significant importance in the field of cancer biology. Effective drug-induced apoptosis is an important factor for establishing the relationship between cancer genetics and treatment sensitivity. The objective of this study was to develop a non-invasive technique to characterize cancer cells that are undergoing drug-induced apoptosis. We used dielectrophoresis to determine apoptotic cells as early as 2h post drug treatment as compared to 24h with standard flow cytometry method using non-small cell lung cancer (NSCLC) adenocarcinoma cell line (HCC1833) as a study model. Our studies have shown significant differences in apoptotic cells by chromatin condensation, formation of apoptotic bodies and exposure of phosphatidylserine (PS) on the extracellular surface when the cells where treated with a potent Bcl-2 family inhibitor drug (ABT-263). Time lapse dielectrophoretic studies were performed over 24h period after exposure to ABT-263 at clinically relevant concentrations. The dielectrophoretic studies were compared to Annexin-V FITC flow assay for the detection of PS in mid-stage apoptosis using flow cytometry. As a result of physical and biochemical changes, inherent dielectric properties of cells undergoing varying stages of apoptosis showed amplified changes in their cytoplasmic and membrane capacitance. In addition, zeta potential of these fixed isolated cells was measured to obtain direct correlation to biomolecular events. PMID:27262539

  18. Adoptive immunotherapy combined chemoradiotherapy for non-small-cell lung cancer: a meta-analysis.

    PubMed

    Qian, Haili; Wang, Haijuan; Guan, Xiuwen; Yi, Zongbi; Ma, Fei

    2016-06-01

    The aim of this study was to compare the efficacies between adoptive immunotherapy combined chemoradiotherapy and chemoradiotherapy alone in patients with non-small-cell lung cancer (NSCLC). The databases PubMed, EMBASE, and Cochrane database were searched to identify eligible clinical trials. Data analyses were carried out using a comprehensive meta-analysis program, version 2 software. A total of seven articles were finally included in the analysis. Meta-analyses showed that compared with chemoradiotherapy alone, adoptive immunotherapy combined with chemoradiotherapy could improve the 2-year overall survival [odds ratio (OR)=2.45, 95% confidence interval (CI): 1.60-3.75, P<0.001], but not 2-year progression-free survival (OR=1.81, 95% CI: 0.61-5.36, P=0.284). Specifically, early (OR=3.32, 95% CI: 1.38-7.95, P<0.01) but not advanced (OR=3.75, 95% CI: 0.96-14.68, P=0.057) NSCLC patients were likely to gain a large benefit from the adoptive immunotherapy. Most of the adoptive immunotherapy-induced adverse effects were self-limited, mainly including fever, shiver, nausea, fatigue, etc. and severe toxicities were not observed. Adoptive immunotherapy combined with chemoradiotherapy can delay the recurrence of NSCLC and improve survival in patients, where the benefits are even more significant in patients with early-stage NSCLC. PMID:26872311

  19. Dependence on the MUC1-C Oncoprotein in Non-Small Cell Lung Cancer Cells

    PubMed Central

    Raina, Deepak; Kosugi, Michio; Ahmad, Rehan; Panchamoorthy, Govind; Rajabi, Hasan; Alam, Maroof; Shimamura, Takeshi; Shapiro, Geoffrey I.; Supko, Jeffrey; Kharbanda, Surender; Kufe, Donald

    2011-01-01

    Non-small cell lung cancer (NSCLC) cells are often associated with constitutive activation of the phosphatidylinositol 3-kinase (PI3K)->Akt->mTOR pathway. The mucin 1 (MUC1) heterodimeric glycoprotein is aberrantly overexpressed in NSCLC and induces gene signatures that are associated with poor survival of NSCLC patients. The present results demonstrate that the MUC1 C-terminal subunit (MUC1-C) cytoplasmic domain associates with PI3K p85 in NSCLC cells. We show that inhibition of MUC1-C with cell-penetrating peptides blocks this interaction with PI3K p85 and suppresses constitutive phosphorylation of Akt and its downstream effector, mTOR. In concert with these results, treatment of NSCLC cells with the MUC1-C peptide inhibitor, GO-203, was associated with downregulation of PI3K->Akt signaling and inhibition of growth. GO-203 treatment was also associated with increases in reactive oxygen species (ROS) and induction of necrosis by a ROS-dependent mechanism. Moreover, GO-203 treatment of H1975 (EGFR L858R/T790M) and A549 (K-Ras G12S) xenografts growing in nude mice resulted in tumor regressions. These findings indicate that NSCLC cells are dependent on MUC1-C for activation of the PI3K->Akt pathway and for survival. PMID:21421804

  20. Surgical pathology of early stage non-small cell lung carcinoma

    PubMed Central

    Beasley, Mary Beth; Dembitzer, Francine R.

    2016-01-01

    The histologic classification of non-small cell lung carcinoma (NSCLC), particularly adenocarcinoma (ADC), has undergone extensive study in recent decades, ultimately resulting in an extensively updated classification system. The 2015 World Health Organization (WHO) classification of ADC provides greatly improved prognostic information in comparison to the 2004 WHO classification. Several issues still require further investigation: lepidic predominant ADC, prognostic significance of poor prognostic subtypes such as micropapillary carcinoma, the more recently described concept of spread of tumor through airspaces (STAS), and the utility of sublobar resections. While limited resection appears to be suitable for tumors with a ground glass radiographic appearance, which typically correspond to adenocarcinoma in situ (MIS) or minimally invasive adenocarcinoma (MIA) histologically, the role of sublobar resection in radiographic solid tumors is not as clear, and the impact of histologic subtypes with a poor prognosis needs further evaluation. Squamous cell carcinoma (SCC) has not been as extensively studied and the current classification lacks subclassification with significant prognostic information. PMID:27429964

  1. Immunotherapy in non-small cell lung cancer: the clinical impact of immune response and targeting.

    PubMed

    Mountzios, Giannis; Linardou, Helena; Kosmidis, Paris

    2016-07-01

    Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. In recent years, through a better understanding of the interactions between the immune system and tumor cells (TC), immunotherapy has emerged as a promising therapeutic strategy. Chemotherapy has long been reported to interfere with the immune response to the tumor and conversely, anti-tumor immunity may add to those effects. Anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, tumor cell vaccines and dendritic cell (DC) vaccines emerged as potent inducers of the immune response against the tumor. More recently the approval of the anti-programmed cell death 1 (anti-PD-1) monoclonal antibodies nivolumab and pembrolizumab for previously treated advanced squamous and non-squamous NSCLC, as well as other immune checkpoint inhibitors delivering promising results, has radically transformed the therapeutic landscape of NSCLC. Combination strategies now appear as the next step. Notwithstanding these successes, immunotherapy still holds significant drawbacks and currently several improvements are needed before routine use in clinical practice, including identification of robust biomarkers for optimal patient selection, as well as defining the best way to evaluate response. PMID:27563655

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

    SciTech Connect

    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

    2012-09-01

    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.

  3. Phosphosignature Predicts Dasatinib Response in Non-small Cell Lung Cancer*

    PubMed Central

    Klammer, Martin; Kaminski, Marc; Zedler, Alexandra; Oppermann, Felix; Blencke, Stephanie; Marx, Sandra; Müller, Stefan; Tebbe, Andreas; Godl, Klaus; Schaab, Christoph

    2012-01-01

    Targeted drugs are less toxic than traditional chemotherapeutic therapies; however, the proportion of patients that benefit from these drugs is often smaller. A marker that confidently predicts patient response to a specific therapy would allow an individual therapy selection most likely to benefit the patient. Here, we used quantitative mass spectrometry to globally profile the basal phosphoproteome of a panel of non-small cell lung cancer cell lines. The effect of the kinase inhibitor dasatinib on cellular growth was tested against the same panel. From the phosphoproteome profiles, we identified 58 phosphorylation sites, which consistently differ between sensitive and resistant cell lines. Many of the corresponding proteins are involved in cell adhesion and cytoskeleton organization. We showed that a signature of only 12 phosphorylation sites is sufficient to accurately predict dasatinib sensitivity. Four of the phosphorylation sites belong to integrin β4, a protein that mediates cell-matrix or cell-cell adhesion. The signature was validated in cross-validation and label switch experiments and in six independently profiled breast cancer cell lines. The study supports that the phosphorylation of integrin β4, as well as eight further proteins comprising the signature, are candidate biomarkers for predicting response to dasatinib in solid tumors. Furthermore, our results show that identifying predictive phosphorylation signatures from global, quantitative phosphoproteomic data is possible and can open a new path to discovering molecular markers for response prediction. PMID:22617229

  4. DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer.

    PubMed

    Sears, Catherine R; Cooney, Sean A; Chin-Sinex, Helen; Mendonca, Marc S; Turchi, John J

    2016-04-01

    Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24h after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism. PMID:26991853

  5. Experience with erlotinib in the treatment of non-small cell lung cancer.

    PubMed

    Landi, Lorenza; Cappuzzo, Federico

    2015-08-01

    Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths. In the last decade, the epidermal growth factor receptor (EGFR) signalling pathway has emerged as one of the most important molecular aberrations, representing an attractive therapeutic target in NSCLC. Drugs interfering with the tyrosine kinase domain of the EGFR (EGFR TKIs), such as erlotinib and gefitinib, have demonstrated efficacy in patients with advanced NSCLC irrespective of therapy line and particularly in patients harbouring activating mutations in the EGFR gene (EGFR(mut+)). Results of large phase III randomized trials clearly established that EGFR TKIs are superior to chemotherapy as frontline treatment in patients with EGFR(mut+), whereas in the EGFR wild-type (EGFR(WT)) or EGFR unknown population, platinum-based chemotherapy remains the standard of care, with no consistent benefit produced by the addition of EGFR TKI. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in the presence of classical EGFR mutations, whereas in the EGFR(WT) population, a similar efficacy to docetaxel or pemetrexed in terms of survival has been demonstrated. Unfortunately, patients who initially responded to EGFR TKIs invariably develop acquired resistance. For such patients there is an urgent need for more effective strategies able to delay or possibly overcome resistance. In the present review we analysed the available data on erlotinib in the treatment of advanced NSCLC. PMID:26063687

  6. Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK.

    PubMed

    Rothschild, Sacha I

    2015-01-01

    Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called "driver mutations") for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed. PMID:26018876

  7. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer.

    PubMed

    Tan, Chee-Seng; Gilligan, David; Pacey, Simon

    2015-09-01

    Discovery of activating mutations in EGFR and their use as predictive biomarkers to tailor patient therapy with EGFR tyrosine kinase inhibitors (TKIs) has revolutionised treatment of patients with advanced EGFR-mutant non-small-cell lung cancer (NSCLC). At present, first-line treatment with EGFR TKIs (gefitinib, erlotinib, and afatinib) has been approved for patients harbouring exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. These agents improve response rates, time to progression, and overall survival. Unfortunately, patients develop resistance, limiting patient benefit and posing a challenge to oncologists. Optimum treatment after progression is not clearly defined. A more detailed understanding of the biology of EGFR-mutant NSCLC and the mechanisms of resistance to targeted therapy mean that an era of treatment approaches based on rationally developed drugs or therapeutic strategies has begun. Combination approaches-eg, dual EGFR blockade-to overcome resistance have been trialled and seem to be promising but are potentially limited by toxicity. Third-generation EGFR-mutant-selective TKIs, such as AZD9291 or rociletininb, which target Thr790Met-mutant tumours, the most common mechanism of EGFR TKI resistance, have entered clinical trials, and exciting, albeit preliminary, efficacy data have been reported. In this Review, we summarise the scientific literature and evidence on therapy options after EGFR TKI treatment for patients with NSCLC, aiming to provide a guide to oncologists, and consider how to maximise therapeutic advances in outcomes in this rapidly advancing area. PMID:26370354

  8. New drugs in the palliative chemotherapy of advanced non-small-cell lung cancer.

    PubMed

    Malayeri, R; Pirker, R; Huber, H

    2001-10-01

    In inoperable advanced non-small-cell lung cancer (NSCLC), palliative chemotherapy is established and aims at palliation of symptoms, improvement of quality of life and prolongation of survival. In the last years, several new drugs with enhanced activity towards NSCLC and improved toxicity profile have been characterised, for example vinorelbine, gemcitabine, paclitaxel and docetaxel. Data from randomised trials suggest that regimens containing new drugs are more active than older combinations. Platin-based combinations of either vinorelbine, gemcitabine or paclitaxel have resulted in better outcome than cisplatin alone and new drugs in combination with platins are more active than the corresponding single agent. Non-platin-based combinations must be considered investigational until their non-inferiority to platin-based protocols has been proven in randomised trials on large patient populations. Patients with good performance status and adequate organ function should receive platin-based chemotherapy that includes the new drugs (vinorelbine, gemcitabine, paclitaxel or docetaxel). New drugs without platins are suitable for elderly patients and patients with poor performance status. Second-line chemotherapy prolongs survival in selected patients and should be particularly offered to patients with good performance status. PMID:11694767

  9. Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells

    PubMed Central

    Marabese, Mirko; Broggini, Massimo; Pastorelli, Roberta

    2014-01-01

    In non-small-cell lung cancer (NSCLC), one-fifth of patients have KRAS mutations, which are considered a negative predictive factor to first-line therapy. Evidence is emerging that not all KRAS mutations have the same biological activities and possible remodeling of cell metabolism by KRAS activation might complicate the scenario. An open question is whether different KRAS mutations at codon-12 affect cellular metabolism differently with possible implications for different responses to cancer treatments. We applied an explorative mass spectrometry-based untargeted metabolomics strategy to characterize the largest possible number of metabolites that might distinguish isogenic NSCLC cells overexpressing mutated forms of KRAS at codon-12 (G12C, G12D, G12V) and the wild-type. The glutamine deprivation assay and real-time PCR were used to confirm the involvement of some of the metabolic pathways highlighted. Cell clones indicated distinct metabolomic profiles in KRAS wild-type and mutants. Clones harboring different KRAS mutations at codon-12 also had different metabolic remodeling, such as a different redox buffering system and different glutamine-dependency not driven by the transcriptional state of enzymes involved in glutaminolysis. These findings indicate that KRAS mutations at codon-12 are associated with different metabolomic profiles that might affect the responses to cancer treatments. PMID:24952473

  10. Particle Therapy for Non-Small Cell Lung Tumors: Where Do We Stand? A Systematic Review of the Literature

    PubMed Central

    Wink, Krista C. J.; Roelofs, Erik; Solberg, Timothy; Lin, Liyong; Simone, Charles B.; Jakobi, Annika; Richter, Christian; Lambin, Philippe; Troost, Esther G. C.

    2014-01-01

    This review article provides a systematic overview of the currently available evidence on the clinical effectiveness of particle therapy for the treatment of non-small cell lung cancer and summarizes findings of in silico comparative planning studies. Furthermore, technical issues and dosimetric uncertainties with respect to thoracic particle therapy are discussed. PMID:25401087

  11. Association of TERT Polymorphisms with Clinical Outcome of Non-Small Cell Lung Cancer Patients.

    PubMed

    Zhao, Xueying; Wang, Shiming; Wu, Junjie; Li, Xiaoying; Wang, Xun; Gao, Zhiqiang; Wu, Wenting; Wang, Haijian; Wang, Jiucun; Qian, Ji; Ma, Ke; Li, Hui; Han, Baohui; Bai, Chunxue; Li, Qiang; Liu, Wenbin; Lu, Daru

    2015-01-01

    TERT is of great importance in cancer initiation and progression. Many studies have demonstrated the TERT polymorphisms as risk factors for many cancer types, including lung cancer. However, the impacts of TERT variants on cancer progression and treatment efficacy have remained controversial. This study aimed to investigate the association of TERT polymorphisms with clinical outcome of advanced non-small cell lung cancer (NSCLC) patients receiving first-line platinum-based chemotherapy, including response rate, clinical benefit, progression-free survival (PFS), overall survival (OS), and grade 3 or 4 toxicity. Seven polymorphisms of TERT were assessed, and a total of 1004 inoperable advanced NSCLC patients treated with platinum-based chemotherapy were enrolled. It is exhibited that the variant heterozygote of rs4975605 showed significant association with a low rate of clinical benefit, and displayed a much stronger effect in never-smoking female subset, leading to the clinical benefit rate decreased from 82.9% (C/C genotype) to 56.4% (C/A genotype; adjusted OR, 3.58; P=1.40×10(-4)). It is also observed that the polymorphism rs2736109 showed significant correlation with PFS (log-rank P=0.023). In age > 58 subgroup, patients carrying the heterozygous genotype had a longer median PFS than those carrying the wild-type genotypes (P=0.002). The results from the current study, for the first time to our knowledge, provide suggestive evidence of an effect of TERT polymorphisms on disease progression variability among Chinese patients with platinum-treated advanced NSCLC. PMID:26020272

  12. Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study

    PubMed Central

    Morrow, C. J.; Trapani, F.; Metcalf, R. L.; Bertolini, G.; Hodgkinson, C. L.; Khandelwal, G.; Kelly, P.; Galvin, M.; Carter, L.; Simpson, K. L.; Williamson, S.; Wirth, C.; Simms, N.; Frankliln, L.; Frese, K. K.; Rothwell, D. G.; Nonaka, D.; Miller, C. J.; Brady, G.; Blackhall, F. H.; Dive, C.

    2016-01-01

    Background Over the past decade, numerous reports describe the generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling and preclinical drug testing, the requirement of a tissue biopsy limits the available patient population, particularly those with advanced oligometastatic disease. Conversely, ‘liquid biopsies’ such as circulating tumour cells (CTCs) are minimally invasive and easier to obtain. Here, we present a clinical case study of a NSCLC patient with advanced metastatic disease, a never smoker whose primary tumour was EGFR and ALK wild-type. We demonstrate for the first time, tumorigenicity of their CTCs to generate a patient CTC-derived eXplant (CDX). Patients and methods CTCs were enriched at diagnosis and again 2 months later during disease progression from 10 ml blood from a 48-year-old NSCLC patient and implanted into immunocompromised mice. Resultant tumours were morphologically, immunohistochemically, and genetically compared with the donor patient's diagnostic specimen. Mice were treated with cisplatin and pemetrexed to assess preclinical efficacy of the chemotherapy regimen given to the donor patient. Results The NSCLC CDX expressed lung lineage markers TTF1 and CK7 and was unresponsive to cisplatin and pemetrexed. Examination of blood samples matched to that used for CDX generation revealed absence of CTCs using the CellSearch EpCAM-dependent platform, whereas size-based CTC enrichment revealed abundant heterogeneous CTCs of which ∼80% were mesenchymal marker vimentin positive. Molecular analysis of the CDX, mesenchymal and epithelial CTCs revealed a common somatic mutation confirming tumour origin and showed CDX RNA and protein profiles consistent with the predominantly mesenchymal phenotype. Conclusions This study shows that the absence of NSCLC CTCs detected by CellSearch (EpCAM+) does not preclude CDX generation

  13. Prognostic impact of cytological fluid tumor markers in non-small cell lung cancer.

    PubMed

    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. PMID:26432331

  14. X-Radiation Induces Non-Small-Cell Lung Cancer Apoptosis by Upregulation of Axin Expression

    SciTech Connect

    Han Yang; Wang Yan; Xu Hongtao; Yang Lianhe; Wei Qiang; Liu Yang; Zhang Yong; Zhao Yue; Dai Shundong; Miao Yuan; Yu Juanhan; Zhang Junyi; Li, Guang; Yuan Ximing; Wang Enhua

    2009-10-01

    Purpose: Axis inhibition (Axin) is an important negative regulator of the Wnt pathway. This study investigated the relationship between Axin expression and sensitivity to X-rays in non-small-cell lung cancer (NSCLC) to find a useful indicator of radiosensitivity. Methods and Materials: Tissue from NSCLC patients, A549 cells, and BE1 cells expressing Axin were exposed to 1-Gy of X-radiation. Axin and p53 expression levels were detected by immunohistochemistry and reverse transcription-PCR. Apoptosis was determined by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay and FACS (fluorescence-activate cell sorter) analysis. Caspase-3 activity was determined by Western blotting. Phospho-JNK expression was determined by immunofluorescence. Results: The expression of Axin was significantly lower in NSCLC tissues than in normal lung tissues (p < 0.05). Axin expression correlates with differentiation, TNM staging, and lymph node metastasis of NSCLC (p < 0.05). Its expression negatively correlates with the expression of p53(mt) (p=0.000) and positively correlates with apoptosis (p=0.002). The prognosis of patients with high expression of Axin was better than those with low expression. X-radiation increases Axin expression in NSCLC tissue, and caspase-3 is significantly higher in samples in which Axin is increased (p < 0.05). Both X-radiation and Axin induce apoptosis of A549 and BE1 cells; however, the combination of the two enhances the apoptotic effect (p < 0.05). In A549 cells, inhibition of p53 blocks Axin-induced apoptosis, whereas in BE1 cells, the JNK pathway is required. Conclusions: Axin induces the p53 apoptotic pathway in cells where this pathway is intact; however, in cells expressing p53(mt), Axin induces apoptosis via the JNK pathway. Elevated Axin expression following X-ray exposure is a reliable indicator for determining the radiosensitivity of NSCLC.

  15. Relationship between vascularity, age and survival in non-small-cell lung cancer.

    PubMed Central

    Chandrachud, L. M.; Pendleton, N.; Chisholm, D. M.; Horan, M. A.; Schor, A. M.

    1997-01-01

    Lung tumours in the elderly show reduced growth potential; impaired angiogenesis may contribute to this phenomenon. Recent studies have suggested that the angiogenic potential of a tumour may be inferred by the vascularity measured in histological sections. The purpose of this study has been to determine whether vascularity is related to age, survival or other clinical parameters in resected non-small-cell lung cancer (NSCLC). A group of 88 consecutive patients with a follow-up period of at least 5 years was selected. The group exhibited a wide age range (37-78 years) and similar survival characteristics to those of the general NSCLC population. Tumour sections were stained with a pan-endothelial antibody (vWF) and vascularity was quantitated, without knowledge of the clinical details, by three methods: highest microvascular density; average microvascular density; and average microvascular volume. The results were analysed by non-parametric statistical tests. A correlation was found between all three methods of quantitation. Vascularity was not associated with age, sex, tumour type, stage, volume, size (TNM-T) nodal status (TNM-N) or survival. However, survival time was generally longer for patients with higher vascularity, reaching borderline significance (P = 0.06) for the average microvascular density values. Higher tumour volume (P = 0.02) and stage (P = 0.05) were associated with lower survival times. Using multivariate survival analysis, tumour volume was the only factor related to survival. We conclude that vascularity is not associated with age and has no significant prognostic value in NSCLC. Images Figure 1 PMID:9374385

  16. 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells.

    PubMed

    Zhang, Yi; Yao, Ke; Shi, Chengcheng; Jiang, Yanan; Liu, Kangdong; Zhao, Song; Chen, Hanyong; Reddy, Kanamata; Zhang, Chengjuan; Chang, Xiaoyu; Ryu, Joohyun; Bode, Ann M; Dong, Ziming; Dong, Zigang

    2015-12-29

    The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6-12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR. PMID:26517520

  17. 244-MPT overcomes gefitinib resistance in non-small cell lung cancer cells

    PubMed Central

    Liu, Kangdong; Zhao, Song; Chen, Hanyong; Reddy, Kanamata; Zhang, Chengjuan; Chang, Xiaoyu; Ryu, Joohyun; Bode, Ann M.; Dong, Ziming; Dong, Zigang

    2015-01-01

    The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer(NSCLC). Several EGFR tyrosine kinase inhibitors(TKIs), such as gefitinib, have been used as effective clinical therapies for patients with NSCLC. Unfortunately, acquired resistance to gefitinib commonly occurs after 6–12 months of treatment. The resistance is associated with the appearance of the L858R/T790M double mutation of the EGFR. In our present study, we discovered a compound,referred to as 244-MPT, which could suppress either gefitinib-sensitive or -resistant lung cancer cell growth and colony formation, and also suppressed the kinase activity of both wildtype and double mutant (L858R/T790M) EGFR. The underlying mechanism reveals that 244-MPT could interact with either the wildtype or double-mutant EGFR in an ATP-competitive manner and inhibit activity. Treatment with 244-MPT could substantially reduce the phosphorylation of EGFR and its downstream signaling pathways, including Akt and ERK1/2 in gefitinib-sensitive and -resistant cell lines. It was equally effective in suppressing EGFR phosphorylation and downstream signaling in NL20 cells transfected with wildtype, single-mutant (L858R) or mutant (L858R/T790M) EGFR. 244-MPT could also induce apoptosis in a gefitinib-resistant cell line and strongly suppress gefitinib-resistant NSCLC tumor growth in a xenograft mouse model. In addition, 244-MPT could effectively reduce the size of tumors in a gefitinib-resistant NSCLC patient-derived xenograft (PDX) SCID mouse model. Overall, 244-MPT could overcome gefitinib-resistance by directly targeting the EGFR. PMID:26517520

  18. Therapeutic value of lymph node dissection for right middle lobe non-small-cell lung cancer

    PubMed Central

    Kuroda, Hiroaki; Mun, Mingyon; Motoi, Noriko; Ishikawa, Yuichi; Nakagawa, Ken; Yatabe, Yasushi; Okumura, Sakae

    2016-01-01

    Background Superior mediastinal and #11i lymph node (LN) metastases are adverse prognostic factors in patients with middle lobe lung cancer. We aimed to clarify the benefit of thorough lymphadenectomy by LN station or zone in middle lobe non-small-cell lung cancer (NSCLC). Methods Among 295 patients who underwent pulmonary resection and thorough lymphadenectomy for primary right middle lobe (RML) NSCLC at two institutions, we enrolled 68 patients (33 men, 35 women) and retrospectively studied their data. We divided each N1 location (i.e., #10, #11s and #11i) into N1(−)N2(+) and N1(+)N2(+) and divided the #12m location into N1(+)N2(−), N1(−)N2(+) and N1(+)N2(+). Results Interlobar node involvement was rare in pN1 NSCLC when compared with that in other N1 nodes. Lymph node dissection (LND) was beneficial when the hilar zone (HZ)/interlobar zone (IZ) LNs were located at the intermediate point of the upper zones (UZs) and subcarinal zones (SCZs), with the therapeutic benefit at the SCZ being 2.8-fold higher than that at the UZ and 9.7-fold higher than that at the lower zone (LZ). Furthermore, LND evidently had greater therapeutic value for the SCZ than the UZ, which was compatible with skip N2 metastases. Conclusions For middle lobe NSCLC, mediastinal LND should be considered a priority in the SCZ than in the UZ. Moreover, the HZ/IZ is central to unfavourable prognoses in patients with pN2 middle lobe NSCLC. PMID:27162652

  19. Methylation Markers of Early-Stage Non-Small Cell Lung Cancer

    PubMed Central

    Lokk, Kaie; Vooder, Tõnu; Kolde, Raivo; Välk, Kristjan; Võsa, Urmo; Roosipuu, Retlav; Milani, Lili; Fischer, Krista; Koltsina, Marina; Urgard, Egon; Annilo, Tarmo

    2012-01-01

    Background Despite of intense research in early cancer detection, there is a lack of biomarkers for the reliable detection of malignant tumors, including non-small cell lung cancer (NSCLC). DNA methylation changes are common and relatively stable in various types of cancers, and may be used as diagnostic or prognostic biomarkers. Methods We performed DNA methylation profiling of samples from 48 patients with stage I NSCLC and 18 matching cancer-free lung samples using microarrays that cover the promoter regions of more than 14,500 genes. We correlated DNA methylation changes with gene expression levels and performed survival analysis. Results We observed hypermethylation of 496 CpGs in 379 genes and hypomethylation of 373 CpGs in 335 genes in NSCLC. Compared to adenocarcinoma samples, squamous cell carcinoma samples had 263 CpGs in 223 hypermethylated genes and 513 CpGs in 436 hypomethylated genes. 378 of 869 (43.5%) CpG sites discriminating the NSCLC and control samples showed an inverse correlation between CpG site methylation and gene expression levels. As a result of a survival analysis, we found 10 CpGs in 10 genes, in which the methylation level differs in different survival groups. Conclusions We have identified a set of genes with altered methylation in NSCLC and found that a minority of them showed an inverse correlation with gene expression levels. We also found a set of genes that associated with the survival of the patients. These newly-identified marker candidates for the molecular screening of NSCLC will need further analysis in order to determine their clinical utility. PMID:22768131

  20. Maackia amurensis agglutinin enhances paclitaxel induced cytotoxicity in cultured non-small cell lung cancer cells.

    PubMed

    Chhetra Lalli, Rakhee; Kaur, Kiranjeet; Dadsena, Shashank; Chakraborti, Anuradha; Srinivasan, Radhika; Ghosh, Sujata

    2015-08-01

    Maackia amurensis agglutinin (MAA) is gaining recognition as the potential diagnostic agent for cancer. Previous studies from our laboratory have demonstrated that this lectin could interact specifically with the cells and biopsy samples of non-small cell lung cancer (NSCLC) origin but not with normal lung fibroblast cells. Moreover, this lectin was also found to induce apoptosis in NSCLC cells. Further, the biological activity of this lectin was shown to survive gastrointestinal proteolysis and inhibit malignant cell growth and tumorigenesis in mice model of melanoma thereby indicating the therapeutic potential of this lectin. Paclitaxel is one of the widely used traditional chemotherapeutic drugs for treatment of NSCLC but it exerts side-effects on normal healthy cells too. Studies have revealed that lectins have potential to act as an adjuvant chemotherapeutic agent in cancer of different origin. Thus, in the present study, an attempt was made to assess the chemo-adjuvant role of MAA in three types of NSCLC cell lines [adenocarcinoma cell line (A549), squamous cell carcinoma cell line (NCI-H520) and large cell carcinoma cell line (NCI-H460)]. We have observed that the non-cytotoxic concentration of this lectin was able to enhance the cytotoxic activity of Paclitaxel even at low dose by inducing apoptosis through intrinsic/mitochondrial pathway in all the three types of NSCLC cell lines, although the involvement of extrinsic pathway of apoptosis in case of NCI-H460 cell line could not be ruled out. Further, this lectin was also found to augment the chemo-preventive activity of this drug by arresting cells in G2-M phase of the cell cycle. Collectively, our results have suggested that Maackia amurensis agglutinin may have the potential to be used as adjuvant chemotherapeutic agent in case of NSCLC. PMID:25978938

  1. DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer.

    PubMed

    Moncho-Amor, V; Ibañez de Cáceres, I; Bandres, E; Martínez-Poveda, B; Orgaz, J L; Sánchez-Pérez, I; Zazo, S; Rovira, A; Albanell, J; Jiménez, B; Rojo, F; Belda-Iniesta, C; García-Foncillas, J; Perona, R

    2011-02-10

    DUSP1/MKP1 is a dual-specific phosphatase that regulates MAPKs activity, with an increasingly recognized role in tumor biology. To understand more about the involvement of DUSP1 in lung cancer, we performed gene expression analyses of parental and DUSP1-interfered H460 non-small-cell lung cancer (NSCLC) cells. Downregulation of DUSP1 induced changes in the expression levels of genes involved in specific biological pathways, including angiogenesis, MAP kinase phosphatase activity, cell-cell signaling, growth factor and tyrosine-kinase receptor activity. Changes in the expression of some of these genes were due to modulation of c-Jun-N-terminal kinase and/or p38 activity by DUSP1. Complementary functional assays were performed to focus on the implication of DUSP1 in angiogenesis and metastasis. In H460 cells, interference of DUSP1 resulted in a diminished capacity to invade through Matrigel, to grow tumors in nude mice and also to induce metastasis through tail-vein injection. Furthermore, the angiogenic potential of H460 cells was also impaired, correlating with a decrease in VEGFC production and indicating that DUSP1 could be required to induce angiogenesis. Finally, we studied whether a similar relationship occurred in patients. In human NSCLC specimens, DUSP1 was mainly expressed in those tumor cells close to CD31 vascular structures and a statistically significant correlation was found between VEGFC and DUSP1 expression. Overall, these results provide evidence for a role of DUSP1 in angiogenesis, invasion and metastasis in NSCLC. PMID:20890299

  2. Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

    PubMed Central

    LIN, SHUANG-YAN; PENG, FANG

    2016-01-01

    The roles of Silent mating type information regulation 2 homolog 1 (SIRT1) and High mobility group A1 (HMGA1) in human diseases have been extensively studied separately; however, to the best of our knowledge, the current study is the first to report on their interrelationship in lung cancer. The association of SIRT1 and HMGA1 in non-small cell lung cancer (NSCLC) was investigated by evaluating their expression and prognostic significance in 260 patients with NSCLC using immunohistochemistry. SIRT1 and HMGA1 expression were found to be significantly correlated with each other (P<0.001), and both were significantly associated with clinicopathological parameters, including histological type and degree of differentiation. In squamous cell carcinoma (SCC), SIRT1+ specimens were significantly associated with shorter overall survival (OS) time (P=0.019). However, in patients with adenocarcinoma (AD), no association was identified between SIRT1 and OS. In addition, HMGA1+ specimens were significantly associated with poor differentiation (P=0.028), and were more frequent in SCC than AD (P=0.015). However, HMGA1 was not associated with OS on univariate Cox regression analysis or Kaplan-Meier analysis (both P>0.05). SIRT1/HMGA1 coexpression was significantly associated with male gender (P=0.016), and moderately and poorly differentiated histological grade (P=0.025). The findings indicate that SIRT1 and HMGA1 may have significant effects during tumor progression in NSCLC, particularly in patients with SCC, and are potentially useful as prognostic indicators for patients with NSCLC. PMID:26834854

  3. Consensus conference: multimodality management of early- and intermediate-stage non-small cell lung cancer.

    PubMed

    Bordoni, Rodolfo

    2008-09-01

    Surgery is the mainstay of treatment in early- and intermediate-stage non-small cell lung cancer (NSCLC), yet recurrences are frequent. Studies have documented the benefits of chemotherapy administered after resection, but a number of questions remain regarding how overall outcomes can be further improved. To provide the oncology community with direction on these issues, a consensus conference of leading experts in the NSCLC field was held at the Fifth Annual Atlanta Lung Cancer Symposium on October 25-27, 2007. The available scientific literature is presented and when such literature is lacking, clinical experience is provided to support the following conclusions. Preoperative staging should be done in accordance with the National Comprehensive Cancer Network guidelines, but endoscopic fine needle aspiration of enlarged mediastinal nodes can be used, and if histology is positive for malignancy, mediastinoscopy can be avoided. Neoadjuvant systemic therapy is not generally recommended but can be considered to downstage an unresectable patient. There is currently no role for preoperative radiation or chemoradiation. Adjuvant systemic therapy is not recommended for stage IA and IB patients; however, adverse prognostic factors are acceptable reasons to consider adjuvant systemic therapy in the latter. Adjuvant systemic therapy is recommended for stage IIA, IIB, and IIIA patients, consistent with recent American Society of Clinical Oncology guidelines. A cisplatin-based regimen should be started within 60 days after surgery, but if relatively contraindicated, carboplatin is an acceptable alternative. Adjuvant radiation therapy is not recommended for N0 and N1 patients, but is used in N2 patients to decrease local recurrence. PMID:18779538

  4. Differential response to ablative ionizing radiation in genetically distinct non-small cell lung cancer cells.

    PubMed

    Oweida, Ayman; Sharifi, Zeinab; Halabi, Hani; Xu, Yaoxian; Sabri, Siham; Abdulkarim, Bassam

    2016-04-01

    Stereotactic ablative radiotherapy (SABR) has emerged as a highly promising treatment for medically inoperable early-stage non-small cell lung cancer patients. Treatment outcomes after SABR have been excellent compared to conventional fractionated radiotherapy (CFRT). However, the biological determinants of the response to ablative doses of radiation remain poorly characterized. Furthermore, there's little data on the cellular and molecular response of genetically distinct NSCLC subtypes to radiation. We assessed the response of 3 genetically distinct lung adenocarcinoma cell lines to ablative and fractionated ionizing radiation (AIR and FIR). We studied clonogenic survival, cell proliferation, migration, invasion, apoptosis and senescence. We also investigated the effect of AIR and FIR on the expression of pro-invasive proteins, epithelial-to-mesenchymal transition (EMT), extracellular signal-regulated kinases (ERK1/2) and the transmembrane receptor cMET. Our findings reveal that AIR significantly reduced cell proliferation and clonogenic survival compared to FIR in A549 cells only. This differential response was not observed in HCC827 or H1975 cells. AIR significantly enhanced the invasiveness of A549 cells, but not HCC827 or H1975 cells compared to FIR. Molecular analysis of pathways involved in cell proliferation and invasion revealed that AIR significantly reduced phosphorylation of ERK1/2 and upregulated cMET expression in A549 cells. Our results show a differential proliferative and invasive response to AIR that is dependent on genetic subtype and independent of intrinsic radioresistance. Further examination of these findings in a larger panel of NSCLC cell lines and in pre-clinical models is warranted for identification of biomarkers of tumor response to AIR. PMID:27096542

  5. The proangiogenic phenotype of natural killer cells in patients with non-small cell lung cancer.

    PubMed

    Bruno, Antonino; Focaccetti, Chiara; Pagani, Arianna; Imperatori, Andrea S; Spagnoletti, Marco; Rotolo, Nicola; Cantelmo, Anna Rita; Franzi, Francesca; Capella, Carlo; Ferlazzo, Guido; Mortara, Lorenzo; Albini, Adriana; Noonan, Douglas M

    2013-02-01

    The tumor microenvironment can polarize innate immune cells to a proangiogenic phenotype. Decidual natural killer (dNK) cells show an angiogenic phenotype, yet the role for NK innate lymphoid cells in tumor angiogenesis remains to be defined. We investigated NK cells from patients with surgically resected non-small cell lung cancer (NSCLC) and controls using flow cytometric and functional analyses. The CD56(+)CD16(-) NK subset in NSCLC patients, which represents the predominant NK subset in tumors and a minor subset in adjacent lung and peripheral blood, was associated with vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and interleukin-8 (IL-8)/CXCL8 production. Peripheral blood CD56(+)CD16(-) NK cells from patients with the squamous cell carcinoma (SCC) subtype showed higher VEGF and PlGF production compared to those from patients with adenocarcinoma (AdC) and controls. Higher IL-8 production was found for both SCC and AdC compared to controls. Supernatants derived from NSCLC CD56(+)CD16(-) NK cells induced endothelial cell chemotaxis and formation of capillary-like structures in vitro, particularly evident in SCC patients and absent from controls. Finally, exposure to transforming growth factor-β(1) (TGFβ(1)), a cytokine associated with dNK polarization, upregulated VEGF and PlGF in peripheral blood CD56(+)CD16(-) NK cells from healthy subjects. Our data suggest that NK cells in NSCLC act as proangiogenic cells, particularly evident for SCC and in part mediated by TGFβ(1). PMID:23441128

  6. Brain metastases in metastatic non-small cell lung cancer responding to single-agent gefitinib: a case report.

    PubMed

    Stemmler, H J; Weigert, O; Krych, M; Schoenberg, S O; Ostermann, H; Hiddemann, W

    2005-08-01

    Brain metastases are a frequent finding in patients with non-small cell lung cancer (NSCLC). The present case reports the clinical course of a patient who was treated with gefitinib alone for progressive brain metastases after whole-brain irradiation treatment (WBRT). A 50-year-old women with primary stage IV NSCLC (bone metastases) developed brain metastases after 3 cycles of chemotherapy consisting of paclitaxel and carboplatin (CBDA). After completion of the WBRT, magnetic resonance imaging (MRI) indicated further progression. Two cycles of temozolomide and topotecan were applied; this was ineffective in preventing central nervous system progression. For symptomatic brain metastatic disease the patient received gefitinib as single-agent treatment. Within a few weeks of treatment there was an obvious clinical improvement. Follow-up of the brain 2 months after the start of treatment showed a decrease in both the size and number of brain metastases. Additional manifestations in the lungs and the skeletal system were re-assessed as stable disease during the treatment with gefitinib. Within 4 months of treatment there were no side-effects such as skin rash or any other systemic toxicity. Gefitinib may therefore have a role in the treatment of brain metastases from NSCLC. PMID:16027524

  7. Docetaxel for non-small-cell lung cancer harboring the activated EGFR mutation with T790M at initial presentation.

    PubMed

    Yamane, Hiromichi; Ochi, Nobuaki; Yasugi, Masayuki; Tabayashi, Takayuki; Yamagishi, Tomoko; Monobe, Yasumasa; Hisamoto, Akiko; Kiura, Katsuyuki; Takigawa, Nagio

    2013-01-01

    A 72-year-old woman was referred to our hospital with Stage IV non-small-cell lung cancer (NSCLC). Chest computed tomography revealed a mass in the upper lobe of the right lung, with pleural effusion. Cytologic examination identified adenocarcinoma cells in the right pleural effusion. Furthermore, both a deletion mutation in exon 19 and a threonine-methionine substitution mutation at position 790 in exon 20 (T790M) were detected in the epidermal growth factor receptors (EGFR) in the malignant cells. As systemic chemotherapy consisting of carboplatin and pemetrexed or erlotinib proved ineffective, docetaxel monotherapy was initiated as a third-line treatment. Following salvage chemotherapy, her Eastern Cooperative Oncology Group performance status improved from 3 to 1, with tumor regression over 5 months. To the best of our knowledge, this is the first report of successful docetaxel treatment for a patient with NSCLC harboring the T790M EGFR-activating mutation identified before treatment with EGFR tyrosine kinase inhibitors. PMID:23493804

  8. Docetaxel for non-small-cell lung cancer harboring the activated EGFR mutation with T790M at initial presentation

    PubMed Central

    Yamane, Hiromichi; Ochi, Nobuaki; Yasugi, Masayuki; Tabayashi, Takayuki; Yamagishi, Tomoko; Monobe, Yasumasa; Hisamoto, Akiko; Kiura, Katsuyuki; Takigawa, Nagio

    2013-01-01

    A 72-year-old woman was referred to our hospital with Stage IV non-small-cell lung cancer (NSCLC). Chest computed tomography revealed a mass in the upper lobe of the right lung, with pleural effusion. Cytologic examination identified adenocarcinoma cells in the right pleural effusion. Furthermore, both a deletion mutation in exon 19 and a threonine–methionine substitution mutation at position 790 in exon 20 (T790M) were detected in the epidermal growth factor receptors (EGFR) in the malignant cells. As systemic chemotherapy consisting of carboplatin and pemetrexed or erlotinib proved ineffective, docetaxel monotherapy was initiated as a third-line treatment. Following salvage chemotherapy, her Eastern Cooperative Oncology Group performance status improved from 3 to 1, with tumor regression over 5 months. To the best of our knowledge, this is the first report of successful docetaxel treatment for a patient with NSCLC harboring the T790M EGFR-activating mutation identified before treatment with EGFR tyrosine kinase inhibitors. PMID:23493804

  9. Pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer.

    PubMed

    Greenhalgh, J; McLeod, C; Bagust, A; Boland, A; Fleeman, N; Dundar, Y; Oyee, J; Dickson, R; Davis, H; Green, J; McKenna, E; Pearson, M

    2010-10-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in accordance with the licensed indication, based upon the evidence submission from the manufacturer (Eli Lilly) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The primary clinical outcome measure was progression free survival (PFS). Secondary outcomes included overall survival (OS), time to worsening of symptoms, objective tumour response rate, adverse events and changes in lung cancer symptom scale. Data for two populations were presented: patients with non-squamous NSCLC histology and patients with adenocarcinoma histology. The clinical evidence was derived from a double-blind, placebo-controlled randomised controlled trial (RCT), the JMEN trial. The trial compared the use of pemetrexed + best supportive care (BSC ) as maintenance therapy, with placebo + BSC in patients with NSCLC (n = 663) who had received four cycles of platinum-based chemotherapy (CTX) and whose disease had not progressed. In the licensed population (patients with non-squamous histology), the trial demonstrated greater median PFS for patients treated with pemetrexed than for patients in the placebo arm [4.5 vs 2.6 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.36 to 0.55, p < 0.00001]. Median OS was also greater for the pemetrexed- treated patients (15.5 vs 10.3 months; HR 0.70; 95% CI 0.56 to 0.88, p = 0.002). In addition, tumour response and disease control rates were statistically significantly greater for patients who received pemetrexed. Patient survival rates at 1 year and 2 years were higher in the pemetrexed arm. The incremental cost-effectiveness ratios (ICERs) estimated by the manufacturer's model were 33,732 pounds per quality adjusted life-year (QALY

  10. TRIM31 is downregulated in non-small cell lung cancer and serves as a potential tumor suppressor.

    PubMed

    Li, Hui; Zhang, Yi; Zhang, Yue; Bai, Xue; Peng, Yang; He, Ping

    2014-06-01

    The present study aims to investigate expression pattern and biological roles of TRIM31 in human non-small cell lung cancer (NSCLC). We examined TRIM31 expression in 116 NSCLC tissues and 20 corresponding normal lung tissues by immumohistochemistry. We found TRIM31 downregulation in 47 out of 116 (40.5 %) cancer samples, which correlated with tumor status (p=0.0132), advanced p-TNM stage (p=0.001), and nodal metastasis (p=0.0382). TRIM31 expression was lower in lung cancer cell lines than normal bronchial cell line HBE. Transfection of TRIM31 plasmid was performed in H157 and H1299 cells. TRIM31 overexpression inhibited cell growth rate and colony formation ability in both cell lines. In addition, expression of cell cycle regulator cyclin D1 and cyclin E were decreased after TRIM31 transfection. In conclusion, TRIM31 might serve as a tumor suppressor in non-small cell lung cancer. PMID:24566900

  11. Targeting and in vivo imaging of non-small-cell lung cancer using nebulized multimodal contrast agents.

    PubMed

    Bianchi, Andrea; Dufort, Sandrine; Lux, François; Fortin, Pierre-Yves; Tassali, Nawal; Tillement, Olivier; Coll, Jean-Luc; Crémillieux, Yannick

    2014-06-24

    One of the main reasons for the dismal prognosis of lung cancer is related to the late diagnosis of this pathology. In this work, we evaluated the potential of optimized lung MRI techniques and nebulized ultrasmall multimodal gadolinium-based contrast agents [ultrasmall rigid platforms (USRPs)] as a completely noninvasive approach for non-small-cell lung cancer (NSCLC) in vivo detection. A mouse model of NSCLC expressing the luciferase gene was developed. Ultrashort echo-time free-breathing MRI acquisitions were performed before and after i.v. or intrapulmonary administration of the nanoparticles to identify and segment the tumor. After orotracheal or i.v. administration of USRPs, an excellent colocalization of the position the tumor with MRI, bioluminescence and fluorescence reflectance imaging, and histology was observed in all mice. Significantly higher signal enhancements and contrast-to-noise ratios were observed with orotracheal administration using lower doses, reducing the toxicity issues and the interobserver variability in tumor detection. The observations suggested the existence of an unknown original mechanism (different from the enhanced permeability and retention effect) responsible for this phenomenon. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify, and longitudinally monitor the development of submillimetric NSCLCs. The absence of ionizing radiation and high resolution MRI, along with the complete noninvasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge this is the first time that the advantages of an orotracheal administration route are demonstrated for the investigation of the pathomorphological changes due to NSCLCs. PMID:24927562

  12. Prognostic significance of circulating laminin gamma2 for early-stage non-small-cell lung cancer

    PubMed Central

    Teng, Yu; Wang, Zitong; Ma, Li; Zhang, Lina; Guo, Yinan; Gu, Meng; Wang, Ziyu; Wang, Yue; Yue, Wentao

    2016-01-01

    Background Laminin gamma2 (Ln-γ2) chain, a distinctive subunit of heterotrimeric laminin-332, is frequently upregulated in carcinomas and is of great importance in cell migration and invasion. Despite this, the status of circulating Ln-γ2 in lung cancer patients is still uncertain. Patients and methods In this retrospective study, serum samples from 538 all-stage (stages I–IV) patients with non-small-cell lung cancer (NSCLC) and 94 age-matched healthy volunteers were investigated by enzyme-linked immunosorbent assay. Data were statistically analyzed in combination with clinicopathological information. Results Circulating Ln-γ2 was markedly increased in NSCLC, even in stage I cases (P<0.01), reflecting the progression of lung cancer. Survival analysis on 370 eligible patients indicated that serum Ln-γ2-negative patients survived much longer compared with Ln-γ2-positive individuals (P=0.028), and it was especially the case for stage I (P<0.001), stage T1 (P=0.001), and stage N0 patients (P=0.038), all of whom represented early-stage cases. For the advanced patients, however, overall survivals were not significantly different among stages II–IV (P=0.830), stages T2–T4 (P=0.575), stages N1–N3 (P=0.669), and stage M1 (P=0.849). Cox analysis subsequently defined serum Ln-γ2 as an independent prognostic indicator of NSCLC, particularly for early-stage patients. Furthermore, we demonstrated the association of serum Ln-γ2 with smoking behavior, but its association with tumor progression and early prognostic significance were not altered in the nonsmoking cohort. Conclusion Our study demonstrated that elevation of circulating Ln-γ2 was an early-emerging event in NSCLC and was significantly associated with poor prognosis in NSCLC, especially for early-stage cases. PMID:27462170

  13. Role of gefitinib in the targeted treatment of non-small-cell lung cancer in Chinese patients

    PubMed Central

    Li, Meng-Jiao; He, Qing; Li, Mei; Luo, Feng; Guan, Yong-Song

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer. Conventional treatment options have limited efficacy because most cases are in the advanced stage at the time of diagnosis. In recent years, gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has shown its good antitumor activities in treating NSCLC in a number of studies. This paper reviews its role in the targeted treatment of NSCLC in Chinese patients. PMID:27022285

  14. Gamma Knife Radiosurgery for Treatment of Cerebral Metastases From Non-Small-Cell Lung Cancer

    SciTech Connect

    Motta, Micaela; Vecchio, Antonella del; Attuati, Luca; Picozzi, Piero; Perna, Lucia; Franzin, Alberto; Bolognesi, Angelo; Cozzarini, Cesare; Calandrino, Riccardo; Mortini, Pietro; Muzio, Nadia di

    2011-11-15

    Purpose: To evaluate clinical and physico-dosimetric variables affecting clinical outcome of patients treated with Gamma Knife radiosurgery (GKRS) for brain metastases from non-small cell lung cancer (NSCLC). Methods and Materials: Between 2001 and 2006, 373 patients (298 men and 75 women, median age 65 years) with brain metastases from NSCLC underwent GKRS. All of them had KPS {>=} 60%, eight or fewer brain metastases, confirmed histopathological diagnosis and recent work-up (<3 months). Thirty-five patients belonged to recursive partitioning analysis (RPA) Class I, 307 patients were in RPA Class II, 7 patients were in RPA Class III. Median tumor volume was 3.6 cm{sup 3}. Median marginal dose was 22.5 Gy at 50% isodose.; median 10 Gy and 12 Gy isodose volumes were 30.8 cm{sup 3} and 15.8 cm{sup 3}, respectively. Follow-up with MRI was performed every 3 months. Overall survival data were collected from internal database, telephone interviews, and identifying registries. Results: Mean follow-up after GKRS was 51 months (range, 6 to 96 months); mean overall survival was 14.2 months. Of 373 patients, 29 were alive at time of writing, 104 had died of cerebral progression, and 176 had died of systemic progression. In 64 cases it was not possible to ascertain the cause. Univariate and multivariate analysis were adjusted for the following: RPA class, surgery, WBRT, age, gender, number of lesions, median tumor volume, median peripheral dose, and 10 Gy and 12 Gy volumes. Identified RPA class and overall tumor volume >5 cc were the only two covariates independently predictive of overall survival in patients who died of cerebral progression. Conclusions: Global volume of brain disease should be the main parameter to consider for performing GKRS, which is a first-line therapy for patient in good general condition and controlled systemic disease.

  15. Pemetrexed clinical studies in performance status 2 patients with non-small cell lung cancer (Review)

    PubMed Central

    ZINNER, RALPH; GRUL, CARLA VISSEREN; SPIGEL, DAVID R.; OBASAJU, COLEMAN

    2016-01-01

    Because poor performance status (PS) is an independent prognostic factor in non-small cell lung cancer (NSCLC), PS scores are widely used by oncologists to make treatment decisions. Advanced NSCLC patients with an Eastern Cooperative Oncology Group PS of 2 have poor prognoses and are frequently excluded from clinical trials. This article reviews the efficacy and safety of pemetrexed in this patient group. We identified English-language literature (through March 2015) involving completed and ongoing studies through searches of PubMed, meeting abstracts, ClinicalTrials.gov and the European Clinical Trials Register; search terms included ‘pemetrexed,’ ‘NSCLC’ and ‘PS2’. Only studies reporting ≥1 subset analysis of PS2 patients receiving pemetrexed were chosen. Our search identified a total of ten pemetrexed studies in PS2 patients. Eight studies included only chemonaive patients, one study included both chemonaive patients and patients with one prior chemotherapy regimen and one study included only patients with one prior regimen. In subset analyses in these studies, PS2 patients had worse outcomes than PS0-1 patients regardless of treatment. In a phase 3 study, chemonaive advanced NSCLC patients with PS2 receiving pemetrexed-carboplatin versus pemetrexed experienced improved overall survival [hazard ratio (HR)=0.62; P=0.001], progression-free survival (HR=0.46; P<0.001) and response (P=0.032). This review confirms the poorer outcomes in PS2 vs. PS0-1 patients. Although it is not an approved combination therapy, in clinical studies, PS2 patients treated with pemetrexed plus carboplatin as first-line therapy had improved response rates and survival. Additional research on PS2 patients is needed. PMID:26530033

  16. Interleukin-10 Haplotype May Predict Survival and Relapse in Resected Non-Small Cell Lung Cancer

    PubMed Central

    Wu, Tzu-Chin; Wang, Lee; Chien, Wen-Pin; Cheng, Ya-Wen; Chen, Chih-Yi; Shieh, Shwn-Huey; Lee, Huei

    2012-01-01

    IL-10 is associated with tumor malignancy via immune escape. We hypothesized that IL-10 haplotypes categorized by IL-10 promoter polymorphisms at –1082A>G, –819C>T, and –592C>A might influence IL-10 expression and give rise to non-small cell lung cancer (NSCLC) patients with poor outcomes and relapse. We collected adjacent normal tissues from 385 NSCLC patients to determine IL-10 haplotypes by direct sequencing and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Of the 385 tumors, 241 were available to evaluate IL-10 mRNA expression levels by real-time RT-PCR. The influence of IL-10 haplotypes on overall survival (OS) and relapse free survival (RFS) were determined by Kaplan-Meier and multivariate Cox regression analysis. The results showed that IL-10 mRNA levels were significantly higher in tumors with the non-ATA haplotype than with the ATA haplotype (P = 0.004). Patients with the non-ATA haplotype had shorter OS and RFS periods than did patients with the ATA haplotype. This may be associated with the observation that the number of tumor-infiltrating lymphocytes was decreased in the tumors with higher levels of IL-10. Consistently, T cells from the peripheral blood of the patients with non-ATA haplotype were more susceptible to apoptosis and less cytotoxic to tumor cells, compared to those from the patients with ATA haplotype. The results suggest that IL-10 can promote tumor malignancy via promoting T cell apoptosis and tumor cell survival, and IL-10 haplotype evaluated by PCR-RFLP or direct sequencing may be used to predict survival and relapse in resected NSCLC, helping clinicians to make appropriate decisions on treatment of the patients. PMID:22848356

  17. AZD9291 in epidermal growth factor receptor inhibitor—resistant non-small-cell lung cancer

    PubMed Central

    2016-01-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60–70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGFR TKI with activity against the activating EGFR mutation, the T790M acquired resistance mutation, and relative sparing of the wild-type EGFR. AZD9291 was investigated in a phase I trial with expansion cohorts in patients with disease progression after EGFR TKI. Patients with and without detectable T790M mutations were enrolled in the trial. The ORR in patients with centrally confirmed and without detectable T790M mutations was 61% (95% CI, 52–70%) and 21% (95% CI, 12–34%), respectively. The PFS observed in patients with centrally confirmed and without detectable T790M mutations was 9.6 months (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1–4.3 months), respectively. At the dose for further investigation, 80 mg daily, the rate of all grade 3-5 drug related adverse events was 11%, and the rates of grade 3 diarrhea and rash were 1% and 0%, respectively. The identification of the T790M resistance mutation and the subsequent development of an agent against the mechanism of resistance provide a template for future drug development for acquired resistance to targeted therapy. PMID:26958499

  18. Cachexia Index in Advanced Non-Small-Cell Lung Cancer Patients

    PubMed Central

    Jafri, Syed Hasan Raza; Previgliano, Carlos; Khandelwal, Keerti; Shi, Runhua

    2015-01-01

    INTRODUCTION Cancer cachexia affects many advanced non-small-cell lung cancer (NSCLC) patients. Cachexia index (CXI) was developed to assess the degree of cachexia in these patients. METHODS Patients with metastatic NSCLC diagnosed between January 1, 2000, and June 30, 2011, at our institution were retrospectively studied. Abdominal computed tomography scans done within 1 month of diagnosis were reviewed to estimate skeletal muscle area (SMA) and skeletal muscle index (SMI) at the L3 level. CXI was developed as follows: CXI=SMI×AlbNLR where SMI is the skeletal muscle index, Alb is the serum albumin, and NLR is the neutrophil-to-lymphocyte ratio. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Survival among various factors was calculated using the log-rank test. Multivariate Cox regression was used to perform survival analysis in order to estimate the effects of various factors. RESULTS Patients were divided into two groups around the median into stage I cachexia (CXI ≥35, n = 56) and stage II cachexia (CXI <35, n = 56). Groups did not differ in age, gender, ethnicity, or histology of cancer. Patients with stage II cachexia had significantly worse PFS (2.45 vs 5.43 months, P < 0.0001) and OS (3.45 vs 8.8 months, P = 0.0001) than those with stage I cachexia. On multivariate analysis adjusting for gender, race, and histology, patients with stage II cachexia were found to have worse PFS (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.27–2.95) and OS (HR 1.53, 95% CI 1.0009–2.34). CONCLUSION The CXI is a novel index for estimating cachexia that also correlates with prognosis in both men and women with advanced NSCLC. PMID:26604850

  19. Rapid Disease Progression With Delay in Treatment of Non-Small-Cell Lung Cancer

    SciTech Connect

    Mohammed, Nasiruddin; Kestin, Larry Llyn; Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar; Wong, Ching-yee Oliver; Margolis, Jeffrey Harold; Chmielewski, Gary William; Welsh, Robert James

    2011-02-01

    Purpose: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. Results: Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. Conclusions: With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

  20. Economic value of gemcitabine compared to cisplatin and etoposide in non-small cell lung cancer.

    PubMed

    Copley-Merriman, C; Corral, J; King, K; Whiteside, R; Voi, M; Dorr, F A; McDonald, R C

    1996-02-01

    Although chemotherapy costs have not been highlighted traditionally, there is increasing pressure to demonstrate the value of new treatments within the health care budget. Pharmaceutical companies are assessing the economic value of their products before launch. Gemcitabine is a nucleoside analogue developed for use in solid tumours. The purpose of this model was to investigate the clinical outcomes and potential cost savings for gemcitabine used as monotherapy compared to cisplatin and etoposide combination therapy in late stage non-small cell lung cancer (NSCLC), in a palliative (as opposed to aggressive) chemotherapy setting. Gemcitabine treatment data were taken from a large NSCLC study and data from retrospective chart reviews identified through the National Oncology Data Base. The model population and effectiveness of the two regimens were judged to be similar, except for baseline performance status. If drug costs were not included, the probability distribution resulting from the simulation showed median cost savings per cycle ranging from $US 1504 to $US 7425, with a medium value of $US 2154. The model suggested that gemcitabine would result in cost savings per cycle more than 90% of the time. Outpatient versus inpatient drug administrations accounted for the majority of potential cost savings. Most of the remaining cost savings were attributable to the difference in febrile neutropenia and antiemetic use. This economic model showed susbstantial savings if gemcitabine was used instead of cisplatin and etoposide combination therapy in the United States' community care setting. Some savings would be realized even if the location of treatment for both regimens was mostly outpatient. Assessment of the product's economic value before launch has assisted in our understanding of the potential areas of cost savings for gemcitabine and has guided us in the design of prospective randomized studies which included pharmacoeconomic endpoints. PMID:8696720

  1. Coexistent autoimmune autonomic ganglionopathy and myasthenia gravis associated with non-small-cell lung cancer.

    PubMed

    Peltier, Amanda C; Black, Bonnie K; Raj, Satish R; Donofrio, Peter; Robertson, David; Biaggioni, Italo

    2010-03-01

    We report the case of a 55-year-old man with non-small-cell lung cancer who underwent radiation, chemotherapy with carbotaxol and paclitaxel, and left upper lobe removal 2 years prior to evaluation. He was referred for disabling orthostatic hypotension (113/69 mm Hg supine and 66/47 mm Hg standing after 10 minutes) without a compensatory heart rate increase (57 to 59 beats per minute), fatigue, and constipation with episodes of ileus. Clinical examination showed mild ptosis bilaterally, fatiguable neck flexor weakness, and hip flexor weakness. Blood pressure response to Valsalva maneuver was abnormal with an absence of phase 4 overshoot and a Valsalva heart rate ratio of 1.04. Plasma norepinephrine level was low (79 pg/ml supine, 330 pg/ml standing). Single-fiber electromyography of the right extensor digitorum communis revealed normal mean consecutive difference (jitter) but several pairs exceeded a jitter of 100 mus. Antibodies against muscle acetylcholine receptor [(AChR) 0.66 nmol/L, normal <0.02 nmol/L] and ganglionic AChR (0.34 nmol/L, normal <0.02 nmol/L) were present. Treatment with plasma exchange normalized responses to standing posture (105/68 supine to 118/82 mm Hg standing, 66 to 79 beats per minute), to Valsalva (normal blood pressure overshoot, hazard ratio 1.47), norepinephrine (194 pg/ml supine, 763 pg/ml standing), and jitter measurements. We conclude that autoimmune autonomic ganglionopathy and myasthenia gravis can coexist and suggest that the latter should be excluded in patients with autoimmune autonomic ganglionopathy who complain of fatigue that shows improvement with non-supine rest. PMID:19882640

  2. Stathmin1 increases radioresistance by enhancing autophagy in non-small-cell lung cancer cells

    PubMed Central

    Zhang, Xi; Ji, Jingfen; Yang, Yu; Zhang, Juan; Shen, Liangfang

    2016-01-01

    Radioresistance has been demonstrated to be involved in the poor prognosis of patients with non-small-cell lung cancer (NSCLC). However, the underlying mechanism remains largely unclear. Investigation on special therapeutic targets associated with radioresistance shows promises for the enhancement of clinical radiotherapy effect toward NSCLC. This study aimed to reveal the role of Stathmin1 (STMN1) in radioresistance in NSCLC as well as the underlying mechanism. Our data showed that the protein levels of STMN1 were significantly upregulated in NSCLC cells subjected to radiation, accompanied with the activation of autophagy. Knockdown of STMN1 expression enhanced the sensitivity of NSCLC cells to X-ray, and the radiation-induced autophagy was also inhibited. Molecular mechanism investigation showed that knockdown of STMN1 expression upregulated the activity of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway in NSCLC cells. Moreover, the activation of PI3K/mTOR signaling showed an inhibitory effect on the autophagy and radioresistance induced by STMN1 in NSCLC cells. In addition, luciferase reporter assay data indicated that STMN1 was a direct target gene of miR-101, which had been reported to be an inhibitor of autophagy. Based on these data, we suggest that as a target gene of miR-101, STMN1 promotes the radioresistance by induction of autophagy through PI3K/mTOR signaling pathway in NSCLC. Therefore, STMN1 may become a potential therapeutic target for NSCLC radiotherapy. PMID:27199567

  3. Neoadjuvant Radiotherapy/Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Yalman, Deniz

    2015-01-01

    Locally advanced non-small cell lung cancer (NSCLC) consists of a heterogeneous group of patients, and the optimal treatment is still controversial. The current standard of care is concurrent chemoradiotherapy. The prognosis is still poor, with high rates of local and distant failure despite multimodality treatment. One of the efforts to improve outcomes in these patients is to use neoadjuvant treatment to improve resectability, and downstaging the nodal disease, which has a clear impact on prognosis. Radiotherapy as the sole neoadjuvant modality has been used historically without any survival benefit, but with increased toxicity. After the demonstrating a survival benefit by combining radiotherapy and chemotherapy, phase II studies were started to determine the neoadjuvant administration of these two modalities together. Although the results of these studies revealed a heterogeneous postinduction pathologic complete response, tumor and nodal down-staging can be achieved at the cost of a slightly higher morbidity and mortality. Subsequent phase III trials also failed to show a survival benefit to surgery, but indicated that there may be a subset of patients with locally advanced disease who can benefit from resection unless pneumonectomy is not provided. In order to increase the efficacy of radiotherapy, hyperfractionated-accelerated schedules have been used with promising complete pathologic response rates, which might improve prognosis. Recently, studies applying high radiotherapy doses in the neoadjuvant setting demonstrated the safety of resection after radiotherapy, with high nodal clearance rates and encouraging long-term survival results. In conclusion, neoadjuvant treatment of locally advanced NSCLC is one of the most challenging issues in the treatment of this disease, but it can be offered to appropriately selected patients, and should be done by a multidisciplinary team. Individual risk profiles, definite role of radiotherapy with optimal timing, and

  4. High-Dose Conformal Radiotherapy for Patients With Stage III Non-Small-Cell Lung Carcinoma

    SciTech Connect

    Nakayama, Hidetsugu; Satoh, Hiroaki; Kurishima, Koichi; Ishikawa, Hiroichi; Tokuuye, Koichi

    2010-11-01

    Purpose: To determine the effectiveness of high-dose conformal radiotherapy to the involved field for patients with Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: Between May 1999 and April 2006, a total of 100 consecutive patients with inoperable Stage IIIA or IIIB NSCLC with a performance score of 0 to 2 and treatment by radical radiotherapy combined with chemotherapy were included. Up to August 2002, 33 patients underwent conventional radiotherapy of 56 Gy to 66 Gy using anteroposterior opposite ports to the primary tumor and elective lymph nodes (conventional group). After September 2002, the remaining 67 patients underwent high-dose radiotherapy of 66 Gy to 84 Gy to the involved volume with three-dimensional (3-D) conformal radiotherapy (conformal group). Results: The median survival was 13.2 months (95% confidence interval [CI], 7.5-18.5 months) in the conventional group and 17.3 months (95% CI, 10.7- 24.0 months) in the conformal group. The overall survival at 3 years were 9.1% (95% CI, -0.7-18.9%) in the conventional group and 31.0% (95% CI, 18.9-43.1%) in the conformal group; the conformal group had a significantly better overall survival (p < 0.05). The radiotherapy method (hazard ratio = 0.55, p < 0.05) and performance status (hazard ratio = 1.48, p < 0.05) were shown to be statistically significant independent prognostic factors. Conclusions: Based on the practical experience reported here, 3-D conformal radiotherapy allowed dose escalation without excessive toxicity, and may improve overall survival rates for patients with Stage III NSCLC.

  5. Prognostic significance of tissue miR-345 downregulation in non-small cell lung cancer

    PubMed Central

    Chen, Liming; Li, Xiaojie; Chen, Xiaojun

    2015-01-01

    Background: MiRNAs might function as oncogenes or tumor suppressor genes in the tumorigenesis process. Dysregulation of miR-345 is a frequent event in many types of human cancers. However, the tissue miR-345 expression level in non-small cell lung cancer (NSCLC) and its potential clinical significance remains unknown. Materials and methods: Real-time PCR was conducted to evaluate the expression level of miR-345 in NSCLC tissues as well as cell lines. Then the association between tissue miR-345 expression level and clinical outcome was investigated. Results: The expression level of miR-345 was significantly decreased in NSCLC tissues and cell lines compared with the controls (P<0.05; P<0.01). Tissue miR-345 expression level was associated with various clinicopathological parameters including LN metastasis (P=0.012), distant metastasis (P=0.007), TNM stage (P=0.008) and grade (P=0.030). In addition, the NSCLC patients in thelow tissue miR-345 expression group had significantly shorter 5-year overall survival time than those in the high tissue miR-345expression group (P=0.016). Multivariate analysis showed that tissue miR-345 was an independent risk factor for NSCLC (HR=3.921, 95% CI: 2.285-10.540; P=0.008). Conclusions: The expression level of miR-345 was reduced in NSCLC tissues and cell lines. Low tissue miR-345 expression was associated with progression and poor prognosis of NSCLC, indicating that tissue miR-345 may serve as a novel prognostic marker in NSCLC. PMID:26885027

  6. Prognostic factors of tumor recurrence in completely resected non-small cell lung cancer

    PubMed Central

    Tantraworasin, Apichat; Saeteng, Somcharoen; Lertprasertsuke, Nirush; Arreyakajohn, Nuttapon; Kasemsarn, Choosak; Patumanond, Jayanton

    2013-01-01

    Background Patients with completely resected non-small cell lung cancer (NSCLC) have an excellent outcome; however tumor recurs in 30%–77% of patients. This study retrospectively analyzed the clinicopathologic features of patients with any operable stage of NSCLC to identify the prognostic factors that influence tumor recurrence, including intratumoral blood vessel invasion (IVI), tumor size, tumor necrosis, and intratumoral lymphatic invasion. Methods From January 2002 to December 2011, 227 consecutive patients were enrolled in this study. They were divided into two groups: the “no recurrence” group and the “recurrence” group. Recurrence-free survival was analyzed by multivariable Cox regression analysis, stratified by tumor staging, chemotherapy, and nodal involvement. Results IVI, tumor necrosis, tumor diameter more than 5 cm, and nodal involvement were identified as independent prognostic factors of tumor recurrence. The hazard ratio (HR) of patients with IVI was 2.1 times higher than that of patients without IVI (95% confident interval [CI]: 1.4–3.2) (P = 0.001).The HR of patients with tumor necrosis was 2.1 times higher than that of patients without tumor necrosis (95% CI: 1.3–3.4) (P = 0.001). Patients who had a maximum tumor diameter greater than 5 cm had significantly higher risk of recurrence than patients who had a maximum tumor diameter of less than 5 cm (HR 1.9, 95% CI: 1.0–3.5) (P = 0.033). Conclusion IVI, tumor diameter more than 5 cm, and tumor necrosis are prognostic factors of tumor recurrence in completely resected NSCLC. Therefore, NSCLC patients, with or without nodal involvement, who have one or more prognostic factors of tumor recurrence may benefit from adjuvant chemotherapy for prevention of tumor recurrence. PMID:23785244

  7. Silence of fibronectin 1 increases cisplatin sensitivity of non-small cell lung cancer cell line.

    PubMed

    Gao, Weiwei; Liu, Ying; Qin, Ruiling; Liu, Daijian; Feng, Qingqing

    2016-07-15

    Fibronectin 1 (FN1) is a member of the glycoprotein family which is widely expressed by multiple cell types and involved in cellular adhesion and migration processes. Recent studies have reported that FN1 might have a role in regulating chemoresistance in tumors. However, the regulation of FN1 on cisplatin resistance in non-small cell lung cancer (NSCLC) has not been investigated. The present study aims to illustrate the effect of FN1 on cisplatin resistance in NSCLC and explore potential mechanisms. In the present study, the mRNA and protein expression levels of FN1 were investigated by RT-PCR and Western blot analysis, respectively, and the 50% inhibitory concentration (IC50) value of cisplatin was measured by MTT assay. Apoptotic ratio and migration were determined using an annexin V-FITC/PI detection kit and a Transwell assay, respectively. The interaction between FN1 and integrin-β1 was evaluated by co-immunoprecipitation assay. The protein expression of β-catenin, cyclin D1 and c-myc were tested using Western blot analysis. The results showed that FN1 was more highly expressed in A549/DDP than in A549 cells, and significantly upregulated by cisplatin treatment in H1299 cells. Knockdown of FN1 reduced the IC50 value of cisplatin, inhibited cell migration and promoted apoptosis. FN1 and integrin-β1 protein directly interacted with each other both in A549 and A549/DDP cells. FN1 silencing suppressed the Wnt/β-catenin signaling pathway, and this effect was dampened by integrin-β1-blocking antibody. Taken together, our findings first suggest that FN1 plays a role in the development of cisplatin resistance in NSCLC, possibly by modulation of β-catenin signaling through interaction with integrin-β1 in NSCLC. PMID:27207836

  8. Efficacy and Safety of Bevacizumab in Active Brain Metastases from Non-Small Cell Lung Cancer

    PubMed Central

    De Braganca, Kevin C.; Janjigian, Yelena Y.; Azzoli, Christopher G.; Kris, Mark G.; Pietanza, Maria C.; Nolan, Craig P.; Omuro, Antonio M.; Holodny, Andrei I.; Lassman, Andrew B.

    2011-01-01

    Background Bevacizumab is effective for the treatment of non-small cell lung cancer (NSCLC). Ongoing trials are exploring the safety of bevacizumab in patients with inactive, previously treated brain metastases. However, bevacizumab safety and efficacy in the treatment of active brain metastases is unknown. Bevacizumab received accelerated FDA approval for progressive glioblastoma, a primary brain tumor, because of high response rates and low incidence of intracranial hemorrhage. Methods We retrospectively identified patients treated with bevacizumab for active (treatment naïve or progressive) central nervous system (CNS) metastases from NSCLC. MRI scans performed at least 6 weeks after initiating bevacizumab were assessed for response. Results There were six patients, four women and two men with a median age of 60 years (range 59–77) at initiation of bevacizumab. Five patients had progressive CNS metastases despite prior treatment including surgery, radiotherapy, and/or chemotherapy; one patient had treatment-naïve brain metastases. Two patients had leptomeningeal metastases, isolated or coexistent with parenchymal brain metastases in one patient each. Bevacizumab was administered alone to one patient and in combination with various cytotoxic chemotherapies in the others. Toxicity included an asymptomatic (Grade 1) intra-tumoral hemorrhage which occurred in one of three patients receiving concurrent anticoagulation with bevacizumab. There was no recurrent CNS bleeding in two patients with a prior history of such hemorrhage. Best response (RECIST) was partial in two, stable disease in three, and progression in one. Median progression-free survival (PFS) was 4.7 months and median overall survival (OS) was 14.1 months following initiation of bevacizumab. Clinical benefit was also observed in the form of improved symptoms and reduced corticosteroid requirements. Conclusions Bevacizumab should be used with caution in patients with active CNS metastases pending

  9. Stathmin1 increases radioresistance by enhancing autophagy in non-small-cell lung cancer cells.

    PubMed

    Zhang, Xi; Ji, Jingfen; Yang, Yu; Zhang, Juan; Shen, Liangfang

    2016-01-01

    Radioresistance has been demonstrated to be involved in the poor prognosis of patients with non-small-cell lung cancer (NSCLC). However, the underlying mechanism remains largely unclear. Investigation on special therapeutic targets associated with radioresistance shows promises for the enhancement of clinical radiotherapy effect toward NSCLC. This study aimed to reveal the role of Stathmin1 (STMN1) in radioresistance in NSCLC as well as the underlying mechanism. Our data showed that the protein levels of STMN1 were significantly upregulated in NSCLC cells subjected to radiation, accompanied with the activation of autophagy. Knockdown of STMN1 expression enhanced the sensitivity of NSCLC cells to X-ray, and the radiation-induced autophagy was also inhibited. Molecular mechanism investigation showed that knockdown of STMN1 expression upregulated the activity of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway in NSCLC cells. Moreover, the activation of PI3K/mTOR signaling showed an inhibitory effect on the autophagy and radioresistance induced by STMN1 in NSCLC cells. In addition, luciferase reporter assay data indicated that STMN1 was a direct target gene of miR-101, which had been reported to be an inhibitor of autophagy. Based on these data, we suggest that as a target gene of miR-101, STMN1 promotes the radioresistance by induction of autophagy through PI3K/mTOR signaling pathway in NSCLC. Therefore, STMN1 may become a potential therapeutic target for NSCLC radiotherapy. PMID:27199567

  10. RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis

    PubMed Central

    Tsuta, K; Kohno, T; Yoshida, A; Shimada, Y; Asamura, H; Furuta, K; Kushima, R

    2014-01-01

    Background: To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors. Methods: We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription–PCR (RT–PCR) were performed to detect RET gene rearrangement. Results: In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B–RET fusion genes, whereas 3 possessed CCDC6–RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P<0.001). Conclusions: The RET rearrangements were observed in 1.2% of NSCLCs. All cases of RET rearrangement were ADCs. The RET rearrangements were more likely to be observed in younger patients. Although cytoplasmic mucin production was at least focally present in 54.5% of RET-rearranged ADCs, specific histological features were not detected. PMID:24504365

  11. Effect of image-guided hypofractionated stereotactic radiotherapy on peripheral non-small-cell lung cancer

    PubMed Central

    Wang, Shu-wen; Ren, Juan; Yan, Yan-li; Xue, Chao-fan; Tan, Li; Ma, Xiao-wei

    2016-01-01

    The objective of this study was to compare the effects of image-guided hypofractionated radiotherapy and conventional fractionated radiotherapy on non-small-cell lung cancer (NSCLC). Fifty stage- and age-matched cases with NSCLC were randomly divided into two groups (A and B). There were 23 cases in group A and 27 cases in group B. Image-guided radiotherapy (IGRT) and stereotactic radiotherapy were conjugately applied to the patients in group A. Group A patients underwent hypofractionated radiotherapy (6–8 Gy/time) three times per week, with a total dose of 64–66 Gy; group B received conventional fractionated radiotherapy, with a total dose of 68–70 Gy five times per week. In group A, 1-year and 2-year local failure survival rate and 1-year local failure-free survival rate were significantly higher than in group B (P<0.05). The local failure rate (P<0.05) and distant metastasis rate (P>0.05) were lower in group A than in group B. The overall survival rate of group A was significantly higher than that of group B (P=0.03), and the survival rate at 1 year was 87% vs 63%, (P<0.05). The median survival time of group A was longer than that of group B. There was no significant difference in the incidence of complications between the two groups (P>0.05). Compared with conventional fractionated radiation therapy, image-guided hypofractionated stereotactic radiotherapy in NSCLC received better treatment efficacy and showed good tolerability. PMID:27574441

  12. Cost-Effectiveness of Multiplexed Predictive Biomarker Screening in Non-Small Cell Lung Cancer

    PubMed Central

    Romanus, Dorothy; Cardarella, Stephanie; Cutler, David; Landrum, Mary Beth; Lindeman, Neal I.; Gazelle, G. Scott

    2015-01-01

    Introduction Population-wide screening for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements to inform cancer therapy in non-small cell lung cancer (NSCLC) is recommended by guidelines. We estimated cost-effectiveness of multiplexed predictive biomarker screening in metastatic NSCLC from a societal perspective in the US. Methods We constructed a micro simulation model to compare the life expectancy and costs of multiplexed testing and molecularly guided therapy vs treatment with cisplatin-pemetrexed (CisPem). All testing interventions included a two-step algorithm of concurrent EGFR mutation and ALK overexpression testing with immunohistochemistry (IHC) followed by ALK rearrangement confirmation with a fluorescence in situ hybridization (FISH) assay for IHC positive results. Three test strategies were included: ‘Test-treat’ approach, where molecularly guided therapy was initiated after obtainment of test results; ‘Empiric switch therapy’, with concurrent initiation of CisPem and testing and immediate switch to test-result conditional treatment after one cycle of CisPem; and ‘Empiric therapy’ approach in which CisPem was continued for four cycles before start of a tyrosine kinase inhibitor (TKI). Results The incremental cost-effectiveness ratio (ICER) for ‘Test-treat’ compared to treatment with CisPem was $136,000 per quality-adjusted life year (QALY) gained. Both empiric treatment approaches had less favorable ICERs.‘Test-treat’ and ‘Empiric switch therapy’ yielded higher expected outcomes in terms of QALYs and life-years (LYs) than ‘Empiric therapy’.These results were robust across plausible ranges of model inputs. Conclusion From a societal perspective, our cost-effectiveness results support the value of multiplexed genetic screening and molecularly guided therapy in metastatic NSCLC. PMID:25590606

  13. Dose escalation with stereotactic body radiation therapy boost for locally advanced non small cell lung cancer

    PubMed Central

    2013-01-01

    Introduction Low survival outcomes have been reported for the treatment of locally advanced non small cell lung cancer (LA-NSCLC) with the standard of care treatment of concurrent chemoradiation (cCRT). We present our experience of dose escalation using stereotactic body radiosurgery (SBRT) following conventional cCRT for patients with LA-NSCLC. Methods Sixteen patients with a median age of 67.5 treated with fractionated SBRT from 2010 to 2012 were retrospectively analyzed. Nine (56%) of the patients had stage IIIB, 6 (38%) has stage IIIA, and 1 (6%) had recurrent disease. Majority of the patients (63%) presented with N2 disease. All patients had a PET CT for treatment planning. Patients received conventional cCRT to a median dose of 50.40 Gy (range 45–60) followed by an SBRT boost with an average dose of 25 Gy (range 20–30) given over 5 fractions. Results With a median follow-up of 14 months (range, 1–14 months), 1-year overall survival (OS), progression free survival (PFS), local control (LC), regional control (RC), and distant control (DC) rates were, 78%, 42%, 76%, 79%, and 71%, respectively. Median times to disease progression and regional failure were 10 months and 18 months, respectively. On univariate analysis, advanced age and nodal status were worse prognostic factors of PFS (p < 0.05). Four patients developed radiation pneumonitis and one developed hemoptysis. Treatment was interrupted in one patient who required hospitalization due to arrhythmias and pneumonia. Conclusion Risk adaptive dose escalation with SBRT following external beam radiotherapy is possible and generally tolerated treatment option for patients with LA-NSCLC. PMID:23842112

  14. Prognostic Factors in Stereotactic Body Radiotherapy for Non-Small-Cell Lung Cancer

    SciTech Connect

    Matsuo, Yukinori; Shibuya, Keiko; Nagata, Yasushi; Takayama, Kenji; Norihisa, Yoshiki; Mizowaki, Takashi; Narabayashi, Masaru; Sakanaka, Katsuyuki; Hiraoka, Masahiro

    2011-03-15

    Purpose: To investigate the factors that influence clinical outcomes after stereotactic body radiotherapy (SBRT) for non-small-cell lung cancer (NSCLC). Methods and Materials: A total of 101 consecutive patients who underwent SBRT with 48 Gy in 4 fractions for histologically confirmed Stage I NSCLC were enrolled in this study. Factors including age, maximal tumor diameter, sex, performance status, operability, histology, and overall treatment time were evaluated with regard to local progression (LP), disease progression (DP), and overall survival (OS) using the Cox proportional hazards model. Prognostic models were built with recursive partitioning analysis. Results: Three-year OS was 58.6% with a median follow-up of 31.4 months. Cumulative incidence rates of LP and DP were 13.2% and 40.8% at 3 years, respectively. Multivariate analysis demonstrated that tumor diameter was a significant factor in all endpoints of LP, DP, and OS. Other significant factors were age in DP and sex in OS. Recursive partitioning analysis indicated a condition for good prognosis (Class I) as follows: female or T1a (tumor diameter {<=}20 mm). When the remaining male patients with T1b-2a (>20 mm) were defined as Class II, 3-year LP, DP, and OS were 6.8%, 23.6%, and 69.9% in recursive partitioning analysis Class I, respectively, whereas these values were 19.9%, 58.3%, and 47.1% in Class II. The differences between the classes were statistically significant. Conclusions: Tumor diameter and sex were the most significant factors in SBRT for NSCLC. T1a or female patients had good prognosis.

  15. Targeting SLC1A5-mediated glutamine dependence in non-small cell lung cancer

    PubMed Central

    Hassanein, Mohamed; Qian, Jun; Hoeksema, Megan D.; Wang, Jing; Jacobovitz, Marie; Ji, Xiangming; Harris, Fredrick T.; Harris, Bradford K.; Boyd, Kelli L.; Chen, Heidi; Eisenberg, Rosana; Massion, Pierre P.

    2015-01-01

    We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non-small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma-L-glutamyl-p-nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p =0.01, HR =1.24, 95% CI: 1.05–1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR =1.45, 95% CI: 1.15–1.50) and multivariate analyses (p =0.04, HR =1.22, 95% CI: 1.01–1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln-dependent NSCLC. PMID:25821004

  16. Tenascin-C serum levels and its prognostic power in non-small cell lung cancer

    PubMed Central

    Zander, Hilke; Meyer, Karl-Frederick; Wolters-Eisfeld, Gerrit; Izbicki, Jakob R.; Bockhorn, Maximilian; Tachezy, Michael

    2016-01-01

    Background Tenascin-C is overexpressed in the stroma of most solid malignancies and may function as a diagnostic tumor marker. This study was conducted to evaluate the potential significance of Tenascin-C as a predictive marker for tumor progression in the sera of non-small cell lung cancer (NSCLC) patients. Results Serum concentration of Tenascin-C is significantly elevated in NSCLC patients compared to healthy controls (p=0.013). The sensitivity of Tenascin-C in detecting NSCLC was 74% at a specificity of 57%. Elevated Tenascin-C serum values are associated with larger tumor size and lymph node involvement (p=0.022 and p=0.036, respectively). The Kaplan-Meyer-curves showed a significant association of Tenascin-C with the patient's overall survival (p=0.004), but not with the recurrence-free survival (p=0.328). Methods We quantified Tenascin-C in the sera of 103 NSCLC patients and 76 healthy blood donors by enzyme-linked immune-absorbance assay tests. Prognostic significance was determined by area under the curve analysis and Youden-index. The results were correlated with clinical, histopathological, and patient survival data (Chi-square test, Kaplan-Meier analysis, log-rank test, multivariate Cox-regression analysis). Conclusion Although significantly elevated in patients with NSCLC, the sensitivity and specificity of the Tenascin-C serum quantification test was low. However, although failing to be an independent prognosticator in multivariate analysis, the results implicate Tenascin-C as a predictive prognostic marker for NSCLC patients. The data must be further validated in future prospective trials with larger patient cohorts. PMID:26967391

  17. Impact of Neoadjuvant Radiation on Survival in Stage III Non-Small-Cell Lung Cancer

    SciTech Connect

    Koshy, Matthew; Goloubeva, Olga; Suntharalingam, Mohan

    2011-04-01

    Purpose: The role of surgery in Stage III non-small-cell lung cancer (NSCLC) is controversial. This study was undertaken to assess the impact of neoadjuvant radiation therapy for Stage III NSCLC. Methods and Materials: This was a retrospective study from the Surveillance, Epidemiology, and End Results (SEER) database that included patients who were 18 years and older with NSCLC classified as Stage III and who underwent definitive therapy from 1988 to 2004. Patients were characterized by type of treatment received. Survival functions were estimated by the Kaplan-Meier method, and Cox regression model was used to analyze trends in overall (OS) and cause-specific survival (CSS). Results: A total of 48,131 patients were selected, with a median follow-up of 10 months (range, 0-203 months). By type of treatment, the 3-year OS was 10% with radiation therapy (RT), 37% with surgery (S), 34% with surgery and postoperative radiation (S-RT), and 45% with neoadjuvant radiation followed by surgery (Neo-RT) (p = 0.0001). Multivariable Cox model identified sex, race, laterality, T stage, N stage, and type of treatment as factors affecting survival. Estimated hazard ratios (HR) adjusted for other variables in regression model showed the types of treatment: S (HR, 1.3; 95% confidence interval [CI], 1.2-1.4), S-RT (HR, 1.2; 95% CI, 1.1-1.3), and RT (HR, 2.3; 95% CI, 2.15-2.53) were associated with significantly worse overall survival when compared with Neo-RT (p = 0.0001). Conclusion: This population based study demonstrates that patients with Stage III NSCLC receiving Neo-RT had significantly improved overall survival when compared with other treatment groups.

  18. Serum HE4: An Independent Prognostic Factor in Non-Small Cell Lung Cancer

    PubMed Central

    Lamy, Pierre-Jean; Plassot, Carine; Pujol, Jean-Louis

    2015-01-01

    Human epididymis secretory protein 4 (HE4) is a secreted glycosylated protein encoded by the WAP four-disulfide core domain 2 (WFDC2) gene, located on a chromosome 20 segment that is frequently amplified in many cancers. This study aimed at determining serum HE4 prognostic value in non-small cell lung cancer (NSCLC), following the REMARK guidelines. Serum samples from 346 consecutive patients with histologically proven and previously untreated NSCLC and 41 patients with benign pulmonary disease were collected at the Montpellier-Nimes Academic Hospital. Work-up investigations performed to determine the disease characteristics and treatment algorithms were congruent with international guidelines. HE4 levels in serum were measured with an ELISA test (Fujirebio Diagnostics) that uses two monoclonal antibodies, 2H5 and 3D8, against the C-WFDC domain of HE4. The area under the ROC curve (i.e., overall ability of HE4 to discriminate between controls and patients) was 0.78 (95% confidence interval [CI], 0.738–0.821; z test P <0.0001). Serum HE4 levels were significantly higher in patients with worse performance status, advanced TNM stage and positive nodal status. In the Cox model, overall survival was shorter in patients with high pretreatment serum HE4 (above 140 pmol/L) than in patients with serum H4 level ≤ 140 pmol/L [median survival: 17.7 weeks (95% CI, 11.9 to 24.9) and 46.4 weeks (95% CI, 38.6 to 56.3), respectively; hazard ratio: 1.48 (95% CI, 1.12 to 1.95) for high HE4; adjusted P = 0.0057]. High serum HE4 level at diagnosis is an independent determinant of poor prognosis in NSCLC. PMID:26030627

  19. AZD9291 in epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

    PubMed

    Stinchcombe, Thomas E

    2016-02-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60-70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGFR TKI with activity against the activating EGFR mutation, the T790M acquired resistance mutation, and relative sparing of the wild-type EGFR. AZD9291 was investigated in a phase I trial with expansion cohorts in patients with disease progression after EGFR TKI. Patients with and without detectable T790M mutations were enrolled in the trial. The ORR in patients with centrally confirmed and without detectable T790M mutations was 61% (95% CI, 52-70%) and 21% (95% CI, 12-34%), respectively. The PFS observed in patients with centrally confirmed and without detectable T790M mutations was 9.6 months (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1-4.3 months), respectively. At the dose for further investigation, 80 mg daily, the rate of all grade 3-5 drug related adverse events was 11%, and the rates of grade 3 diarrhea and rash were 1% and 0%, respectively. The identification of the T790M resistance mutation and the subsequent development of an agent against the mechanism of resistance provide a template for future drug development for acquired resistance to targeted therapy. PMID:26958499

  20. Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2

    PubMed Central

    Wang, Yao-Chen; He, Tsung-Ying; Lee, Ming-Ching; Yeh, Sauh-Der; Chen, Chih-Yi; Lee, Huei

    2015-01-01

    Nrf2 is a key transcription factor for genes coding for antioxidants, detoxification enzymes, and multiple drug resistance and it also confers resistance to anticancer drugs. Here, we hypothesized that mutant p53 could upregulate Nrf2 expression at the transcriptional level, thereby conferring cisplatin resistance in non-small cell lung cancer (NSCLC). Luciferase reporter assays and real-time PCR analysis indicated that the Nrf2 promoter activity and its mRNA levels were markedly suppressed by wild-type p53, but not by mutant p53. Chromatin immunoprecipitation (ChIP) further confirmed that wild-type p53 binds at the p53 putative binding site to block Sp1 binding to the Nrf2 promoter and consequently to suppress the Nrf2 promoter activity. The MTT assay indicated that an increase in Nrf2 expression by mutant p53 is responsible for cisplatin resistance. Among the Nrf2 downstream genes, Bcl-2 and Bcl-xL contribute more strongly to Nrf2-mediated cisplatin resistance when compared with heme oxygenase 1 (HO-1). Cox regression analysis showed that patients with high-Nrf2, high-Bcl-2, high-Bcl-xL mRNA tumors were more commonly occurred unfavorable response to cisplatin-based chemotherapy than their counterparts. The prognostic significance of Nrf2 mRNA levels on OS and RFS was also observed in patients who have received cisplatin-based chemotherapy, particularly in p53-mutant patients. Collectively, mutant p53 may confer cisplatin resistance via upregulation of Nrf2 expression, and Nrf2 mRNA level may predict chemotherapeutic response and outcomes in NSCLC. PMID:26497680

  1. Surgical Outcomes of Synchronous Multiple Primary Non-Small Cell Lung Cancers

    PubMed Central

    Zhang, Zhirong; Gao, Shugeng; Mao, Yousheng; Mu, Juwei; Xue, Qi; Feng, Xiaoli; He, Jie

    2016-01-01

    The prognostic indicators for synchronous multiple primary non-small cell lung cancer (NSCLC) vary across reports. In present study, the prognostic factors for the patients with synchronous multiple primary NSCLC were analyzed in a large cohort. A total of 285 patients with synchronous multiple primary NSCLC who underwent radical surgical resection and with complete follow-up information were included in this study. The Kaplan-Meier method were used for survival analysis, Cox proportional hazards regression models were used for risk factors evaluation. Among them, 94 (33.0%) patients had bilateral tumors and 51 (17.9%) had multiple (≥3) tumors. The 5-year disease-free survival (DFS) and overall survival (OS) rate was 58.7% and 77.6%, respectively. Univariate analysis identified parameters conferring shorter OS including male gender, symptomatic disease, negative family history, large maximal tumor size, not all adenocarcinomas, advanced highest T stage, and lymph node involvement. Multivariate analysis showed that male gender (p = 0.020), symptomatic disease (p = 0.017), and lymph node involvement (p < 0.001) were independent adverse prognosticators. For patients with multiple adenocarcinomas, the 5-year DFS and OS rate was 59.6% and 82.4%, respectively. The subtypes other than lepidic predominant (p < 0.001) and lymph node involvement (p = 0.002) were the independent unfavorable prognosticators. In conclusion, we identified independent prognosticators which will provide the valuable clues for postoperative management of patients with synchronous multiple primary NSCLC. PMID:27254665

  2. Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma

    SciTech Connect

    Xu, Jie; Zeng, Li-Fan; Shen, Weihua; Turchi, John J.; Zhang, Zhong-Yin

    2013-10-04

    Highlights: •SHP2 is required for EGFR inhibitor resistant NSCLC H1975 cell proliferation. •SHP2 inhibitor blocks EGF-stimulated ERK1/2 activation and proliferation. •SHP2 inhibitor exhibits marked anti-tumor activity in H1975 xenograft mice. •SHP2 inhibitor synergizes with PI3K inhibitor in suppressing cell growth. •Targeting SHP2 represents a novel strategy for EGFR inhibitor resistant NSCLCs. -- Abstract: Targeted therapy with inhibitors of epidermal growth factor receptor (EGFR) has produced a noticeable benefit to non-small cell lung cancer (NSCLC) patients whose tumors carry activating mutations (e.g. L858R) in EGFR. Unfortunately, these patients develop drug resistance after treatment, due to acquired secondary gatekeeper mutations in EGFR (e.g. T790M). Given the critical role of SHP2 in growth factor receptor signaling, we sought to determine whether targeting SHP2 could have therapeutic value for EGFR inhibitor resistant NSCLC. We show that SHP2 is required for EGF-stimulated ERK1/2 phosphorylation and proliferation in EGFR inhibitor resistant NSCLC cell line H1975, which harbors the EGFR T790M/L858R double-mutant. We demonstrate that treatment of H1975 cells with II-B08, a specific SHP2 inhibitor, phenocopies the observed growth inhibition and reduced ERK1/2 activation seen in cells treated with SHP2 siRNA. Importantly, we also find that II-B08 exhibits marked anti-tumor activity in H1975 xenograft mice. Finally, we observe that combined inhibition of SHP2 and PI3K impairs both the ERK1/2 and PI3K/AKT signaling axes and produces significantly greater effects on repressing H1975 cell growth than inhibition of either protein individually. Collectively, these results suggest that targeting SHP2 may represent an effective strategy for treatment of EGFR inhibitor resistant NSCLCs.

  3. Marsdenia tenacissima extract restored gefitinib sensitivity in resistant non-small cell lung cancer cells.

    PubMed

    Han, Shu-Yan; Zhao, Ming-Bo; Zhuang, Gui-Bao; Li, Ping-Ping

    2012-01-01

    Most non-small cell lung cancer (NSCLC) patients responding to gefitinib harbor activating mutations in the epidermal growth factor receptor (EGFR). However, the responsive cases eventually develop the resistance to gefitinib. Besides, K-ras mutations were identified as the primary resistance to gefitinib. We investigated whether Marsdenia tenacissima extract (MTE, trade name: Xiao-Ai-Ping injection) combined with gefitinib could overcome the resistance of NSCLC cells to gefitinib. NSCLC cell lines with different sensitivities to gefitinib were studied. Cell growth and apoptosis were evaluated by MTT assay and flow cytometry, respectively. The EGFR-related signaling molecule phosphorylation was assessed by Western blotting. We found that MTE inhibited cell growth in gefitinib-sensitive and -resistant cells. In gefitinib-resistant cells, the MTE→MTE+gefitinib (M→M+G) treatment was most potent over the concurrent administration of MTE and gefitinib (M+G) or gefitinib→gefitinib+MTE (G→G+M) treatment in cell growth inhibition and apoptosis induction. The M→M+G treatment significantly reduced the phosphorylation of EGFR downstream signaling molecules PI3K/Akt/mTOR and ERK, on which MTE and gefitinib alone had no obvious effects on the resistant cells. The M→M+G treatment attenuated c-Met phosphorylation in H460 and H1975 as well. Thus, we found that the M→M+G treatment improved the sensitivity of resistant NSCLC cells carrying T790M or K-ras mutations to gefitinib, suggesting that the M→M+G treatment may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLC. PMID:21757251

  4. A comparison of methods for EGFR mutation testing in non-small cell lung cancer.

    PubMed

    Young, Elizabeth C; Owens, Martina M; Adebiyi, Idowu; Bedenham, Tina; Butler, Rachel; Callaway, Jonathan; Cranston, Treena; Crosby, Charlene; Cree, Ian A; Dutton, Laura; Faulkes, Catherine; Faulkner, Claire; Howard, Emma; Knight, Julia; Huang, Yuanxue; Lavender, Louise; Lazarou, Lazarus P; Liu, Hongxiang; Mair, Debbie; Milano, Antonio; Sandell, Stacey; Skinner, Alison; Wallace, Andrew; Williams, Maggie; Spivey, Vicky; Goodall, John; Frampton, Jonathan; Ellard, Sian

    2013-12-01

    EGFR mutation testing of tumor samples is routinely performed to predict sensitivity to treatment with tyrosine kinase inhibitors for patients with non-small cell lung cancer. At least 9 different methodologies are employed in UK laboratories, and the aim of this study was to compare the sensitivity of different methods for the detection of EGFR mutations. Participating laboratories were sent coded samples with varying mutation loads (from 0% to 15%) to be tested for the p.Leu858Arg (p.L858R) missense mutation and c.2235_2249del exon 19 deletion. The p.L858R mutation and deletions within exon 19 of the EGFR gene account for ∼90% of mutation-positive cases. The 11 laboratories used their standard testing method(s) and submitted 15 sets of results for the p.L858R samples and 10 for the exon 19 deletion. The p.Leu858Arg (p.L858R) mutation was detected at levels between 1% and 7.5% by Sanger sequencing, pyrosequencing, real-time polymerase chain reaction (PCR), amplification refractory mutation system, and capillary electrophoresis single-strand conformation analysis. The c.2235_2249del mutation was detected at 1% to 5% by fragment size analysis, Sanger sequencing or real-time PCR. A mutation was detected in 24/25 (96%) of the samples tested which contained 5% mutated DNA. The 1% sensitivity claimed for commercial real-time PCR-targeted EGFR tests was achieved and our results show greater sensitivity for the Sanger sequencing and pyrosequencing screening methods compared to the 10% to 20% detection levels cited on clinical diagnostic reports. We conclude that multiple methodologies are suitable for the detection of acquired EGFR mutations. PMID:24193010

  5. Proteasome inhibition improves fractionated radiation treatment against non-small cell lung cancer: an antioxidant connection.

    PubMed

    Grimes, Kristopher Ray; Daosukho, Chotiros; Zhao, Yunfeng; Meigooni, Ali; St Clair, William

    2005-10-01

    Non-small cell lung cancer frequently presents as a locally advanced disease. In this setting, radiation has a prominent role in cancer therapy. However, tumor adaptation to oxidative stress may lessen the efficacy of radiation therapy. Recent studies demonstrate that proteasome inhibitors increase the efficacy of radiation against a range of tumors. Although proteasome inhibition impacts on NF-kappaB translocation, the precise mechanism through which proteasome inhibitors induce tumor cell death and promote radiation efficacy remains unclear. The purpose of this study is to evaluate the potential of the proteasome inhibitor, MG-132, to improve the efficacy of radiation therapy and to determine whether its effect is linked to the suppression of the antioxidant enzyme, manganese superoxide dismutase (MnSOD). Human NSCLC (A549) cells were utilized both in vivo and in vitro to evaluate proteasome inhibition on radiation response. In vivo, mice that received combined treatments of 2.5 microg/g body weight MG-132 and 30 Gy demonstrated a delay in tumor regrowth in comparison to the 30 Gy control group. In vitro, clonegenic survival assays confirmed a dose-dependent enhancement of radiation sensitivity in combination with MG-132 and a significant interaction between the two. The levels of IkappaB-alpha, a NF-kappaB target gene and also an inhibitor of NF-kappaB nuclear translocation, decreased in a time-dependent manner following administration of MG-132 confirming the inhibition of the 26S proteasome. The MnSOD protein level was increased consistent with lower levels of IkappaB-alpha, confirming a NF-kappaB-mediated effect. Cells treated with radiation demonstrated an induction of MnSOD; however, the administration of MG-132 suppressed this induction These results support the hypothesis that proteasome inhibitors such as MG-132 can increase the efficacy of radiation therapy, in part, by suppression of cytoprotective NF-kappaB-mediated MnSOD expression. PMID:16142322

  6. Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer.

    PubMed

    Mauceri, Helena J; Sutton, Harold G; Darga, Thomas E; Kocherginsky, Masha; Kochanski, Joel; Weichselbaum, Ralph R; Vokes, Everett E

    2012-05-01

    Signaling pathways that activate mTOR (mammalian target of rapamycin) are altered in many human cancers and these alterations are associated with prognosis and treatment response. mTOR inhibition can restore sensitivity to DNA damaging agents such as cisplatin. The rapamycin derivative everolimus exhibits antitumor activity and is approved for patients with renal cell cancer. Clinically, everolimus has also been evaluated in patients with advanced non-small cell lung cancer (NSCLC) that were refractory to chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors. We tested the effects of combined treatment with everolimus (RAD001) and fractionated radiation using a xenograft model of human NSCLC (A549 cells). In growth studies, mean tumor volume was reduced in the everolimus plus 30 Gy cohort with significant tumor growth suppression compared to 30 Gy alone (p=0015), or everolimus alone (p<0.001, ANOVA). everolimus (20 nM) significantly reduced protein levels of the mTOR downstream effector p70-S6K compared with radiation and vehicle (p=0.05, ANOVA) and significantly suppressed phospho-p70-S6K levels compared with all other treatments (p<0.001, ANOVA). We also evaluated everolimus and radiation effects on gene expression in A549 cells. Everolimus ± 5 Gy suppressed endothelin 1 and lactate dehydrogenase expression and increased VEGFA, p21, hypoxia-inducible factor-1α and SLC2A1 (facilitated glucose transporter 1). mTOR mRNA levels were unaffected while TNF-α levels were increased with everolimus + 5 Gy compared to either treatment alone. These findings suggest that everolimus increases the antitumor activity of radiation. Clinical trials combining everolimus with fractionated radiation in patients with NSCLC are warranted. PMID:22294050

  7. Dose escalation for unresectable locally advanced non-small cell lung cancer: end of the line?

    PubMed

    Hong, Julian C; Salama, Joseph K

    2016-02-01

    Radiation Therapy Oncology Group (RTOG) 0617 was a randomized trial that investigated both the impact of radiation dose-escalation and the addition of cetuximab on the treatment of non-small cell lung cancer (NSCLC). The results of RTOG 0617 were surprising, with the dose escalation randomization being closed prematurely due to futility stopping rules, and cetuximab ultimately showing no overall survival benefit. Locally advanced unresectable NSCLC has conventionally been treated with concurrent chemoradiation. Though advances in treatment technology have improved the ability to deliver adequate treatment dose, the foundation for radiotherapy (RT) has remained the same since the 1980s. Since then, progressive studies have sought to establish the safety and efficacy of escalating radiation dose to loco-regional disease. Though RTOG 0617 did not produce the anticipated result, much interest remains in dose escalation and establishing an explanation for the findings of this study. Cetuximab was also not found to provide a survival benefit when applied to an unselected population. However, planned retrospective analysis suggests that those patients with high epidermal growth factor receptor (EGFR) expression may benefit, suggesting that cetuximab should be applied in a targeted fashion. We discuss the results of RTOG 0617 and additional findings from post-hoc analysis that suggest that dose escalation may be limited by normal tissue toxicity. We also present ongoing studies that aim to address potential causes for mortality in the dose escalation arm through adaptive or proton therapy, and are also leveraging additional concurrent systemic agents such as tyrosine kinase inhibitors (TKIs) for EGFR-activating mutations or EML4-ALK rearrangements, and poly (ADP-ribose) polymerase (PARP) inhibitors. PMID:26958507

  8. Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

    PubMed Central

    Facchinetti, Francesco; Di Maio, Massimo; Graziano, Paolo; Bria, Emilio; Rossi, Giulio; Novello, Silvia

    2016-01-01

    Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient. PMID:27413712

  9. Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen.

    PubMed

    Forsberg, G; Ohlsson, L; Brodin, T; Björk, P; Lando, P A; Shaw, D; Stern, P L; Dohlsten, M

    2001-07-01

    Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA(D227A)bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a Kd of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA(D227A)tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA(D227A)induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10(-10)M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA(D227A)against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA(D227A). Thus, 5T4FabV13-SEA(D227A)has highly attractive properties for therapy of human NSCLC. PMID:11437414

  10. Surgical Outcomes of Synchronous Multiple Primary Non-Small Cell Lung Cancers.

    PubMed

    Zhang, Zhirong; Gao, Shugeng; Mao, Yousheng; Mu, Juwei; Xue, Qi; Feng, Xiaoli; He, Jie

    2016-01-01

    The prognostic indicators for synchronous multiple primary non-small cell lung cancer (NSCLC) vary across reports. In present study, the prognostic factors for the patients with synchronous multiple primary NSCLC were analyzed in a large cohort. A total of 285 patients with synchronous multiple primary NSCLC who underwent radical surgical resection and with complete follow-up information were included in this study. The Kaplan-Meier method were used for survival analysis, Cox proportional hazards regression models were used for risk factors evaluation. Among them, 94 (33.0%) patients had bilateral tumors and 51 (17.9%) had multiple (≥3) tumors. The 5-year disease-free survival (DFS) and overall survival (OS) rate was 58.7% and 77.6%, respectively. Univariate analysis identified parameters conferring shorter OS including male gender, symptomatic disease, negative family history, large maximal tumor size, not all adenocarcinomas, advanced highest T stage, and lymph node involvement. Multivariate analysis showed that male gender (p = 0.020), symptomatic disease (p = 0.017), and lymph node involvement (p < 0.001) were independent adverse prognosticators. For patients with multiple adenocarcinomas, the 5-year DFS and OS rate was 59.6% and 82.4%, respectively. The subtypes other than lepidic predominant (p < 0.001) and lymph node involvement (p = 0.002) were the independent unfavorable prognosticators. In conclusion, we identified independent prognosticators which will provide the valuable clues for postoperative management of patients with synchronous multiple primary NSCLC. PMID:27254665

  11. Identification of Logic Relationships between Genes and Subtypes of Non-Small Cell Lung Cancer

    PubMed Central

    Su, Yansen; Pan, Linqiang

    2014-01-01

    Non-small cell lung cancer (NSCLC) has two major subtypes: adenocarcinoma (AC) and squamous cell carcinoma (SCC). The diagnosis and treatment of NSCLC are hindered by the limited knowledge about the pathogenesis mechanisms of subtypes of NSCLC. It is necessary to research the molecular mechanisms related with AC and SCC. In this work, we improved the logic analysis algorithm to mine the sufficient and necessary conditions for the presence states (presence or absence) of phenotypes. We applied our method to AC and SCC specimens, and identified lower and higher logic relationships between genes and two subtypes of NSCLC. The discovered relationships were independent of specimens selected, and their significance was validated by statistic test. Compared with the two earlier methods (the non-negative matrix factorization method and the relevance analysis method), the current method outperformed these methods in the recall rate and classification accuracy on NSCLC and normal specimens. We obtained biomarkers. Among biomarkers, genes have been used to distinguish AC from SCC in practice, and other six genes were newly discovered biomarkers for distinguishing subtypes. Furthermore, NKX2-1 has been considered as a molecular target for the targeted therapy of AC, and other genes may be novel molecular targets. By gene ontology analysis, we found that two biological processes (‘epidermis development’ and ‘cell adhesion’) were closely related with the tumorigenesis of subtypes of NSCLC. More generally, the current method could be extended to other complex diseases for distinguishing subtypes and detecting the molecular targets for targeted therapy. PMID:24743794

  12. Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer

    PubMed Central

    Singh, Anju; Misra, Vikas; Thimmulappa, Rajesh K; Lee, Hannah; Ames, Stephen; Hoque, Mohammad O; Herman, James G; Baylin, Stephen B; Sidransky, David; Gabrielson, Edward; Brock, Malcolm V; Biswal, Shyam

    2006-01-01

    Background Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs. Methods and Findings Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps. Conclusions This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer

  13. Overexpression of periostin predicts poor prognosis in non-small cell lung cancer

    PubMed Central

    HONG, LING-ZHI; WEI, XIAO-WEI; CHEN, JIN-FEI; SHI, YI

    2013-01-01

    The periostin protein, encoded by the POSTN gene, is a component of the extracellular matrix, which is expressed by fibroblasts and has been observed in a variety of human malignancies. The present study aimed to detect the expression of periostin in the tissues of non-small cell lung cancer (NSCLC) patients and benign lung tumors, and to correlate the results with the clinicopathological data of the subjects, in order to evaluate periostin as a potential prognostic marker. In total, 49 NSCLC patients and 6 benign lung tumors were included in this study. The protein level of periostin was detected in paired normal/paratumor/cancer tissues by a western blot analysis and the mRNA level in paired normal/cancer tissues was detected by quantitative polymerase chain reaction (qPCR). The results were then correlated with established biological and prognostic factors. Immunohistochemistry was used to confirm the location of periostin in the NSCLC tissues. Uni- and multivariate analyses were performed using Cox’s proportional hazards regression model. The protein level of periostin was elevated in the cancer tissue of the NSCLC patients compared with the normal (P=0.017) and paratumor (P=0.000) tissues. The expression level in the male patients was much higher than in the female patients at the protein (P=0.001) and mRNA (P=0.010) levels. The mRNA level in the non-adenocarcinoma (non-ADC) patients was much higher than in the adenocarcinoma (ADC) patients (P=0.029). Periostin was demonstrated higher expression at the protein level in the pseudotumors and tuberculosis patients than in the adjacent (P=0.016) and surrounding tissues (P=0.001). Immunostaining indicated that high levels of periostin were present in the mesenchymal areas, but not in the cancer cells themselves. The patients with tumors exhibiting high-level periostin expression showed a significantly shorter survival time (P=0.036, log-rank test). The 3-year survival rate was 81.5% for patients with low

  14. Long-term survival outcomes of video-assisted thoracic surgery for patients with non-small cell lung cancer

    PubMed Central

    Shao, Wenlong; Xiong, Xinguo; Chen, Hanzhang; Liu, Jun; Yin, Weiqiang; Li, Shuben; Xu, Xin; Zhang, Xin

    2014-01-01

    Background Video-assisted thoracic surgery (VATS) has been shown to be a safe alternative to conventional thoracotomy for patients with non-small cell lung cancer (NSCLC). However, popularization of this relatively novel technique has been slow, partly due to concerns about its long-term outcomes. The present study aimed to evaluate the long-term survival outcomes of patients with NSCLC after VATS, and to determine the significant prognostic factors on overall survival. Methods Consecutive patients diagnosed with NSCLC referred to one institution for VATS were identified from a central database. Patients were treated by either complete-VATS or assisted-VATS, as described in previous studies. A number of baseline patient characteristics, clinicopathologic data and treatment-related factors were analyzed as potential prognostic factors on overall survival. Results Between January 2000 and December 2007, 1,139 patients with NSCLC who underwent VATS and fulfilled a set of predetermined inclusion criteria were included for analysis. The median age of the entire group was 60 years, with 791 male patients (69%). The median 5-year overall survival for Stage I, II, III and IV disease according to the recently updated TNM classification system were 72.2%, 47.5%, 29.8% and 28.6%, respectively. Female gender, TNM stage, pT status, and type of resection were found to be significant prognostic factors on multivariate analysis. Conclusions VATS offers a viable alternative to conventional open thoracotomy for selected patients with clinically resectable NSCLC. PMID:25232210

  15. Concomitant 5-fluorouracil infusion and high-dose radiation for stage III non-small cell lung cancer

    SciTech Connect

    Lokich, J.; Chaffey, J.; Neptune, W. )

    1989-09-01

    Thirty patients with Stage III non-small cell lung cancer were entered on a trial to evaluate the feasibility of combined radiation and concomitant 5-fluorouracil infusion. Patients had received prior debulking surgery (nine), induction chemotherapy (16), or no therapy (five). Radiation employed standard fractionation (180-200 rad/day) administered to a median cumulative dose of 5500 rad (range, 4500-6200 rad). 5-Fluorouracil was infused 24 hours per day throughout the period of radiation at a dose of 300 mg/m2/day for a median of 42 days (range, 28-56 days). Radiation complications included pneumonitis three of 30 (10%) and esophagitis (27%). Chemotherapy complications included stomatitis, two of 27 (7%), and hand-foot syndrome, three of 30 (10%). Treatment interruptions were necessary in six of 30 (20%) and four of 30 required parenteral nutrition. At a median follow-up of 12 months 26/30 (87%) maintained local control and eight had distant metastases (three of whom presented with Stage IV disease). 5-Fluorouracil delivered continuously throughout standard fractionation radiation to high cumulative doses is feasible and practical. Comparative clinical trials of the various combined radiation and chemotherapy schedules employed are in order. One additional clinical observation was the identification of six of 30 (20%) with brain metastases at presentation or after 12 months, all of whom had adenocarcinoma histologic subtype.

  16. Optimal pharmacotherapeutic strategies for elderly patients with advanced non-small cell lung cancer.

    PubMed

    Quoix, Elisabeth

    2011-11-01

    Increases in both life expectancy and cancer incidence with age result in a significant rise in lung cancer rates among elderly patients, with a median age at diagnosis of between 63 and 70 years. However, elderly patients are under-represented in clinical trials and generally receive suboptimal treatment, mainly because of fears about increased toxicity of chemotherapy. Indeed, physiological modification of renal and haematopoietic functions with age together with co-morbidity and associated polypharmacy may alter the metabolism of chemotherapy drugs, resulting in greater toxicity. Moreover, performance status (PS), the main prognostic factor in younger patients, does not correlate well with geriatric indexes such as activities of daily living, cognition and physical performance, and comprehensive geriatric assessment is important in elderly patients. Until 2010, based on the small number of clinical trials designed for elderly patients, monotherapy was the recommended treatment for those with advanced non-small cell lung cancer (NSCLC), whereas for fit younger patients, a platinum-based doublet was and continues to be the recommended first-line therapy. However, at the plenary session of the 2010 Annual Meeting of the American Society of Clinical Oncology, results were presented from a randomized controlled trial conducted by the French Intergroup of Thoracic Oncology that demonstrated that in PS 0-2 patients aged≥70 years with advanced NSCLC, monthly carboplatin with weekly paclitaxel resulted in significantly longer survival than single-agent therapy (vinorelbine or gemcitabine). It should be noted that even in a priori unfavourable prognostic subgroups (patients with a PS score of 2, those aged>80 years or those with an activities of daily living scale score of <6), doublet therapy was associated with a survival advantage over monotherapy. Thus, the new paradigm of treatment of elderly patients with advanced NSCLC and a PS score of 0-2 should now be monthly

  17. Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study

    PubMed Central

    2011-01-01

    Background Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. Methods Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5 × 107 DC cells administered subcutaneous and intravenously two times at two week intervals. The immunologic response, safety and tolerability to the vaccine were evaluated by the lymphoproliferation assay and clinical and laboratorial evolution, respectively. Results The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.005). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. Conclusion Despite the small sample size, the results on the immune response, safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment. Trial Registration Current Controlled Trials: ISRCTN45563569 PMID:21682877

  18. Erlotinib Hydrochloride and Cetuximab in Treating Patients With Advanced Gastrointestinal Cancer, Head and Neck Cancer, Non-Small Cell Lung Cancer, or Colorectal Cancer

    ClinicalTrials.gov

    2015-09-28

    Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Gastrointestinal Stromal Tumor; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer

  19. Targeted therapies in development for non-small cell lung cancer

    PubMed Central

    Reungwetwattana, Thanyanan; Dy, Grace Kho

    2013-01-01

    The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by “druggable” protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

  20. [Single-dose palliative radiotherapy in inoperable non-small-cell lung carcinoma].

    PubMed

    Scolaro, T; Bacigalupo, A; Giudici, S; Guenzi, M; Vitale, V

    1995-12-01

    The treatment of choice for advanced inoperable non-small cell lung cancer (NSCLC) is radiation therapy. Palliative radiotherapy schedules vary considerably in different centers, but a 30-Gy dose given in ten fractions over two weeks is a typical standard schedule. Our study was aimed at investigating whether a shorter course of only one 10-Gy fraction allows good palliation in the treatment of inoperable NSCLC patients whose main symptoms are related to an intrathoracic lesion. Patients of both sexes and any age, untreated with radiotherapy, with inoperable and histologically or cytologically proved NSCLC were examined. Seventeen patients, too advanced for radical "curative" radiotherapy and whose main symptoms were related to primary intrathoracic lesions, entered the study even though they had metastases. On admission, 76% (13/17) of patients had cough 76% (13/17) dyspnea, 70.7% (12/17) chest pain and 23.6% (4/17) hemoptysis. They received a single dose of 10 Gy, delivered with an 18-Mv linear accelerator via anteroposteriorly opposing portals without spinal cord shielding. Treatment volume usually included the macroscopically detected lesion identified with a CT simulator. Palliation of symptoms was achieved in high rates of patients: 46% for cough, 69% for dyspnea, 83% for pain and 75% for hemoptysis. These results were obtained within one month of treatment. Unfortunately, palliation of symptoms did not last long, decreasing to 42% within two months of the end of treatment and to 32% at three months. Four patients were retreated, one patient three months and three patients two months after the end of radiotherapy. Ten Gy to the target volume were administered as retreatment with spinal cord shielding. Side-effects were mild: nausea in 3 patients (17%), vomiting in one patient (5%) and grade-II dysphagia in two patients were observed and classified according to WHO criteria. Pain increased 24 hours after radiotherapy in five patients. We can conclude that

  1. Overall survival in non-small cell lung cancer—what is clinically meaningful?

    PubMed Central

    Fenchel, Klaus; Sellmann, Ludger

    2016-01-01

    The development of molecularly targeted therapies [tyrosine kinase inhibitors (TKIs) and monoclonal antibodies] has significantly improved outcomes for patients with advanced or metastatic non-small cell lung cancer (NSCLC) resulting in improved progression-free survival (PFS), overall survival (OS) and quality of life (QoL). In addition, targeting the immune axis (CTLA-4, PD-1/PD-L1) has also shown promising results. Major goals of almost all clinical trials based on histology and molecular markers for NSCLC patients are improvements of OS and QoL. However, in the majority of these trials only small incremental improvements in OS were seen. Food and Drug Administration (FDA) and other health authorities have recommended to consider OS to be the standard clinical benefit endpoint that should be used to establish the efficacy of a treatment for NSCLC patients, however, the question remains what is clinically meaningful and how can this outcome be measured. According to suggestions of the American Society of Clinical Oncology (ASCO) Cancer Research Committee a relative improvement in median OS of at least 20% (3–4 months) is regarded to define a clinically meaningful improvement in outcome of NSCLC patients. However, this should not diminish PFS as a valid endpoint since a PFS improvement can also result in a meaningful palliation (e.g., painful bone metastases). Other factors (e.g., QoL) may also be involved to measure and to define the clinical importance of a given trial result. Using the “Quality-adjusted Time Without Symptoms of Toxicity” (Q-TWiST) analysis method it has been demonstrated that a clinically important and meaningful difference for Q-TWiST is 10–15% of OS in a study. Trials that are designed with less ambitious goals, however, may still be of benefit to individual NSCLC patients if the trial endpoints are met. Since there is no single factor which will make a trial clinically meaningful, these recommendations, however, are not intended to

  2. Effect of Recombinant Human Endostatin on Radiosensitivity in Patients With Non-Small-Cell Lung Cancer

    SciTech Connect

    Jiang Xiaodong; Dai Peng; Wu Jin; Song Daan; Yu Jinming

    2012-07-15

    Purpose: To observe the effects of recombinant human endostatin (RHES) on the radiosensitivity of non-small cell lung cancer (NSCLC). Methods and Materials: First, 10 hypoxia-positive cases of pathology-diagnosed NSCLC selected from 15 patients were used to determine the normalization window, a period during which RHES improves NSCLC hypoxia. Second, 50 hypoxia-positive cases of pathology-diagnosed NSCLC (Stages I-III) were randomly divided into a RHES plus radiotherapy group (25 cases) and a radiotherapy-alone group (25 cases). Intensity = modulated radiotherapy with a total dose of 60 Gy in 30 fractions for 6 weeks was adopted in the two groups. The target area included primary foci and metastatic lymph nodes. In the RHES plus radiotherapy group, RHES (15 mg/day) was intravenously given during the normalization window. Results: After RHES administration, the tumor-to=normal tissue radioactivity ratio and capillary permeability surface were first decreased and then increased, with their lowest points on the fifth day compared with the first day (all p < 0.01). Blood flow was first increased and then decreased, with the highest point on the fifth day, compared with the first and tenth day (all p < 0.01). In the RHES plus radiotherapy group and the radiotherapy-alone group, the total effective rates (complete response plus partial response) were 80% and 44% (p = 0.009), respectively. The median survival times were 21.1 {+-} 0.97 months and 16.5 {+-} 0.95 months (p = 0.004), respectively. The 1-year and 2-year local control rates were 78.9 {+-} 8.4% and 68.1 {+-} 7.8% (p = 0.027) and 63.6 {+-} 7.2% and 43.4 {+-} 5.7% (p = 0.022), respectively. The 1-year and 2-year overall survival rates were 83.3 {+-} 7.2% and 76.6 {+-} 9.3% (p = 0.247) and 46.3 {+-} 2.4% and 37.6 {+-} 9.1% (p = 0.218), respectively. Conclusion: The RHES normalization window is within about 1 week after administration. RHES combined with radiotherapy within the normalization window has better short

  3. Erlotinib for the treatment of relapsed non-small cell lung cancer.

    PubMed

    McLeod, C; Bagust, A; Boland, A; Hockenhull, J; Dundar, Y; Proudlove, C; Davis, H; Green, J; Macbeth, F; Stevenson, J; Walley, T; Dickson, R

    2009-06-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of erlotinib for the treatment of relapsed non-small cell lung cancer (NSCLC), according to its licensed indication, based upon the evidence submission from Roche Products to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence includes one randomised controlled trial (RCT) (BR21) investigating the effect of erlotinib versus placebo, which demonstrates that erlotinib significantly increases median overall survival, progression-free survival and response rate compared with placebo. The majority of patients in the trial experienced non-haematological drug-related adverse effects. Currently there are no trials that directly compare erlotinib with any other second-line chemotherapy agent. For the purposes of indirect comparison, the manufacturer's submission provides a narrative discussion of data from 11 RCTs investigating the use of docetaxel. From these data the manufacturer concludes that erlotinib has similar clinical efficacy levels to docetaxel but results in fewer serious haematological adverse events; however, it is difficult to compare the results of BR21 with those of the docetaxel trials or with current UK clinical practice because, for example, the BR21 patient population is younger than that expected to present in UK clinical practice and almost half of the BR21 participants received erlotinib as third-line chemotherapy, with third-line chemotherapy being rare in the UK. The manufacturer's submission included a three-state model comparing erlotinib with docetaxel, reporting an incremental cost-effectiveness ratio (ICER) of 1764 pounds per quality-adjusted life-year (QALY) gained for erlotinib compared with docetaxel. Rerunning the manufacturer's economic model with varied parameters and assumptions increases the ICER to in excess of 52

  4. Targeted therapies in development for non-small cell lung cancer.

    PubMed

    Reungwetwattana, Thanyanan; Dy, Grace Kho

    2013-01-01

    The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

  5. Association between MGMT Promoter Methylation and Non-Small Cell Lung Cancer: A Meta-Analysis

    PubMed Central

    Gu, Changmei; Lu, Jiachun; Cui, Tianpen; Lu, Cheng; Shi, Hao; Xu, Wenmao; Yuan, Xueli; Yang, Xiaobo; Huang, Yangxin; Lu, Meixia

    2013-01-01

    Background O6-methylguanine-DNA methyltransferase (MGMT) is one of most important DNA repair enzyme against common carcinogens such as alkylate and tobacco. Aberrant promoter methylation of the gene is frequently observed in non-small cell lung cancer (NSCLC). However, the importance of epigenetic inactivation of the gene in NSCLC published in the literature showed inconsistence. We quantified the association between MGMT promoter methylation and NSCLC using a meta-analysis method. Methods We systematically reviewed studies of MGMT promoter methylation and NSCLC in PubMed, EMBASE, Ovid, ISI Web of Science, Elsevier and CNKI databases and quantified the association between MGMT promoter methylation and NSCLC using meta-analysis method. Odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated to evaluate the strength of association. Potential sources of heterogeneity were assessed by subgroup analysis and meta-regression. Results A total of 18 studies from 2001 to 2011, with 1, 160 tumor tissues and 970 controls, were involved in the meta-analysis. The frequencies of MGMT promote methylation ranged from 1.5% to 70.0% (median, 26.1%) in NSCLC tissue and 0.0% to 55.0% (median, 2.4%) in non-cancerous control, respectively. The summary of OR was 4.43 (95% CI: 2.85, 6.89) in the random-effects model. With stratification by potential source of heterogeneity, the OR was 20.45 (95% CI: 5.83, 71.73) in heterogeneous control subgroup, while it was 4.16 (95% CI: 3.02, 5.72) in the autologous control subgroup. The OR was 5.31 (95% CI: 3.00, 9.41) in MSP subgroup and 3.06 (95% CI: 1.75, 5.33) in Q-MSP subgroup. Conclusion This meta-analysis identified a strong association between methylation of MGMT gene and NSCLC. Prospective studies should be required to confirm the results in the future. PMID:24086261

  6. Disturbed Th17/Treg Balance in Patients with Non-small Cell Lung Cancer.

    PubMed

    Duan, Min-Chao; Han, Wei; Jin, Pei-Wen; Wei, Yu-Ping; Wei, Qiu; Zhang, Liang-Ming; Li, Jun-Chen

    2015-12-01

    The fine balance of T help-17 (Th17)/regulatory T(Treg) cells is crucial for maintenance of immune homeostasis. However, there is little information concerning the role played in non-small cell lung cancer (NSCLC) by Th17/Treg cells. The objective of this study was to investigate the variation of Th17 and Treg cells in the peripheral blood of patients with NSCLC. Blood samples were collected from 19 patients with NSCLC and 19 healthy donors. Samples were processed to detect CD4(+)IL-17(+) Th17 cells and CD4(+)CD25(+)Foxp3(+) Treg cells by flow cytometry, and related gene expressions were assessed by real-time quantitative polymerase chain reaction. The concentrations of interleukin (IL)-1β, IL-6, IL-10, IL-17, IL-23, and transforming growth factor-beta (TGF-β1) were also measured by enzyme-linked immunosorbent assay analysis (ELISA). The frequency of circulating Th17 cells and Treg cells was increased in samples derived from patients with NSCLC, accompanied by the upregulation of Foxp3 and RORγt. However, a negative correlation between Treg cells and Th17 cells was found in patients with NSCLC. Additionally, the Th17/Treg ratio and the related cytokines were also significantly higher in patients with NSCLC than in healthy controls. Furthermore, the frequency of Th17 cells was positively correlated with IL-1β, IL-6, and IL-23 in patients with NSCLC, and the frequency of Treg cells was positively correlated with TGF-β1 and IL-10. More importantly, the Th17/Treg ratio was positively correlated with the CEA concentrations in patients with NSCLC. Our data indicated that Th17 and Treg subset are involved in the immunopathology of NSCLC. Distinct cytokine environment might play a key role in the differentiation of the Th17 and Treg cells in NSCLC. Reconstituting an adequate balance between Th17 and Treg may be beneficial in the treatment of NSCLC. PMID:26077695

  7. Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer

    PubMed Central

    Takigawa, N; Kiura, K; Segawa, Y; Watanabe, Y; Kamei, H; Moritaka, T; Shibayama, T; Ueoka, H; Gemba, K; Yonei, T; Tabata, M; Shinkai, T; Hiraki, S; Takemoto, M; Kanazawa, S; Matsuo, K; Tanimoto, M

    2006-01-01

    Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0–4.9). PMID:17031394

  8. Updating advances on recombinant human endostatin combined with radiotherapy for non-small cell lung cancer with brain metastasis

    PubMed Central

    Qiao, Yun

    2012-01-01

    Brain metastases (BM) heavily affects the prognosis of advanced non-small cell lung cancer (NSCLC). Although whole-brain radiotherapy remains the mainstream therapy for BM caused by NSCLC, the effectiveness is unsatisfactory. Endostar, a recombinant human endostatin (RHES), has shown certain therapeutic effect on advanced NSCLC. This article reviews the feasibility of Endostar combined with radiotherapy in the treatment of BM caused by NSCLC. PMID:25806159

  9. An unusual case of non-small cell lung cancer presenting with renal angle pain and hematuria.

    PubMed

    Peedell, Clive; Dykes, Rachel

    2007-07-01

    A 53-year-old woman was referred urgently to the urology department with a history of worsening right renal angle pain and associated hematuria. Further investigations revealed the presence of a primary non-small cell lung cancer (NSCLC) invading the posterior chest wall with an associated vaginal metastasis. To our knowledge, this is only the second case report in the literature of a vaginal metastasis from NSCLC. PMID:17607127

  10. Video-assisted thoracoscopic surgery for non-small-cell lung cancer is beneficial to elderly patients

    PubMed Central

    Wang, Yan

    2015-01-01

    The aim of this study was to explore whether video-assisted thoracoscopic surgery (VATS) has short or long-term benefits in elderly patients with non-small-cell lung cancer compared with open surgery. Between June 2007 and December 2014, 579 patients older than 70 years underwent radical pulmonary resection for non-small-cell lung cancer, including 138 who received VATS and 441 who received open surgery. A retrospective pair-matched study was performed to compare 194 patients (97 pairs) who underwent either VATS or open resection. Patients were matched by age, sex, comorbidity, American Society of Anesthesiologists (ASA) score, tumor location, clinical TNM stage, and extent of pulmonary resection. Short and long-term outcomes were compared between the two groups. The overall incidence of postoperative 30-day complications was significantly lower in the VATS group than in the open surgery group. The major postoperative 30-day complication trended lower in the VATS group but was not significantly different. The length of postoperative hospital stay was significantly shorter. Kaplan-Meier analysis showed that 5-year disease-free survival and overall survival was similar between the two groups. In summary, in surgical management of elderly patients with non-small-cell lung cancer, VATS is associated with lower rates of morbidity as well as comparable disease-free survival and overall survival outcomes. PMID:26550301

  11. Elevated 68Ga Prostate-Specific Membrane Antigen Activity in Metastatic Non-Small Cell Lung Cancer.

    PubMed

    Shetty, Deepa; Loh, Han; Bui, Chuong; Mansberg, Robert; Stevanovic, Amanda

    2016-05-01

    A 71-year-old man with a background of treated stage IIIB non-small cell lung cancer was referred for Ga prostate-specific membrane antigen (PSMA) PET/CT for staging of prostate cancer. In addition to the PSMA uptake in the known prostate malignancy, the study also demonstrated increased PSMA uptake in an enlarging left lower lobe lung mass with diffusely increased PSMA uptake in an enlarged thyroid gland and bilateral enlarged supraclavicular lymph nodes. Fine-needle aspiration biopsy of the thyroid gland and a left supraclavicular lymph node demonstrated metastatic adenocarcinoma from a primary lung cancer. PMID:26828144

  12. Second-line erlotinib in patients with advanced non-small-cell lung cancer: subgroup analyses from the TRUST study.

    PubMed

    Heigener, David F; Wu, Yi-Long; van Zandwijk, Nico; Mali, Pekka; Horwood, Keith; Reck, Martin

    2011-11-01

    Erlotinib is a highly potent inhibitor of epidermal growth factor receptor tyrosine-kinase activity that significantly prolongs overall survival in patients with non-small-cell lung cancer (NSCLC), and improves symptom control and quality of life compared with placebo. The safety and efficacy of erlotinib has been investigated in a large, international, phase IV, open-label study (TRUST) in patients (n=6665) with advanced stage IIIB/IV NSCLC. An analysis of efficacy and safety outcomes is reported for patients receiving erlotinib as second-line therapy in TRUST (n=3224). Best response data were available for all 3224 patients. Complete response, partial response and stable disease were achieved in 25 (<1%), 368 (14%) and 1444 (54%) patients, respectively, for a disease control rate of 68%. Median progression-free and overall survivals were 13.6 weeks and 8.6 months, respectively; 1-year survival was 39.4%. Safety data were available for all patients. Of these, 389 patients (12%) had an erlotinib-related adverse event (AE) other than pre-specified AEs defined in the protocol; only 96 patients (3%) had an erlotinib-related AE ≥ grade 3. Of 1376 patients (43%) with serious AEs (SAEs), only 122 (4%) had treatment-related SAEs and most were gastrointestinal disorders (mainly diarrhoea and nausea). No treatment-related SAE occurred in ≥ 1% of patients. Data on the incidence of erlotinib-related rash were collected for all patients, 2302 (71%) of whom experienced rash. Of these rash events, 83% were of grade 1/2. These data confirm the good efficacy and tolerability of second-line erlotinib in a broad range of patients with NSCLC. PMID:21439671

  13. Tetrandrine Combined with Gemcitabine and Cisplatin for Patients with Advanced Non-Small Cell Lung Cancer Improve Efficacy

    PubMed Central

    Liu, Wenchao; Zhang, Ju; Ying, Cheng; Wang, Qianrong; Yan, Chen; Jingyue, Yang; Zhaocai, Yu; Yan, Xue; Heng-jun, Shi; Lin, Jiang

    2012-01-01

    Lung cancer has the highest morbidity and mortality of any malignant tumor. To improve efficacy and reduce toxicity in patients with advanced non-small cell lung cancer (NSCLC), it is important to integrate traditional and conventional medicine. Two hundred and forty patients with advanced NSCLC were randomized to tetrandrine plus GP or GP only. We infused gemcitabine on days 1 and 8; cisplatin on day 1. The tetrandrine group received continuous i.v. infusion for 10 days, with treatment repeated every 21 days. After 2 consecutive treatment cycles, we used RECIST criteria to evaluate short-term efficacy. Quality of life (QOL) was assessed according to Karnofsky score (KPS) and body weight change. We used NCI CTC 3.0 to evaluate treatment toxicity. The short-term objective response rate was 36.1% in the tetrandrine group and 24.3% in the controls (P=0.057). The short-term disease control rate was 63.9% in the tetrandrine group and 52.3% in the controls (P=0.081). The 1-year survival rates were 45.7% and 31.3%, respectively (P=0.059). KPS scores improved by 49.1% and 32.4%, respectively (P=0.012). Body weight increased by 28.7% in the tetrandrine group and 16.2% in the controls (P=0.027). The incidence of grade 2-4 leukopenia, thrombocytopenia, nausea, and vomiting in the tetrandrine group was 38.0%, 19.4%, 46.3%, and 16.7%, respectively; the control group figures were 53.2%, 34.2%, 63.0% and 27.9% (P<0.05). Tetrandrine may improve short-term efficacy and survival in patients with advanced NSCLC. Tetrandrine may also mitigate adverse reactions to chemotherapy and improve QOL for patients with NSCLC. PMID:23675254

  14. How today's developments in the treatment of non-small cell lung cancer will change tomorrow's standards of care.

    PubMed

    Kris, Mark G

    2005-10-01

    Cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin; Bristol-Myers Squibb), together with newer chemotherapies, such as docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), paclitaxel (Taxol; Bristol-Myers Squibb), vinorelbine (Navelbine; GlaxoSmith-Kline, Philadelphia, http://www.gsk.com), pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, http://www.lilly.com), and gemcitabine (Gemzar; Eli Lilly and Company), have improved treatment outcomes in both advanced non-small cell lung cancer (NSCLC) and in the adjuvant/neoadjuvant setting. Newer systemic treatments for NSCLC, used in advanced stage IV management, are beginning to be studied in earlier stages of the disease, when treatment is better tolerated and potentially curative. Hopefully, newer agents with proven efficacies in advanced disease will enhance curability. Following the successful addition of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, http://www.gene.com) to carboplatin/paclitaxel in advanced disease, bevacizumab is now being incorporated into adjuvant and neoadjuvant trials. Trials in stage IB-IIIA patients will study neoadjuvant docetaxel/cisplatin/bevacizumab. The discovery that patients with exon 19 and 21 mutations in the epidermal growth factor receptor gene EGFR have around an 80% response rate to gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE, http:// www.astrazeneca-us.com) and that this response confers survival benefit indicates its potential utility for mutation-positive patients with advanced- and earlier-stage disease. Clinical characteristics, such as never smoking status and adenocarcinoma, and especially bronchioloalveolar carcinoma histological features, can also identify individuals likely to respond to EGFR tyrosine kinase inhibitors. Studies of neoadjuvant erlotinib (Tarceva; OSI Pharmaceuticals, Inc., Melville, NY, http

  15. Plasma LUNX mRNA, a non-invasive specific biomarker for diagnosis and prognostic prediction of non-small cell lung cancer

    PubMed Central

    Zhou, Hong-Xing; Yang, Ming-Xia; Wang, Yan; Cao, Wen-Ming; Lu, Ke-Feng; Zong, Ling-Yan; Wu, Rong-Qiang; Zhang, Ping

    2016-01-01

    Lung cancer is the most common cancer worldwide. However, no specific biomarker has been found in diagnosis and evaluation of therapeutic efficacy for lung cancer. The human lung-specific X protein gene (LUNX) was recently identified with a feature of lung tissue specificity. We applied the fluorescent quantitative polymerase chain reaction method to examine LUNX mRNA in plasma and peripheral blood mononuclear cells (PBMC) in patients with non-small cell lung cancer (NSCLC), benign lung diseases, extrapulmonary tumors, and healthy subjects. The results showed that LUNX mRNA in both of plasma and PBMC were significantly higher in lung cancer patients compared to other groups. In plasma, there were higher sensitivity and negative predictive value of LUNX mRNA than in PBMC. Patients with III~IV stages of lung cancer had more LUNX mRNA in plasma than the early stage of lung cancer sufferers. After a period of therapy, significant reductions of plasma LUNX mRNA in patients with I and II stages of lung cancer were found. Levels of plasma LUNX mRNA in patients who had succeeded to respond to therapy decreased compared to prior treatment. On the other hand, the post-treatment level was obviously increased in patients that had failed to respond to therapy. Patients with negative plasma LUNX mRNA after therapy displayed a favorable prognosis and survival rate. These preliminary data suggested that cell-free LUNX mRNA in plasma as a non-invasive biomarker, is superior to peripheral intracellular LUNX mRNA, and plays a critical role in specific diagnosis and prognostic prediction of non-small cell lung cancer.

  16. Maintenance treatment with chemotherapy and immunotherapy in non-small cell lung cancer: a case report

    PubMed Central

    Llanos, Anabella; Savignano, Mariana; Cinat, Gabriela

    2012-01-01

    A 53-years-old woman was diagnosed with lung adenocarcinoma state IV (synchronous pleural involvement) in April 2009. First-line systemic treatment included six cycles of Carboplatin, Paclitaxel, and Bevacizumab. Partial response was achieved. Maintenance therapy with Bevacizumab and Pemetrexed was given from September 2009 to February 2010. No response changes were observed. Immunotherapy was initiated, and then Pemetrexed was given with the same disease status. Both treatments were well tolerated. Immunotherapy toxicity included reaction at the site of injection grade 2. At present, the patient is still on this treatment. Given the poor prognosis of patients with advanced lung cancer, the combination of both treatments during the stable phase of the disease may improve progression-free survival. PMID:23112957

  17. Extended resection of non-small cell lung cancer invading the left atrium, is it worth the risk?

    PubMed

    Galvaing, Geraud; Chadeyras, Jean Baptiste; Merle, Patrick; Tardy, Marie M; Naamee, Adel; Bailly, Patrick; Filaire, Marc

    2015-12-01

    Only few reports of surgical approach to T4 lung carcinoma invading the heart have been reported in the medical literature. It is also controversial if such cancer should be treated by surgery. The aim of this review is to assess the current risk/benefit ratio of the surgical management of non-small cell lung cancer (NSCLC) invading the left atrium, especially in the light of a multidisciplinary approach. We also expose our surgical experience and the procedure we have developed in order to increase our rate of complete resection as this criterion appears to be mandatory as well as patients' nodal status in order to increase life expectancy. PMID:26730755

  18. AB 40. Six minute walking test and DLCO for non-small cell lung cancer. Easy performed tests in every day practice

    PubMed Central

    Zarogoulidis, Paul; Kerenidi, Theodora; Kontakiotis, Theodoros; Tremma, Ourania; Porpodis, Konstantinos; Kallianos, Anastasios; Rapti, Ageliki; Foroulis, Christoforos; Zissimopoulos, Athanasios; Courcoutsakis, Nikolaos; Tsakiridis, Kosmas; Mylwnaki, Efi; Zarogoulidis, Konstantinos

    2012-01-01

    Background Several studies have demonstrated that reduced lung function is a significant risk factor for lung cancer and increase surgical risk in patients with operable stages of lung cancer. The aim of the study was to perform pulmonary function tests and investigate which is a favorable respiratory function test for overall survival between lung cancer stages. Methods Lung function tests were performed to lung cancer patients with non-small cell lung cancer of stage I, II, III and IV (241 patients in total). They had the last follow-up consecutively between December 2006 and July 2008. The staging was decided according to the sixth edition of TNM classification of NSCLC. The Forced Expiratory Volume in 1sec (FEV1), Forced Vital Capacity (FVC) and Carbon Monoxide Diffusing Capacity (DLCO) were measured according to American Thoracic Society/European Respiratory Society guidelines. The 6 Minute Walking Test (6MWT) was measured according to the American Thoracic Society. Results There was a significant association of the DLCO upon diagnosis and overall survival for stage II (P<0.007) and IV (P<0.003). Furthermore, there was a significant association between 6MWT and overall survival for stage III (P<0.001) and stage IV (P<0.010). Conclusions The significance for each lung function test is different among the stages of NSCLC. DLCO and 6MWT upon admission are the most valuable prognostic factors for overall survival of NSCLC.

  19. Six minute walking test and carbon monoxide diffusing capacity for non-small cell lung cancer: easy performed tests in every day practice

    PubMed Central

    Kerenidi, Theodora; Huang, Haidong; Kontakiotis, Theodoros; Tremma, Ourania; Porpodis, Konstantinos; Kalianos, Anastasios; Rapti, Ageliki; Foroulis, Christoforos; Zissimopoulos, Athanasios; Courcoutsakis, Nikolaos; Zarogoulidis, Konstantinos

    2012-01-01

    Background Several studies have demonstrated that reduced lung function is a significant risk factor for lung cancer and increased surgical risk in patients with operable stages of lung cancer. The aim of the study was to perform pulmonary function tests and investigate which is a favorable respiratory function test for overall survival between lung cancer stages. Methods Lung function tests were performed to lung cancer patients with non-small cell lung cancer of stage I, II, III and IV (241 patients in total). They had the last follow-up consecutively between December 2006 and July 2008. The staging was decided according to the sixth edition of TNM classification of NSCLC. The Forced Expiratory Volume in 1sec (FEV1), Forced Vital Capacity (FVC) and Carbon Monoxide Diffusing Capacity (DLCO) were measured according to American Thoracic Society/European Respiratory Society guidelines. The 6 Minute Walking Test (6MWT) was measured according to the American Thoracic Society. Results There was a significant association of the DLCO upon diagnosis and overall survival for stage II (P<0.007) and IV (P<0.003). Furthermore, there was a significant association between 6MWT and overall survival for stage III (P<0.001) and stage IV (P<0.010). Conclusions The significance for each lung function test is different among the stages of NSCLC. DLCO and 6MWT upon admission are the most valuable prognostic factors for overall survival of NSCLC. PMID:23205280

  20. Effects of selenomethionine on acute toxicities from concurrent chemoradiation for inoperable stage III non-small cell lung cancer

    PubMed Central

    Mix, Michael; Ramnath, Nithya; Gomez, Jorge; de Groot, Charles; Rajan, Saju; Dibaj, Shiva; Tan, Wei; Rustum, Youcef; Jameson, Michael B; Singh, Anurag K

    2015-01-01

    AIM: To prospectively determine the safety and tolerability of oral L-selenomethionine (SLM) with concurrent chemoradiation (CCRT) for Stage III non-small cell lung cancer (NSCLC) and estimate if the incidence and/or severity of adverse events could be reduced by its use. METHODS: Sixteen patients with stage III NSCLC were accrued to this single arm, phase II study. CCRT consisted of radiation given at 2 Gy per fraction for 30-33 fractions, 5 d per week with concurrent weekly IV paclitaxel 50 mg/m2 followed by carboplatin dosed at an area under the time-concentration curve of 2. SLM was dosed in a loading phase at 4800 μg twice daily for one week prior to CCRT followed by once daily dosing during treatment. RESULTS: No selenium-related toxicity was observed. Analysis revealed grade 3 or higher esophagitis in 3 of 16 patients (19%), pneumonitis in 0, leukopenia in 2 (12.5%), and anemia in 1 (6%); the latter two were significantly reduced when compared to the protocol-stated expected rate of 35% (P = 0.045 for leukopenia, and P < 0.01 for anemia). Median overall survival was 14.9 mo and median failure-free survival was 9 mo (95%CI: 3.3-21.5). CONCLUSION: There may be some protective benefit of selenium in the setting of CCRT for inoperable NSCLC. The data suggests decreased rates of myelosuppression when compared to similarly-treated historical and contemporary controls. Further evaluation of selenium in this setting may be warranted. PMID:26468452

  1. Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC).

    PubMed

    Cohen, Martin H; Cortazar, Patricia; Justice, Robert; Pazdur, Richard

    2010-01-01

    On July 2, 2009, the U.S. Food and Drug Administration approved pemetrexed injection (Alimta® Injection; Eli Lilly and Company, Indianapolis, IN) for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based doublet induction chemotherapy. A double-blind study of pemetrexed plus best supportive care versus placebo plus best supportive care was conducted. Pemetrexed, 500 mg/m(2) i.v., was administered every 21 days until disease progression. Folic acid, vitamin B(12), and a corticosteroid were given to all study patients. There were 663 randomized patients (pemetrexed, 441; placebo, 222). Treatments were well balanced with respect to baseline disease characteristics and stratification factors. The median overall survival (OS) time for intent-to-treat (ITT) patients was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65-0.95; p = .012). Median OS times were 15.5 months versus 10.3 months for patients with nonsquamous histologies receiving pemetrexed and placebo, respectively (HR, 0.70; 95% CI, 0.56-0.88). The median OS time in patients with squamous histology receiving pemetrexed was 9.9 months, versus 10.8 months for those receiving placebo (HR, 1.07; 95% CI, 0.77-1.50). A significantly longer progression-free survival interval for both the ITT and nonsquamous patient populations receiving pemetrexed maintenance therapy was also observed. The most common (>5%) adverse reactions in patients receiving pemetrexed were hematologic toxicity, an increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy, and skin rash. PMID:21148615

  2. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer

    PubMed Central

    Morse, Michael A; Garst, Jennifer; Osada, Takuya; Khan, Shubi; Hobeika, Amy; Clay, Timothy M; Valente, Nancy; Shreeniwas, Revati; Sutton, Mary Ann; Delcayre, Alain; Hsu, Di-Hwei; Le Pecq, Jean-Bernard; Lyerly, H Kim

    2005-01-01

    Background There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). Methods This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. Results Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. Conclusion Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors PMID:15723705

  3. Comparison of Serum MicroRNA21 and Tumor Markers in Diagnosis of Early Non-Small Cell Lung Cancer

    PubMed Central

    Sun, Mingzhong; Song, Jiangxiang; Zhou, Zhongwei; Zhu, Rong; Jin, Hao; Ji, Yuqiao; Lu, Qiang; Ju, Huixiang

    2016-01-01

    Objective. To compare the clinical value of serum microRNA21 (miR21) and other tumor markers in early diagnosis of non-small cell lung cancer (NSCLC). Methods. Serums carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), neuron-specific enolase (NSE), and miR21 were detected in 50 NSCLC cases and 60 healthy control individuals. Results. Average serums miR21, CEA, NSE, and CYFRA21-1 levels were significantly higher in the case group than in control group (P < 0.01). Analysis of areas under the receiver operating characteristic (ROC) curve (AUC) revealed that CEA had the highest diagnostic efficiency for NSCLC. Serums miR21 and CYFRA21-1 levels were significantly lower at TNM stages I-II than stages III-IV (P < 0.05). Further, logistic multivariate regression analysis showed that the incidence of early NSCLC (TNM stages I-II) was correlated with serums CYFRA21-1 (OR = 1.076) and miR21 (OR = 2.473) levels (P < 0.05). By AUC analysis, miR21 had the highest diagnostic efficiency for early NSCLC, and single or combined detection of serums CYFRA21-1 and miR21 levels showed improved diagnostic efficiency for joint detection of both markers. Conclusions. Serum miR21 could serve as an important marker for auxiliary diagnosis of early NSCLC, while joint detection of serums miR21 and CYFRA21-1 levels could improve diagnostic efficiency. PMID:26880855

  4. Prognostic value of serum cytokeratin 19 fragments (Cyfra 21-1) in patients with non-small cell lung cancer.

    PubMed

    Xu, Youtao; Xu, Lei; Qiu, Mantang; Wang, Jie; Zhou, Qing; Xu, Lin; Wang, Jian; Yin, Rong

    2015-01-01

    The role of serum CYFRA 21-1 level in patients with non-small cell lung cancer (NSCLC) remains to be defined. To re-evaluate the impact of serum CYFRA 21-1 in NSCLC survival, we performed this meta-analysis. Databases were searched to identify relevant studies reported after the publication of a meta-analysis in 2004. Totally, 31 studies with 6394 patients were included in this meta-analysis. The pooled Hazard ratios (HRs) indicated that high CYFRA 21-1 level was associated with poor prognosis on overall survival (OS) in patients with NSCLC (HR = 1.60; 95%CI = 1.36-1.89; P < 0.001). The pooled HRs were 2.18 (95%CI = 1.70, 2.80; P = 0.347) for patients at stage I-IIIA and 1.47 (95%CI = 1.02, 2.11; P < 0.001) for stage IIIB-IV. When stratified by surgical intervention, pooled HRs were 1.94 (95%CI = 1.42-2.67; P < 0.001) for studies with surgery and 1.24 (95%CI = 0.79-1.95; P < 0.001) for studies without surgery. Significant associations were also found in the patients treated with EGFR-TKIs (HR = 1.83; 95%CI = 1.31-2.58; P = 0.011) and platinum-based regimen (HR = 1.53; 95%CI = 1.18-1.99; P = 0.001). Meta-analysis of CYFRA 21-1 related to PFS was performed and pooled HR was 1.41 (95%CI = 1.19-1.69; P < 0.001). Our results indicate that high level of serum CYFRA 21-1 is a negative prognostic indicator of patients with NSCLC. PMID:25901419

  5. Concomitant chemoradiotherapy with docetaxel and cisplatin followed by consolidation chemotherapy in locally advanced unresectable non-small cell lung cancer

    PubMed Central

    Eroglu, Celalettin; Orhan, Okan; Unal, Dilek; Dogu, Gamze G.; Karaca, Halit; Dikilitas, Mustafa; Oztürk, Ahmet; Ozkan, Metin; Kaplan, Bünyamin

    2013-01-01

    OBJECTIVES: To evaluate treatment results and toxicities in patients who received concomitant chemoradiotherapy (CRT) followed by consolidation with docetaxel and cisplatin in locally advanced unresectable non-small cell lung cancer (NSCLC). METHODS: Ninety three patients were included in this retrospective study. The patients received 66 Gy radiotherapy and weekly 20 mg/m2 docetaxel and 20 mg/m2 cisplatin chemotherapy concomitantly. One month later than the end of CRT, consolidation chemotherapy with four cycles of docetaxel 75 mg/m2 and cisplatin 75 mg/m2 were administered at each 21 days. RESULTS: Median age of the patients was 57 (range, 30-74). Following concomitant CRT, 14 patients (15%) showed complete and 50 patients (54%) showed partial response (total response rate was 69%). The median follow-up was 13 months (range: 2-51 months). The median overall survival was 18 months (95% confidential interval [CI]: 13.8-22.1 months); local control was 15 months (95% CI: 9.3-20.6 months); progression-free survival was 9 months (95% CI: 6.5-11.4 months). Esophagitis in eight (9%) patients, neutropenia in seven (8%) patients and pneumonitis in eight (9%) patients developed as grade III-IV toxicity due to concomitant CRT. CONCLUSION: Concomitant CRT with docetaxel and cisplatin followed by docetaxel and cisplatin consolidation chemotherapy might be considered as a feasible, and well tolerated treatment modality with high response rates despite the fact that it has not a survival advantage in patients with locally advanced unresectable NSCLC. PMID:23741274

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

    SciTech Connect

    Rusch, V.W.; Griffin, B.R.; Livingston, R.B. )

    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.

  7. Erlotinib and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Kidney, Colorectal, Head and Neck, Pancreatic, or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2014-06-10

    ; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Colon Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Stage IV Rectal Cancer; Stage IV Renal Cell Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  8. Palliation of symptoms in non-small cell lung cancer: a study by the Yorkshire Regional Cancer Organisation Thoracic Group.

    PubMed Central

    Muers, M F; Round, C E

    1993-01-01

    BACKGROUND--Although most treatment for non-small cell lung cancer is palliative, data on the adequacy of symptom control are scanty and there has been little discussion about the appropriate indices. METHODS--Two hundred and eighty nine unselected patients presenting sequentially to six specialists were studied; 242 cases were confirmed histologically and all were managed as non-small cell lung cancer. At presentation and two monthly for one year or until death each of 12 symptoms was graded by a physician at a clinic interview on a four point scale as absent, mild, moderate, or severe. For each symptom a palliative index (median duration of control/median duration of survival) was calculated, where control was defined as an improvement in symptoms of any severity by one grade or more. RESULTS--Sixty four (22%) patients had surgery, 15 (5%) radical and 107 (37%) palliative radiotherapy, and 103 (36%) best supportive care. Analysis showed that most symptoms inexorably worsened with time. The palliation index for haemoptysis was 86%, chest pain 73%, cough 34%, and breathlessness 30%; for systemic symptoms it was 54% for anorexia and 47% for malaise. Palliation was poor in many patients after surgery. Breathlessness was a particular problem in the group having best supportive care. CONCLUSIONS--The frequency of most symptoms in non-small cell lung cancer increases inexorably with time until malaise and anorexia are almost universal. Haemoptysis and chest pain are better palliated than cough and breathlessness. Present treatments fail to give adequate palliation for many patients, and the emphasis in future therapeutic studies should be on the relief of the more severe symptoms. PMID:7685550

  9. Lung Radiofrequency Ablation for the Treatment of Unresectable Recurrent Non-Small-Cell Lung Cancer After Surgical Intervention

    SciTech Connect

    Kodama, Hiroshi Yamakado, Koichiro; Takaki, Haruyuki; Kashima, Masataka; Uraki, Junji; Nakatsuka, Atsuhiro; Takao, Motoshi; Taguchi, Osamu; Yamada, Tomomi; Takeda, Kan

    2012-06-15

    Purpose: A retrospective evaluation was done of clinical utility of lung radiofrequency (RF) ablation in recurrent non-small-cell lung cancer (NSCLC) after surgical intervention. Methods: During May 2003 to October 2010, 44 consecutive patients (26 male and 18 female) received curative lung RF ablation for 51 recurrent NSCLC (mean diameter 1.7 {+-} 0.9 cm, range 0.6 to 4.0) after surgical intervention. Safety, tumor progression rate, overall survival, and recurrence-free survival were evaluated. Prognostic factors were evaluated in multivariate analysis. Results: A total of 55 lung RF sessions were performed. Pneumothorax requiring pluerosclerosis (n = 2) and surgical suture (n = 1) were the only grade 3 or 4 adverse events (5.5%, 3 of 55). During mean follow-up of 28.6 {+-} 20.3 months (range 1 to 98), local tumor progression was found in 5 patients (11.4%, 5 of 44). The 1-, 3-, and 5-year overall survival rates were 97.7, 72.9, and 55.7%, respectively. The 1- and 3-year recurrence-free survival rates were 76.7 and 41.1%, respectively. Tumor size and sex were independent significant prognostic factors in multivariate analysis. The 5-year survival rates were 73.3% in 18 women and 60.5% in 38 patients who had small tumors measuring {<=}3 cm. Conclusion: Our results suggest that lung RF ablation is a safe and useful therapeutic option for obtaining long-term survival in treated patients.

  10. [INTRAOPERATIVE DETECTION OF SENTINEL LYMPH NODES USING INFRARED IMAGING SYSTEM IN LOCAL NON-SMALL CELL CARCINOMA OF LUNG].

    PubMed

    Akopov, A L; Papayan, G V; Chistyakov, I V; Karlson, A; Gerasin, A V; Agishev, A S

    2015-01-01

    The article presents the results of the first domestic experience of intraoperative fluorescence mapping of sentinel lymph nodes in lung cancer. The research included 10 patients, who underwent surgery over the period of time from September 2013 to May 2014. After performing thoracotomy, the solution of indocyanine green (ICG) was injected using subpleural position above the tumor in 3-4 points. Fluorescence (ICG) image guided surgery was carried out by using infrared radiation (wave length 808 nm) on lung surface, root of lung, mediastinum in real time. Fluorescence lymph nodes were mapped. In case that metastatic lesions weren't revealed in sentinel lymph nodes, they weren't noted in other nodes. Method specificity consisted of 100%. Biopsy and histological study of sentinel lymph nodes mapped during fluorescence (ICG) image guided surgery could be useful for prevention of lymphodissection in patients with non-small cell carcinoma of lung. PMID:26601511

  11. Knockdown of Aurora-B inhibits the growth of non-small cell lung cancer A549 cells

    PubMed Central

    YU, JING JING; ZHOU, LONG DIAN; ZHAO, TIAN TIAN; BAI, WEI; ZHOU, JING; ZHANG, WEI

    2015-01-01

    Elevated expression of Aurora-B affects cell apoptosis and proliferation in a variety of solid tumors. However, the role of Aurora-B has been poorly evaluated in non-small cell lung cancer (NSCLC). In the present study, it was found that Aurora-B was overexpressed in tissue specimens obtained from 174 patients with lung cancer. It was also demonstrated that knockdown of Aurora-B induces apoptosis and inhibits the growth of lung cancer A549 cells in vitro and in vivo. Furthermore, it was found that silencing Aurora-B decreased the activity of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Therefore, it was concluded that knockdown of Aurora-B induces apoptosis and inhibits growth in NSCLC A549 cells, in addition to inhibiting the activity of the PI3K/AKT signaling pathway. Targeting Aurora-B may provide a novel target for lung cancer therapy. PMID:26622725

  12. Diffuse Idiopathic Skeletal Hyperostosis (DISH) and non small cell lung cancer: case presentation and review of the literature.

    PubMed

    Tomos, Ioannis; Vlami, Aikaterini; Karakatsani, Anna; Korbila, Ioanna; Manali, Effrosyni D; Papiris, Spyros A

    2016-01-01

    Diffuse idiopathic skeletal hyperostosis (DISH), also known as Forestier's disease, is a systemic non inflammatory disease of unknown cause. It is characterized by the presence of osteophytes due to calcification and ossification of spinal ligaments and entheses. Moreover, diffuse idiopathic skeletal hyperostosis has been associated with a variety of metabolic disorders. However, to the best of our knowledge no association with non small cell lung cancer (NSCLC) has been reported so far. In the present study we report a case of a patient with NSCLC and DISH. PMID:27238170

  13. Advances in molecular biology of lung disease: aiming for precision therapy in non-small cell lung cancer.

    PubMed

    Rooney, Claire; Sethi, Tariq

    2015-10-01

    Lung cancer is the principal cause of cancer-related mortality in the developed world, accounting for almost one-quarter of all cancer deaths. Traditional treatment algorithms have largely relied on histologic subtype and have comprised pragmatic chemotherapy regimens with limited efficacy. However, because our understanding of the molecular basis of disease in non-small cell lung cancer (NSCLC) has improved exponentially, it has become apparent that NSCLC can be radically subdivided, or molecularly characterized, based on recurrent driver mutations occurring in specific oncogenes. We know that the presence of such mutations leads to constitutive activation of aberrant signaling proteins that initiate, progress, and sustain tumorigenesis. This persistence of the malignant phenotype is referred to as "oncogene addiction." On this basis, a paradigm shift in treatment approach has occurred. Rational, targeted therapies have been developed, the first being tyrosine kinase inhibitors (TKIs), which entered the clinical arena > 10 years ago. These were tremendously successful, significantly affecting the natural history of NSCLC and improving patient outcomes. However, the benefits of these drugs are somewhat limited by the emergence of adaptive resistance mechanisms, and efforts to tackle this phenomenon are ongoing. A better understanding of all types of oncogene-driven NSCLC and the occurrence of TKI resistance will help us to further develop second- and third-generation small molecule inhibitors and will expand our range of precision therapies for this disease. PMID:26182407

  14. The significance of PIWI family expression in human lung embryogenesis and non-small cell lung cancer

    PubMed Central

    Navarro, Alfons; Tejero, Rut; Viñolas, Nuria; Cordeiro, Anna; Marrades, Ramon M.; Fuster, Dolors; Caritg, Oriol; Moises, Jorge; Muñoz, Carmen; Molins, Laureano; Ramirez, Josep; Monzo, Mariano

    2015-01-01

    The expression of Piwi-interacting RNAs, small RNAs that bind to PIWI proteins, was until recently believed to be limited to germinal stem cells. We have studied the expression of PIWI genes during human lung embryogenesis and in paired tumor and normal tissue prospectively collected from 71 resected non-small-cell lung cancer patients. The mRNA expression analysis showed that PIWIL1 was highly expressed in 7-week embryos and downregulated during the subsequent weeks of development. PIWIL1 was expressed in 11 of the tumor samples but in none of the normal tissue samples. These results were validated by immunohistochemistry, showing faint cytoplasmic reactivity in the PIWIL1-positive samples. Interestingly, the patients expressing PIWIL1 had a shorter time to relapse (TTR) (p = 0.006) and overall survival (OS) (p = 0.0076) than those without PIWIL1 expression. PIWIL2 and 4 were downregulated in tumor tissue in comparison to the normal tissue (p < 0.001) and the patients with lower levels of PIWIL4 had shorter TTR (p = 0.048) and OS (p = 0.033). In the multivariate analysis, PIWIL1 expression emerged as an independent prognostic marker. Using 5-Aza-dC treatment and bisulfite sequencing, we observed that PIWIL1 expression could be regulated in part by methylation. Finally, an in silico study identified a stem-cell expression signature associated with PIWIL1 expression. PMID:25742785

  15. Rapid Response of Advanced Squamous Non-Small Cell Lung Cancer with Thrombocytopenia after First-Line Treatment with Pembrolizumab Plus Autologous Cytokine-Induced Killer Cells

    PubMed Central

    Hui, Zhenzhen; Zhang, Xinwei; Ren, Baozhu; Li, Runmei; Ren, Xiubao

    2015-01-01

    We present the first clinical evidence of advanced squamous non-small cell lung cancer with severe thrombocytopenia showing dramatic improvement after first-line treatment with pembrolizumab plus autologous cytokine-induced killer cells. PMID:26734004

  16. The Use of the Active Breathing Coordinator Throughout Radical Non-Small-Cell Lung Cancer (NSCLC) Radiotherapy

    SciTech Connect

    Brock, Juliet; McNair, Helen A.; Panakis, Niki; Symonds-Tayler, Richard; Evans, Phil M.; Brada, Michael

    2011-10-01

    Purpose: To assess feasibility and reproducibility of an Active Breathing Coordinator (ABC) used throughout radical radiotherapy for non-small-cell lung cancer, and compare lung dosimetric parameters between free-breathing and ABC plans. Methods and Materials: A total of 18 patients, recruited into an approved study, had free-breathing and ABC breath-hold treatment plans generated. Lung volume, the percentage volume of lung treated to a dose of {>=}20 Gy (V{sub 20}), and mean lung dose (MLD) were compared. Treatment (64 Gy in 32 fractions, 5 days/week) was delivered in breath-hold. Repeat breath-hold computed tomography scans were used to assess change in gross tumor volume (GTV) size and position. Setup error was also measured and potential GTV-planning target volume (PTV) margins calculated. Results: Seventeen of 18 patients completed radiotherapy using ABC daily. Intrafraction tumor position was consistent, but interfraction variation had mean (range) values of 5.1 (0-25), 3.6 (0-9.7), and 3.5 (0-16.6) mm in the superoinferior (SI), right-left (RL), and anteroposterior (AP) directions, respectively. Tumor moved partially outside the PTV in 5 patients. Mean reduction in GTV from planning to end of treatment was 25% (p = 0.003). Potentially required PTV margins were 18.1, 11.9, and 11.9 mm in SI, RL, and AP directions. ABC reduced V{sub 20} by 13% (p = 0.0001), V{sub 13} by 12% (p = 0.001), and MLD by 13% (p < 0.001) compared with free-breathing; lung volume increased by 41% (p < 0.001). Conclusions: Clinically significant movements of GTV were seen during radiotherapy for non-small-cell lung cancer using ABC. Image guidance is recommended with ABC. The use of ABC can reduce dose volume parameters determining lung toxicity, and might allow for equitoxic radiotherapy dose escalation.

  17. The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer.

    PubMed

    Bremnes, Roy M; Busund, Lill-Tove; Kilvær, Thomas L; Andersen, Sigve; Richardsen, Elin; Paulsen, Erna Elise; Hald, Sigurd; Khanehkenari, Mehrdad Rakaee; Cooper, Wendy A; Kao, Steven C; Dønnem, Tom

    2016-06-01

    A malignant tumor is not merely an accumulation of neoplastic cells, but constitutes a microenvironment containing endothelial cells, fibroblasts, structural components, and infiltrating immune cells that impact tumor development, invasion, metastasis, and outcome. Hence, the evolution of cancers reflects intricate cellular and molecular interactions between tumor cells and constituents of the tumor microenvironment. Recent studies have shed new light on this complex interaction between tumor and host immune cells and the resulting immune response. The composition of the immune microenvironment differs across patients as well as in cancers of the same type, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, and macrophages. The type, density, location, and organization of immune cells within solid tumors define the immune contexture, which has proved to be a major determinant of tumor characteristics and patient outcome. Lung cancer consists mostly of non-small cell lung cancer (85%); it is our most deadly malignant disease, with the 5-year survival rate being merely 15%. This review focuses on the immune contexture; the tumor-suppressing roles of tumor-infiltrating lymphocytes; and the relevance of this immune contexture for cancer diagnostics, prognostication, and treatment allocation, with an emphasis on non-small cell lung cancer. PMID:26845192

  18. Potentially Curative Radiotherapy for Non-Small-Cell Lung Cancer in Norway: A Population-Based Study of Survival

    SciTech Connect

    Strand, Trond-Eirik; Brunsvig, Paal Fredrik; Johannessen, Dag Clement; Sundstrom, Stein; Wang, Mari; Hornslien, Kjersti; Bremnes, Roy Martin; Stensvold, Andreas; Garpestad, Oddveig; Norstein, Jarle

    2011-05-01

    Purpose: The efficacy of curative irradiation in the treatment of non-small-cell lung cancer patients is considered limited. The purpose of this study was to evaluate long-term survival in a population-based approach. Methods and Materials: Cases of non-small-cell lung cancer diagnosed from 1993 to 2001 were identified in the Cancer Registry of Norway. Electronic linkage with national data from the hospitals' radiotherapy verification systems identified those who received potentially curative doses ({>=}50 Gy). Hospital records were reviewed for all patients. Results: A total of 497 patients (336 men) were identified with a radiation dose of {>=}50 Gy delivered to the lung region. Of these, 41% received 60 Gy or more. The majority (70%) of patients included had advanced stage disease: 24% Stage IIIA and