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Sample records for advanced nsclc treated

  1. Optimal tumor shrinkage predicts long-term outcome in advanced nonsmall cell lung cancer (NSCLC) treated with target therapy

    PubMed Central

    He, Xiaobo; Zhang, Yang; Ma, Yuxiang; Zhou, Ting; Zhang, Jianwei; Hong, Shaodong; Sheng, Jin; Zhang, Zhonghan; Yang, Yunpeng; Huang, Yan; Zhang, Li; Zhao, Hongyun

    2016-01-01

    Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as standard therapies for advanced nonsmall cell lung cancer (NSCLC) patients with EGFR mutation positive. Because these targeted therapies could cause tumor necrosis and shrinkage, the purpose of the study is to search for a value of optimal tumor shrinkage as an appropriate indicator of outcome for advanced NSCLC. A total of 88 NSCLC enrollees of 3 clinical trials (IRESSA registration clinical trial, TRUST study and ZD6474 study), who received Gefitinib (250 mg, QD), Erlotinib (150 mg, QD), and ZD6474 (100 mg, QD), respectively, during December 2003 and October 2007, were retrospectively analyzed. The response evaluation criteria in solid tumors (RECIST) were used to identify responders, who had complete response (CR) or partial responses (PR) and nonresponders who had stable disease (SD) or progressive disease (PD). Receiver operating characteristics (ROC) analysis was used to find the optimal tumor shrinkage as an indicator for tumor therapeutic outcome. Univariate and multivariate Cox regression analyses were performed to compare the progression-free survival (PFS) and overall survival (OS) between responders and nonresponders stratified based on radiologic criteria. Among the 88 NSCLC patients, 26 were responders and 62 were nonresponders based on RECIST 1.0. ROC indicated that 8.32% tumor diameter shrinkage in the sum of the longest tumor diameter (SLD) was the cutoff point of tumor shrinkage outcomes, resulting in 46 responders (≤8.32%) and 42 nonresponders (≥8.32%). Univariate and multivariate Cox regression analyses indicated that (1) the responders (≤8.32%) and nonresponders (≥ −8.32%) were significantly different in median PFS (13.40 vs 1.17 months, P < 0.001) and OS (19.80 vs 7.90 months, P < 0.001) and (2) –8.32% in SLD could be used as the optimal threshold for PFS (hazard ratio [HR], 8.11, 95% CI, 3.75 to 17.51, P < 0.001) and OS

  2. Recent Advances in Immunotherapy in Metastatic NSCLC

    PubMed Central

    Bansal, Pranshu; Osman, Diaa; Gan, Gregory N.; Simon, George R.; Boumber, Yanis

    2016-01-01

    Non-small cell lung cancer (NSCLC) is one of most common malignancies and the leading cause of cancer deaths worldwide. Despite advances in targeted therapies, majority of NSCLC patients do not have targetable genomic alterations. Nevertheless, recent discovery that NSCLC is an immunogenic tumor type, and several breakthroughs in immunotherapies have led to rapid expansion of this new treatment modality in NSCLC with recent FDA approvals of programed death receptor-1 inhibitors, such as nivolumab and pembrolizumab. Here, we review promising immunotherapeutic approaches in metastatic NSCLC, including checkpoint inhibitors, agents with other mechanisms of action, and immunotherapy combinations with other drugs. With advent of immunotherapy, therapeutic options in metastatic NSCLC are rapidly expanding with the hope to further expand life expectancy in metastatic lung cancer. PMID:27896216

  3. Tyrosine kinase inhibitors in advanced NSCLC: A case report.

    PubMed

    Alves, Ana Ferreira; Liebermann, Marco

    2008-10-01

    Erlotinib is a molecule that selectively inhibits epidermal growth factor receptor (EGFR) tyrosine kinase activity. The authors present a case that exemplifies the use of erlotinib as second line therapy for non-small cell lung cancer (NSCLC). This case is about a 76 years old woman, non-smoker, with advanced lung adenocarcinoma (stage IIIB) previously treated with two cycles of standard chemotherapy, which were interrupted by serious adverse reactions. Rev Port Pneumol 2008; XIV (Supl 3): S23-S28.

  4. Molecular targeted therapy in the treatment of advanced stage non-small cell lung cancer (NSCLC).

    PubMed

    Kumarakulasinghe, Nesaretnam Barr; van Zanwijk, Nico; Soo, Ross A

    2015-04-01

    Historically, patients with advanced stage non-small cell lung cancer (NSCLC) were treated with chemotherapy alone, but a therapeutic plateau has been reached. Advances in the understanding of molecular genetics have led to the recognition of multiple molecularly distinct subsets of NSCLC. This in turn has led to the development of rationally directed molecular targeted therapy, leading to improved clinical outcomes. Tumour genotyping for EGFR mutations and ALK rearrangement has meant chemotherapy is no longer given automatically as first-line treatment but reserved for when patients do not have a 'druggable' driver oncogene. In this review, we will address the current status of clinically relevant driver mutations and emerging new molecular subsets in lung adenocarcinoma and squamous cell carcinoma, and the role of targeted therapy and mechanisms of acquired resistance to targeted therapy.

  5. RAGE Genetic Polymorphisms Are Associated with Risk, Chemotherapy Response and Prognosis in Patients with Advanced NSCLC

    PubMed Central

    Hua, Feng; Wang, Bin; Mao, Wei; Feng, Xueren

    2012-01-01

    Aim To explore the association between genetic polymorphisms of the receptor for advanced glycation end-products (RAGE) and susceptibility, chemotherapy response rate and prognosis of non-small cell lung cancer (NSCLC). Method This is a prospective study in which 562 patients with NSCLC and 764 healthy controls were enrolled. Three RAGE genetic polymorphisms, namely, −429T/C, −374T/A and 82G/S were genotyped. Platinum-based chemotherapy was given to 432 subjects with advanced inoperable NSCLC and their responses to chemotherapy were evaluated. Results All the polymorphic genotypes of RAGE polymorphisms were associated with susceptibility for NSCLC. Only the 82G/S polymorphisms denoted a significant difference between responders and non-responders to chemotherapy. The 82SS genotype and 82S allele distribution not only increased the NSCLC risk, but also was associated with a lower chemotherapy response rate and poor prognosis, indicated by overall survival and progression free survival. Conclusion The 82G/S genetic polymorphism of RAGE gene might be used as a genetic marker to screen for patients sensitive to thermotherapy and to predict the prognosis of NSCLC. PMID:23071492

  6. Bisphosphonates enhance EGFR-TKIs efficacy in advanced NSCLC patients with EGFR activating mutation: A retrospective study

    PubMed Central

    Cai, Xiao-Hong; Yao, Wen-Xiu; Xu, Yong; Liu, Xiao-Ke; Zhu, Wen-Jiang; Wang, Yan; Zhou, Jin; Lu, You; Wang, Yong-Sheng

    2016-01-01

    Background Bisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations. Methods Between January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed. Results Among the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798). Conclusions Concomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases. PMID:26624882

  7. Aberrant Promoter Methylation of Caveolin-1 Is Associated with Favorable Response to Taxane-Platinum Combination Chemotherapy in Advanced NSCLC

    PubMed Central

    Brodie, Seth A.; Lombardo, Courtney; Li, Ge; Kowalski, Jeanne; Gandhi, Khanjan; You, Shaojin; Khuri, Fadlo R.; Marcus, Adam; Vertino, Paula M.; Brandes, Johann C.

    2014-01-01

    Purpose Aberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancer-associated gene loci and correlated results with clinical outcomes. Methods We studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates. Results Cav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance  = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03–0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention. Conclusions CAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae. PMID:25222296

  8. The Influence of Biomarker Mutations and Systemic Treatment on Cerebral Metastases from NSCLC Treated with Radiosurgery

    PubMed Central

    Lee, Min Ho; Kong, Doo-Sik; Seol, Ho Jun; Nam, Do-Hyun; Lee, Jung-Il

    2017-01-01

    Objective The purpose of this study was to analyze outcomes and identify prognostic factors in patients with cerebral metastases from non-small cell lung cancer (NSCLC) treated with gamma knife radiosurgery (GKS) particularly, focusing on associations of biomarkers and systemic treatments. Methods We retrospectively reviewed the medical records of 134 patients who underwent GKS for brain metastases due to NSCLC between January 2002 and December 2012. Representative biomarkers including epidermal growth factor receptor (EGFR) mutation, K-ras mutation, and anaplastic lymphoma kinase (ALK) mutation status were investigated. Results The median overall survival after GKS was 22.0 months (95% confidence interval [CI], 8.8–35.1 months). During follow-up, 63 patients underwent salvage treatment after GKS. The median salvage treatment-free survival was 7.9 months (95% CI, 5.2–10.6 months). Multivariate analysis revealed that lower recursive partition analysis (RPA) class, small number of brain lesions, EGFR mutation (+), and ALK mutation (+) were independent positive prognostic factors associated with longer overall survival. Patients who received target agents 30 days after GKS experienced significant improvements in overall survival and salvage treatment-free survival than patients who never received target agents and patients who received target agents before GKS or within 30 days (median overall survival: 5.0 months vs. 18.2 months, and 48.0 months with p-value=0.026; median salvage treatment-free survival: 4.3 months vs. 6.1 months and 16.6 months with p-value=0.006, respectively). To assess the influence of target agents on the pattern of progression, cases that showed local recurrence and new lesion formation were analyzed according to target agents, but no significant effects were identified. Conclusion The prognosis of patients with brain metastases of NSCLC after GKS significantly differed according to specific biomarkers (EGFR and ALK mutations). Our results

  9. Long-lasting control with erlotinib in advanced non-small cell lung cancer (NSCLC).

    PubMed

    Guimarães, Teresa; Castro, Ana; Cortesão, Nuno; Ferreira, Jorge; João, Fernanda

    2008-10-01

    The authors present a clinical case of a caucasian male patient, 59 years-old, non-smoker, with an advanced non-small cell lung carcinoma (NSCLC), with 3 years of follow-up, received erlotinib for 18 months, after failure of more than one chemotherapy schedule, without evidence of oncologic progression. The patient evidences excellent quality of life, controlled sintomatology, recovery of the capacity of tolerance to the effort and it maintains his professional activities. The treatment with erlotinib has been well tolerated, although exhibiting grade 1 cutaneous toxicity. Rev Port Pneumol 2008; XIV (Supl 3): S9-S15.

  10. The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC.

    PubMed

    Manegold, Christian; Dingemans, Anne-Marie C; Gray, Jhanelle E; Nakagawa, Kazuhiko; Nicolson, Marianne; Peters, Solange; Reck, Martin; Wu, Yi-Long; Brustugun, Odd Terje; Crinò, Lucio; Felip, Enriqueta; Fennell, Dean; Garrido, Pilar; Huber, Rudolf M; Marabelle, Aurélien; Moniuszko, Marcin; Mornex, Françoise; Novello, Silvia; Papotti, Mauro; Pérol, Maurice; Smit, Egbert F; Syrigos, Kostas; van Meerbeeck, Jan P; van Zandwijk, Nico; Chih-Hsin Yang, James; Zhou, Caicun; Vokes, Everett

    2017-02-01

    Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types.

  11. Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC.

    PubMed

    Paz-Ares, Luis; Soulières, Denis; Moecks, Joachim; Bara, Ilze; Mok, Tony; Klughammer, Barbara

    2014-08-01

    Patients with non-small-cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6-13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0-9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3-6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy.

  12. Prognostic value of plasma EGFR ctDNA in NSCLC patients treated with EGFR-TKIs

    PubMed Central

    Zhang, Chengjuan; Wei, Bing; Li, Peng; Yang, Ke; Wang, Zhizhong; Ma, Jie; Guo, Yongjun

    2017-01-01

    Objective Epidermal growth factor receptor (EGFR) specific mutations have been known to improve survival of patients with non-small-cell lung carcinoma (NSCLC). However, whether there are any changes of EGFR mutations after targeted therapy and its clinical significance is unclear. This study was to identify the status of EGFR mutations after targeted therapy and predict the prognostic significance for NSCLC patients. Methods A total of forty-five (45) NSCLC patients who received EGFR-TKI therapy were enrolled. We identified the changes of EGFR mutations in plasma ctDNA by Amplification Refractory Mutation System (ARMS) PCR technology. Results In the 45 cases of NSCLC with EGFR mutations, the EGFR mutation status changed in 26 cases, in which, 12 cases (26.7%) from positive to negative, and 14 cases (31.1%) from T790M mutation negative to positive after TKI targeted therapy. The T790M occurance group had a shorter Progression -Free-Survival (PFS) than the groups of EGFR mutation undetected and EGFR mutation turned out to have no change after EGFR-TKI therapy (p < 0.05). Conclusions According to this study, it’s necessary to closely monitor EGFR mutations during follow-up to predict the prognosis of NSCLC patients who are to receive the TKI targeted therapy. PMID:28333951

  13. Pooled analysis of clinical outcome for EGFR TKI-treated patients with EGFR mutation-positive NSCLC

    PubMed Central

    Paz-Ares, Luis; Soulières, Denis; Moecks, Joachim; Bara, Ilze; Mok, Tony; Klughammer, Barbara

    2014-01-01

    Patients with non-small-cell lung cancer (NSCLC) appear to gain particular benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKI) if their disease tests positive for EGFR activating mutations. Recently, several large, controlled, phase III studies have been published in NSCLC patients with EGFR mutation-positive tumours. Given the increased patient dataset now available, a comprehensive literature search for EGFR TKIs or chemotherapy in EGFR mutation-positive NSCLC was undertaken to update the results of a previously published pooled analysis. Pooling eligible progression-free survival (PFS) data from 27 erlotinib studies (n = 731), 54 gefitinib studies (n = 1802) and 20 chemotherapy studies (n = 984) provided median PFS values for each treatment. The pooled median PFS was: 12.4 months (95% accuracy intervals [AI] 11.6–13.4) for erlotinib-treated patients; 9.4 months (95% AI 9.0–9.8) for gefitinib-treated patients; and 5.6 months (95% AI 5.3–6.0) for chemotherapy. Both erlotinib and gefitinib resulted in significantly longer PFS than chemotherapy (permutation testing; P = 0.000 and P = 0.000, respectively). Data on more recent TKIs (afatinib, dacomitinib and icotinib) were insufficient at this time-point to carry out a pooled PFS analysis on these compounds. The results of this updated pooled analysis suggest a substantial clear PFS benefit of treating patients with EGFR mutation-positive NSCLC with erlotinib or gefitinib compared with chemotherapy. PMID:25100284

  14. Unravelling signal escape through maintained EGFR activation in advanced non-small cell lung cancer (NSCLC): new treatment options.

    PubMed

    Remon, Jordi; Besse, Benjamin

    2016-01-01

    The discovery of activating epidermal growth factor receptor (EGFR) mutations has opened up a new era in the development of more effective treatments for patients with non-small cell lung cancer (NSCLC). However, patients with EGFR-activating mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) ultimately develop acquired resistance (AR). Among known cases of patients with AR, 70% of the mechanisms involved in the development of AR to EGFR TKI have been identified and may be categorised as either secondary EGFR mutations such as the T790M mutation, activation of bypass track signalling pathways such as MET amplification, or histologic transformation. EGFR-mutant NSCLC tumours maintain oncogenic addiction to the EGFR pathway beyond progression with EGFR TKI. Clinical strategies that can be implemented in daily clinical practice to potentially overcome this resistance and prolong the outcome in this subgroup of patients are presented.

  15. Unravelling signal escape through maintained EGFR activation in advanced non-small cell lung cancer (NSCLC): new treatment options

    PubMed Central

    Remon, Jordi; Besse, Benjamin

    2016-01-01

    The discovery of activating epidermal growth factor receptor (EGFR) mutations has opened up a new era in the development of more effective treatments for patients with non-small cell lung cancer (NSCLC). However, patients with EGFR-activating mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) ultimately develop acquired resistance (AR). Among known cases of patients with AR, 70% of the mechanisms involved in the development of AR to EGFR TKI have been identified and may be categorised as either secondary EGFR mutations such as the T790M mutation, activation of bypass track signalling pathways such as MET amplification, or histologic transformation. EGFR-mutant NSCLC tumours maintain oncogenic addiction to the EGFR pathway beyond progression with EGFR TKI. Clinical strategies that can be implemented in daily clinical practice to potentially overcome this resistance and prolong the outcome in this subgroup of patients are presented. PMID:27843631

  16. Recent Advances in Targetable Therapeutics in Metastatic Non-Squamous NSCLC

    PubMed Central

    Bansal, Pranshu; Osman, Diaa; Gan, Gregory N.; Simon, George R.; Boumber, Yanis

    2016-01-01

    Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC). With the discovery of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and effective targeted therapies, therapeutic options are expanding for patients with lung adenocarcinoma. Here, we review novel therapies in non-squamous NSCLC, which are directed against oncogenic targets, including EGFR, ALK, ROS1, BRAF, MET, human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2), RET, and NTRK. With the rapidly evolving molecular testing and development of new targeted agents, our ability to further personalize therapy in non-squamous NSCLC is rapidly expanding. PMID:27200298

  17. Development of a Patient-Reported Outcome Instrument to Evaluate Symptoms of Advanced NSCLC: Qualitative Research and Content Validity of the Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ)

    PubMed Central

    Atkinson, Thomas M.; DeBusk, Kendra P.A.; Liepa, Astra M.; Scanlon, Michael; Coons, Stephen Joel

    2016-01-01

    PURPOSE To describe the process and results of the preliminary qualitative development of a new symptom-based PRO measure intended to assess treatment benefit in advanced non-small cell lung cancer (NSCLC) clinical trials. METHODS Individual qualitative interviews were conducted with adult NSCLC (Stage I–IV) patients in the US. Experienced interviewers conducted concept elicitation (CE) and cognitive interviews using semi-structured interview guides. The CE interview guide was used to elicit spontaneous reports of symptom experiences along with probing to further explore and confirm concepts. Interview transcripts were coded and analyzed by professional qualitative coders using Atlas.ti software, and were summarized by like-content using an iterative coding framework. Data from the CE interviews were considered alongside existing literature and clinical expert opinion during an item-generation process, leading to development of a preliminary version of the NSCLC Symptom Assessment Questionnaire (NSCLC-SAQ). Three waves of cognitive interviews were conducted to evaluate concept relevance, item interpretability, and structure of the draft items to facilitate further instrument refinement. FINDINGS Fifty-one patients (mean age 64.9 [SD=11.2]; 51.0% female) participated in the CE interviews. A total of 1,897 expressions of NSCLC-related symptoms were identified and coded in interview transcripts, representing approximately 42 distinct symptom concepts. A 9-item initial draft instrument was developed for testing in three waves of cognitive interviews with additional NSCLC patients (n=20), during which both paper and electronic versions of the instrument were evaluated and refined. Participant responses and feedback during cognitive interviews led to the removal of 2 items and substantial modifications to others. IMPLICATIONS The NSCLC-SAQ is a 7-item PRO measure intended for use in advanced NSCLC clinical trials to support medical product labelling. The NSCLC-SAQ uses

  18. Recent advances in epigenomics in NSCLC: real-time detection and therapeutic implications.

    PubMed

    Di Paolo, Antonello; Del Re, Marzia; Petrini, Iacopo; Altavilla, Giuseppe; Danesi, Romano

    2016-08-01

    NSCLC is an aggressive disease with one of the poorer prognosis among cancers. The disappointing response to chemotherapy drives the search for genetic biomarkers aimed at both attaining an earlier diagnosis and choosing the most appropriate chemotherapy. In this scenario, epigenomic markers, such as DNA methylation, histone acetylation and the expression of noncoding RNAs, have been demonstrated to be reliable for the stratification of NSCLC patients. Newest techniques with increased sensitivity and the isolation of nucleic acids from plasma may allow an early diagnosis and then monitoring the efficacy over time. However, prospective confirmatory studies are still lacking. This article presents an overview of the epigenetic markers evaluated in NSCLC and discusses the role of their real-time detection in the clinical management of the disease.

  19. Energy balance in patients with advanced NSCLC, metastatic melanoma and metastatic breast cancer receiving chemotherapy--a longitudinal study.

    PubMed

    Harvie, M N; Howell, A; Thatcher, N; Baildam, A; Campbell, I

    2005-02-28

    Chemotherapy exerts a variable effect on nutritional status. It is not known whether loss of body fat or fat-free mass (FFM) during chemotherapy relates to diminished dietary intake, failure to meet elevated energy requirements, or to the presence of an acute-phase response. We sought to determine prospective measurements of body mass and composition, resting energy expenditure, energy and protein intake, and C-reactive protein over a course of chemotherapy in 82 patients with advanced cancer. There was a large dropout from the study. Prospective measurements were obtained in 19 patients with non-small-cell lung cancer (NSCLC), 12 with metastatic melanoma and 10 with metastatic breast cancer. There were significant increases in energy intake among patients with metastatic breast cancer, 873 (266-1480) kJ (mean 95% CI; P<0.01), and metastatic melanoma, 2513 (523-4503) kJ (P<0.01). Breast cancer patients gained percentage body fat over the course of treatment, 2.1 (0.8-3.5%). Gain or loss of body fat correlated to mean energy intake throughout chemotherapy in patients with NSCLC (Rs=0.751; P<0.01) and metastatic breast cancer (Rs=0.617; P<0.05). The ability to meet or exceed energy requirements led to gains in body fat among patients with metastatic breast cancer and NSCLC, but did not prevent loss of FFM in these groups.

  20. Pathway Targeted Immunotherapy: Rationale and Evidence of Durable Clinical Responses with a Novel, EGF-directed Agent for Advanced NSCLC.

    PubMed

    Rosell, Rafael; Neninger, Elia; Nicolson, Marianne; Huber, Rudolf M; Thongprasert, Sumitra; Parikh, Purvish M; D'Hondt, Erik

    2016-11-01

    Abnormalities in the epidermal growth factor (EGF) and EGFR pathway promote progression of NSCLC. Immunization with EGF vaccine induces specific, neutralizing anti-EGF antibodies that prevent binding of the ligand to its receptor. This concept of pathway targeted immunotherapy (PTI) was validated in vitro by dose-related suppression of EGFR, Akt, and Erk1/2 phosphorylation in cell lines with different mutations. A randomized phase II trial showed improved overall survival (OS) in subgroups with advanced NSCLC showing a clear immunologic response. By per-protocol analysis of the ensuing phase IIb trial, patients receiving EGF PTI survived 3 months longer than controls (12.43 versus 9.43 months; hazard ratio = 0.77 [95% confidence interval, 0.61-0.98]). These data were confirmed in a larger trial showing an OS benefit over control of >3 months. The variable most strongly correlated with efficacy was circulating EGF at enrolment. Patients with serum EGF levels >250 pg/mL benefited most from treatment with EGF PTI. Of 188 patients tested, 94 were above this biomarker threshold. The OS benefit from active versus control treatment was 6.7 months. More than 15% of patients had responses for >5 years. Long-term survivors are seen in all EGF PTI trials. Treatment is well-tolerated, induces high anti-EGF antibody titers, reduces levels of circulating serum EGF, achieves durable responses, and significantly prolongs OS. A threshold of 250 pg/mL has been set to enrich the study population in the ongoing pivotal trial. This biomarker-guided study in an enriched population of patients with both squamous and nonsquamous stage IV NSCLC aims to replicate the favorable efficacy/tolerability balance of earlier studies.

  1. Low Prognostic Nutritional Index Correlates with Worse Survival in Patients with Advanced NSCLC following EGFR-TKIs

    PubMed Central

    Qin, Tao; Hu, Zhi-Huang; Hong, Shao-Dong; Zhou, Ting; Huang, Yan; Zhao, Hong-Yun; Zhang, Li

    2016-01-01

    Objective This study was designed to demonstrate the prognostic value of prognostic nutritional index (PNI), a reflection systemic immunonutritional status, on the long-term survival of patients taking epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Methods In this retrospective study, eligible advanced NSCLC patients with sensitive EGFR mutations (exon 19 deletion or L858R in exon 21) were included to investigate the correlation between the PNI and overall survival (OS). The PNI was calculated as 10 x serum albumin value (g/dl) + 0.005 x peripheral lymphocyte count (per mm3). The prognostic significance of PNI and other clinicopathologic factors was identified by univariate and multivariate analysis. Results Finally, 144 patients met the inclusion criteria. The optimal cut-off value of PNI for survival stratification was 48.78. Compared with high PNI group (n = 81), low PNI (n = 63) was significantly associated with elevated C-reactive protein (CRP) level and non-response to TKIs. Overall survival was superior in the high PNI group (HR, 0.44, p = 0.004), especially for patient with L858R (HR, 0.37, p = 0.009) rather than 19 deletion (HR, 0.69, p = 0.401). The independent prognostic value of PNI was validated by multivariate analysis. Conclusion This pilot investigation demonstrated that low prognostic nutritional index correlates with worse survival for patients with advanced NSCLC and taking EGFR-TKIs. The assessment of a convenient index, known as PNI, worth attention in routine clinical practice for patients following EGFR-TKIs treatment. PMID:26784943

  2. Safety, immunogenicity and preliminary efficacy of multiple-site vaccination with an Epidermal Growth Factor (EGF) based cancer vaccine in advanced non small cell lung cancer (NSCLC) patients

    PubMed Central

    2011-01-01

    The prognosis of patients with advanced non small cell lung (NSCLC) cancer remains dismal. Epidermal Growth Factor Receptor is over-expressed in many epithelial derived tumors and its role in the development and progression of NSCLC is widely documented. CimaVax-EGF is a therapeutic cancer vaccine composed by human recombinant Epidermal Growth Factor (EGF) conjugated to a carrier protein, P64K from Neisseria Meningitides. The vaccine is intended to induce antibodies against self EGF that would block EGF-EGFR interaction. CimaVax-EGF has been evaluated so far in more than 1000 advanced NSCLC patients, as second line therapy. Two separate studies were compared to assess the impact of high dose vaccination at multiple anatomic sites in terms of immunogenicity, safety and preliminary efficacy in stage IIIb/IV NSCLC patients. In both clinical trials, patients started vaccination 1 month after finishing first line chemotherapy. Vaccination at 4 sites with 2.4 mg of EGF (high dose) was very safe. The most frequent adverse events were grade 1 or 2 injection site reactions, fever, headache and vomiting. Patients had a trend toward higher antibody response. The percent of very good responders significantly augmented and there was a faster decrease of circulating EGF. All vaccinated patients and those classified as good responders immunized with high dose at 4 sites, had a large tendency to improved survival. PMID:22024351

  3. Optimizing the use of epidermal growth factor receptor inhibitors in advanced non-small-lung cancer (NSCLC)

    PubMed Central

    Shash, Emad; Peccatori, Fedro Alessandro; Azim, Hatem A

    2011-01-01

    Lung cancer is the leading cause of cancer-related death in US and Europe. Treatment with a platinum-based chemotherapy remains the standard of care, however with modest effect on quality of life and overall survival which seldom reaches 1 year. Recently, several classes of targeted agents have emerged showing promising results. In particular, agents targeting the epidermal growth factor receptor (EGFR) showed impressive clinical activity both in the first line and salvage settings. However, it is evident that these drugs are not effective in all patients. Putting into consideration the very high cost of these agents, there is an urgent need to provide reliable tools to identify those patients that would derive the maximum benefit from these drugs. Several predictive biomarkers were developed to identify those patients who would derive the maximal benefit of these drugs. In this review we will discuss the recent updates on the role of EGFR inhibitors in the treatment of advanced NSCLC and the role of predictive bio-markers in patient selection. PMID:22263061

  4. A retrospective analysis of efficacy and safety of adding bevacizumab to chemotherapy as first- and second-line therapy in advanced non-small-cell lung cancer (NSCLC).

    PubMed

    Quan, Rencui; Huang, Jiaxing; Chen, Nan; Fang, Wenfeng; Hu, Zhihuang; Zhan, Jianhua; Zhou, Ting; Zhang, Li; Zhang, Hongyu

    2016-08-01

    Several phase III clinical trials had authenticated that the addition of bevacizumab to paclitaxel plus carboplatin or gemcitabine plus cisplatin showed encouraging efficacy as first-line therapy for advanced NSCLC patients. However, the benefits of adding bevacizumab to other chemotherapy regimens in first- or second-line therapy have not been reported. To compare the clinical efficacy and safety of bevacizumab concomitant with chemotherapy regimens in patients with advanced NSCLC as first- or second-line therapy, we retrospectively reviewed the effects of adding bevacizumab to chemotherapy regimens in naive-chemotherapy and pre-chemotherapy patients with advanced non-squamous NSCLC. A total of 79 patients with advanced non-squamous NSCLC received at least two cycles of bevacizumab with chemotherapy between October 2010 and December 2013 were selected. Our primary end points were overall response rate (ORR) and disease control rate (DCR). The secondary objective was overall survival (OS) and safety. Seventy-nine patients were included in this study. Overall response rates at first evaluation (after 2 cycles) were 23.1 % (9/39) and 5.0 % (2/40) in first- and second-line therapy (P = 0.020), respectively. And disease control rates were 84.6 % (33/39) and 50 % (20/40), respectively (P = 0.001). The median OS were 27.2 months (95 % CI 13.3-41.1 months) and 29.6 months (95 % CI 6.7-52.5 months), respectively (P = 0.740). Grade 3-4 adverse events included leukopenia (2/39), and neutropenia (3/39) in first-line therapy versus neutropenia (1/40) and thrombocytopenia (2/40) in second-line treatment. In our experience, combination of bevacizumab and chemotherapy had encouraging anti-tumor efficacy as both first- and second-line therapy.

  5. A short radiotherapy course for locally advanced non-small cell lung cancer (NSCLC): effective palliation and patients' convenience.

    PubMed

    Plataniotis, G A; Kouvaris, J R; Dardoufas, C; Kouloulias, V; Theofanopoulou, M A; Vlahos, L

    2002-02-01

    In order to facilitate patients with symptomatic locally advanced NSCLC, especially those coming from remote areas we have employed two palliative RT schedules. The first (S1) is the well known from Medical Research Council (MRC) randomized studies 2 x 8.5 Gy one week apart and the second (S2) is a two-day RT schedule: three fractions of 4.25 Gy are given on the first day and two fractions of 4.25 Gy on the second day. The records of 92 patients were reviewed (48 for S1 and 44 for S2). Patients, disease characteristics and results were similar for both groups; rates of symptom disappearance were for S1 and S2, respectively: cough 24 and 20%, hemoptysis 60 and 67%, chest pain 57 and 64% and dyspnoea 55 and 45% The overall condition improved in 39 and 36%, respectively. The median palliation time in days was in S1 and S2, respectively: cough 70 and 66, haemoptysis 133 and 139, chest pain 68 and 62 and dyspnoea 74 and 69 days. The median survival was 25 weeks in both S1 and S2 groups (P=0.89 log-rank test). At 52 weeks (one year), ten (21%) and seven (16%) of the patients were alive in S1 and S2 groups, respectively. At 104 weeks, the corresponding figures were two (4%) and two (4.7%) for S1 and S2. Our results are in accordance to those reported in literature regarding the safety and efficacy of palliative hypofractionated radiotherapy schemes. Their use in selected patients could be cost-effective and convenient for patients especially those coming from remote areas.

  6. Bisphosphonates enhance antitumor effect of EGFR-TKIs in patients with advanced EGFR mutant NSCLC and bone metastases

    PubMed Central

    Zhang, Guowei; Cheng, Ruirui; Zhang, Zengli; Jiang, Tao; Ren, Shengxiang; Ma, Zhiyong; Zhao, Sha; Zhou, Caicun; Zhang, Jun

    2017-01-01

    Whether bisphosphonates could enhance the effect of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation and bone metastases (BM) remains unknown. EGFR mutation status were collected from 1560 patients with NSCLC and BM. 356 NSCLC patients with EGFR mutation and BM were identified. Among them, 91 patients received EGFR-TKIs alone and 105 patients received EGFR-TKIs plus bisphosphonates as first-line therapy. Comparing to TKIs alone, EGFR-TKIs plus bisphosphonates had a statistically significant longer progression-free survival (PFS: 11.6 vs. 9.3 months; HR = 0.68, P = 0.009), while a similar overall survival (OS: 20.5 vs. 19.5 months; HR = 0.95, P = 0.743) in patients with EGFR-mutant NSCLC and BM. The incidence of skeletal-related events in combined group was numerically lower than that in EGFR-TKIs alone group (29.7% vs. 39.4%, P = 0.147). In multivariate analysis, EGFR mutation was found to be a significant independent prognostic factor for OS in NSCLC patients with BM (HR = 0.710, P = 0.021). In conclusion, EGFR mutation was the significant independent prognostic factor for OS and the addition of bisphosphonates to EGFR-TKIs could enhance the antitumor effect of EGFR-TKIs in patients with EGFR-mutant NSCLC and BM. PMID:28211502

  7. Down-regulation of miR-503 expression predicate advanced mythological features and poor prognosis in patients with NSCLC

    PubMed Central

    Liu, Lei; Qu, Weiqing; Zhong, Zhaokun

    2015-01-01

    Objective: We aimed to explore what impact miR-503 has on the prognosis of patients with non-small cell lung cancer (NSCLC). Methods: Cancer and matched non-malignant lung tissue specimens were collected from 109 patients who underwent surgery in Tanisha Hospital from Jun 2006 to July 2013. Overall survival (OS) curves were analyzed using the Lapland-Meier method, and the differences were examined using log-rank tests. Cox proportional- hazards regression analysis was applied in order to estimate univariate and multivariate hazard ratios for OS. Results: The relative expression of miR-503 in NSCLC tissues (0.366 ± 0.130) was significantly lower than that in matched noncancerous lung tissues (1.667 ± 1.047, P < 0.01). Statistically significant association was observed between miR-503 expression and lymphatic invasion (P = 0.005), distant metastasis (P = 0.002), TNM stage (P = 0.008), and tumor grade (P = 0.043). Lapland Meier analysis clearly illustrated that the patients with the lower expression of miR-503 had a worse outcome compared to patients with higher miR-503 expression (P = 0.004). Furthermore, multivariate analysis revealed that miR-503 expression level was an independent prognostic factor for overall survival (HR = 3.992, 95% CI: 2.276-9.872; P = 0.018) in NSCLC. Conclusion: In patients with NSCLC, low miR-503 expression is an independent prognostic factor. PMID:26191272

  8. Longitudinal monitoring of EGFR mutations in plasma predicts outcomes of NSCLC patients treated with EGFR TKIs: Korean Lung Cancer Consortium (KLCC-12-02).

    PubMed

    Lee, Ji Yun; Qing, Xu; Xiumin, Wei; Yali, Bai; Chi, Sangah; Bak, So Hyeon; Lee, Ho Yun; Sun, Jong-Mu; Lee, Se-Hoon; Ahn, Jin Seok; Cho, Eun Kyung; Kim, Dong-Wan; Kim, Hye Ryun; Min, Young Joo; Jung, Sin-Ho; Park, Keunchil; Mao, Mao; Ahn, Myung-Ju

    2016-02-09

    We hypothesized that plasma-based EGFR mutation analysis for NSCLC may be feasible for monitoring treatment response to EGFR TKIs and also predict drug resistance.Clinically relevant mutations including exon 19 deletion (ex19del), L858R and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples (n = 367) from 81 NSCLC patients treated with EGFR TKI. Of a total 58 baseline cell-free DNA (cfDNA) samples available for ddPCR analysis, 43 (74.1%) had the same mutation in the matched tumors (clinical sensitivity: 70.8% [17/24] for L858R and 76.5% [26/34] for ex19del). The concordance rates of plasma with tissue-based results of EGFR mutations were 87.9% for L858R and 86.2% for ex19del. All 40 patients who were detected EGFR mutations at baseline showed a dramatic decrease of mutant copies (>50%) in plasma during the first two months after treatment. Median progression-free survival (PFS) was 10.1 months for patients with undetectable EGFR v 6.3 months for detectable EGFR mutations in blood after two-month treatment (HR 3.88, 95% CI 1.48-10.19, P = 0.006). We observed emerging resistance with early detection of T790M as a secondary mutation in 14 (28.6%) of 49 patients. Plasma-based EGFR mutation analysis using ddPCR can monitor treatment response to EGFR TKIs and can lead to early detection of EGFR TKIs resistance. Further studies confirming clinical implications of EGFR mutation in plasma are warranted to guide optimal therapeutic strategies upon knowledge of treatment response and resistance.

  9. DCE-MRI Perfusion and Permeability Parameters as predictors of tumor response to CCRT in Patients with locally advanced NSCLC

    PubMed Central

    Tao, Xiuli; Wang, Lvhua; Hui, Zhouguang; Liu, Li; Ye, Feng; Song, Ying; Tang, Yu; Men, Yu; Lambrou, Tryphon; Su, Zihua; Xu, Xiao; Ouyang, Han; Wu, Ning

    2016-01-01

    In this prospective study, 36 patients with stage III non-small cell lung cancers (NSCLC), who underwent dynamic contrast-enhanced MRI (DCE-MRI) before concurrent chemo-radiotherapy (CCRT) were enrolled. Pharmacokinetic analysis was carried out after non-rigid motion registration. The perfusion parameters [including Blood Flow (BF), Blood Volume (BV), Mean Transit Time (MTT)] and permeability parameters [including endothelial transfer constant (Ktrans), reflux rate (Kep), fractional extravascular extracellular space volume (Ve), fractional plasma volume (Vp)] were calculated, and their relationship with tumor regression was evaluated. The value of these parameters on predicting responders were calculated by receiver operating characteristic (ROC) curve. Multivariate logistic regression analysis was conducted to find the independent variables. Tumor regression rate is negatively correlated with Ve and its standard variation Ve_SD and positively correlated with Ktrans and Kep. Significant differences between responders and non-responders existed in Ktrans, Kep, Ve, Ve_SD, MTT, BV_SD and MTT_SD (P < 0.05). ROC indicated that Ve < 0.24 gave the largest area under curve of 0.865 to predict responders. Multivariate logistic regression analysis also showed Ve was a significant predictor. Baseline perfusion and permeability parameters calculated from DCE-MRI were seen to be a viable tool for predicting the early treatment response after CCRT of NSCLC. PMID:27762331

  10. Economic evaluation of nivolumab for the treatment of second-line advanced squamous NSCLC in Canada: a comparison of modeling approaches to estimate and extrapolate survival outcomes.

    PubMed

    Goeree, Ron; Villeneuve, Julie; Goeree, Jeff; Penrod, John R; Orsini, Lucinda; Tahami Monfared, Amir Abbas

    2016-06-01

    Background Lung cancer is the most common type of cancer in the world and is associated with significant mortality. Nivolumab demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients with advanced squamous non-small cell lung cancer (NSCLC) who were previously treated. The cost-effectiveness of nivolumab has not been assessed in Canada. A contentious component of projecting long-term cost and outcomes in cancer relates to the modeling approach adopted, with the two most common approaches being partitioned survival (PS) and Markov models. The objectives of this analysis were to estimate the cost-utility of nivolumab and to compare the results using these alternative modeling approaches. Methods Both PS and Markov models were developed using docetaxel and erlotinib as comparators. A three-health state model was used consisting of progression-free, progressed disease, and death. Disease progression and time to progression were estimated by identifying best-fitting survival curves from the clinical trial data for PFS and OS. Expected costs and health outcomes were calculated by combining health-state occupancy with medical resource use and quality-of-life assigned to each of the three health states. The health outcomes included in the model were survival and quality-adjusted-life-years (QALYs). Results Nivolumab was found to have the highest expected per-patient cost, but also improved per-patient life years (LYs) and QALYs. Nivolumab cost an additional $151,560 and $140,601 per QALY gained compared to docetaxel and erlotinib, respectively, using a PS model approach. The cost-utility estimates using a Markov model were very similar ($152,229 and $141,838, respectively, per QALY gained). Conclusions Nivolumab was found to involve a trade-off between improved patient survival and QALYs, and increased cost. It was found that the use of a PS or Markov model produced very similar estimates of expected cost

  11. Medical treatment choices for patients affected by advanced NSCLC in routine clinical practice: results from the Italian observational "SUN" (Survey on the lUng cancer maNagement) study.

    PubMed

    Gridelli, Cesare; Ardizzoni, Andrea; Barni, Sandro; Crinò, Lucio; Caprioli, Alberto; Piazza, Elena; Lorusso, Vito; Barbera, Santi; Zilembo, Nicoletta; Gebbia, Vittorio; Adamo, Vincenzo; Pela, Riccardo; Marangolo, Maurizio; Morena, Raffaella; Filippelli, Gianfranco; Buscarino, Calogero; Alabiso, Oscar; Maione, Paolo; Venturino, Paola; De Marinis, Filippo

    2011-12-01

    Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers, and the majority of people diagnosed with NSCLC have locally advanced or metastatic disease. Treatment algorithms have rapidly changed in the last 10 years because of the introduction of new chemotherapeutic and targeted agents in clinical practice. SUN is a 1-year longitudinal observational multicenter study that has consecutively enrolled patients affected by stage IIIB or IV NSCLC with the aim to describe the pattern of care and evolving approaches in the treatment of advanced NSCLC. 987 consecutive NSCLC patients were enrolled between January 2007 and March 2008 at the 74 participating centers throughout Italy and a 12-month follow-up was performed. Cyto-histological diagnosis was performed mainly by broncoscopy with only 24% by CT-scan guided fine-needle aspiration biopsy. 91.4% of the patients received a first-line medical treatment and 8.6% supportive care only. Median age of patients receiving first-line treatment was 66 years. First-line chemotherapy consisted of a single agent in 20% of patients and combination chemotherapy in 80%. The most frequently used chemotherapy regimens were cisplatin plus gemcitabine and carboplatin plus gemcitabine. Median survival of patients receiving first-line chemotherapy was 9.1 months. 32% percent of patients received a second-line treatment that consisted of chemotherapy in 71% of cases and erlotinib in 29%. Overall third-line treatment was given to 7.3% of patients. These results showed a pattern of care for advanced NSCLC that reflects the current clinical practice in Italy at the study time with a high adherence to the International guidelines by the Italian Oncologists.

  12. Gefitinib ('Iressa', ZD1839) may restore chemosensitivity in NSCLC patients?

    PubMed

    Fujiwara, Keiichi; Kiura, Katsuyuki; Gemba, Kenichi; Ogata, Yoshiko; Hotta, Katsuyuki; Kishino, Daizo; Tabata, Masahiro; Ueoka, Hiroshi; Tanimoto, Mitsune

    2005-01-01

    Gefitinib ('Iressa, ZD1839) has promising antitumor activity in non-small cell lung cancer (NSCLC). However, patients with advanced NSCLC have few treatment options available if they are refractory to gefitinib. We describe four cases of patients with advanced NSCLC who previously responded to gefitinib and obtained significant tumor regression through retreatment with other cytotoxic agents. Gefitinib might restore chemosensitivity to previously chemorefractory patients.

  13. Focus on Nivolumab in NSCLC

    PubMed Central

    Cortinovis, Diego L.; Canova, Stefania; Abbate, Marida; Colonese, Francesca; Bidoli, Paolo

    2016-01-01

    Immunotherapy is changing the treatment of non-small cell lung cancer (NSCLC). The PD-1 inhibitor nivolumab has demonstrated meaningful results in terms of efficacy with a good safety profile. The novel approach to treating NSCLC using immunotherapy still has unsolved questions and challenging issues. The main doubts regarding the optimal selection of the patient are the role of this drug in first line of treatment, the individualization of the correct methodology of radiologic assessment and efficacy analysis, the best management of immune-mediated adverse events, and how to overcome the immunoresistance. The aim of this review is to analyze literature data on nivolumab in lung cancer with a focus on critical aspects related to the drug in terms of safety, the use in clinical practice, and possible placement in the treatment algorithm. PMID:28018902

  14. Advanced lymphosarcoma treated by total body irradiation.

    PubMed Central

    Chaffey, J. T.; Rosenthal, D. S.; Pinkus, F.; Hellman, S.

    1975-01-01

    Twenty-five cases of clinical Stage III and Stage IV lymphosarcoma primarily treated by total body irradiation (TBI) are reported. Fifteen cases demonstrated nodular histology and 10 demonstrated diffuse histology by the Rappaport criteria. Treatments were 15 rad given twice weekly, calculated to midpelvis, to a total dose of 150 rad. Toxicity was confined to thrombocytopenia, one-third of patients requiring interruptions in the treatment course to allow platelet count recovery. Five patients had additional local irradiation. Complete responses were seen in 80% of patients and partial responses in 20%. Sixteen patients (64%) have been in continuous, unmaintained remission since treatments for variable periods to 39 months. Of 9 patients with clinically recurrent disease, 3 received further TBI and are in remission, 3 are in remission on chemotherapy, one patient has died, failing on all therapy, and 2 have not been treated. One patient died of pneumonia at 12 months, without clinical evidence of disease. Overall, actuarial survival is 87% at 2 years and compares well with survival in a sequential combination drug treated group of patients matched for age, sex, and histology, though differences are not statistically significant in these small groups. Total body irradiation is an effective systemic agent in the management of advanced lymphosarcoma and should be considered in treating this disease. PMID:810155

  15. Superior efficacy of co-treatment with the dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A against NSCLC

    PubMed Central

    Quan, Taihao; Li, Longshan; Quan, Chunji; Piao, Yingshi; Jin, Tiefeng; Lin, Zhenhua

    2016-01-01

    Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. NSCLC development and progression have recently been correlated with the heightened activation of histone deacetylases (HDACs) and PI3K/Akt signaling pathways. Targeted inhibition of these proteins is promising approach for the development of novel therapeutic strategies to treat patients with advanced NSCLC. For this reason, we combined a dual PI3K and mTOR inhibitor, BEZ235 with the HDAC inhibitor Trichostatin A (TSA), to determine their combined effects on human NSCLC. In this study, we initially discovered that co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of NSCLC cell proliferation and induction of apoptosis. The combination treatment also synergistically suppressed NSCLC migration, invasion and the NSCLC epithelial-mesenchymal transition (EMT) in vitro. The synergistic effect was also evidenced by declines in xenograft growth and metastasis rates and in ki-67 protein expression in vivo. Together, these results indicated that BEZ235 and TSA combination treatment significantly increased anti-tumor activities compared with BEZ235 and TSA alone, supporting a further evaluation of combination treatment for NSCLC. PMID:27507059

  16. Use advanced methods to treat wastewater

    SciTech Connect

    Davis, M. )

    1994-08-01

    Common sense guidelines offer plausible, progressive techniques to treat wastewater. Because current and pending local, state and federal regulations are ratcheting lower effluent discharge limits, familiar treatment methods, such as biological, don't meet new restrictions. Now operating facilities must combine traditional methods with advanced remedial options such as thermal, physical, electro and chemical treatments. these new techniques remove organics, metals, nonhazardous dissolved salts, etc., but carry higher operating and installation costs. Due to tighter effluent restrictions and pending zero-discharge initiatives, managers of operating facilities must know and understand the complexity, composition and contaminant concentration of their wastewaters. No one-size-fits-all solution exists. However, guidelines can simplify decision making and help operators nominate the most effective and economical strategy to handle their waste situation. The paper describes the common treatment and the importance of alternatives, then describes biological, electro, physical, thermal, and chemical treatments.

  17. Single-agent maintenance therapy for advanced non-small cell lung cancer (NSCLC): a systematic review and Bayesian network meta-analysis of 26 randomized controlled trials

    PubMed Central

    Zeng, Xiaoning; Ma, Yuan

    2016-01-01

    Background The benefit of maintenance therapy has been confirmed in patients with non-progressing non-small cell lung cancer (NSCLC) after first-line therapy by many trials and meta-analyses. However, since few head-to-head trials between different regimens have been reported, clinicians still have little guidance on how to select the most efficacious single-agent regimen. Hence, we present a network meta-analysis to assess the comparative treatment efficacy of several single-agent maintenance therapy regimens for stage III/IV NSCLC. Methods A comprehensive literature search of public databases and conference proceedings was performed. Randomized clinical trials (RCTs) meeting the eligible criteria were integrated into a Bayesian network meta-analysis. The primary outcome was overall survival (OS) and the secondary outcome was progression free survival (PFS). Results A total of 26 trials covering 7,839 patients were identified, of which 24 trials were included in the OS analysis, while 23 trials were included in the PFS analysis. Switch-racotumomab-alum vaccine and switch-pemetrexed were identified as the most efficacious regimens based on OS (HR, 0.64; 95% CrI, 0.45–0.92) and PFS (HR, 0.54; 95% CrI, 0.26–1.04) separately. According to the rank order based on OS, switch-racotumomab-alum vaccine had the highest probability as the most effective regimen (52%), while switch-pemetrexed ranked first (34%) based on PFS. Conclusions Several single-agent maintenance therapy regimens can prolong OS and PFS for stage III/IV NSCLC. Switch-racotumomab-alum vaccine maintenance therapy may be the most optimal regimen, but should be confirmed by additional evidence. PMID:27781159

  18. Serum proteomic test in advanced non-squamous non-small cell lung cancer treated in first line with standard chemotherapy

    PubMed Central

    Grossi, F; Rijavec, E; Genova, C; Barletta, G; Biello, F; Maggioni, C; Burrafato, G; Sini, C; Dal Bello, M G; Meyer, K; Roder, J; Roder, H; Grigorieva, J

    2017-01-01

    Background: VeriStrat is a blood-based proteomic test with predictive and prognostic significance in second-line treatments for non-small cell lung cancer (NSCLC). This trial was designed to investigate the role of VeriStrat in first-line treatment of advanced NSCLC with standard chemotherapy. Here we present the results for 76 non-squamous patients treated with a combination of carboplatin or cisplatin with pemetrexed. Methods: The test-assigned classifications of VeriStrat Good or VeriStrat Poor to samples collected at baseline. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and objective response. Exploratory analyses of end points separately in carboplatin/pemetrexed and cisplatin/pemetrexed subgroups were also conducted. Results: Patients classified as VeriStrat Good had longer PFS and OS than VeriStrat Poor: 6.5 vs 1.6 months and 10.8 vs 3.4 months, respectively; the corresponding hazard ratios (HRs) were 0.36 (P<0.0001) and 0.26 (P<0.0001); they were also more likely to achieve objective response. Prognostic significance of VeriStrat was confirmed in multivariate analysis. Significant differences in OS and PFS between Veristrat classifications were also found when treatment subgroups were analysed separately. Conclusions: The trial demonstrated clinical utility of VeriStrat as a prognostic test for standard first-line chemotherapy of non-squamous advanced NSCLC. PMID:27898657

  19. Recent advances in understanding and treating vasculitis

    PubMed Central

    Koster, Matthew J.; Warrington, Kenneth J.

    2016-01-01

    Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are near universally fatal conditions if untreated. Although effective therapeutic options are available for these diseases, treatment regimens are associated with both short- and long-term adverse effects. The recent identification of effective B-cell-targeted therapy with an anti-CD20 monoclonal antibody has transformed the treatment landscape of AAV. Questions, nevertheless, remain regarding the appropriate timing, dose, frequency, duration, and long-term effects of treatment. The aim of this article is to provide an overview of the current information, recent advances, ongoing clinical trials, and future treatment possibilities in AAV. PMID:27347395

  20. Advances in understanding and treating ADHD

    PubMed Central

    2011-01-01

    Attention deficit hyperactivity disorder (ADHD) is a neurocognitive behavioral developmental disorder most commonly seen in childhood and adolescence, which often extends to the adult years. Relative to a decade ago, there has been extensive research into understanding the factors underlying ADHD, leading to far more treatment options available for both adolescents and adults with this disorder. Novel stimulant formulations have made it possible to tailor treatment to the duration of efficacy required by patients, and to help mitigate the potential for abuse, misuse and diversion. Several new non-stimulant options have also emerged in the past few years. Among these, cognitive behavioral interventions have proven popular in the treatment of adult ADHD, especially within the adult population who cannot or will not use medications, along with the many medication-treated patients who continue to show residual disability. PMID:21658285

  1. SU-E-J-266: Cone Beam Computed Tomography (CBCT) Inter-Scan and Inter-Observer Tumor Volume Variability Assessment in Patients Treated with Stereotactic Body Radiation Therapy (SBRT) for Early Stage Non-Small Cell Lung Cancer (NSCLC)

    SciTech Connect

    Hou, Y; Aileen, C; Kozono, D; Killoran, J; Wagar, M; Lee, S; Hacker, F; Aerts, H; Lewis, J; Mak, R

    2015-06-15

    Purpose: Quantification of volume changes on CBCT during SBRT for NSCLC may provide a useful radiological marker for radiation response and adaptive treatment planning, but the reproducibility of CBCT volume delineation is a concern. This study is to quantify inter-scan/inter-observer variability in tumor volume delineation on CBCT. Methods: Twenty earlystage (stage I and II) NSCLC patients were included in this analysis. All patients were treated with SBRT with a median dose of 54 Gy in 3 to 5 fractions. Two physicians independently manually contoured the primary gross tumor volume on CBCTs taken immediately before SBRT treatment (Pre) and after the same SBRT treatment (Post). Absolute volume differences (AVD) were calculated between the Pre and Post CBCTs for a given treatment to quantify inter-scan variability, and then between the two observers for a given CBCT to quantify inter-observer variability. AVD was also normalized with respect to average volume to obtain relative volume differences (RVD). Bland-Altman approach was used to evaluate variability. All statistics were calculated with SAS version 9.4. Results: The 95% limit of agreement (mean ± 2SD) on AVD and RVD measurements between Pre and Post scans were −0.32cc to 0.32cc and −0.5% to 0.5% versus −1.9 cc to 1.8 cc and −15.9% to 15.3% for the two observers respectively. The 95% limit of agreement of AVD and RVD between the two observers were −3.3 cc to 2.3 cc and −42.4% to 28.2% respectively. The greatest variability in inter-scan RVD was observed with very small tumors (< 5 cc). Conclusion: Inter-scan variability in RVD is greatest with small tumors. Inter-observer variability was larger than inter-scan variability. The 95% limit of agreement for inter-observer and inter-scan variability (∼15–30%) helps define a threshold for clinically meaningful change in tumor volume to assess SBRT response, with larger thresholds needed for very small tumors. Part of the work was funded by a Kaye

  2. Survival Analysis of Advanced Non-Small Cell Lung Cancer Patients Treated by Using Wheel Balance Cancer Therapy.

    PubMed

    Kim, Jongmin; Cho, Chong-Kwan; Yoo, Hwa-Seung

    2016-12-01

    Objective To investigate the clinical effect and the overall survival (OS) rate of patients with advanced non-small cell lung cancer (NSCLC) who have undergone Wheel Balance Cancer Therapy (WBCT). Methods The cases of 33 patients with advanced NSCLC who were treated with WBCT at the East West Cancer Center (EWCC) between October 4, 2004, and October 3, 2013, without undergoing concurrent conventional treatment were analyzed. The Kaplan-Meier method was used to estimate the OS of the cases, and the median OS was calculated according to age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), conventional-treatment history, WBCT treatment duration, and histological tumor type. Results The median OS of all patients was 31.1 (95% confidence interval [CI] = 3.5-58.7) months; the OS rates were 63.6% and 24.2% at years 1 and 2, respectively. The median OS rates of patients under and over 65 years were 45.2 (95% CI = 13.5-76.9) and 19.5 (95% CI = 7.1-31.8) months, respectively (P = .189). The median OS rates of patients who received WBCT for >14 days but <28 days and those who received WBCT for ≥28 days were 16.2 (95% CI = 13.3-19.2) and 45.2 (95% CI = 14.4-76.0) months, respectively (P = .437). The median OS rates of patients who had undergone prior conventional treatment and those who had not were 45.2 (95% CI = 9.1-81.3) and 3.9 (95% CI = unable to calculate) months, respectively (P = .000). The median OS rates of patients with squamous cell carcinoma (SCC) and non-SCC lung cancer were 5.6 (95% CI = unable to calculate) and 45.2 (95% CI = 9.1-81.3) months, respectively (P = .262). The median OS rate of patients with ECOG PS ≥3 was 14.3 (95% CI = 8.8-19.8) months; that of patients ECOG PS <3 could not be calculated. However, the mean OS rates of patients with ECOG PS <3 and with ECOG PS ≥3 were 85.7 (95% CI = 58.4-113.0) and 12.7 (95% CI = 8.5-16.9) months, respectively (P = .000). No severe adverse events were encountered. Conclusions Our study

  3. Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy.

    PubMed

    Bartucci, M; Svensson, S; Romania, P; Dattilo, R; Patrizii, M; Signore, M; Navarra, S; Lotti, F; Biffoni, M; Pilozzi, E; Duranti, E; Martinelli, S; Rinaldo, C; Zeuner, A; Maugeri-Saccà, M; Eramo, A; De Maria, R

    2012-05-01

    Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.

  4. Circulating Plasma MicroRNAs As Diagnostic Markers for NSCLC

    PubMed Central

    Hou, Jinpao; Meng, Fei; Chan, Lawrence W. C.; Cho, William C. S.; Wong, S. C. Cesar

    2016-01-01

    Lung cancer is the most common cause of cancer deaths all over the world, in which non-small cell lung cancer (NSCLC) accounts for ~85% of cases. It is well known that microRNAs (miRNAs) play a critical role in various cellular processes, mediating post-transcriptional silencing either by mRNA degradation through binding the 3′ UTR of target mRNA or by translational inhibition of the protein. In the past decade, miRNAs have also been increasingly identified in biological fluids such as human serum or plasma known as circulating or cell-free miRNAs, and may function as non-invasive diagnostic markers for various cancer types including NSCLC. Circulating tumor cells (CTCs) are those cells that are shed from solid tumors and then migrate into the circulation. However, reports concerning the roles of CTCs are quite rare, which may be attributed to the difficulties in the enrichment and detection of CTCs in the circulation. Although, there have been reassuring advances in identifying circulating miRNA-panels, which are assumed to be of diagnostic value in NSCLC early stage, some issues remain concerning the reliability of using miRNA panels as a diagnostic tool for NSCLC. In the current review, we are aiming at providing insights into the miRNAs biology, the mechanisms of miRNAs release into the bloodstream, cell-free miRNAs as the diagnostic markers for NSCLC and the current limitations of CTCs as diagnostic markers in NSCLC. PMID:27857721

  5. Immunotherapies for NSCLC: Are We Cutting the Gordian Helix?

    PubMed

    Dempke, Wolfram C M; Sellmann, Ludger; Fenchel, Klaus; Edvardsen, Klaus

    2015-11-01

    Chemotherapy is currently the standard-of-care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Molecular-targeted therapies have provided improvement in outcomes. However, these treatments only offer a clear benefit in subsets of tumors harbouring the appropriate genomic alteration (mutation, amplification, translocation). Recent advances in immunotherapy have highlighted the potential of immuno-oncology-based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. Blocking inhibitory pathways such as the cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) checkpoint pathways with monoclonal antibodies has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand-1(PD-L1) antibodies have shown durable responses in NSCLC, with a favourable safety profile and manageable side-effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naïve patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted-agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC. The emerging data not only offer the hope of a better cancer therapy but also provide evidence that changes our understanding on how the host immune system interacts with human cancer. It is therefore conceivable that agents blocking the CTLA-4/PD-1/PD-L1 axis will provide valuable additions to the growing armamentarium of targeted-agents.

  6. Concomitant etoposide and cisplatin provided improved survival compared with docetaxel and cisplatin in patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy

    PubMed Central

    Sen, Fatma; Tambas, Makbule; Ozkaya, Kubra; Guveli, Murat Emin; Ciftci, Rumeysa; Ozkan, Berker; Oral, Ethem Nezih; Saglam, Esra Kaytan; Saip, Pinar; Toker, Alper; Demir, Adalet; Firat, Pinar; Aydiner, Adnan; Eralp, Yesim

    2016-01-01

    Abstract Presently, there is no consensus regarding which chemotherapy regimen is best to administer with radiotherapy in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). Herein, our aim was to compare the outcome of patients treated with either etoposide–cisplatin (EP) or docetaxel–cisplatin (DP) in this curative setting. Patients treated with either EP or DP and concurrent radiotherapy from 2004 to2012 were identified and their detailed medical records and follow-up information were obtained for analysis in this retrospective study. Survival rates were compared using Cox proportional hazards regression models with adjustments for confounding parameters provided by propensity score methods. A total of 105 patients were treated with concurrent chemoradiotherapy for LA-NSCLC (stage IIB-IIIA-IIIB). The median ages were 54 years (range, 32–70 years) and 55 years (range, 37–73 years) in the EP (n = 50) and DP (n = 55) groups, respectively. The median follow-up time was 27 months (range, 1–132 months) in the EP group and 19 months (range, 1–96 months) in DP group. There was no significant difference in baseline clinicopathologic features including age, sex, performance status, histologic subtype, and clinical TNM stages between groups. In the univariate analysis, the median overall survival of patients treated with EP was higher than that of patients treated with DP (41 vs. 20 months, P = 0.003). Multivariate analysis further revealed a survival advantage with EP compared with DP (hazard ratio [HR], 0.46; 95% confidence interval: 0.25–0.83; P = 0.009). The toxicity profile of the 2treatment groups was similar except that pulmonary toxicity was higher in the DP group (grade 3–4: 0% vs. 6%, P = 0.024). Concurrent chemoradiotherapy with EP may provide more favorable outcomes than DP and with an acceptable safety profile. PMID:27472701

  7. How I treat patients with advanced systemic mastocytosis.

    PubMed

    Valent, Peter; Sperr, Wolfgang R; Akin, Cem

    2010-12-23

    Advanced systemic mastocytosis (SM) is a rare myeloid neoplasm characterized by uncontrolled accumulation of neoplastic mast cells (MCs) in various organs with consecutive impairment of organ function, drug resistance, and a poor prognosis. Advanced SM may present as smoldering or slowly progressing neoplasm but may also present as rapidly progressing aggressive SM or even as MC leukemia. Approximately half of the patients have an associated hematologic non-MC-lineage disease (SM-AHNMD) or develop an AHNMD over time. Drug resistance may not only result from the KIT mutant D816V that is found in most patients, but also from KIT-independent pro-oncogenic signaling pathways that play a role in disease evolution. In patients with slow progression, advanced SM can often be kept under control for months with interferon-α or 2CdA. By contrast, in rapidly progressing aggressive SM and MC leukemia, even polychemotherapy and hematopoietic stem cell transplantation may fail, which points to the need to develop new drugs and treatment concepts for these patients. In SM-AHNMD, separate treatment plans should be established for the SM component and the AHNMD component of the disease, with recognition that the AHNMD often has to be managed and treated as a secondary and thus a high-risk neoplasm.

  8. Near Infrared Photoimmunotherapy in the Treatment of Pleural Disseminated NSCLC: Preclinical Experience

    PubMed Central

    Sato, Kazuhide; Nagaya, Tadanobu; Choyke, Peter L.; Kobayashi, Hisataka

    2015-01-01

    Pleural metastases are common in patients with advanced thoracic cancers and are a cause of considerable morbidity and mortality yet is difficult to treat. Near Infrared Photoimmunotherapy (NIR-PIT) is a cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to NIR-light. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of pleural disseminated non-small cell lung carcinoma (NSCLC). In vitro and in vivo experiments were conducted with a HER2, luciferase and GFP expressing NSCLC cell line (Calu3-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT cytotoxicity was assessed with dead staining, luciferase activity, and GFP fluorescence intensity. In vivo NIR-PIT was performed in mice with tumors implanted intrathoracic cavity or in the flank, and assessed by tumor volume and/or bioluminescence and fluorescence thoracoscopy. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. In vivo NIR-PIT led significant reductions in both tumor volume (p = 0.002 vs. APC) and luciferase activity (p = 0.0004 vs. APC) in a flank model, and prolonged survival (p < 0.0001). Bioluminescence indicated that NIR-PIT lead to significant reduction in pleural dissemination (1 day after PIT; p = 0.0180). Fluorescence thoracoscopy confirmed the NIR-PIT effect on disseminated pleural disease. In conclusion, NIR-PIT has the ability to effectively treat pleural metastases caused by NSCLC in mice. Thus, NIR-PIT is a promising therapy for pleural disseminated tumors. PMID:25897335

  9. Pemetrexed single agent chemotherapy in previously treated patients with locally advanced or metastatic non-small cell lung cancer

    PubMed Central

    Russo, Francesca; Bearz, Alessandra; Pampaloni, Gianni

    2008-01-01

    Background The main objective of this study was to evaluate the safety of second-line pemetrexed in Stage IIIB or IV NSCLC. Methods Overall, 95 patients received pemetrexed 500 mg/m2 i.v. over Day 1 of a 21-day cycle. Patients also received oral dexamethasone, oral folic acid and i.m. vitamin B12 supplementation to reduce toxicity. NCI CTC 2.0 was used to rate toxicity. All the adverse events were graded in terms of severity and relation to study treatment. Dose was reduced in case of toxicity and treatment was delayed for up to 42 days from Day 1 of any cycle to allow recovering from study drug-related toxicities. Tumor response was measured using the RECIST criteria. Results Patients received a median number of 4 cycles and 97.8% of the planned dose. Overall, 75 patients (78.9% of treated) reported at least one adverse event: 34 (35.8%) had grade 3 as worst grade and only 5 (5.2%) had grade 4. Drug-related events occurred in 57.9% of patients. Neutropenia (8.4%) and leukopenia (6.3 %) were the most common grade 3/4 hematological toxicities. Grade 3 anemia and thrombocytopenia were reported in 3.2% and 2.1% of patients, respectively. Diarrhea (6.3%), fatigue (3.2%) and dyspnea (3.2%) were the most common grade 3/4 non-hematological toxicities. The most common drug-related toxicities (any grade) were pyrexia (11.6%), vomiting, nausea, diarrhea and asthenia (9.5%) and fatigue (8.4%). Tumor Response Rate (CR/PR) in treated patients was 9.2%. The survival at 4.5 months (median follow-up) was 79% and the median PFS was 3.1 months. Twenty patients (21.1%) died mainly because of disease progression. Conclusion Patients with locally advanced or metastatic NSCLC could benefit from second-line pemetrexed, with a low incidence of hematological and non-hematological toxicities. PMID:18667090

  10. Impact of Angiotensin I-converting Enzyme Inhibitors and Angiotensin II Type-1 Receptor Blockers on Survival of Patients with NSCLC

    PubMed Central

    Miao, Lili; Chen, Wei; Zhou, Ling; Wan, Huanying; Gao, Beili; Feng, Yun

    2016-01-01

    It has been shown that angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can decrease tumor growth and tumor-associated angiogenesis and inhibit metastasis. Epidermal growth factor receptor (EGFR) mutations are found in approximately 30% of patients with advanced non-small cell lung cancer (NSCLC) in East Asia and in 10–15% of such patients in Western countries. We retrospectively identified 228 patients with histologically confirmed advanced NSCLC and 73 patients with early stage disease; 103 of these patients took antihypertensive drugs, and 112 received treatment with EGFR tyrosine kinase inhibitors (TKIs). There was a significant difference in progression-free survival after first-line therapy (PFS1) between the ACEI/ARB group and the non-ACEI/ARB group. For the patients treated with TKIs, there was a significant difference in PFS but not in overall survival (OS) between the ACEI/ARB group and the non-ACEI/ARB group. For the patients with advanced NSCLC, there was a significant difference in PFS1 between the ACEI/ARB group and the non-ACEI/ARB group. ACEI/ARB in combination with standard chemotherapy or TKIs had a positive effect on PFS1 or OS, regardless of whether the lung cancer was in the early or advanced stage. PMID:26883083

  11. Inhaled sodium cromoglycate to treat cough in advanced lung cancer patients.

    PubMed

    Moroni, M; Porta, C; Gualtieri, G; Nastasi, G; Tinelli, C

    1996-07-01

    C-fibres probably represent the common final pathway in both ACE inhibitors and neoplastic cough. A recent report demonstrated that inhaled sodium cromoglycate is an effective treatment for ACE inhibitors' cough; this effect might be due to the suppression of afferent unmyelinated C-fibres. We tested the hypothesis that inhaled sodium cromoglycate might also be effective in lung cancer patients who presented with irritative neoplastic cough. Twenty non-small-cell lung cancer (NSCLC) patients complaining of cough resistant to conventional treatment were randomised to receive, in a double-blind trial, either inhaled sodium cromoglycate or placebo. Patients recorded cough severity daily, before and during treatment, on a 0 to 4 scale. The efficacy of treatment was tested with the Mann-Whitney U-test for non-parametric measures, comparing the intergroup differences in the measures of summary of symptom scores calculated in each patient before and after treatment. We report that inhaled sodium cromoglycate can reduce cough, also in NSCLC patients and that such reduction, observed in all patients treated, is statistically significant (P < 0.001). Inhaled sodium cromoglycate appears to be a cost-effective and safe treatment for lung cancer-related cough.

  12. Inhaled sodium cromoglycate to treat cough in advanced lung cancer patients.

    PubMed Central

    Moroni, M.; Porta, C.; Gualtieri, G.; Nastasi, G.; Tinelli, C.

    1996-01-01

    C-fibres probably represent the common final pathway in both ACE inhibitors and neoplastic cough. A recent report demonstrated that inhaled sodium cromoglycate is an effective treatment for ACE inhibitors' cough; this effect might be due to the suppression of afferent unmyelinated C-fibres. We tested the hypothesis that inhaled sodium cromoglycate might also be effective in lung cancer patients who presented with irritative neoplastic cough. Twenty non-small-cell lung cancer (NSCLC) patients complaining of cough resistant to conventional treatment were randomised to receive, in a double-blind trial, either inhaled sodium cromoglycate or placebo. Patients recorded cough severity daily, before and during treatment, on a 0 to 4 scale. The efficacy of treatment was tested with the Mann-Whitney U-test for non-parametric measures, comparing the intergroup differences in the measures of summary of symptom scores calculated in each patient before and after treatment. We report that inhaled sodium cromoglycate can reduce cough, also in NSCLC patients and that such reduction, observed in all patients treated, is statistically significant (P < 0.001). Inhaled sodium cromoglycate appears to be a cost-effective and safe treatment for lung cancer-related cough. PMID:8688342

  13. Adding Ipsilateral V{sub 20} and V{sub 30} to Conventional Dosimetric Constraints Predicts Radiation Pneumonitis in Stage IIIA-B NSCLC Treated With Combined-Modality Therapy

    SciTech Connect

    Ramella, Sara; Trodella, Lucio; Mineo, Tommaso Claudio; Pompeo, Eugenio; Stimato, Gerardina; Gaudino, Diego; Valentini, Vincenzo; Cellini, Francesco; Ciresa, Marzia; Fiore, Michele; Piermattei, Angelo; Russo, Patrizia; Cesario, Alfredo; D'Angelillo, Rolando M.

    2010-01-15

    Purpose: To determine lung dosimetric constraints that correlate with radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional radiation therapy and concurrent chemotherapy. Methods and Materials: Between June 2002 and December 2006, 97 patients with locally advanced non-small-cell lung cancer were treated with concomitant radiochemotherapy. All patients underwent complete three-dimensional treatment planning (including dose-volume histograms), and patients were treated only if the percentage of total lung volume exceeding 20 Gy (V{sub 20}) and 30 Gy (V{sub 30}), and mean lung dose (MLD) had not exceeded the constraints of 31%, 18%, and 20 Gy, respectively. The total and ipsilateral lung dose-volume histogram parameters, planning target volume, and total dose delivered were analyzed and correlated with pneumonitis incidence. Results: If dose constraints to the total lung were respected, the most statistically significant factors predicting pneumonitis were the percentage of ipsilateral lung volume exceeding 20 Gy (V{sub 20}ipsi), percentage of ipsilateral lung volume exceeding 30 Gy (V{sub 30}ipsi), and planning target volume. These parameters divided the patients into low- and high-risk groups: if V{sub 20}ipsi was 52% or lower, the risk of pneumonitis was 9%, and if V{sub 20}ipsi was greater than 52%, the risk of pneumonitis was 46%; if V{sub 30}ipsi was 39% or lower, the risk of pneumonitis was 8%, and if V{sub 30}ipsi was greater than 39%, the risk of pneumonitis was 38%. Actuarial curves of the development of pneumonitis of Grade 2 or higher stratified by V{sub 20}ipsi and V{sub 30}ipsi were created. Conclusions: The correlation between pneumonitis and dosimetric constraints has been validated. Adding V{sub 20}ipsi and V{sub 30}ipsi to the classical total lung constraints could reduce pulmonary toxicity in concurrent chemoradiation treatment. V{sub 20}ipsi and V{sub 30}ipsi are important if the V{sub 20} to the total lung, V

  14. Nintedanib in NSCLC: evidence to date and place in therapy

    PubMed Central

    Bronte, Giuseppe; Passiglia, Francesco; Galvano, Antonio; Barraco, Nadia; Listì, Angela; Castiglia, Marta; Rizzo, Sergio; Fiorentino, Eugenio; Bazan, Viviana; Russo, Antonio

    2016-01-01

    The treatment of advanced non-small cell lung cancer (NSCLC) is currently driven by the detection of targetable oncogenic drivers, i.e. epidermal growth factor receptor, echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase, etc. Those patients who are wildtype for known and valuable oncogenes can receive standard chemotherapy as first-line treatment, with the possibility of adding bevacizumab. With regard to second-line treatment, nintedanib can improve the efficacy of docetaxel. Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors. The usefulness of nintedanib as an anticancer agent for NSCLC has been proved by both preclinical and clinical phase I and II trials; however, its approval for the use in clinical practice has been possible because of the positive results of the LUME-Lung 1 trial (nintedanib + docetaxel versus docetaxel alone) in terms of progression-free survival and overall survival, and a manageable tolerability profile. Therefore, the good results seen in the clinical trials with nintedanib in the second-line setting for NSCLC patients with adenocarcinoma subtype are encouraging enough to recommend it in clinical practice. PMID:27239237

  15. Nintedanib in NSCLC: evidence to date and place in therapy.

    PubMed

    Bronte, Giuseppe; Passiglia, Francesco; Galvano, Antonio; Barraco, Nadia; Listì, Angela; Castiglia, Marta; Rizzo, Sergio; Fiorentino, Eugenio; Bazan, Viviana; Russo, Antonio

    2016-05-01

    The treatment of advanced non-small cell lung cancer (NSCLC) is currently driven by the detection of targetable oncogenic drivers, i.e. epidermal growth factor receptor, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase, etc. Those patients who are wildtype for known and valuable oncogenes can receive standard chemotherapy as first-line treatment, with the possibility of adding bevacizumab. With regard to second-line treatment, nintedanib can improve the efficacy of docetaxel. Nintedanib is a tyrosine kinase inhibitor targeting three angiogenesis-related transmembrane receptors. The usefulness of nintedanib as an anticancer agent for NSCLC has been proved by both preclinical and clinical phase I and II trials; however, its approval for the use in clinical practice has been possible because of the positive results of the LUME-Lung 1 trial (nintedanib + docetaxel versus docetaxel alone) in terms of progression-free survival and overall survival, and a manageable tolerability profile. Therefore, the good results seen in the clinical trials with nintedanib in the second-line setting for NSCLC patients with adenocarcinoma subtype are encouraging enough to recommend it in clinical practice.

  16. Combination Therapy Shows Promise for Treating Advanced Breast Cancer

    Cancer.gov

    Adding the drug everolimus (Afinitor®) to exemestane helped postmenopausal women whose advanced breast cancer had stopped responding to hormonal therapy live about 4 months longer without the disease progressing than women who received exemestane alone.

  17. Prognostic value of metabolic metrics extracted from baseline PET images in NSCLC

    PubMed Central

    Carvalho, Sara; Leijenaar, Ralph T.H.; Velazquez, Emmanuel Rios; Oberije, Cary; Parmar, Chintan; van Elmpt, Wouter; Reymen, Bart; Troost, Esther G.C.; Oellers, Michel; Dekker, Andre; Gillies, Robert; Aerts, Hugo J.W.L.; Lambin, Philippe

    2015-01-01

    Background Maximum, mean and peak SUV of primary tumor at baseline FDG-PET scans, have often been found predictive for overall survival in non-small cell lung cancer (NSCLC) patients. In this study we further investigated the prognostic power of advanced metabolic metrics derived from Intensity-Volume Histograms (IVH) extracted from PET imaging. Methods A cohort of 220 NSCLC patients (mean age, 66.6 years; 149 men, 71 women), stages I-IIIB, treated with radiotherapy with curative intent were included (NCT00522639). Each patient underwent standardized pre-treatment CT-PET imaging. Primary GTV was delineated by an experienced radiation oncologist on CT-PET images. Common PET descriptors such as maximum, mean and peak SUV, and metabolic tumor volume (MTV) were quantified. Advanced descriptors of metabolic activity were quantified by IVH. These comprised 5 groups of features: Absolute and Relative Volume above Relative Intensity threshold (AVRI and RVRI), Absolute and Relative Volume above Absolute Intensity threshold (AVAI and RVAI), and Absolute Intensity above Relative Volume threshold (AIRV). MTV was derived from the IVH curves for volumes with SUV above 2.5, 3 and 4, and of 40% and 50% maximum SUV. Univariable analysis using Cox Proportional Hazard Regression was performed for overall survival assessment. Results Relative volume above higher SUV (80 %) was an independent predictor of OS (p = 0.05). None of the possible surrogates for MTV based on volumes above SUV of 3, 40% and 50% of maximum SUV showed significant associations with OS (p (AVAI3) = 0.10, p (AVAI4) = 0.22, p (AVRI40%) = 0.15, p (AVRI50%) = 0.17). Maximum and peak SUV (r = 0.99) revealed no prognostic value for OS (p (maximum SUV) = 0.20, p (peak SUV) = 0.22). Conclusions New methods using more advanced imaging features extracted from PET were analyzed. Best prognostic value for OS of NSCLC patients was found for relative portions of the tumor above higher uptakes (80% SUV). PMID:24047338

  18. Recent Advances in Understanding, Diagnosing, and Treating Ovarian Cancer

    PubMed Central

    Mills, Kathryn; Fuh, Katherine

    2017-01-01

    Ovarian cancer, a term that encompasses ovarian, fallopian, and peritoneal cancers, is the leading cause of gynecologic cancer mortality. To improve patient outcomes, the field is currently focused on defining the mechanisms of cancer formation and spread, early diagnosis and prevention, and developing novel therapeutic options. This review summarizes recent advances in these areas. PMID:28184293

  19. Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells.

    PubMed

    Filosto, Simone; Baston, David S; Chung, Samuel; Becker, Cathleen R; Goldkorn, Tzipora

    2013-08-01

    The EGF receptor (EGFR) is a proto-oncogene commonly dysregulated in several cancers including non-small cell lung carcinoma (NSCLC) and, thus, is targeted for treatment using tyrosine kinase inhibitors (TKI) such as erlotinib. However, despite the efficacy observed in patients with NSCLC harboring oncogenic variants of the EGFR, general ineffectiveness of TKIs in patients with NSCLC who are current and former smokers necessitates identification of novel mechanisms to overcome this phenomenon. Previously, we showed that NSCLC cells harboring either wild-type (WT) EGFR or oncogenic mutant (MT) L858R EGFR become resistant to the effects of TKIs when exposed to cigarette smoke, evidenced by their autophosphorylation and prolonged downstream signaling. Here, we present Src as a target mediating cigarette smoke-induced resistance to TKIs in both WT EGFR- and L858R MT EGFR-expressing NSCLC cells. First, we show that cigarette smoke exposure of A549 cells leads to time-dependent activation of Src, which then abnormally binds to the WT EGFR causing TKI resistance, contrasting previous observations of constitutive binding between inactive Src and TKI-sensitive L858R MT EGFR. Next, we show that Src inhibition restores TKI sensitivity in cigarette smoke-exposed NSCLC cells, preventing EGFR autophosphorylation in the presence of erlotinib. Furthermore, we show that overexpression of a dominant-negative Src (Y527F/K295R) restores TKI sensitivity to A549 exposed to cigarette smoke. Importantly, the TKI resistance that emerges even in cigarette smoke-exposed L858R EGFR-expressing NSCLC cells could be eliminated with Src inhibition. Together, these findings offer new rationale for using Src inhibitors for treating TKI-resistant NSCLC commonly observed in smokers.

  20. Nivolumab: a review in advanced squamous non-small cell lung cancer.

    PubMed

    Keating, Gillian M

    2015-11-01

    Nivolumab (Opdivo(®); Nivolumab BMS™) was the first programmed death (PD)-1 immune checkpoint inhibitor to be approved for use in advanced, squamous non-small cell lung cancer (NSCLC) following prior chemotherapy. In the pivotal CheckMate 017 trial, intravenous nivolumab 3 mg/kg every 2 weeks was associated with significantly better overall survival and progression-free survival and a significantly higher overall response rate than intravenous docetaxel in the second-line treatment of advanced, squamous NSCLC. Nivolumab was also better tolerated than docetaxel in CheckMate 017, and its adverse event profile (which included immune-mediated adverse events) was manageable. In conclusion, nivolumab represents an important advance in previously-treated, advanced, squamous NSCLC.

  1. Recent advances in treating Parkinson’s disease

    PubMed Central

    Oertel, Wolfgang H.

    2017-01-01

    This article summarizes (1) the recent achievements to further improve symptomatic therapy of motor Parkinson’s disease (PD) symptoms, (2) the still-few attempts to systematically search for symptomatic therapy of non-motor symptoms in PD, and (3) the advances in the development and clinical testing of compounds which promise to offer disease modification in already-manifest PD. However, prevention (that is, slowing or stopping PD in a prodromal stage) is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder (RBD) —a methodological challenge to be met in the future. PMID:28357055

  2. Advanced carcinoma of the stomach treated with definitive proton therapy

    SciTech Connect

    Koyama, S.; Kawanishi, N.; Fukutomi, H.; Osuga, T.; Iijima, T.; Tsujii, H.; Kitagawa, T. )

    1990-04-01

    We report the case of a 72-yr-old man who suffered from severe chronic emphysema with poor pulmonary function, and who had advanced cancer of the stomach. Proton beam radiotherapy was applied to the lesion, since surgery was contraindicated. The total dose to the stomach lesion was 61 Gy in 7 wk. The tumor on the stomach regressed, with flattening of the round wall of the lesion. The reactive changes of the proton beam radiotherapy, based on the histopathological examination, revealed extensive tumor necrosis and sparing of vital architecture of normal tissue around the irradiated tumor tissue. Only small clusters of vital or devitalized tumor cells with less than approximately 5% of the whole tumor tissue remained after treatment. We suggest that a high dose of radiation delivered by well-defined proton field could result in an improved therapeutic outcome without undue risk of injury to normal tissue.

  3. Recent advances in herbal medicines treating Parkinson's disease.

    PubMed

    Li, Xu-Zhao; Zhang, Shuai-Nan; Liu, Shu-Min; Lu, Fang

    2013-01-01

    Herbal medicines have attracted considerable attention in recent years, which are used to treat Parkinson's disease (PD) in China based on traditional Chinese medicine or modern pharmacological theories. We summarized and analyzed the anti-Parkinsonian activities of herbal medicines and herbal formulations investigated in PD models and provide future references for basic and clinical investigations. All the herbal medicines and herbal formulations were tested on PD models in vitro and in vivo. The relevant compounds and herbal extracts with anti-Parkinsonian activities were included and analyzed according to their genera or pharmacological activities. A total of 38 herbal medicines and 11 herbal formulations were analyzed. The relevant compounds, herbal extracts and formulations were reported to be effective on PD models by modulating multiple key events or signaling pathways implicated in the pathogenesis of PD. The plant species of these herbal medicines belong to 24 genera and 18 families, such as Acanthopanax, Alpinia and Astragalus, etc. These herbal medicines can be an alternative and valuable source for anti-Parkinsonian drug discovery. The plant species in these genera and families may be the most promising candidates for further investigation and deserve further consideration in clinical trials. Active components in some of the herbal extracts and the compatibility law of herbal formulations remain to be further investigated.

  4. Recent advances in understanding and treating nephrotic syndrome

    PubMed Central

    Bierzynska, Agnieszka; Saleem, Moin

    2017-01-01

    Idiopathic nephrotic syndrome (INS) is one of the most common glomerular diseases in children and adults, and the central event is podocyte injury. INS is a heterogeneous disease, and treatment is largely empirical and in many cases unsuccessful, and steroids are the initial mainstay of therapy. Close to 70% of children with INS have some response to steroids and are labelled as steroid-‘sensitive’, and the rest as steroid-‘resistant’ (also termed focal segmental glomerulosclerosis), and single-gene mutations underlie a large proportion of the latter group. The burden of morbidity is enormous, both to patients with lifelong chronic disease and to health services, particularly in managing dialysis and transplantation. The target cell of nephrotic syndrome is the glomerular podocyte, and podocyte biology research has exploded over the last 15 years. Major advances in genetic and biological understanding now put clinicians and researchers at the threshold of a major reclassification of the disease and testing of targeted therapies both identified and novel. That potential is based on complete genetic analysis, deep clinical phenotyping, and the introduction of mechanism-derived biomarkers into clinical practice. INS can now be split off into those with a single-gene defect, of which currently at least 53 genes are known to be causative, and the others. Of the others, the majority are likely to be immune-mediated and caused by the presence of a still-unknown circulating factor or factors, and whether there is a third (or more) mechanistic group or groups remains to be discovered. Treatment is therefore now being refined towards separating out the monogenic cases to minimise immunosuppression and further understanding how best to stratify and appropriately direct immunosuppressive treatments within the immune group. Therapies directed specifically towards the target cell, the podocyte, are in their infancy but hold considerable promise for the near future. PMID

  5. Focus on Nintedanib in NSCLC and Other Tumors

    PubMed Central

    Manzo, Anna; Carillio, Guido; Montanino, Agnese; Costanzo, Raffaele; Sandomenico, Claudia; Rocco, Gaetano; Morabito, Alessandro

    2016-01-01

    Nintedanib is a new triple angiokinase inhibitor that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptors. Evidence about its efficacy in addition to second-line chemotherapy in non-small cell lung cancer (NSCLC) has been produced by two large randomized phase III clinical trials (LUME-Lung 1 and LUME-Lung 2), conducted in patients with pretreated NSCLC, without major risk factors for bleeding. In the LUME-Lung 1, the addition of nintedanib to docetaxel significantly improved progression-free survival, which was the primary end point of the trial (3.4 vs. 2.7 months, hazard ratio: 0.79; p = 0.0019). Furthermore, a significant improvement in median overall survival (from 10.3 to 12.6 months) was observed in patients with adenocarcinoma histology, with a greater advantage in patients who progressed within 9 months after start of first-line treatment (from 7.9 to 10.9 months) and in patients who were most refractory to first-line chemotherapy (from 6.3 to 9.8 months). Adverse events were more common in the docetaxel plus nintedanib group, and they included diarrhea and increased liver enzymes, while no statistically significant increase in the incidence of bleeding and hypertension events by the addition of nintedanib was observed. On these bases, the combination of docetaxel and nintedanib can be considered a new option for the second-line treatment for patients with advanced NSCLC with adenocarcinoma histology. Future challenges are the identification of predictive factors to help the decision of using nintedanib in eligible patients. PMID:28066768

  6. Farletuzumab for NSCLC: exploiting a well-known metabolic pathway for a new therapeutic strategy.

    PubMed

    Bronte, Giuseppe; Lo Vullo, Francesca; Pernice, Gianfranco; Galvano, Antonio; Fiorentino, Eugenio; Cicero, Giuseppe; Bazan, Viviana; Rolfo, Christian; Russo, Antonio

    2015-01-01

    Introduction: The therapeutic options for NSCLC are limited barring targeted drugs, such as EGFR tyrosine-kinase inhibitors and anaplastic lymphoma kinase inhibitors, for patients bearing oncogenic mutations. Platinum-based chemotherapy remains the best strategy for most patients. New targeted drugs, including mAbs and small molecules, are currently under clinical investigation for treating NSCLC patients. Areas covered: The authors of this article focus on farletuzumab , a mAb targeting folate receptor, which has been studied in ovarian cancer and various other malignancies. In this review, the authors review its potential as therapy for NSCLC, because of the biological rationale provided by the expression of folate receptor α in most of lung adenocarcinoma. The authors provide details of farletuzumab's mechanism of action and discuss the results from completed Phase I and Phase II clinical trials. They also highlight ongoing trials. Expert opinion: There are an increasing number of treatment options for NSCLC and it is hoped that farletuzumab could be added to them. That being said, further evidence for its use with NSCLC patients is still needed. It could have a synergic effect with pemetrexed, because these two drugs have a similar target, namely the folate pathway. This combined action could provide an improved efficacy, although there are some concerns about increased toxicity. However, the authors do note that the combination of farletuzumab with other cytotoxic drugs has not been shown to increase toxicity alone.

  7. LDA-SVM-based EGFR mutation model for NSCLC brain metastases: an observational study.

    PubMed

    Hu, Nan; Wang, Ge; Wu, Yu-Hao; Chen, Shi-Feng; Liu, Guo-Dong; Chen, Chuan; Wang, Dong; He, Zhong-Shi; Yang, Xue-Qin; He, Yong; Xiao, Hua-Liang; Huang, Ding-De; Xiong, Kun-Lin; Wu, Yan; Huang, Ming; Yang, Zhen-Zhou

    2015-02-01

    Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non-small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC. Observation and model set-up. This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China. The study included 31 NSCLC patients with brain metastases. Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy. Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients. EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values. The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this small cohort of

  8. Eligibility of patients with advanced non-small cell lung cancer for phase III chemotherapy trials

    PubMed Central

    2009-01-01

    Background Evidence that chemotherapy improves survival and quality of life in patients with stage IIIB & IV non small cell lung cancer (NSCLC) is based on large randomized controlled trials. The purpose of this study was to determine eligibility of patients with advanced NSCLC for major chemotherapy trials. Methods Physicians treating stage IIIB/IV NSCLC at Sydney Cancer Centre assessed patient eligibility for the E1594, SWOG9509 and TAX326 trials for patients presenting from October 2001 to December 2002. A review of the centre's registry was used to obtain missing data. Results 199 patients with advanced NSCLC were registered during the 14-month period. Characteristics of 100 patients were defined prospectively, 85 retrospectively: 77% males, median age 68 (range 32–88), 64% stage IV disease. Only 35% met trial eligibility for E1594 and 28% for SWOG9509 and TAX326. Common reasons for ineligibility were: co-morbidities 75(40%); ECOG Performance Status ≥2 72(39%); symptomatic brain metastasis 15(8%); and previous cancers 21(11%). Many patients were ineligible by more than one criterion. Conclusion The majority of patients with advanced NSCLC were ineligible for the large chemotherapy trials. The applicability of trial results to advanced lung cancer populations may be limited. Future trials should be conducted in a more representative population. PMID:19402889

  9. Intercalated chemotherapy and erlotinib for non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations

    PubMed Central

    Zwitter, Matjaz; Rajer, Mirjana; Stanic, Karmen; Vrankar, Martina; Doma, Andrej; Cuderman, Anka; Grmek, Marko; Kern, Izidor; Kovac, Viljem

    2016-01-01

    ABSTRACT Among attempts to delay development of resistance to tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor (EGFR), intercalated therapy has not been properly evaluated. In a phase II trial, 38 patients with EGFR mutated NSCLC in advanced stage were treated with 4 to 6 3-weekly cycles of intercalated schedule with gemcitabine (1250 mg/m2, days 1 and 4), cisplatin (75 mg/m2, day 2) and erlotinib (150 mg, days 5 – 15), followed by continuous erlotinib as maintenance. In addition to standard radiologic evaluation according to RECIST, PET/CT was done prior to treatment and at 6 months, using PERCIST as a method for assessment of response. The primary endpoint was progression-free survival (PFS). In general, tolerance to treatment was good, even among 8 patients with performance status 2–3 and 13 patients with brain metastases; grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. Complete response (CR) or partial response (PR) were seen in 15 (39.5%) and 17 (44.7%) cases, respectively. All cases of CR were confirmed also by PET/CT. Median PFS was 23.4 months and median overall survival (OS) was 38.3  months. After a median follow-up of 35 months, 8 patients are still in CR and on maintenance erlotinib. In conclusion, intercalated treatment for treatment-naive patients with EGFR activating mutations leads to excellent response rate and prolonged PFS and survival. Comparison of the intercalated schedule to monotherapy with TKIs in a randomized trial is warranted. PMID:27261103

  10. Efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement

    PubMed Central

    Li, Wei; Li, Xuefei; Zhao, Sha; Liu, Xiaozhen; Jia, Yijun; Yang, Hui; Ren, Shengxiang; Zhou, Caicun

    2016-01-01

    Background ROS1 rearrangement is a novel molecular subgroup of non-small-cell lung cancer (NSCLC). This study aimed to investigate the efficacy of crizotinib and pemetrexed-based chemotherapy in Chinese NSCLC patients with ROS1 rearrangement. Results A total of 2309 patients received ROS1 fusion detection and 51(2.2%) patients had ROS1 rearrangement. There was no significant difference between ROS1 fusion-positive and fusion-negative cohorts in demographic data. For the ROS1 fusion-positive patients, crizotinb-treated group had a higher overall response rate (ORR, 80.0%), disease control rate (DCR, 90.0%) and longer progression-free survival (PFS, 294 days) compared with the rates in pemetrexed-treated group (ORR, 40.8%; DCR, 71.4%; PFS, 179 days) and non-pemetrexed-treated group (ORR, 25.0%; DCR, 47.7%; PFS, 110 days). Besides, ORR, DCR and PFS were similar in three major ROS1 fusion partners. For the first-line treatment, patients received pemetrexed had a significant longer PFS than those received non-pemetrexed chemotherapy (209 vs. 146 days, P = 0.0107). In pemetrexed-treated cohorts, ROS1-positive patients with low TS expression had a statistically significant longer PFS than those with high TS expression (184 vs. 110 days, P = 0.0105). Materials and methods We retrospectively identified patients with NSCLC who were screened for ROS1 fusion using multiplex reverse transcription-polymerase chain reaction (RT-PCR) from October 2013 to February 2016. The thymidylate synthase (TS) mRNA levels were tested using quantitative real-time RT-PCR. Conclusions Crizotinib was also highly active at treating Chinese NSCLC patients with ROS1 rearrangement. TS expression could predict the efficacy of pemetrexed-based therapy in ROS1 fusion-positive patients. PMID:27738334

  11. PD-L1 expression as predictive biomarker in patients with NSCLC: a pooled analysis

    PubMed Central

    Natoli, Clara; Rizzo, Sergio; Galvano, Antonio; Listì, Angela; Cicero, Giuseppe; Rolfo, Christian; Santini, Daniele; Russo, Antonio

    2016-01-01

    Background Clinical trials of immune checkpoints modulators, including both programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, have recently shown promising activity and tolerable toxicity in pre-treated NSCLC patients. However the predictive role of PD-L1 expression is still controversial. This pooled analysis aims to clarify the association of clinical objective responses to anti PD-1/PD-L1 monoclonal antibodies (MoAbs) and tumor PD-L1 expression in pre-treated NSCLC patients. Methods Data from published studies, that evaluated efficacy and safety of PD-1/PD-L1 inhibitors in pre-treated NSCLC patients, stratified by tumor PD-L1 expression status (immunohistochemistry, cut-off point 1%), were collected by searching in PubMed, Cochrane Library, American Society of Clinical Oncology, European Society of Medical Oncology and World Conference of Lung Cancer, meeting proceedings. Pooled Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated for the Overall Response Rate (ORR) (as evaluated by Response Evaluation Criteria in Solid Tumors, version 1.1), according to PD-L1 expression status. Results A total of seven studies, with 914 patients, were eligible. Pooled analysis showed that patients with PD-L1 positive tumors (PD-L1 tumor cell staining ≥1%), had a significantly higher ORR, compared to patients with PD-L1 negative tumors (OR: 2.44; 95% CIs: 1.61-3.68). Conclusions PD-L1 tumor over-expression seems to be associated with higher clinical activity of anti PD-1/PD-L1 MoAbs, in pre-treated NSCLC patients, suggesting a potential role of PD-L1 expression, IHC cut-off point 1%, as predictive biomarker for the selection of patients to treat with immune-checkpoint inhibitors. PMID:26918451

  12. A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

    PubMed Central

    Russo, Alessandro; Franchina, Tindara; Rita Ricciardi, Giuseppina Rosaria; Picone, Antonio; Ferraro, Giuseppa; Zanghì, Mariangela; Toscano, Giuseppe; Giordano, Antonio; Adamo, Vincenzo

    2015-01-01

    The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy. The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with. PMID:26308162

  13. NEUTROPHIL/LYMPHOCYTE RATIO AND PLATELET/LYMPHOCYTE RATIO IN PATIENTS WITH NSCLC

    PubMed Central

    Cukic, Vesna

    2016-01-01

    Objective: to compare neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in patients with NSCLC (Non- Small- Cell Lung Cancer): with and without metastases at the time of diagnosis to find out if there is the importance of these cell ratios in the assessment of severity NSCLC. Material and Methods: this is the retrospective analysis of NRL and PRL in patients with NSCLC at the time of the diagnosis of disease before any anti tumor treatment (chemotherapy, radiotherapy, surgery). 57 of patients with NSCLC treated in the first three months of 2016. year were chosen at random regardless of sex and age. We examined full blood count cells (FBC), calculated NLR and PLR in every patient and compared obtained values in patients with and patients without metastases. Results: In 57 patients with NSCLC there were 15 males with metastases, 28 without metastases, and 8 females with metastases, 6 without metastases. Since there was no regularity in the distribution of obtained values of NLR and PLR we made the Mann-Whitney U test. Mean values are presented with a median and interquartile percentiles. There was no significant difference in NLR between patients without and with metastases (p = 0.614; p = NS) as well as in PLR (p=0,068; p=NS). Conclusion: There must be a link between the immune status of the organism and lung cancer development. Immune cells have become of interest in recent years and much work has been done to study their role in the genesis of cancer but it did not give satisfactory results. Further clinical studies on large number of patients and further laboratory examination of the role of immune cells in cancer development and suppression are required. PMID:27999489

  14. The effect of locoregional therapies in patients with advanced hepatocellular carcinoma treated with sorafenib

    PubMed Central

    Sarpel, Umut; Spivack, John H.; Berger, Yaniv; Heskel, Marina; Aycart, Samantha N.; Sweeney, Robert; Edwards, Martin P.; Labow, Daniel M.; Kim, Edward

    2016-01-01

    Background & aims It is unknown whether the addition of locoregional therapies (LRTx) to sorafenib improves prognosis over sorafenib alone in patients with advanced hepatocellular carcinoma (HCC). The aim of this study was to assess the effect of LRTx in this population. Methods A retrospective analysis was performed of patients with advanced HCC as defined by extrahepatic metastasis, lymphadenopathy >2 cm, or gross vascular invasion. Sorafenib therapy was required for inclusion. Survival of patients who received LRTx after progression to advanced stage was compared to those who did not receive LRTx. Results Using an intention to treat analysis of 312 eligible patients, a propensity weighted proportional hazards model demonstrated LRTx as a predictor of survival (HR = 0.505, 95% CI: 0.407–0.628; P < 0.001). The greatest benefit was seen in patients with the largest tumor burden (HR = 0.305, 95% CI: 0.236–0.393; P < 0.01). Median survival in the sorafenib arm was 143 days (95% CI: 118–161) vs. 247 days (95% CI: 220–289) in the sorafenib plus LRTx arm (P < 0.001). Conclusions These results demonstrate a survival benefit with the addition of LRTx to sorafenib for patients with advanced HCC. These findings should prompt a prospective clinical trial to further assess the role of LRTx in patients with advanced HCC. PMID:27154804

  15. Incidence and risk of hypomagnesemia in advanced cancer patients treated with cetuximab: A meta-analysis.

    PubMed

    Chen, Peng; Wang, Long; Li, Hao; Liu, Bing; Zou, Zui

    2013-06-01

    Hypomagnesemia is a serious adverse event for patients treated with cetuximab, an inhibitor of endothelial growth factor receptor (EGFR). However, no significant association has yet been established between cetuximab and hypomagnesemia in randomized controlled clinical trials (RCTs). The present study conducted a systematic review and meta-analysis of published RCTs to assess the overall risk of hypomagnesemia associated with cetuximab. PubMed, the Cochrane Central Register of Controlled Trials, Embase and the American Society of Clinical Oncology conferences were searched for relevant RCTs. Quantitative analysis was carried out to evaluate the association between hypomagnesemia and cetuximab. A total of 7,045 patients with a variety of advanced cancers from 10 trials were included in the analysis. The overall incidence of grade 3/4 hypomagnesemia in patients receiving cetuximab was 3.9% [95% confidence interval (CI), 2.6-4.3%]. Patients treated with cetuximab had a significantly increased risk of grade 3/4 hypomagnesemia compared with patients treated with control medication, with a relative risk (RR) of 8.60 (95% CI, 5.08-14.54). Risk was observed to vary with tumor type. The study concluded that cetuximab is associated with a significant risk of hypomagnesemia in patients with advanced cancer receiving concurrent chemotherapy.

  16. ERβ localization influenced outcomes of EGFR-TKI treatment in NSCLC patients with EGFR mutations

    PubMed Central

    Wang, Zhijie; Li, Zhenxiang; Ding, Xiaosheng; Shen, Zhirong; Liu, Zhentao; An, Tongtong; Duan, Jianchun; Zhong, Jia; Wu, Meina; Zhao, Jun; Zhuo, Minglei; Wang, Yuyan; Wang, Shuhang; Sun, Yu; Bai, Hua; Wang, Jie

    2015-01-01

    Effects of estrogen receptorβ (ERβ) localization on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) are unknown. First, we analyzed the relationship between ERβ localization determined by immunohistochemistry and EGFR-TKI outcomes in 184 patients with advanced NSCLC and found that ERβ expression localized in the cytoplasm and/or nucleus. The frequency of cytoplasmic ERβ (c-ERβ) and nuclear ERβ (n-ERβ) co-expression was 12% (22/184). C-ERβ and n-ERβ co-expression was correlated with poor median progression-free survival compared to patients without co-expression. In subsequent in vitro experiments, PC9 cells transfected with ERβ isoform1 (ERβ1, strong expression of both c-ERβ and n-ERβ) were more resistant to gefitinib than PC9 cells transfected with ERβ isoform2 or 5 (ERβ2 or ERβ5, strong expression of ERβ in cytoplasm but not nucleus). Resistance was identified due to interactions between ERβ1 and other isoforms, and mediated by activation of non-genomic pathways. Moreover, gefitinib resistance was reversed by a combination treatment with gefitinib and fulvestrant, both in cell lines and in one NSCLC patient. These results suggested that c-ERβ and n-ERβ co-expression was a potential molecular indicator of EGFR-TKI resistance, which might be overcome by combining EGFR-TKI and ER antagonist. PMID:26096604

  17. Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer.

    PubMed

    Keating, Gillian M

    2016-06-01

    The programmed death (PD)-1 immune checkpoint inhibitor nivolumab (Opdivo(®)) is approved in the USA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who have progression on or after platinum-based chemotherapy and in the EU for the treatment of adults with locally advanced or metastatic NSCLC after prior chemotherapy. In previously-treated patients with advanced nonsquamous NSCLC, overall survival was significantly prolonged and the overall response rate was significantly higher in patients who received intravenous nivolumab 3 mg/kg every 2 weeks versus intravenous docetaxel in the pivotal CheckMate 057 trial. Progression-free survival did not significantly differ between patients receiving nivolumab and those receiving docetaxel. Intravenous nivolumab had a manageable adverse event profile (including immune-mediated adverse events) and was better tolerated than docetaxel in the CheckMate 057 trial. Thus, nivolumab is an important new option for use in previously-treated patients with advanced nonsquamous NSCLC.

  18. Personalizing NSCLC therapy by characterizing tumors using TKI-PET and immuno-PET.

    PubMed

    Bahce, I; Yaqub, M; Smit, E F; Lammertsma, A A; van Dongen, G A M S; Hendrikse, N H

    2016-05-31

    Non-small cell lung cancer (NSCLC) therapy has entered a rapidly advancing era of precision medicine with an ever increasing number of drugs directed against a variety of specific tumor targets. Amongst these new agents, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) are most frequently used. However, as only a sensitive subgroup of patients benefits from targeting drugs, predictive biomarkers are needed. Positron emission tomography (PET) may offer such a biomarker for predicting therapy efficacy. Some of the TKIs and mAbs that are in clinical use can be radioactively labeled and used as tracers. PET can visualize and quantify tumor specific uptake of radiolabeled targeting drugs, allowing for characterization of their pharmacokinetic behavior. In this review, the clinical potential of PET using radiolabeled TKIs (TKI-PET) and mAbs (immuno-PET) in NSCLC is discussed, and an overview is provided of the most relevant preclinical and clinical studies.

  19. Unexpected toxicity to aquatic organisms of some aqueous bisphenol A samples treated by advanced oxidation processes.

    PubMed

    Tišler, Tatjana; Erjavec, Boštjan; Kaplan, Renata; Şenilă, Marin; Pintar, Albin

    2015-01-01

    In this study, photocatalytic and catalytic wet-air oxidation (CWAO) processes were used to examine removal efficiency of bisphenol A from aqueous samples over several titanate nanotube-based catalysts. Unexpected toxicity of bisphenol A (BPA) samples treated by means of the CWAO process to some tested species was determined. In addition, the CWAO effluent was recycled five- or 10-fold in order to increase the number of interactions between the liquid phase and catalyst. Consequently, the inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated higher concentrations of some toxic metals like chromium, nickel, molybdenum, silver, and zinc in the recycled samples in comparison to both the single-pass sample and the photocatalytically treated solution. The highest toxicity of five- and 10-fold recycled solutions in the CWAO process was observed in water fleas, which could be correlated to high concentrations of chromium, nickel, and silver detected in tested samples. The obtained results clearly demonstrated that aqueous samples treated by means of advanced oxidation processes should always be analyzed using (i) chemical analyses to assess removal of BPA and total organic carbon from treated aqueous samples, as well as (ii) a battery of aquatic organisms from different taxonomic groups to determine possible toxicity.

  20. Are immune checkpoint blockade monoclonal antibodies active against CNS metastases from NSCLC?—current evidence and future perspectives

    PubMed Central

    O’Kane, Grainne M.

    2016-01-01

    Brain metastases occur in approximately half of patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis and an inferior quality of life. Historically systemic therapy has had a limited role in CNS disease with a reliance placed on local treatments. The emergence of targeted therapies and immune checkpoint inhibitors (ICIs) in recent years has dramatically changed the treatment landscape of NSCLC. Programmed cell death-1 (PD-1) inhibitors have demonstrated efficacy in three randomized trials and now represent standard second line therapy after platinum failure. Trials have largely excluded patients with symptomatic or untreated CNS disease as the brain has been considered an ‘immune-privileged’ organ. We review the evidence and future prospects of ICIs in treating brain metastases in NSCLC. PMID:28149757

  1. Are immune checkpoint blockade monoclonal antibodies active against CNS metastases from NSCLC?-current evidence and future perspectives.

    PubMed

    O'Kane, Grainne M; Leighl, Natasha B

    2016-12-01

    Brain metastases occur in approximately half of patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis and an inferior quality of life. Historically systemic therapy has had a limited role in CNS disease with a reliance placed on local treatments. The emergence of targeted therapies and immune checkpoint inhibitors (ICIs) in recent years has dramatically changed the treatment landscape of NSCLC. Programmed cell death-1 (PD-1) inhibitors have demonstrated efficacy in three randomized trials and now represent standard second line therapy after platinum failure. Trials have largely excluded patients with symptomatic or untreated CNS disease as the brain has been considered an 'immune-privileged' organ. We review the evidence and future prospects of ICIs in treating brain metastases in NSCLC.

  2. Anti-angiogenic drugs for second-line treatment of NSCLC patients: just new pawns on the chessboard?

    PubMed

    Bronte, Giuseppe; Passiglia, Francesco; Galvano, Antonio; Russo, Antonio

    2016-01-01

    Tumor angiogenesis is one of the main pathways targeted to treat cancer. Bevacizumab added survival benefit when combined with platinum-based chemotherapy in NSCLC. Recently, Phase III trials showed survival benefit when anti-angiogenic drugs are added to docetaxel as second-line treatment for NSCLC. These anti-angiogenic agents include nintedanib and ramucirumab, a tyrosine-kinase inhibitor and a monoclonal antibody, respectively, which target receptors involved in angiogenesis. These studies have some similarities and differences. We propose a new algorithm for treatment sequences in performance status 0-1 patients with non-oncogene-addicted NSCLC type adenocarcinoma. Indeed clearer scientific evidences are available for this subgroup of patients.

  3. U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive.

    PubMed

    Malik, Shakun M; Maher, Virginia Ellen; Bijwaard, Karen E; Becker, Robert L; Zhang, Lijun; Tang, Shenghui W; Song, Pengfei; Liu, Qi; Marathe, Anshu; Gehrke, Brenda; Helms, Whitney; Hanner, Diane; Justice, Robert; Pazdur, Richard

    2014-04-15

    On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%-70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%-59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen.

  4. SBRT for oligoprogressive oncogene addicted NSCLC.

    PubMed

    Basler, L; Kroeze, S G C; Guckenberger, M

    2017-04-01

    Lung cancer is one of the leading causes of cancer death in men and women and treatment outcome continues to lag behind other common cancer types. A subset of lung adenocarcinoma patients exhibit a somatic mutation in EGFR or an ALK rearrangement. In these patients, targeted TKI therapy results in higher response rates, improved PFS and reduced side effects compared with platinum-based chemotherapy. Despite initial activity of the TKIs, ultimately all patients present with disease progression after about a year on TKI therapy due to resistance development. About 15-47% of patients present with limited oligoprogressive disease (OPD): such patients show only a limited number of metastases with progression in radiological imaging. Radical local treatment to all oligoprogressive lesions is thought to eradicate the de-differentiated clones and restore overall sensitivity of the metastatic disease. Retrospective studies suggest that aggressive local treatment using stereotactic body radiotherapy (SBRT), surgery or others can be used to eradicate TKI-resistant subpopulations enabling prolonged TKI treatment "beyond progression", which may lead to increased PFS and overall survival. This review focuses on the biological background of resistance development, systemic and local treatment options with a focus on SBRT, as well as challenges in defining the state of OPD and current clinical studies in oligoprogressive oncogene addicted NSCLC.

  5. DNA Repair Capacity in Peripheral Lymphocytes Predicts Survival of Patients With Non–Small-Cell Lung Cancer Treated With First-Line Platinum-Based Chemotherapy

    PubMed Central

    Wang, Li-E; Yin, Ming; Dong, Qiong; Stewart, David J.; Merriman, Kelly W.; Amos, Christopher I.; Spitz, Margaret R.; Wei, Qingyi

    2011-01-01

    Purpose Platinum-based regimens are the standard chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC). DNA repair capacity (DRC) in tumor cells plays an important role in resistance to platinum-based drugs. We have previously reported that efficient DRC, as assessed by an in vitro lymphocyte-based assay, was a determinant of poor survival in patients with NSCLC in a relatively small data set. In this larger independent study of 591 patients with NSCLC, we further evaluated whether DRC in peripheral lymphocytes predicts survival of patients with NSCLC who receive platinum-based chemotherapy. Patients and Methods All patients were recruited at The University of Texas MD Anderson Cancer Center and donated blood samples before the start of any chemotherapy. We measured DRC in cultured T lymphocytes by using the host-cell reactivation assay, and we assessed associations between DRC in peripheral lymphocytes and survival of patients with NSCLC who were treated with first-line platinum-based chemotherapy. Results We found an inverse association between DRC in peripheral lymphocytes and patient survival. Compared with patients in the low tertile of DRC, patients with NSCLC in the high tertile of DRC had significantly worse overall and 3-year survival (adjusted hazard ratio [HR], 1.33; 95% CI, 1.04 to 1.71; P = .023; and HR, 1.35; 95% CI, 1.04 to 1.76; P = .025, respectively). This trend was more pronounced in patients with early-stage tumors, adenocarcinoma, or squamous cell carcinoma. Conclusion We confirmed that DRC in peripheral lymphocytes is an independent predictor of survival for patients with NSCLC treated with platinum-based chemotherapy. PMID:21947825

  6. A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor.

    PubMed

    Shen, Weitao; Zhang, Xuyao; Fu, Xiang; Fan, Jiajun; Luan, Jingyun; Cao, Zhonglian; Yang, Ping; Xu, Zhongyuan; Ju, Dianwen

    2017-03-30

    Recombinant human arginase (rhArg), an enzyme capable of depleting arginine, has been shown to be an effective therapeutic approach for various cancers. Non-small-cell lung cancer (NSCLC), a histological subtype of pulmonary carcinoma, has a high rate of morbidity and mortality in the world. Thus, the need for novel and more effective treatment is urgent. In this study, it is the first time to report that rhArg could induce significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells. Subsequently, our research revealed that rhArg dramatically stimulated autophagic response in NSCLC cells, which was proved by the formation and accumulation of autophagosomes and the conversion of microtubule-associated protein light chain 3 (LC3) from LC3-I to LC3-II. Furthermore, blocking autophagy by chloroquine or LY294002 remarkably enhanced rhArg-induced cytotoxicity and caspase-dependent apoptosis, suggesting that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells. Further experiments showed that two signaling pathways including the Akt/mTOR and extracellular signal-regulated kinase pathway, and mitochondrial-derived reactive oxygen species (ROS) production were involved in rhArg-induced autophagy and apoptosis. Meanwhile, N-acetyl-L-cysteine, a common antioxidant, was employed to scavenge ROS, and we detected that it could significantly block rhArg-induced autophagy and cytotoxicity, indicating that ROS played a vital role in arginine degradation therapy. Besides, xenograft experiment showed that combination with autophagy inhibitor potentiated the anti-tumor efficacy of rhArg in vivo. Therefore, these results provided a novel prospect and viewpoint that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells, and treatment with rhArg alone or combined with autophagy inhibitor could be a novel and promising therapeutic approach for NSCLC in vivo and in vitro.

  7. Maintenance therapy in NSCLC: why? To whom? Which agent?

    PubMed Central

    2011-01-01

    Maintenance therapy is emerging as a treatment strategy in the management of advanced non small cell lung cancer (NSCLC). Initial trials addressing the question of duration of combination chemotherapy failed to show any overall survival benefit for the prolonged administration over a fixed number of cycles with an increased risk for cumulative toxicity. Nowadays several agents with different ways of administration and a different pattern of toxicity have been formally investigated in the maintenance setting. Maintenance strategies include continuing with an agent already present in the induction regimen or switching to a different one. Taking into consideration that no comparative trials of maintenance with different chemotherapy drugs or targeted agents have been conducted, the choice and the duration of maintenance agents is largely empirical. Furthermore, it is still unknown and it remains an open question if this approach needs to be proposed to every patient in the case of partial/complete response or stable disease after the induction therapy. Here, we critically review available data on maintenance treatment, discussing the possibility to tailor the right treatment to the right patient, in an attempt to optimize costs and benefits of an ever-growing panel of different treatment options. PMID:21548925

  8. Circulating DNA in diagnosis and monitoring EGFR gene mutations in advanced non-small cell lung cancer

    PubMed Central

    Del Re, Marzia; Danesi, Romano; Tiseo, Marcello

    2015-01-01

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are current treatments for advanced non-small cell lung cancer (NSCLC) harboring activating EGFR gene mutations. Histological or cytological samples are the standard tumor materials for EGFR mutation analysis. However, the accessibility of tumor samples is not always possible and satisfactory in advanced NSCLC patients. Moreover, totality of EGFR mutated NSCLC patients will develop resistance to EGFR-TKIs. Repeat biopsies to study genetic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumor heterogeneity. Thus, exploring accurate and less invasive techniques to (I) diagnosis EGFR mutation if tissue is not available or not appropriate for molecular analysis and to (II) monitor EGFR-TKI treatment are needed. Circulating DNA fragments carrying tumor specific sequence alterations [circulating cell-free tumor DNA (cftDNA)] are found in the cell-free fraction of blood, representing a variable and generally small fraction of the total circulating DNA. cftDNA has a high degree of specificity to detect EGFR gene mutations in NSCLC. Studies have shown the feasibility of using cftDNA to diagnosis of EGFR activating gene mutations and also to monitor tumor dynamics in NSCLC patients treated with EGFR-TKIs. These evidences suggested that non-invasive techniques based on blood samples had a great potential in EGFR mutated NSCLC patients. In this review, we summarized these non-invasive approaches and relative scientific data now available, considering their possible applications in clinical practice of NSCLC treatment. PMID:26629427

  9. Correlation between epidermal growth factor receptor tyrosine kinase inhibitor efficacy and circulating tumor cell levels in patients with advanced non-small cell lung cancer

    PubMed Central

    He, Wenjie; Li, Wenhui; Jiang, Bo; Chang, Li; Jin, Congguo; Tu, Changlin; Li, Yunfen

    2016-01-01

    Objective The aim of this study was to investigate the correlation between the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and circulating tumor cell (CTC) levels in patients with advanced non-small cell lung cancer (NSCLC). The efficacy of EGFR-TKIs in reducing CTC counts in patients with advanced NSCLC was studied. Patients and methods A total of 66 patients with advanced NSCLC were enrolled and divided into two groups (those with high CTC counts and those with low CTC counts) based on the patients’ median CTC counts. All the patients were treated with an EGFR-TKI, and the treatment efficacy and prognoses were compared. Results The treatment efficacies were 53.3% (16/30) and 27.8% (10/36) for the low CTC group and high CTC group, respectively, and this difference was statistically significant (P<0.05). The median overall survival was 22.8 months (95% confidence interval [CI]: 18.9–26.8 months) for the low CTC group and 18.3 months (95% CI: 2.9–8.2 months) for the high CTC group. The median progression-free survival was 11.5 months (95% CI: 8.1–15 months) and 5.6 months (95% CI: 2.9–8.2 months) for the low and high CTC groups, respectively, and the difference was statistically significant (P<0.05). Conclusion The CTC count can be used as an index for predicting the EGFR-TKI effect on patients with advanced NSCLC. Efficacy and prognosis of EGFR-TKI treatment and CTC count were considered important, and the CTC count could be used to predict the efficacy of EGFR-TKI treatment and prognosis of advanced NSCLC. The change in CTC expression levels can be used as an index for evaluating the prognosis of patients with advanced NSCLC. PMID:28003764

  10. Bioenergy from Coastal bermudagrass receiving subsurface drip irrigation with advance-treated swine wastewater.

    PubMed

    Cantrell, Keri B; Stone, Kenneth C; Hunt, Patrick G; Ro, Kyoung S; Vanotti, Matias B; Burns, Joseph C

    2009-07-01

    Coastal bermudagrass (Cynodon dactylon L.) may be a potentially important source of bio-based energy in the southern US due to its vast acreage. It is often produced as part of a waste management plan with varying nutrient composition and energy characteristics on fields irrigated with livestock wastewater. The objective of this study was to determine the effect of subsurface drip irrigation with treated swine wastewater on both the quantity and quality of bermudagrass bioenergy. The treated wastewater was recycled from an advanced treatment system and used for irrigation of bermudagrass in two crop seasons. The experiment had nine water and drip line spacing treatments arrayed in a randomized complete block-design with four replicates. The bermudagrass was analyzed for calorific and mineral contents. Bermudagrass energy yields for 2004 and 2005 ranged from 127.4 to 251.4MJ ha(-1). Compared to irrigation with commercial nitrogen fertilizer, the least biomass energy density was associated with bermudagrass receiving treated swine wastewater. Yet, in 2004 the wastewater irrigated bermudagrass had greater hay yields leading to greater energy yield per ha. This decrease in energy density of wastewater irrigated bermudagrass was associated with increased concentrations of K, Ca, and Na. After thermal conversion, these compounds are known to remain in the ash portion thereby decreasing the energy density. Nonetheless, the loss of energy density using treated effluent via SDI may be offset by the positive influence of these three elements for their catalytic properties in downstream thermal conversion processes such as promoting a lesser char yield and greater combustible gas formation.

  11. Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK

    PubMed Central

    Storozhuk, Y; Hopmans, S N; Sanli, T; Barron, C; Tsiani, E; Cutz, J-C; Pond, G; Wright, J; Singh, G; Tsakiridis, T

    2013-01-01

    Background: We examined the potential of metformin (MET) to enhance non-small cell lung cancer (NSCLC) responses to ionising radiation (IR). Methods: Human NSCLC cells, mouse embryonic fibroblasts from wild-type and AMP-activated kinase (AMPK) α1/2-subunit−/− embryos (AMPKα1/2−/−-MEFs) and NSCLC tumours grafted into Balb/c-nude mice were treated with IR and MET and subjected to proliferation, clonogenic, immunoblotting, cell cycle and apoptosis assays and immunohistochemistry (IHC). Results: Metformin (2.5 μℳ–5 mℳ) inhibited proliferation and radio-sensitised NSCLC cells. Metformin (i) activated the ataxia telengiectasia-mutated (ATM)–AMPK–p53/p21cip1 and inhibited the Akt–mammalian target of rapamycin (mTOR)–eIF4E-binding protein 1 (4EBP1) pathways, (ii) induced G1 cycle arrest and (iii) enhanced apoptosis. ATM inhibition blocked MET and IR activation of AMPK. Non-small cell lung cancer cells with inhibited AMPK and AMPKα1/2−/−-MEFs were resistant to the antiproliferative effects of MET and IR. Metformin or IR inhibited xenograft growth and combined treatment enhanced it further than each treatment alone. Ionising radiation and MET induced (i) sustained activation of ATM–AMPK–p53/p21cip1 and inhibition of Akt–mTOR–4EBP1 pathways in tumours, (ii) reduced expression of angiogenesis and (iii) enhanced expression of apoptosis markers. Conclusion: Clinically achievable MET doses inhibit NSCLC cell and tumour growth and sensitise them to IR. Metformin and IR mediate their action through an ATM–AMPK-dependent pathway. Our results suggest that MET can be a clinically useful adjunct to radiotherapy in NSCLC. PMID:23632475

  12. An observational study of insomnia and nightmare treated with trazodone in patients with advanced cancer.

    PubMed

    Tanimukai, Hitoshi; Murai, Tasuku; Okazaki, Namiko; Matsuda, Yoichi; Okamoto, Yoshiaki; Kabeshita, Yasunobu; Ohno, Yumiko; Tsuneto, Satoru

    2013-06-01

    Patients with cancer often experience insomnia. Nightmares are also a strong factor that interferes with the maintenance of comfortable and satisfying sleep. However, the prevalence and standard treatment of nightmares in patients with cancer have not been established yet. We aimed to treat insomnia and nightmares with trazodone. From 2008 to 2011, trazodone was prescribed to 30 patients with cancer who reported experiencing insomnia with or without nightmares to the palliative care team in Osaka University Hospital. Effective treatment was seen in 15 patients (50%). Four patients with cancer reported having severe nightmares and 2 patients had beneficial effects, with frightening dreams transformed into acceptable ones. Trazodone may be an effective drug for the treatment of insomnia and nightmares in patients with advanced cancer.

  13. Prognostic Significance of p16 Expression in Advanced Cervical Cancer Treated With Definitive Radiotherapy

    SciTech Connect

    Schwarz, Julie K.; Lewis, James S.; Pfeifer, John; Huettner, Phyllis; Grigsby, Perry

    2012-09-01

    Purpose: The purpose of this study was to evaluate the prognostic significance of p16 immunohistochemistry (IHC) in patients with advanced cervical cancer treated with radiation therapy. Materials and Methods: This was a retrospective study of 126 patients with International Federation of Gynecology and Obstetrics Stages Ib1-IVb cervical cancer treated with radiation. Concurrent cisplatin chemotherapy was given to 108 patients. A tissue microarray (TMA) was constructed from the paraffin-embedded diagnostic biopsy specimens. Immunoperoxidase staining was performed on the TMA and a p16 monoclonal antibody was utilized. IHC p16 extent was evaluated and scored in quartiles: 0 = no staining, 1 = 1-25% of cells staining, 2 = 26 to 50%, 3 = 51 to 75%, and 4 = 76 to 100%. Results: The p16 IHC score was 4 in 115 cases, 3 in 1, 2 in 3 and 0 in 7. There was no relationship between p16 score and tumor histology. Patients with p16-negative tumors were older (mean age at diagnosis 65 vs. 52 years for p16-positive tumors; p = 0.01). The 5-year cause-specific survivals were 33% for p16-negative cases (score = 0) compared with 63% for p16-positive cases (scores 1, 2, 3 or 4; p = 0.07). The 5-year recurrence-free survivals were 34% for those who were p16-negative vs. 57% for those who were p16-positive (p = 0.09). In addition, patients with p16-positive tumors (score > 0) were more likely to be complete metabolic responders as assessed by the 3-month posttherapy 18 [F]-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomograph compared with patients with p16-negative tumors (p = 0.03). Conclusion: p16 expression is predictive of improved survival outcome after chemoradiation therapy for advanced-stage invasive cervical carcinoma. Further testing will be needed to evaluate p16-negative cervical tumors.

  14. Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo.

    PubMed

    Giladi, Moshe; Weinberg, Uri; Schneiderman, Rosa S; Porat, Yaara; Munster, Michal; Voloshin, Tali; Blatt, Roni; Cahal, Shay; Itzhaki, Aviran; Onn, Amir; Kirson, Eilon D; Palti, Yoram

    2014-10-01

    Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-treating fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC.

  15. Salvage treatment with apatinib for advanced non-small-cell lung cancer

    PubMed Central

    Song, Zhengbo; Yu, Xinmin; Lou, Guangyuan; Shi, Xun; Zhang, Yiping

    2017-01-01

    Objective No definitive chemotherapeutic regimen has been established in patients with non-small-cell lung cancer (NSCLC) who failed second- or third-line treatment. The aim of this study was to evaluate apatinib, a VEGFR-2 inhibitor, in advanced NSCLC as salvage treatment. Methods We evaluated the efficacy and toxicity of apatinib in patients with previously treated advanced NSCLC from 2014 to 2015 in Zhejiang Cancer Hospital. Survival analysis was performed by the Kaplan–Meier method. Results Forty-two patients were included in the present study. Four patients achieved partial response, and 22 achieved stable disease, representing a response rate of 9.5% and a disease control rate of 61.9%. Median progression-free survival and overall survival were 4.2 and 6.0 months, respectively. The toxicities associated with apatinib were generally acceptable with a total grade 3/4 toxicity of 50%. Conclusion Apatinib appears to have some activity against advanced NSCLC when utilized as salvage treatment. PMID:28367065

  16. Computational fluid dynamic study on obstructive sleep apnea syndrome treated with maxillomandibular advancement.

    PubMed

    Yu, Chung-Chih; Hsiao, Hung-Da; Lee, Lung-Cheng; Yao, Chih-Min; Chen, Ning-Hung; Wang, Chau-Jan; Chen, Yu-Ray

    2009-03-01

    Maxillomandibular advancement is one of the treatments available for obstructive sleep apnea. The influence of this surgery on the upper airway and its mechanism are not fully understood. The present research simulates the flow fields of narrowed upper airways of 2 patients with obstructive sleep apnea treated with maxillomandibular advancement. The geometry of the upper airway was reconstructed from computed tomographic images taken before and after surgery. The consequent three-dimensional surface model was rendered for measurement and computational fluid dynamics simulation. Patients showed clinical improvement 6 months after surgery. The cross-sectional area of the narrowest part of the upper airway was increased in all dimensions. The simulated results showed a less constricted upper airway, with less velocity change and a decreased pressure gradient across the whole conduit during passage of air. Less breathing effort is therefore expected to achieve equivalent ventilation with the postoperative airway. This study demonstrates the possibility of computational fluid dynamics in providing information for understanding the pathogenesis of OSA and the effects of its treatment.

  17. TIPE2 suppresses angiogenesis and non-small cell lung cancer (NSCLC) invasiveness via inhibiting Rac1 activation and VEGF expression

    PubMed Central

    Li, Zequn; Guo, Chun; Liu, Xianglan; Zhou, Chengjun; Zhu, Faliang; Wang, Xiaoyan; Wang, Qun; Shi, Yongyu; Wang, Jianing; Zhao, Wei; Zhang, Lining

    2016-01-01

    Non-small cell lung cancer (NSCLC) is one of the leading causes of all cancer-related deaths worldwide. Despite extensive efforts to improve the diagnosis and treatment of this neoplasm, limited progress has been made. Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2 or TNFAIP8L2) is a newly introduced negative immune regulator, which also controls tumorigenesis. However, the role of TIPE2 in angiogenesis is unknown. In the present study, we investigated the expression and roles of TIPE2 in NSCLC. TIPE2 upregulation in human NSCLC tissues was negatively associated with the primary tumor size, lymph node metastasis, and advanced clinical stage, which can be used to predict lymph node metastasis. Moreover, overexpression of TIPE2 not only inhibited the colony formation, migration, and invasion of NSCLC cells but also indirectly suppressed the proliferation, migration, and tube formation of vascular endothelial cells. Furthermore, TIPE2 suppressed tumor invasiveness and angiogenesis via inhibiting the activation of Rac1 and subsequently weakening its downstream effects, including F-actin polymerization and VEGF expression. Collectively, these results indicate that TIPE2 plays a key role in NSCLC metastasis, suggesting that forced TIPE2 expression might be a novel strategy for the treatment of NSCLC. PMID:27556698

  18. Outcomes and predictors of localized or locally-advanced prostate cancer treated by radiotherapy in Indonesia

    PubMed Central

    Supit, Wempy; Mochtar, Chaidir Arif; Santoso, Rachmat Budi; Umbas, Rainy

    2013-01-01

    Purpose: Presently there is no published data on the outcomes of localized or locally-advanced prostate cancer (PCa) treated by external-beam radiotherapy (RT) in Indonesia. Methods: This study retrospectively analyzed 96 patients with localized or locally-advanced PCa treated by RT from year 1995 to 2009, at the national referral hospital and the national cancer hospital of Indonesia. Cumulative prostate and pelvic radiation dose/type was <70 Gy conventional RT in 84.4% patients, and ≥70 Gy Three dimensional-conformal or intensity modulated RT in 15.6% patients. Overall survival (OS) and biochemical progression-free survival (BFS) were estimated by Kaplan-Meier. Predictors of OS and biochemical recurrence were analyzed by multivariate Cox regressions. Results: The median follow-up was 61 months (range, 24 to 169 months). There were 3.1% low-risk, 26% intermediate-risk, and 70.8% high-risk cases. More than half of the patients (52.1%) had pretreatment prostate-specific antigen (PSA) >20 ng/mL. The 5-year survival outcome of low-risk, intermediate-risk, and high-risk patients were: OS, 100%, 94.7%, and 67.9% (P=0.297); and BFS, 100%, 94.1%, and 57.1% (P=0.016), respectively. In the high-risk group, the 5-year OS was 88.3% in patients who received adjuvant hormonal androgen deprivation therapy (HT), compared to 53% in RT only, P=0.08. Significant predictors of OS include high-risk group (hazard Ratio [HR], 9.35; 95% confidence interval [CI], 1.52 to 57.6; P=0.016), adjuvant therapy (HR, 0.175; 95% CI, 0.05 to 0.58; P=0.005), detection by transurethral resection of the prostate (TUR-P) (HR, 6.81; 95% CI, 2.28 to 20.33; P=0.001), and pretreatment PSA (HR, 1.003; 95% CI, 1.00 to 1.005; P=0.039). The sole predictor of biochemical failure was pretreatment PSA (P=0.04), with odds ratio of 4.52 (95% CI, 1.61 to 12.65) for PSA >20 ng/mL. Conclusions: RT is an effective treatment modality for localized or locally-advanced PCa in Indonesian patients, with outcomes and

  19. Chinese Herbal Formulation PHY906 and Sorafenib Tosylate in Treating Patients With Advanced Liver Cancer

    ClinicalTrials.gov

    2017-03-08

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Advanced Adult Hepatocellular Carcinoma; BCLC Stage B Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma

  20. Vandetanib: An overview of its clinical development in NSCLC and other tumors.

    PubMed

    Morabito, A; Piccirillo, M C; Costanzo, R; Sandomenico, C; Carillio, G; Daniele, G; Giordano, P; Bryce, J; Carotenuto, P; La Rocca, A; Di Maio, M; Normanno, N; Rocco, G; Perrone, F

    2010-09-01

    Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR) and Ret tyrosine kinases involved in tumor growth, progression and angiogenesis. Phase I studies indicated that the recommended dose of vandetanib as a single agent is 300 mg/day. Rash, diarrhea, hypertension and asymptomatic Q-Tc prolongation were the most common adverse events. Four randomized phase III clinical trials evaluated the efficacy of vandetanib in non-small cell lung cancer (NSCLC) in combination with docetaxel (ZODIAC), pemetrexed (ZEAL) or as a single agent (ZEST and ZEPHYR). Only the ZODIAC trial met its primary endpoint (progression-free survival [PFS]), while no study showed an advantage in overall survival with vandetanib. No significant antitumor activity has been observed in small cell lung cancer, advanced ovarian, colorectal, breast, prostate cancer and multiple myeloma. In advanced metastatic medullary thyroid cancer, one randomized phase III clinical trial has demonstrated that vandetanib can significantly improve response rate, PFS and time to worsening of pain. Several key questions remain to be addressed regarding the identification of clinical or molecular biomarkers predictive of response, the choice of the optimal dose or schedule of vandetanib and the safety of long-term administration. The results of ongoing trials in untreated patients with advanced NSCLC and other tumors should better define the optimal clinical application of vandetanib.

  1. Treatments for EGFR-mutant non-small cell lung cancer (NSCLC): The road to a success, paved with failures.

    PubMed

    Lee, Dae Ho

    2017-02-04

    The discovery of epidermal growth factor receptor (EGFR) activating mutations in non-small cell lung cancer (NSCLC) and the success story of EGFR tyrosine kinases inhibitors (TKIs) have changed the paradigm of cancer therapy from empirical cytotoxic chemotherapy to molecular-targeted cancer therapy. As a result, EGFR TKI therapy, including gefitinib, erlotinib and afatinib, has become the standard therapy for NSCLC patients with EGFR activating mutation as first-line therapy. However, most patients inevitably progress despite initial dramatic and rapid response to EGFR TKIs and therefore during the last decade, a lot of efforts have been made to identify and overcome various resistance mechanisms. Fortunately, T790M secondary mutation, the main resistance mechanism, can be overcome by newly developed third-generation EGFR TKIs, such as osimertinib, while most combination trials trying to overcome resistance mechanisms other than T790M mutation have failed so far. To make it worse, spatial and temporal tumor heterogeneity and clonal selection or evolution are also identified in EGFR mutant NSCLC tumors. Nevertheless, advance of comprehensive and more sensitive molecular diagnostics and monitoring technology, such as next-generation sequencing and dynamic monitoring technology using circulating biomarker and development of new cancer medicine with different mechanisms from EGFR TKIs, especially immune checkpoint inhibitors, might affect or change the treatment paradigm of EGFR mutant NSCLC in the near future.

  2. Advanced oxidation treatment of physico-chemically pre-treated olive mill industry effluent.

    PubMed

    Gomec, Cigdem Y; Erdim, Esra; Turan, Ilknur; Aydin, Ali F; Ozturk, Izzet

    2007-08-01

    In this study, the applicability of physico-chemical methods was investigated for the pre-treatment of the olive mill effluents prior to the discharge into the common sewerage ending with a municipal wastewater treatment plant. The samples were taken from an olive oil industry operated as three-phase process located in Turkey. Various pre-treatment methods including acid craking, polyelectrolyte and lime additions were applied. Advanced oxidation study using Fenton's process was also investigated following pre-treatment by acid cracking and cationic polyelectrolyte. Acid cracking alone gave satisfactory treatment efficiencies and polyelectrolite additions to the acid-cracked samples enhanced treatment efficiency. Since a complete treatment plant is available at the end of the sewer system, results indicated that the effluents of the investigated industry could be discharged into the municipal sewerage in the case of total chemical oxygen demand (COD(tot)), suspended solid (SS) and volatile suspended solid (VSS) concentrations according to the Turkish Water Pollution Control Regulation after pre-treatment with 5 ppm anionic polyelectrolyte following acid cracking. The minimum COD(tot), SS and VSS removals were observed when raw wastewater was pre-treated with lime and the discharge standards to the municipal sewer system could not be met. Advanced oxidation with Fenton's process was applied after acid cracking and cationic polyelectrolyte treatment in order to investigate further reduction in chemical oxygen demand (COD) concentration for minimizing the influence of this industrial discharge on the existing municipal wastewater treatment plant. Results indicated that COD(tot) removal increased up to 89% from 74% after Fenton's oxidation for the acid cracked samples in which cationic polyelectrolite (10 ppm) was added.

  3. Relationship of ethnicity and overall survival in patients treated with sorafenib for advanced hepatocellular carcinoma

    PubMed Central

    Renouf, Daniel J.; Gill, Sharlene; Cheung, Winson Y.; Lim, Howard J.

    2014-01-01

    Background Although both the SHARP and the Asian-Pacific trials showed improved overall survival (OS) for sorafenib, the magnitude of benefit was substantially less for Asians, who have a higher prevalence of hepatitis B viral (HBV) infection. Whether the worse prognosis is related to ethnicity or to the etiology of hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to identify prognostic factors among patients with HCC who received sorafenib in British Columbia (BC), which has a sizeable Asian population. Methods A total of 255 consecutive patients with advanced HCC who initiated sorafenib from January 2008 to February 2013 were identified using our pharmacy database. Clinicopathological variables and outcomes were retrospectively collected. Prognostic factors were assessed by univariate and multivariate analyses. Results Median age was 63 years, 80.2% were men, and 38% were Asian. Among them, 34.5% had HBV and 29.8% had hepatitis C viral (HCV) infection. In addition, 68.6% had cirrhosis and 45.9% had liver-limited disease. Median progression-free and OS were 3.7 [95% confidence interval (CI): 3.3-4.2] and 7.5 months (95% CI: 5.7-9.2), respectively. On multivariate analysis, Eastern Cooperative Oncology Group performance status (ECOG PS) and HCV positivity correlated with better OS (P<0.001 and 0.04, respectively), but ethnicity did not (P=0.622). Conclusions When treated with sorafenib at the same institution, Asians and Caucasians with advanced HCC had similar OS. ECOG PS and HCV were the only significant prognostic factors. A higher proportion of HCV positivity might explain why the SHARP trial achieved better OS when compared to the Asian-Pacific trial. PMID:25083298

  4. Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A.

    PubMed

    Chao, Ting-Ting; Wang, Cheng-Yi; Chen, Yen-Lin; Lai, Chih-Cheng; Chang, Fang-Yu; Tsai, Yi-Ting; Chao, Chung-Hao H; Shiau, Chung-Wai; Huang, Yuh-Chin T; Yu, Chong-Jen; Chen, Kuen-Feng

    2015-02-10

    Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutation. We found afatinib can also induce apoptosis in NSCLC cells without EGFR mutation through CIP2A pathway. Four NSCLC cell lines (H358 H441 H460 and A549) were treated with afatinib to determine their sensitivity to afatinib-induced cell death and apoptosis. The effects of CIP2A on afatinib-induced apoptosis were confirmed by overexpression and knockdown of CIP2A expression in the sensitive and resistant cells, respectively. Reduction of Elk-1 binding to the CIP2A promoter and suppression of CIP2A transcription were analyzed. In vivo efficacy of afatinib against H358 and H460 xenografts tumors were also determined in nude mice. Afatinib induced significant cell death and apoptosis in H358 and H441 cells, but not in H460 or A549 cells. The apoptotic effect of afatinib in sensitive cells was associated with downregulation of CIP2A, promotion of PP2A activity and decrease in AKT phosphorylation. Afatinib suppressed CIP2A at the gene transcription level by reducing the promoter binding activity of Elk-1. Clinical samples showed that higher CIP2A expression predicted a poor prognosis and Elk-1 and CIP2A expressions were highly correlated. In conclusion, afatinib induces apoptosis in NSCLC without EGFR mutations through Elk-1/CIP2A/PP2A/AKT pathway.

  5. Accumulation of advanced glycation end products and chronic complications in ESRD treated by dialysis.

    PubMed

    Meerwaldt, Robbert; Zeebregts, Clark J; Navis, Gerjan; Hillebrands, Jan-Luuk; Lefrandt, Joop D; Smit, Andries J

    2009-01-01

    Cardiovascular and connective tissue disorders are very common in patients with end-stage renal disease (ESRD), and the accumulation of advanced glycation end products (AGEs) is significantly increased in these patients. Accumulation of AGEs is believed to have a role in tissue protein aging and the pathogenesis of such age-related diseases as diabetes and ESRD. AGEs accumulate in patients with ESRD as a result of nonenzymatic glycation, oxidative stress, and diminished clearance of AGE precursors. Some AGEs show characteristic brown pigmentation and fluorescence, form protein-protein cross-links, and may ligate with AGE-specific receptors, inducing oxidative stress and cytokine production. This review focuses on the clinical relevance of AGE accumulation in patients with ESRD treated by dialysis for the development of long-term complications. The formation and accumulation of AGEs in patients with ESRD are discussed, as well as the relationship between AGE accumulation and such major complications of ESRD as cardiovascular and connective tissue disorders.

  6. Treating solid dairy manure using microwave-enhanced advanced oxidation process.

    PubMed

    Kenge, Anju A; Liao, Ping H; Lo, Kwang V

    2009-08-01

    The microwave enhanced advanced oxidation process (MW/H(2)O(2)-AOP) was used to treat separated solid dairy manure for nutrient release and solids reduction. The MW/H(2)O(2)-AOP was conducted at a microwave temperature of 120 degrees C for 10 minutes, and at three pH conditions of 3.5, 7.3 and 12. The hydrogen peroxide dosage at approximately 2 mL per 1% TS for a 30 mL sample was used in this study, reflecting a range of 0.53-0.75 g H(2)O(2)/g dry sludge. The results indicated that substantial quantities of nutrients could be released into the solution at pH of 3.5. However, at neutral and basic conditions only volatile fatty acids and soluble chemical oxygen demand could be released. The analyses on orthophosphate, soluble chemical oxygen demands and volatile fatty acids were re-examined for dairy manure. It was found that the orthophosphate concentration for untreated samples at a higher % total solids (TS) was suppressed and lesser than actual. To overcome this difficulty, the initial orthophosphate concentration had to be measured at 0.5% TS.

  7. Microwave enhanced advanced oxidation process for treating dairy manure at low pH.

    PubMed

    Lo, Kwang V; Chan, Winnie W I; Yawson, Selina K; Liao, Ping H

    2012-01-01

    This study investigated the treatment of dairy manure using the microwave enhanced advanced oxidation process (MW-AOP) at pH 2. An experimental design was developed based on a statistical program using response surface methodology to explore the effects of temperature, hydrogen peroxide dosage and heating time on sugar production, nutrient release and solids destruction. Temperature, hydrogen peroxide dosage and acid concentration were key factors affecting reducing sugar production. The highest reducing sugar yield of 7.4% was obtained at 160°C, 0 mL, 15 min heating time, and no H(2)O(2) addition. Temperature was a dominant factor for an increase of soluble chemical oxygen demand (SCOD) in the treated dairy manure. The important factors for volatile fatty acids (VFA) production were microwave temperature and hydrogen peroxide dosage. Temperature was the most important parameter, and heating time, to a lesser extent affecting orthophosphate release. Heating time, hydrogen peroxide dosage and temperature were significant factors for ammonia release. There was a maximum of 96% and 196% increase in orthophosphate and ammonia concentration, respectively at 160°C, 0.5 mL H(2)O(2) and 15 min heating time. The MW-AOP is an effective method in dairy manure treatment for sugar production, nutrient solubilisation, and solids disintegration.

  8. CT Findings of Patients Treated with Irreversible Electroporation for Locally Advanced Pancreatic Cancer

    PubMed Central

    Akinwande, Olaguoke; Ahmad, Shakeeb S.; Van Meter, Tracy; Schulz, Brittany; Martin, Robert C. G.

    2015-01-01

    Introduction. In patients with locally advanced pancreatic cancer (LAPC), IRE has been shown to be safe for local disease control and palliation. As IRE continues to gain acceptance it is important to characterize the expected imaging findings. Materials and Methods. A review of our prospective soft tissue ablation registry from July 2010 to June 2013 was performed on patients who had undergone IRE for LAPC. Five masses treated with intraoperative IRE ablation for pancreatic tumors that underwent CT imaging before and after ablation were reviewed. Results and Discussion. Following IRE, the postablation bed is larger than the original ablated tumor. This ablation zone may get smaller in size (due to decreased edema and hyperemia) in the following months and more importantly remains stable provided there is no recurrence. In cases of recurrent disease there is increased size of the ablation bed, mass effect, and new or worsening vascular encasement or occlusion. Conclusion. CT imaging remains the best current imaging modality to assess post-IRE ablation changes. Serial imaging over at least 2–6 months must be employed to detect recurrence by comparing with prior studies in conjunction with clinical and serum studies. Larger imaging studies are underway to evaluate a more ideal imaging modality for this unique patient population. PMID:26649039

  9. Chromosomal copy number changes of locally advanced rectal cancers treated with preoperative chemoradiotherapy

    PubMed Central

    Grade, Marian; Gaedcke, Jochen; Wangsa, Danny; Varma, Sudhir; Beckmann, Jaje; Liersch, Torsten; Hess, Clemens; Becker, Heinz; Difilippantonio, Michael J.; Ried, Thomas; Ghadimi, B. Michael

    2009-01-01

    Introduction Standard treatment of rectal cancer patients comprises preoperative chemoradiotherapy followed by radical surgery. However, clinicians are faced with the problem that response rates vary from one individual to another. Predictive biomarkers would therefore be helpful. Materials and Methods In order to identify genomic imbalances that might assist in stratifying tumors into responsive or non-responsive, we used metaphase comparative genomic hybridization to prospectively analyze pre-therapeutic biopsies from 42 patients with locally advanced rectal cancers. These patients were subsequently treated with 5-FU based preoperative chemoradiotherapy. Results Based on downsizing of the T-category, 21 rectal cancers were later classified as responsive, while 21 were non-responsive. Comparing these two groups, we could show that gains of chromosomal regions 7q32-q36 and 7q11-q31, and amplifications of 20q11-q13 were significantly associated with responsiveness to preoperative chemoradiotherapy (P<0.05). However, the probability to detect these copy number changes by chance is high (P=0.21). Conclusion Our primary results suggest that pre-therapeutic evaluation of chromosomal copy number changes may be of value for response prediction of rectal cancers to preoperative chemoradiotherapy. This will require validation in a larger cohort of patients. PMID:19602460

  10. Arginase-1 mRNA expression correlates with myeloid-derived suppressor cell levels in peripheral blood of NSCLC patients.

    PubMed

    Heuvers, Marlies E; Muskens, Femke; Bezemer, Koen; Lambers, Margaretha; Dingemans, Anne-Marie C; Groen, Harry J M; Smit, Egbert F; Hoogsteden, Henk C; Hegmans, Joost P J J; Aerts, Joachim G J V

    2013-09-01

    Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature and progenitor myeloid cells with immunosuppressive activity that are increased in cancer patients. Until now, the characterization of MDSC in humans was very challenging. The aim of this study was to determine the characterization and optimal assessment of MDSC and to investigate their presence and function in blood of advanced-stage NSCLC patients. We determined MDSC and lymphocyte populations in peripheral blood mononuclear cells (PBMC) samples of 185 treatment-naïve NSCLC patients and 20 healthy controls (HC). NSCLC patients had an increased population of PMN-MDSC compared to HC (p < 0.0001). Frequencies of CD4(+) and CD8(+) T-cells were significantly decreased in NSCLC patients (p < 0.0001 and p = 0.05). We found that PMN-MDSC were able to suppress T-cell proliferation in vitro. qRT-PCR showed that arginase-1 (Arg-1) mRNA is mainly expressed by MDSC and that the level of Arg-1 in PBMC correlates with the frequency of MDSC in PBMC (Spearman's rho: 0.797). There were significant differences in MDSC and lymphocyte populations between NSCLC patients and HC. We found that MDSC frequencies are stable up to six hours at room temperature after blood was drawn and that cryopreservation leads to a strong decrease of MDSC in PBMC. We show that Arg-1 mRNA expression is a valuable method to determine the levels of MDSC in peripheral blood of cancer patients. This method is therefore a useful alternative for the complex flowcytometric analysis in large multicenter patient studies.

  11. Prognostic and Predictive Role of the VeriStrat® Plasma Test in Patients with Advanced Non-Small Cell Lung Cancer Treated with Erlotinib or Placebo in the NCIC Clinical Trials Group BR.21 Trial

    PubMed Central

    Carbone, David P.; Ding, Keyue; Roder, Heinrich; Grigorieva, Julia; Roder, Joanna; Tsao, Ming-Sound; Seymour, Lesley; Shepherd, Frances A.

    2013-01-01

    Introduction We investigated the predictive and prognostic effects of VeriStrat®, a serum or plasma based assay, on response and survival in a subset of patients enrolled on the NCIC Clinical Trials Group (CTG) BR.21 phase III trial of erlotinib versus placebo in previously treated advanced non-small cell lung cancer (NSCLC) patients. Methods Pretreatment plasma samples were available for 441 of 731 enrolled patients and were provided as anonymized aliquots to Biodesix. The VeriStrat test was performed in a CLIA-accredited laboratory at Biodesix, Inc. Results (Good, Poor) were returned to NCIC CTG, who performed all statistical analyses. Results VeriStrat testing was successful in 436 samples (98.9%), with 61% classified as Good. VeriStrat was prognostic for overall survival in both erlotinib-treated patients and those on placebo, independent of clinical covariates. For VeriStrat Good patients, the median survival was 10.5 months on erlotinib vs. 6.6 months for placebo (HR 0.63, 95% C.I. 0.47–0.85, P=0.002). For VeriStrat Poor patients, the median survival was 4 months for patients receiving erlotinib, and 3.1 months for placebo (HR: 0.77, 95% C.I. 0.55–1.06, P=0.11). VeriStrat was predictive for objective response (P =0.002), but was not able to predict for differential survival benefit from erlotinib (interaction p-value 0.48). Similar results were found for progression-free survival (PFS). Conclusion We were able to confirm that VeriStrat is predictive of objective response to erlotinib. VeriStrat is prognostic for both OS and PFS, independent of clinical features, but is not predictive of differential survival benefit vs. placebo. PMID:23059783

  12. Osimertinib (AZD9291) and CNS Response in Two Radiotherapy-Naïve Patients with EGFR-Mutant and T790M-Positive Advanced Non-Small Cell Lung Cancer.

    PubMed

    Ricciuti, Biagio; Chiari, Rita; Chiarini, Pietro; Crinò, Lucio; Maiettini, Daniele; Ludovini, Vienna; Metro, Giulio

    2016-08-01

    The discovery of sensitizing epidermal growth factor receptor (EGFR) mutations as a predictive marker of sensitivity to first-generation EGFR tyrosine kinase inhibitors (TKIs) has dramatically changed the paradigm of care for advanced non-small cell lung cancer (NSCLC) patients. Unfortunately, the majority of patients with EGFR-mutant NSCLC treated with EGFR-TKIs develop acquired resistance within 14-16 months. T790M mutation recently emerged as a major determinant of acquired resistance to gefitinib and erlotinib. Osimertinib (AZD9291) is a novel mono-anilino-pyrimidine third-generation EGFR TKI targeting both sensitizing and T790M EGFR-mutation which showed promising results in T790M-positive NSCLC. Here we report two cases of gefitinib- or erlotinib-pretreated NSCLCs with a T790M mutation-positive (as assessed on plasma through the therascreen EGFR test) disease and untreated, asymptomatic central nervous system metastases that responded to treatment with osimertinib.

  13. Reduction of organic trace compounds and fresh water consumption by recovery of advanced oxidation processes treated industrial wastewater.

    PubMed

    Bierbaum, S; Öller, H-J; Kersten, A; Klemenčič, A Krivograd

    2014-01-01

    Ozone (O(3)) has been used successfully in advanced wastewater treatment in paper mills, other sectors and municipalities. To solve the water problems of regions lacking fresh water, wastewater treated by advanced oxidation processes (AOPs) can substitute fresh water in highly water-consuming industries. Results of this study have shown that paper strength properties are not impaired and whiteness is slightly impaired only when reusing paper mill wastewater. Furthermore, organic trace compounds are becoming an issue in the German paper industry. The results of this study have shown that AOPs are capable of improving wastewater quality by reducing organic load, colour and organic trace compounds.

  14. Effects of monascin on anti-inflammation mediated by Nrf2 activation in advanced glycation end product-treated THP-1 monocytes and methylglyoxal-treated wistar rats.

    PubMed

    Lee, Bao-Hong; Hsu, Wei-Hsuan; Huang, Tao; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-02-13

    Hyperglycemia is associated with advanced glycation end products (AGEs). This study was designed to evaluate the inhibitory effects of monascin on receptor for advanced glycation end product (RAGE) signal and THP-1 monocyte inflammation after treatment with S100b, a specific ligand of RAGE. Monascin inhibited cytokine production by S100b-treated THP-1 monocytes via up-regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and alleviated p47phox translocation to the membrane. Methylglyoxal (MG, 600 mg/kg bw) was used to induce diabetes in Wistar rats. Inhibitions of RAGE and p47phox by monascin were confirmed by peripheral blood mononuclear cells (PBMCs) of MG-induced rats. Silymarin (SM) was used as a positive control group. It was found that monascin promoted heme oxygenase-1 (HO-1) expression mediated by Nrf2. Suppressions of AGEs, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-β) in serum of MG-induced rats were attenuated in the monascin administration group treated with retinoic acid (RA). RA treatment resulted in Nrf2 inactivation by increasing RA receptor-α (RARα) activity, suggesting that RA acts as an inhibitor of Nrf2. The results showed that monascin exerted anti-inflammatory and antioxidative effects mediated by Nrf2 to prevent the development of diseases such as type 2 diabetes caused by inflammation.

  15. Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line

    PubMed Central

    Sullivan, Ivana; Planchard, David

    2017-01-01

    Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the

  16. Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line.

    PubMed

    Sullivan, Ivana; Planchard, David

    2016-01-01

    Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (EGFR) are now standard treatment in the clinic for patients with advanced EGFR mutant non-small-cell lung cancer (NSCLC). First-generation EGFR TKIs, binding competitively and reversibly to the ATP-binding site of the EGFR tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating EGFR mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the EGFR T790M resistance mutation. The second-generation EGFR/HER TKIs were developed to treat resistant disease, targeting not only T790M but EGFR-activating mutations and wild-type EGFR. Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type EGFR. The third-generation EGFR TKIs selectively and irreversibly target EGFR T790M and activating EGFR mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation EGFR TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type EGFR. Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating EGFR mutations. Among the third-generation EGFR TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic EGFR T790M NSCLC patients who have progressed on or after EGFR TKI therapy. In this review, we summarize the available post-progression therapies including third-generation EGFR inhibitors and combination treatment strategies for treating patients with NSCLC harboring EGFR mutations and address the

  17. Perilesional edema in brain metastasis from non-small cell lung cancer (NSCLC) as predictor of response to radiosurgery (SRS).

    PubMed

    Tini, Paolo; Nardone, Valerio; Pastina, Pierpaolo; Battaglia, Giuseppe; Vinciguerra, Claudia; Carfagno, Tommaso; Rubino, Giovanni; Carbone, Salvatore Francesco; Sebaste, Lucio; Cerase, Alfonso; Federico, Antonio; Pirtoli, Luigi

    2017-03-04

    Radiosurgery (SRS) is widely used in the treatment of brain oligo-metastases from NSCLC. The aim of present study is to evaluate the extent of perilesional edema in brain metastases as predictive factor of treatment response. This single center retrospective study included 42 consecutive patients (January 2011-December 2014) with 1-2 brain metastasis from NSCLC treated with Radiosurgery (SRS). Extent of perilesional edema was measured as maximal extension from the edge of lesion and classified as minor (<10 mm) or major (≥10 mm). We analyzed Modality of Brain Recurrence (MBR), classified as in-field or out-of- field, and Brain Progression Free-Survival (BPFS) after treatment stratified according to extent of perilesional edema. Analyzing modality of brain recurrence and BPFS, after a median follow-up of 6 months, we found that patients with minor edema had a better radiological response to SRS with none in-field recurrences and a lower risk of the onset of new brain lesions (out-of-field recurrence). Instead, patients group with major edema had a worse response rate of lesions treated, further, a higher risk of out-of-field brain relapse. Extent of perilesional edema in brain metastasis from NSCLC could be a predictive factor of response and brain progression after SRS treatment alone.

  18. EGFR inhibitor and chemotherapy combinations for acquired TKI resistance in EGFR-mutant NSCLC models.

    PubMed

    Laurila, Niina; Koivunen, Jussi P

    2015-07-01

    Acquired resistance to EGFR TKIs is the most important limiting factor for treatment efficiency in EGFR-mutant NSCLC. Although the continuation of EGFR TKI beyond disease progression in combination with chemotherapy is often suggested as a strategy for treating acquired resistance, the optimal treatment sequence for EGFR TKI and chemotherapy is unknown. In the current work, NSCLC cell lines PC9ER, H1975 and HCC827GR, representing the acquired TKI resistance genotypes (T790M, cMET), were exposed to a chemotherapeutic agent, cisplatin or paclitaxel, in combination with EGFR TKIs (erlotinib, WZ4002) in vitro and analysed for cytotoxicity and apoptotic response. The result showed that all the combinations of EGFR TKIs with a chemotherapeutic agent tested had a synergistic effect on cytotoxicity and increased the apoptotic response. The sequences involving a chemotherapeutic agent concurrently with an EGFR TKI or preceding it were the most efficient strategies. Our in vitro models suggest that the combination of an EGFR TKI and chemotherapy is beneficial in cases of acquired EGFR TKI resistance. Furthermore, the sequence of chemotherapy followed by EGFR TKI is significantly more powerful than the reversed order, so that an intercalated approach is likely to be the most active strategy in clinical use and ought to be tested in a randomized clinical trial.

  19. Targeting Redox Homeostasis in LKB1-deficient NSCLC

    DTIC Science & Technology

    2014-09-01

    lactate production using an exponential growth model (24). Oxygen consumption rate (OCR) was measured using the Oxygraph-2K (Oroboros, Innsbruck...signaling and cell growth , as well as activation of apoptosis. These findings will be important for designing targeted treatments for LKB1-deficient...epidermal growth factor receptor; NSCLC, non-small cell lung cancer; ROS, reactive oxygen species 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF

  20. ADVANCED TOOLS FOR ASSESSING SELECTED PRESCRIPTION AND ILLICIT DRUGS IN TREATED SEWAGE EFFLUENTS AND SOURCE WATERS

    EPA Science Inventory

    The purpose of this poster is to present the application and assessment of advanced technologies in a real-world environment - wastewater effluent and source waters - for detecting six drugs (azithromycin, fluoxetine, omeprazole, levothyroxine, methamphetamine, and methylenedioxy...

  1. Ursolic acid sensitizes radioresistant NSCLC cells expressing HIF-1α through reducing endogenous GSH and inhibiting HIF-1α

    PubMed Central

    Song, Bing; Zhang, Qian; Yu, Maohu; Qi, Xinrong; Wang, Gang; Xiao, Linlin; Yi, Qiyi; Jin, Wensen

    2017-01-01

    In previous studies, the present authors demonstrated that effective sensitization of ionizing radiation-induced death of tumor cells, including non-small cell lung cancer (NSCLC) cells, could be produced by oleanolic acid (OA), a pentacyclic triterpenoid present in plants. In the present study, it was investigated whether ursolic acid (UA), an isomer of OA, had also the capacity of sensitizing radioresistant NSCLC cells. The radioresistant cell line H1299/M-hypoxia inducible factor-1α (HIF-1α) was established by transfection with a recombinant plasmid expressing mutant HIF-1α (M-HIF-1α). Compared with parental H1299 cells and H1299 cells transfected with empty plasmid, H1299/M-HIF-1α cells had lower radiosensitivity. Following the use of UA to treat NSCLC cells, elevation of the radiosensitivity of cells was observed by MTT assay. The irradiated H1299/M-HIF-1α cells were more sensitive to UA pretreatment than the irradiated cells with empty plasmid and control. The alteration of DNA damage in the irradiated cells was further measured using micronucleus (MN) assay. The combination of UA treatment with radiation could induce the increase of cellular MN frequencies, in agreement with the change in the tendency observed in the cell viability assay. It was further shown that the endogenous glutathione (GSH) contents were markedly attenuated in the differently irradiated NSCLC cells with UA (80 µmol/l) pretreatment through glutathione reductase/5,5′-dithiobis-(2-nitrob-enzoic acid) (DTNB) recycling assay. The results revealed that UA treatment alone could effectively decrease the GSH content in H1299/M-HIF-1α cells. In addition, the inhibition of HIF-1α expression in radioresistant cells was confirmed by western blotting. It was then concluded that UA could upregulate the radiosensitivity of NSCLC cells, and in particular reduce the refractory response of cells expressing HIF-1α to ionizing radiation. The primary mechanism is associated with reduction of

  2. SIRT1 is highly expressed in brain metastasis tissues of non-small cell lung cancer (NSCLC) and in positive regulation of NSCLC cell migration.

    PubMed

    Han, Lin; Liang, Xiao-Hua; Chen, Li-Xin; Bao, Shi-Min; Yan, Zhi-Qiang

    2013-01-01

    Brain metastases are a frequent and ongoing major complication of non-small cell lung cancer (NSCLC). To deepen our understanding to the underlying mechanisms by which NSCLC cells metastasize to brain and hence to improve the therapy, a high throughput RNAi screening with shRNA library of 153 epigenetic genes was subjected to A549, a NSCLC cell line with high migration ability, to examine the effects of these genes on cell migration by wound-healing assay. The screening results showed that knockdown of 2 genes (KDM5B and SIRT1) dramatically and specifically inhibits A549 migration but not affects the proliferation, which was subsequently confirmed through transwell migration assay. Furthermore, SIRT1 is found to be highly expressed in brain metastasis tissues of NSCLC, compared to the NSCLC tissues, suggesting that SIRT1 may play roles in brain metastasis of NSCLC. The relationship between SIRT1 expression and cell migration ability was further investigated in three NSCLC cell lines and the result indicated that SIRT1 expression is tightly correlated with cell migration ability. Collectively, our work provides potential biomarker and therapeutic target for brain metastasis of NSCLC.

  3. Study of Functional Infrared Imaging for Early Detection of Mucositis in Locally Advanced Head and Neck Cancer Treated With Chemoradiotherapy

    PubMed Central

    Cohen, Ezra E.W.; Ahmed, Omar; Kocherginsky, Masha; Shustakova, Galyna; Kistner-Griffin, Emily; Salama, Joseph K.; Yefremenko, Volodymyr; Novosad, Valentyn

    2013-01-01

    Background and Purpose Chemoradiotherapy (CRT) has led to improved efficacy in treating locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) but has led to almost universal in-field mucositis. Patients treated with the same regimen often have differences in mucositis occurrence and severity. Mucositis induced via radiation is known to represent an intense inflammatory response histologically. We hypothesized that patients destined to display severe mucocutaneous toxicity would demonstrate greater alterations in thermal intensity early in therapy than identically treated counterparts. This will allow identification of patients that will require more intensive supportive care using thermal imaging technology. Materials and Methods Subjects with LA-SCCHN (oral cavity or oropharynx) being treated with the identical chemoradiotherapy regimen underwent baseline and weekly thermal imaging. Changes in skin temperature caused by mucositis and dermatitis compared with a reference area (T were calculated and correlated to grade of mucositis based on NCI-CTCAE 3.0. Results Thirty-four subjects were enrolled. Grade 3 mucositis and dermatitis was observed in 53% and 21%, respectively. We observed a statistically significant positive association between an early rise in T and mucositis grade (p value=0.03). Conclusions Thermal imaging is able to detect small and early changes in skin surface temperature that may be associated with development of mucositis in patients being treated with chemoradiotherapy. PMID:23988569

  4. Parenteral Nutrition for Patients Treated for Locally Advanced Inoperable Tumors of the Head and Neck

    ClinicalTrials.gov

    2017-03-10

    Squamous Cell Carcinoma of the Hypopharynx Stage III; Squamous Cell Carcinoma of the Hypopharynx Stage IV; Laryngeal Squamous Cell Carcinoma Stage III; Laryngeal Squamous Cell Carcinoma Stage IV; Oropharyngeal Squamous Cell Carcinoma Stage III; Oropharyngeal Squamous Cell Carcinoma Stage IV; Squamous Cell Carcinoma of the Oral Cavity Stage III; Squamous Cell Carcinoma of the Oral Cavity Stage IV; Locally Advanced Malignant Neoplasm

  5. ADVANCED TOOLS FOR ASSESSING SELECTED PRESCRIPTION AND ILLICIT DRUGS IN TREATED SEWAGE EFFLUENTS AND SOURCE WATERS

    EPA Science Inventory

    The purpose of this poster is to present the application and assessment of advanced state-of-the-art technologies in a real-world environment - wastewater effluent and source waters - for detecting six drugs [azithromycin, fluoxetine, omeprazole, levothyroxine, methamphetamine, m...

  6. Advanced thymic cancer treated with carboplatin and paclitaxel in a patient undergoing hemodialysis.

    PubMed

    Miura, Satoru; Kagamu, Hiroshi; Sakai, Takehito; Nozaki, Koichiro; Asakawa, Katsuaki; Moro, Hiroshi; Okajima, Masaaki; Watanabe, Satoshi; Yamamoto, Suguru; Iino, Noriaki; Goto, Shin; Kazama, Junichiro James; Yoshizawa, Hirohisa; Narita, Ichiei

    2015-01-01

    A 53-year-old man with an asymptomatic anterior mediastinal tumor undergoing hemodialysis was referred to our institution. He was diagnosed with thymic basaloid carcinoma based on the findings of a chest tomography-guided biopsy and successfully treated with carboplatin (300 mg/m(2)/day) and paclitaxel (200 mg/m(2)/day) on day 1 for six three-week cycles. To our knowledge, this is the first report regarding the efficiency of a carboplatin dose-definition method based on the body surface area with paclitaxel in a hemodialysis patient. This report may therefore be useful for treating hemodialysis patients who are candidates for carboplatin and paclitaxel therapy.

  7. TU-F-12A-05: Sensitivity of Textural Features to 3D Vs. 4D FDG-PET/CT Imaging in NSCLC Patients

    SciTech Connect

    Yang, F; Nyflot, M; Bowen, S; Kinahan, P; Sandison, G

    2014-06-15

    Purpose: Neighborhood Gray-level difference matrices (NGLDM) based texture parameters extracted from conventional (3D) 18F-FDG PET scans in patients with NSCLC have been previously shown to associate with response to chemoradiation and poorer patient outcome. However, the change in these parameters when utilizing respiratory-correlated (4D) FDG-PET scans has not yet been characterized for NSCLC. The Objectives: of this study was to assess the extent to which NGLDM-based texture parameters on 4D PET images vary with reference to values derived from 3D scans in NSCLC. Methods: Eight patients with newly diagnosed NSCLC treated with concomitant chemoradiotherapy were included in this study. 4D PET scans were reconstructed with OSEM-IR in 5 respiratory phase-binned images and corresponding CT data of each phase were employed for attenuation correction. NGLDM-based texture features, consisting of coarseness, contrast, busyness, complexity and strength, were evaluated for gross tumor volumes defined on 3D/4D PET scans by radiation oncologists. Variation of the obtained texture parameters over the respiratory cycle were examined with respect to values extracted from 3D scans. Results: Differences between texture parameters derived from 4D scans at different respiratory phases and those extracted from 3D scans ranged from −30% to 13% for coarseness, −12% to 40% for contrast, −5% to 50% for busyness, −7% to 38% for complexity, and −43% to 20% for strength. Furthermore, no evident correlations were observed between respiratory phase and 4D scan texture parameters. Conclusion: Results of the current study showed that NGLDM-based texture parameters varied considerably based on choice of 3D PET and 4D PET reconstruction of NSCLC patient images, indicating that standardized image acquisition and analysis protocols need to be established for clinical studies, especially multicenter clinical trials, intending to validate prognostic values of texture features for NSCLC.

  8. Tumor-penetration and antitumor efficacy of cetuximab are enhanced by co-administered iRGD in a murine model of human NSCLC

    PubMed Central

    Zhang, Yang; Yang, Jie; Ding, Manhua; Li, Liantao; Lu, Zheng; Zhang, Qing; Zheng, Junnian

    2016-01-01

    Lung cancer is the leading cause of cancer-associated mortality, worldwide. For this reason, novel therapies are required for the treatment of this devastating disease. Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR), which is overexpressed in a variety of solid tumors, including non-small cell lung cancer (NSCLC). The therapeutic efficacy of cetuximab for NSCLC is limited to use as a monotherapy or in combination with chemotherapy. The objective of the present study was to develop a novel strategy to enhance the therapeutic efficacy of cetuximab for NSCLC by a co-administration with the tumor-penetrating internalizing RGD peptide (iRGD). Human NSCLC subcutaneous xenograft models established with the A549 cell line in nude mice were treated with 30 mg/kg cetuximab, 4 mg/kg iRGD, cetuximab plus iRGD or phosphate-buffered saline. The tumor-penetration, in vivo therapeutic efficacy and involved mechanism were evaluated. The present study showed that the A549 xenograft model is sensitive to the co-administration of cetuximab and iRGD. Treatment with cetuximab plus iRGD resulted in a significant increase in the tumor-penetration of cetuximab and tumor reduction compared with cetuximab monotherapy. In conclusion, iRGD enhances the effects of co-administered cetuximab in an NSCLC model. The combined application of cetuximab and iRGD may be a novel strategy to enhance the clinical therapeutic efficacy of cetuximab for the treatment of NSCLC. PMID:27899989

  9. Matrine promotes the efficacy and safety of platinum-based doublet chemotherapy for advanced non-small cell lung cancer

    PubMed Central

    Rong, Biaoxue; Zhao, Chongchong; Gao, Wenlong; Yang, Shuanying

    2015-01-01

    Purpose: Many studies have investigated the efficacy of matrine combined with platinum-based doublet chemotherapy (PBDC) versus PBDC alone for treating advanced non-small cell lung cancer (NSCLC). This study is an analytic value of available evidence. Methods: twenty-two studies reporting matrine combined with PBDC versus PBDC alone for treating advanced NSCLC were reviewed. Pooled odds ratios and hazard ratio with 95% confidence intervals were calculated using either the fixed effects model or random effects model. Results: The overall response rate (ORR) and disease control rate (DCR) of matrine combined with PBDC for treating NSCLC were significantly higher than those of PBDC alone, with 15.1% and 19.7% improvement, respectively (P < 0.00001). In addition, the mean survival time (MST) and quality of life (QOL) were improved after the treatment of matrine combined with PBDC (P < 0.00001). The main adverse effects found in this review were hematological reactions, nausea and vomiting. Matrine combined with PBDC had a lower incidence of adverse reactions compared with PBDC alone (P < 0.05). Conclusions: Matrine combined with PBDC was associated with higher RR, DCR, and MST as well as superior QOL profiles compared with PBDC alone. Matrine combined with PBDC decrease the incidence of adverse reactions compared with PBDC alone. PMID:26628952

  10. Treatment algorithm based on the multivariate survival analyses in patients with advanced hepatocellular carcinoma treated with trans-arterial chemoembolization

    PubMed Central

    Prajapati, Hasmukh J.

    2017-01-01

    Purpose To develop the treatment algorithm from multivariate survival analyses (MVA) in patients with Barcelona clinic liver cancer (BCLC) C (advanced) Hepatocellular carcinoma (HCC) patients treated with Trans-arterial Chemoembolization (TACE). Methods Consecutive unresectable and non-tranplantable patients with advanced HCC, who received DEB TACE were studied. A total of 238 patients (mean age, 62.4yrs) was included in the study. Survivals were analyzed according to different parameters from the time of the 1st DEB TACE. Kaplan Meier and Cox Proportional Hazard model were used for survival analysis. The SS was constructed from MVA and named BCLC C HCC Prognostic (BCHP) staging system (SS). Results Overall median survival (OS) was 16.2 months. In HCC patients with venous thrombosis (VT) of large vein [main portal vein (PV), right or left PV, hepatic vein, inferior vena cava] (22.7%) versus small vein (segmental/subsegmental PV) (9.7%) versus no VT had OSs of 6.4 months versus 20 months versus 22.8 months respectively (p<0.001). On MVA, the significant independent prognostic factors (PFs) of survival were CP class, eastern cooperative oncology group (ECOG) performance status (PS), single HCC<5 cm, site of VT, metastases, serum creatinine and serum alpha-feto protein. Based on these PFs, the BCHP staging system was constructed. The OSs of stages I, II and III were 28.4 months, 11.8 months and 2.4 months accordingly (p<0.001). The treatment plan was proposed according to the different stages. Conclusion On MVA of patients with advanced HCC treated with TACE, significant independent prognostic factors (PFs) of survival were CP class, ECOG PS, single HCC<5 cm or others, site of VT, metastases, serum creatinine and serum alpha-feto protein. New BCHP SS was proposed based on MVA data to identify the suitable advanced HCC patients for TACE treatments. PMID:28170405

  11. A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil.

    PubMed

    Méndez, Miguel; Salut, Antonieta; García-Girón, Carlos; Navalon, Marta; Diz, Pilar; García López, Maria José; España, Pilar; de la Torre, Ascensión; Martínez del Prado, Purificación; Duarte, Isabel; Pujol, Eduardo; Arizcun, Alberto; Cruz, Juan Jesús

    2003-11-01

    This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.

  12. Impact of COPD in patients with lung cancer and advanced disease treated with chemotherapy and/or tyrosine kinase inhibitors.

    PubMed

    Izquierdo, José Luis; Resano, Pilar; El Hachem, Abdulkader; Graziani, Desiré; Almonacid, Carlos; Sánchez, Ignacio M

    2014-01-01

    While it is relatively well known that the prognosis of patients with lung cancer (LC) treated with surgery is worse in the presence of chronic obstructive pulmonary disease (COPD), it is unknown if this assessment can be extrapolated to patients with advanced disease treated with chemotherapy and/or tyrosine kinase inhibitors. The aim of our study is to analyze the clinical characteristics and survival rates in patients with LC and COPD, and to compare these to the patients without airflow obstruction. From 471 evaluable patients, 324 (69%) were not treated with surgery due to disseminated disease (stages 3B and 4). Of them, 47.7% also had COPD. All patients were treated at the moment of diagnosis according to National Comprehensive Cancer Network guidelines with platinum-based chemotherapy or tyrosine kinase inhibitors. Kaplan-Meier curves showed no significant differences in overall survival between COPD and non-COPD patients (log-rank P=0.65). In the multivariate Cox proportional hazard model adjusting for the most relevant variables, the adjusted hazard ratio (HRadj) was statistically significant for performance status (HRadj =1.33, 95% confidence interval [CI]: 1.11-1.59; P=0.002) and clinical stage (HRadj =0.67, 95% CI: 0.50-0.89; P=0.006), but not for COPD status (HRadj =1.20, 95% CI: 0.83-1.50; P=0.46). Our conclusion is that at present, when using standard care in advanced LC (stages 3B and 4), COPD does not have a significant deleterious impact on overall survival.

  13. Chemotherapy plus dendritic cells co-cultured with cytokine-induced killer cells versus chemotherapy alone to treat advanced non-small-cell lung cancer: A meta-analysis

    PubMed Central

    Sun, Huanhuan; Zheng, Xiaobin; Wang, Shuncong; Hong, Guobin; Mallampati, Saradhi; Sun, Hongliu; Zhou, Xiuling; Cheng, Zhibin; Zhang, Hongyu; Ma, Haiqing

    2016-01-01

    This study was aimed to investigate the efficacy and safety of the combination treatment of dendritic cells co-cultured with cytokine-induced killer cells and chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC). Literatures were searched from the Cochrane Library Central, PubMed, Web of Science and EMBASE. The primary endpoint of interest was overall survival (OS), and secondary endpoints were disease control rate (DCR) and progression free survival (PFS). Finally 7 trials published between January 2005 and March 2016 met inclusion criteria and totally 610 patients were enrolled. The combination group showed advance in DCR (RR = 1.31, 95% CI = 1.13-1.52, p = 0.0004), 1-year OS (RR = 1.18, 95% CI = 1.05-1.33, p = 0.007), and 2-year OS (RR = 1.37, 95% CI = 1.10-1.70, p = 0.005), with statistical significance. The proportions of CD3+ T cells (p = 0.002), NK cells (p = 0.02) and NKT cells (p = 0.001) were significantly higher in the peripheral blood of combination group, compared with those of the control group. Moreover, adverse reactions were obviously decreased in the combination group. However, no significant difference was identified in ORR and PFS between two groups (p > 0.05). In conclusion, the combination therapy was safe and applicable for patients with advanced NSCLC. PMID:27863436

  14. Combined preputial advancement and phallopexy as a revision technique for treating paraphimosis in a dog.

    PubMed

    Wasik, S M; Wallace, A M

    2014-11-01

    A 7-year-old neutered male Jack Russell terrier-cross was presented for signs of recurrent paraphimosis, despite previous surgical enlargement of the preputial ostium. Revision surgery was performed using a combination of preputial advancement and phallopexy, which resulted in complete and permanent coverage of the glans penis by the prepuce, and at 1 year postoperatively, no recurrence of paraphimosis had been observed. The combined techniques allow preservation of the normal penile anatomy, are relatively simple to perform and provide a cosmetic result. We recommend this combination for the treatment of paraphimosis in the dog, particularly when other techniques have failed.

  15. Zinc finger nuclease technology: advances and obstacles in modelling and treating genetic disorders.

    PubMed

    Jabalameli, Hamid Reza; Zahednasab, Hamid; Karimi-Moghaddam, Amin; Jabalameli, Mohammad Reza

    2015-03-01

    Zinc finger nucleases (ZFNs) are engineered restriction enzymes designed to target specific DNA sequences within the genome. Assembly of zinc finger DNA-binding domain to a DNA-cleavage domain enables the enzyme machinery to target unique locus in the genome and invoke endogenous DNA repair mechanisms. This machinery offers a versatile approach in allele editing and gene therapy. Here we discuss the architecture of ZFNs and strategies for generating targeted modifications within the genome. We review advances in gene therapy and modelling of the disease using these enzymes and finally, discuss the practical obstacles in using this technology.

  16. Efficacy of Second-line Tyrosine Kinase Inhibitors in the Treatment of Metastatic Advanced Non-small-cell Lung Cancer Harboring Exon 19 and 21 EGFR Mutations

    PubMed Central

    Zheng, Zhen; Jin, Xiance; Lin, Baochai; Su, Huafang; Chen, Hanbin; Fei, Shaoran; Zhao, Lihao; Deng, Xia; Xie, Deyao; Xie, Congying

    2017-01-01

    Background: Although superior clinical benefits of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the treatment of advanced non-small-cell lung cancer (NSCLC) had been reported with different sensitivity, the sensitivity of second-line TKIs in NSCLC patients with different EFGR mutations was unknown. The purpose of this study is to investigate the clinical outcome of second-line EGFR-TKIs in the treatment of NSCLC patients according to different EGFR genotypes. Methods: The treatment outcomes of 166 NSCLC patients with different EGFR mutations treated by second-line TKIs were retrospectively reviewed. The efficacy was evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. Results: The disease control rate (DCR) and objective response rate (ORR) of enrolled NSCLC patients were 77.7% and 11.4%, respectively. The exon 19 deletion group had a significantly longer median progression-free survival (PFS) (6.7 vs. 4.5 months, P=0.002) and overall survival (OS) (13.7 vs. 11.7 months, P=0.02) compared with the exon 19 L858R mutation group for NSCLC patients, as well for patients with brain metastasis [PFS: (6.7 vs. 3.9 months, p<0.001), OS: (13.7 vs. 7.9 months, p=0.006)]. No significant difference on PFS and OS was observed between exon 19 deletion and L858R mutation group for patients with bone metastasis. EGFR genotype and ECOG PS were independent predictors of PFS. Never smoking, exon 19 deletion, EGOC PS (0-1) and no brain metastasis were correlated with longer OS. No significant difference on side effect between exon 19 and 21 mutation group was observed. Conclusions: NSCLC patients harboring exon 19 deletion achieved better PFS and OS than those with L858R mutation, indicating that EGFR mutation is a significant prognostic factor for advanced NSCLC patients with and without brain metastasis receiving second-line EGFR-TKIs treatment. PMID:28367239

  17. Research on treating neuropsychiatric symptoms of advanced dementia with non-pharmacological strategies, 1998–2008: a systematic literature review

    PubMed Central

    Kverno, Karan S.; Black, Betty S.; Nolan, Marie T.; Rabins, Peter V.

    2011-01-01

    Background Advanced dementia is characterized by severe cognitive and functional impairments that lead to almost total dependency in self-care. Neuropsychiatric symptoms (NPS) are common in advanced dementia, diminishing quality of life and increasing the care burden. The challenge for health care providers is to find safe and effective treatments. Non-pharmacological interventions offer the potential for safer alternatives to pharmacotherapy, but little is known about their efficacy. This review evaluates the published literature on non-pharmacological interventions for treating NPS in advanced dementia. Methods A literature search was undertaken to find non-pharmacological intervention studies published between 1998 and 2008 that measured NPS outcomes in individuals diagnosed with advanced dementia. Strict inclusion criteria initially required that all study participants have severe or very severe dementia, but this range was later broadened to include moderately severe to very severe stages. Results Out of 215 intervention studies, 21 (9.8%) specifically focused on treatments for individuals with moderately severe to very severe dementia. The studies provide limited moderate to high quality evidence for the use of sensory-focused strategies, including aroma, preferred or live music, and multi-sensory stimulation. Emotion-oriented approaches, such as simulated presence may be more effective for individuals with preserved verbal interactive capacity. Conclusions Most studies of interventions for dementia-related NPS have focused on individuals with mild to moderate cognitive impairment. Individuals with severe cognitive impairment do not necessarily respond to NPS treatments in the same manner. Future studies should be specifically designed to further explore the stage-specific efficacy of non-pharmacological therapies for patients with advanced dementia. Areas of particular need for further research include movement-based therapies, hands-on (touch) therapies

  18. Serum VEGFR-3 and survival of advanced gastric cancer patients treated with FOLFOX

    PubMed Central

    Ni, Xue-Feng; Wu, Chang-Ping; Jiang, Jing-Ting

    2010-01-01

    AIM: To explore if vascular endothelial growth factor receptor-3 (VEGFR-3) and carcinoembryonic antigen (CEA) can predict overall survival in advanced gastric cancer. METHODS: VEGFR-3 level was assessed by enzyme-linked immunosorbent assay, and CEA was assessed by chemiluminescence immunoassay in the sera of 81 advanced gastric cancer patients before treatment with oxaliplatin plus 5-fluorouracil and folinic acid. RESULTS: Median survival time in patients with a low serum VEGFR-3 level was significantly longer than in those with a higher VEGFR-3 level (15.4 mo vs 7.7 mo, P < 0.001). Patients with a low CEA level had a longer survival than those with a higher CEA level (15.8 mo vs 8.6 mo, P < 0.001). Thirty-nine patients with low VEGFR-3 and low CEA levels had a median survival of 19.7 mo (P = 0.0006). The hazard ratio for patients with a high VEGFR-3 level was 2.443 (P = 0.002). CONCLUSION: High serum VEGFR-3 level is correlated significantly with poor survival. In patients with a high serum level of VEGFR-3, alternative chemotherapy regimens should be considered. PMID:20440858

  19. Advances in understanding and treating liver diseases during pregnancy: A review.

    PubMed

    Kamimura, Kenya; Abe, Hiroyuki; Kawai, Hirokazu; Kamimura, Hiroteru; Kobayashi, Yuji; Nomoto, Minoru; Aoyagi, Yutaka; Terai, Shuji

    2015-05-07

    Liver disease in pregnancy is rare but pregnancy-related liver diseases may cause threat to fetal and maternal survival. It includes pre-eclampsia; eclampsia; haemolysis, elevated liver enzymes, and low platelets syndrome; acute fatty liver of pregnancy; hyperemesis gravidarum; and intrahepatic cholestasis of pregnancy. Recent basic researches have shown the various etiologies involved in this disease entity. With these advances, rapid diagnosis is essential for severe cases since the decision of immediate delivery is important for maternal and fetal survival. The other therapeutic options have also been shown in recent reports based on the clinical trials and cooperation and information sharing between hepatologist and gynecologist is important for timely therapeutic intervention. Therefore, correct understandings of diseases and differential diagnosis from the pre-existing and co-incidental liver diseases during the pregnancy will help to achieve better prognosis. Therefore, here we review and summarized recent advances in understanding the etiologies, clinical courses and management of liver disease in pregnancy. This information will contribute to physicians for diagnosis of disease and optimum management of patients.

  20. Cancer-related Fatigue in Patients with Advanced Cancer Treated with Autonomic Nerve Pharmacopuncture.

    PubMed

    Park, Ji-hye; Jeon, Hyung-jun; Kang, Hwi-joong; Jeong, In-Sook; Cho, Chong-kwan; Yoo, Hwa-seung

    2015-06-01

    The purpose of this study was to observe the effects of autonomic nerve pharmacopuncture (ANP) treatment on cancer-related fatigue (CRF) in patients with advanced cancer. This observational case study was conducted at the East West Cancer Center of Daejeon University's Dunsan Korean Medical Hospital. Two patients were observed. One patient was diagnosed with left thymic cancer metastatic to the left pleura. The other patient had terminal-stage cervical cancer with iliac bone and lumbar 5 metastases. We injected mountain ginseng pharmacopuncture (MGP) into acupoints alongside the spine (Hua-Tuo-Jia-Ji-Xue, EX B2). We examined the patients for CRF using the Korean version of the Revised Piper Fatigue Scale (RPFS-K), which is a self-assessment tool. The scores on the RPFS-K for both patients tended to decrease during the treatment. Laboratory findings, including hematological changes, were also checked. Liver and renal function tests showed that the treatment was safe. Although further large-population studies are necessary, this case study suggests that ANP has a favorable effect on CRF in patients with advanced cancer.

  1. miR-25 modulates NSCLC cell radio-sensitivity through directly inhibiting BTG2 expression

    SciTech Connect

    He, Zhiwei Liu, Yi Xiao, Bing Qian, Xiaosen

    2015-02-13

    A large proportion of the NSCLC patients were insensitive to radiotherapy, but the exact mechanism is still unclear. This study explored the role of miR-25 in regulating sensitivity of NSCLC cells to ionizing radiation (IR) and its downstream targets. Based on measurement in tumor samples from NSCLC patients, this study found that miR-25 expression is upregulated in both NSCLC and radio-resistant NSCLC patients compared the healthy and radio-sensitive controls. In addition, BTG expression was found negatively correlated with miR-25a expression in the both tissues and cells. By applying luciferase reporter assay, we verified two putative binding sites between miR-25 and BTG2. Therefore, BTG2 is a directly target of miR-25 in NSCLC cancer. By applying loss-and-gain function analysis in NSCLC cell lines, we demonstrated that miR-25-BTG2 axis could directly regulated BTG2 expression and affect radiotherapy sensitivity of NSCLC cells. - Highlights: • miR-25 is upregulated, while BTG2 is downregulated in radioresistant NSCLC patients. • miR-25 modulates sensitivity to radiation induced apoptosis. • miR-25 directly targets BTG2 and suppresses its expression. • miR-25 modulates sensitivity to radiotherapy through inhibiting BTG2 expression.

  2. Early tumor shrinkage as a predictor of favorable outcomes in patients with advanced pancreatic cancer treated with FOLFIRINOX

    PubMed Central

    Kubota, Yutaro; Tagawa, Teppei; Yamamoto, Taikan; Ikusue, Toshikazu; Uto, Yu; Miyashita, Kouichirou; Toshima, Hirokazu; Kobayashi, Kouji; Hisamatsu, Atsushi; Ichikawa, Wataru; Sekikawa, Takashi; Shimada, Ken; Sasaki, Yasutsuna

    2016-01-01

    There are several reports on the correlation between early tumor shrinkage (ETS) or depth of response (DpR) and survival in chemotherapies for colorectal cancer; however, few studies have investigated it in pancreatic cancer. We therefore investigated whether the ETS will predict outcomes in 59 patients with advanced pancreatic cancer treated with FOLFIRINOX therapy. The association of ETS with progression-free survival (PFS) and overall survival (OS) was evaluated but also we addressed to the correlation between outcomes and DpR. ETS was defined as a reduction ≥ 20% of target lesions' diameters measured at 6 to 8 weeks from treatment start. DpR was percentage of maximal tumor shrinkage observed at the nadir diameter compared with baseline. Among 47 evaluable patients for the ETS, 12 (25.5%) patients experienced ETS. The ETS was significantly associated with better PFS (9.0 vs. 4.2 months) as well as OS (24.0 vs. 9.1 months); moreover, the association had a statistically significance for PFS but a strong trend for OS in multivariate analysis. The DpR was statistically significantly but weakly associated with OS. In conclusion, this is the first report that the early response to chemotherapy may predict favorable outcomes in patients with advanced pancreatic cancer treated with FOLFIRINOX therapy. PMID:27634903

  3. Genetic characterization drives personalized therapy for early-stage non-small-cell lung cancer (NSCLC) patients and survivors with metachronous second primary tumor (MST)

    PubMed Central

    Ding, Xingchen; Wang, Linlin; Liu, Xijun; Sun, Xindong; Yu, Jinming; Meng, Xue

    2017-01-01

    Abstract Rationale: The pathogenesis and progression of lung cancer is a complicated process in which many genes take part. But molecular gene testing is typically only performed in advanced-stage non-squamous non-small-cell lung cancer (NSCLC). The value of tyrosine kinase inhibitors (TKI) administration is not widely recognized with respect to early-stage NSCLC. Patient concerns: Here, we present a case of a man, heavy smoker who initially presented with stage IA lung adenocarcinoma (LADC). Three years after a lung lobectomy, he was diagnosed with advanced lung squamous cell carcinoma (SCC), according to laboratory, imaging, and pathological examinations. Diagnoses The case initially had an early-stage LADC with an L858R epidermal growth factor receptor (EGFR) mutation. A subsequent advanced SCC bearing EGFR L858R/T790M mutations occurred 3 years after surgery. Interventions: The comprehensive therapy we utilized, including surgical resection for the early-stage lesion and GP chemotherapy and local radiotherapy as the first line therapy along with gefitinib maintenance treatment for the advanced metachronous second primary tumors (MST). Outcomes: The synthetical therapy, have resulted in our patient with remaining alive and progression free for 4.5 years. Lessons: This case suggests that changes in molecular pathology should be monitored closely throughout cancer progression to guide personalized therapy and improve prognosis. We further review administration of TKI to early-stage NSCLC and to the metachronous second primary tumors (MST) in survivors. PMID:28272214

  4. Improved survival with stereotactic ablative radiotherapy (SABR) over lobectomy for early stage non-small cell lung cancer (NSCLC): addressing the fallout of disruptive randomized data

    PubMed Central

    Kavanagh, Brian D.; Karam, Sana D.

    2015-01-01

    The gold-standard therapy for early stage non-small cell lung cancer (esNSCLC) has historically been lobectomy with mediastinal lymph node dissection. However, up to one-third of patients with esNSCLC are considered medically-inoperable due to factors such as advanced age and comorbid illnesses. The past decade has witnessed a dramatic increase in the use of high-dose conformal radiotherapy delivered over 1-5 fractions, synonymously termed stereotactic ablative radiotherapy (SABR) or stereotactic body radiation therapy (SBRT). High rates of tumor control and favorable toxicity profiles have led to the adoption of SABR as the treatment of choice for medically-inoperable patients. Limited but growing data exist using SABR for medically-operable patients who are also candidates for lobectomy. A recent pooled analysis of two multicenter prospective randomized trials, the STARS (NCT00840749) and ROSEL (NCT00687986) protocols, published by Chang and colleagues (PMID 25981812) reported improved overall survival (OS) and reduced toxicity with SABR over lobectomy for medically-operable patients with esNSCLC. In this article we review the outcomes of this analysis in the context of existing radiotherapy and surgical data for NSCLC. Further, we discuss the potential causes and implications of these provocative results, including the shifting balance between oncologic control and treatment-related mortality in comparisons of SABR and surgical resection, termed the Head Start Effect. PMID:26244136

  5. Intractable hypoglycaemia in a patient with advanced carcinoid syndrome successfully treated with hepatic embolization.

    PubMed

    Kyriacou, Angelos; Mansoor, Was; Lawrance, Jeremy; Trainer, Peter J

    2016-01-01

    A male patient presented at the age of 54 years with metastatic pancreatic neuroendocrine tumour (NET). He was managed with interferon and multiple courses of MIBG therapy which controlled his disease for about seven years. He then developed symptomatic hypoglycaemia which resolved with the introduction of somatostatin analogue treatment and further therapeutic MIBG. However, three years later he was admitted to hospital with severe and intractable hypoglycaemia, which persisted despite treatment with dietary manipulation, diazoxide, long-acting octreotide injections, intravenous infusion of dextrose and octreotide and everolimus. Bland hepatic embolization was attempted as a last resort and resulted in prompt and dramatic improvement of his condition with no hypoglycaemia for five months. We recommend that hepatic embolization should be considered in patients with advanced and metastatic NETs accompanied by refractory hypoglycaemia, with the aim of symptomatic relief and palliation, and possibly some survival benefit.

  6. Nanoparticle Albumin-Bound Rapamycin in Treating Patients With Advanced Cancer With mTOR Mutations

    ClinicalTrials.gov

    2016-12-20

    Advanced Malignant Neoplasm; Cervical Squamous Cell Carcinoma; Endometrial Carcinoma; Malignant Uterine Neoplasm; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Cervical Carcinoma; Recurrent Head and Neck Carcinoma; Recurrent Malignant Neoplasm; Recurrent Ovarian Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Solid Neoplasm; Stage III Bladder Cancer; Stage III Prostate Cancer; Stage III Renal Cell Cancer; Stage IIIA Breast Cancer; Stage IIIA Cervical Cancer; Stage IIIA Ovarian Cancer; Stage IIIB Breast Cancer; Stage IIIB Cervical Cancer; Stage IIIB Ovarian Cancer; Stage IIIC Breast Cancer; Stage IIIC Ovarian Cancer; Stage IV Breast Cancer; Stage IV Ovarian Cancer; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IVA Bladder Cancer; Stage IVA Cervical Cancer; Stage IVB Bladder Cancer; Stage IVB Cervical Cancer

  7. Intraperitoneal chemotherapy for locally advanced gastric cancer to prevent and treat peritoneal carcinomatosis

    PubMed Central

    2016-01-01

    Gastric cancer (GC) is one of the leading causes of cancer death in both sexes in the world. The overall survival (OS) of GC patients is still unsatisfactory. The peritoneal dissemination is the most common type of recurrence in advanced GC. The rationale for administering chemotherapeutic drugs directly into peritoneal cavity is supported by the relative transport barrier that is formed by the tissue surrounding the peritoneal space. Intraperitoneal (IP) chemotherapy with taxanes is safe and feasible. Further randomized phase III clinical trials are needed to validate IP chemotherapy with taxanes for peritoneal carcinomatosis (PC) from GC. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) used as prophylaxis against peritoneal recurrence in patients with high risk GC is safe, significantly improves the survival and reduces the risk of peritoneal recurrence. A drug delivery system with anticancer drugs seem to be have a pharmacokinetic advantage but further randomized clinical trials are needed to validate its effect. PMID:28138628

  8. Application of UV based advanced oxidation to treat sulfolane in an aqueous medium.

    PubMed

    Yu, Linlong; Mehrabani-Zeinabad, Mitra; Achari, Gopal; Langford, Cooper H

    2016-10-01

    Several oxidative methods were studied to degrade sulfolane in an aqueous medium. These include UVA and UVC irradiation with suitable photoactive oxidants, including ozone, H2O2, and TiO2 based photocatalysis and their combinations. Since sulfolane lacks absorption bands in the UV range beyond 200 nm, initiation of reactions depends on the spectra and photochemistry of the oxidants. Among all the advanced oxidation processes investigated, combinations of (a) UVC with H2O2 and O3 (b) UVC with H2O2 and (c) UVC with O3 led to the highest rate of sulfolane loss in synthetic water samples. Experiments on sulfolane contaminated groundwater samples also indicated that these three combinations can efficiently degrade sulfolane. Furthermore, a synergistic effect was observed in the combination of H2O2 and O3 photolysis.

  9. Challenges in Facing the Lung Cancer Epidemic and Treating Advanced Disease in Latin America.

    PubMed

    Raez, Luis E; Santos, Edgardo S; Rolfo, Christian; Lopes, Gilberto; Barrios, Carlos; Cardona, Andres; Mas, Luis A; Arrieta, Oscar; Richardet, Eduardo; Vallejos S, Carlos; Wistuba, Ignacio; Gandara, David; Hirsch, Fred R

    2017-01-01

    Lung cancer, the deadliest cancer worldwide, is of particular concern in Latin America. The rising incidence poses a myriad of challenges for the region, which struggles with limited resources to meet the health care needs of its low- and middle-income populations. In this environment, we are concerned that governments are relatively unaware of the pressing need to implement effective strategies for screening, diagnosis, and treatment of lung cancer. The region has also been slow in adopting molecularly-based therapies in the treatment of advanced disease: testing for epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements are not routine, and access to targeted agents such as monoclonal antibodies and tyrosine kinase inhibitors is problematic. In this paper, we review the current situation in the management of lung cancer in Latin America, hoping that this initiative will help physicians, patient associations, industry, governments, and other stakeholders better face this epidemic in the near future.

  10. EXCESS MORTALITY IN PATIENTS WITH ADVANCED CHRONIC HEPATITIS C TREATED WITH LONG-TERM PEGINTERFERON

    PubMed Central

    Di Bisceglie, Adrian M.; Stoddard, Anne M.; Dienstag, Jules L.; Shiffman, Mitchell L.; Seeff, Leonard B.; Bonkovsky, Herbert L.; Morishima, Chihiro; Wright, Elizabeth C.; Snow, Kristin K.; Lee, William M.; Fontana, Robert J.; Morgan, Timothy R.; Ghany, Marc G.

    2011-01-01

    Background/Aims Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The HALT-C Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who had failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis was to describe the frequency and causes of death among this cohort of patients. Methods Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or non-liver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Results Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%) of which 76 were considered liver-related (62%) and 46 non-liver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years, the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, p=0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, p=0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to non-liver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality, and only one death was suspected to be a direct complication of peginterferon. Conclusions Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to non-liver-related causes among patients with bridging fibrosis. PMID:21480316

  11. Effect of ABCG2/BCRP Expression on Efflux and Uptake of Gefitinib in NSCLC Cell Lines

    PubMed Central

    Galetti, Maricla; Petronini, Pier Giorgio; Fumarola, Claudia; Cretella, Daniele; La Monica, Silvia; Bonelli, Mara; Cavazzoni, Andrea; Saccani, Francesca; Caffarra, Cristina; Andreoli, Roberta; Mutti, Antonio; Tiseo, Marcello; Ardizzoni, Andrea; Alfieri, Roberta R.

    2015-01-01

    Background BCRP/ABCG2 emerged as an important multidrug resistance protein, because it confers resistance to several classes of cancer chemotherapeutic agents and to a number of novel molecularly-targeted therapeutics such as tyrosine kinase inhibitors. Gefitinib is an orally active, selective EGFR tyrosine kinase inhibitor used in the treatment of patients with advanced non small cell lung cancer (NSCLC) carrying activating EGFR mutations. Membrane transporters may affect the distribution and accumulation of gefitinib in tumour cells; in particular a reduced intracellular level of the drug may result from poor uptake, enhanced efflux or increased metabolism. Aim The present study, performed in a panel of NSCLC cell lines expressing different ABCG2 plasma membrane levels, was designed to investigate the effect of the efflux transporter ABCG2 on intracellular gefitinib accumulation, by dissecting the contribution of uptake and efflux processes. Methods and Results Our findings indicate that gefitinib, in lung cancer cells, inhibits ABCG2 activity, as previously reported. In addition, we suggest that ABCG2 silencing or overexpression affects intracellular gefitinib content by modulating the uptake rather than the efflux. Similarly, overexpression of ABCG2 affected the expression of a number of drug transporters, altering the functional activities of nutrient and drug transport systems, in particular inhibiting MPP, glucose and glutamine uptake. Conclusions Therefore, we conclude that gefitinib is an inhibitor but not a substrate for ABCG2 and that ABCG2 overexpression may modulate the expression and activity of other transporters involved in the uptake of different substrates into the cells. PMID:26536031

  12. Cixutumumab and Doxorubicin Hydrochloride in Treating Patients With Unresectable, Locally Advanced, or Metastatic Soft Tissue Sarcoma

    ClinicalTrials.gov

    2016-05-16

    Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Undifferentiated High Grade Pleomorphic Sarcoma of Bone; Childhood Angiosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Malignant Peripheral Nerve Sheath Tumor; Childhood Pleomorphic Rhabdomyosarcoma; Childhood Rhabdomyosarcoma With Mixed Embryonal and Alveolar Features; Childhood Synovial Sarcoma; Dermatofibrosarcoma Protuberans; Malignant Adult Hemangiopericytoma; Malignant Childhood Hemangiopericytoma; Metastatic Childhood Soft Tissue Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Untreated Childhood Rhabdomyosarcoma

  13. Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy.

    PubMed

    Ezewuiro, Obiageli; Grushko, Tatyana A; Kocherginsky, Masha; Habis, Mohammed; Hurteau, Jean A; Mills, Kathryn A; Hunn, Jessica; Olopade, Olufunmilayo I; Fleming, Gini F; Romero, Iris L

    2016-01-01

    There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.

  14. Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy

    PubMed Central

    Ezewuiro, Obiageli; Grushko, Tatyana A.; Kocherginsky, Masha; Habis, Mohammed; Hurteau, Jean A.; Mills, Kathryn A.; Hunn, Jessica; Olopade, Olufunmilayo I.; Fleming, Gini F.; Romero, Iris L.

    2016-01-01

    There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9%) had diabetes and used metformin, 28 (8.0%) had diabetes but did not use metformin, and 291 (83.4%) did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006). In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023). The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin. PMID:26788855

  15. Conventional and advanced oxidation processes used in disinfection of treated urban wastewater.

    PubMed

    Rodríguez-Chueca, J; Ormad, M P; Mosteo, R; Sarasa, J; Ovelleiro, J L

    2015-03-01

    The purpose of the current study is to compare the inactivation of Escherichia coli in wastewater effluents using conventional treatments (chlorination) and advanced oxidation processes (AOPs) such as UV irradiation, hydrogen peroxide (H2O2)/solar irradiation, and photo-Fenton processes. In addition, an analysis of the operational costs of each treatment is carried out taking into account the optimal dosages of chemicals used. Total inactivation of bacteria (7.5 log) was achieved by means of chlorination and UV irradiation. However, bacterial regrowth was observed 6 hours after the completion of UV treatment, obtaining a disinfection value around 3 to 4 log. On the other hand, the combination H2O2/solar irradiation achieved a maximum inactivation of E. coli of 3.30 ± 0.35 log. The photo-Fenton reaction achieved a level of inactivation of 4.87 ± 0.10 log. The order of disinfection, taking into account the reagent/cost ratio of each treatment, is as follows: chlorination > UV irradiation > photo-Fenton > H2O2/sunlight irradiation.

  16. Two-year follow-up in patients treated with emphysematous lung sealant for advanced emphysema.

    PubMed

    Kramer, Mordechai R; Refaely, Yael; Maimon, Nimrod; Rosengarten, Dror; Fruchter, Oren

    2013-11-01

    Endoscopic lung volume-reduction therapy for emphysema has been associated with therapeutic responses smaller in magnitude and less durable than surgical volume reduction (LVRS). Bronchoscopic emphysematous lung sealant (ELS) therapy has been shown to produce improvements in pulmonary function similar to surgery at 1 year. This case series summarizes safety and efficacy data of all patients from the initial ELS study out to 2 years. Between 1 and 2 years, there were three all-cause adverse events requiring hospitalization. One patient went on to successful lung transplant. Improvements relative to baseline in spirometry (change in FEV1: + 14.3 ± 33.1%; change in FVC: + 5.8 ± 23.2%) and diffusing capacity (change in diffusing capacity of the lung for carbon monoxide: + 10.6 ± 20.6%) were observed at 2 years. An exponential model fit to FEV₁ data at 6, 12, 18, and 24 months predicted improvements from a baseline of > 5% out to 4.1 years, similar to what has been reported following surgery. This report confirms long-term safety and efficacy following ELS therapy in advanced emphysema. Studies in a larger cohort are needed to define the role of ELS therapy in the treatment algorithm of patients with this condition.

  17. Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer

    ClinicalTrials.gov

    2017-03-17

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Endometrial Serous Adenocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Lung Carcinoid Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Metastatic Digestive System Neuroendocrine Tumor G1; Ovarian Carcinosarcoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Polypeptide Tumor; Recurrent Adult Liver Carcinoma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IIIC Uterine Corpus Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  18. Combined V-Y Fasciocutaneous Advancement and Gluteus Maximus Muscle Rotational Flaps for Treating Sacral Sores

    PubMed Central

    Choi, Eun Jeong; Moon, Suk Ho; Lee, Yoon Jae

    2016-01-01

    The sacral area is the most common site of pressure sore in bed-ridden patients. Though many treatment methods have been proposed, a musculocutaneous flap using the gluteus muscles or a fasciocutaneous flap is the most popular surgical option. Here, we propose a new method that combines the benefits of these 2 methods: combined V-Y fasciocutaneous advancement and gluteus maximus muscle rotational flaps. A retrospective review was performed for 13 patients who underwent this new procedure from March 2011 to December 2013. Patients' age, sex, accompanying diseases, follow-up duration, surgical details, complications, and recurrence were documented. Computed tomography was performed postoperatively at 2 to 4 weeks and again at 4 to 6 months to identify the thickness and volume of the rotational muscle portion. After surgery, all patients healed within 1 month; 3 patients experienced minor complications. The average follow-up period was 13.6 months, during which time 1 patient had a recurrence (recurrence rate, 7.7%). Average thickness of the rotated muscle was 9.43 mm at 2 to 4 weeks postoperatively and 9.22 mm at 4 to 6 months postoperatively (p = 0.087). Muscle thickness had not decreased, and muscle volume was relatively maintained. This modified method is relatively simple and easy for reconstructing sacral sores, provides sufficient padding, and has little muscle donor-site morbidity. PMID:27366755

  19. Occurrence and Removal of Organic Micropollutants in Landfill Leachates Treated by Electrochemical Advanced Oxidation Processes.

    PubMed

    Oturan, Nihal; van Hullebusch, Eric D; Zhang, Hui; Mazeas, Laurent; Budzinski, Hélène; Le Menach, Karyn; Oturan, Mehmet A

    2015-10-20

    In recent years, electrochemical advanced oxidation processes have been shown to be an effective alternative for the removal of refractory organic compounds from water. This study is focused on the effective removal of recalcitrant organic matter (micropollutants, humic substances, etc.) present in municipal solid waste landfill leachates. A mixture of eight landfill leachates has been studied by the electro-Fenton process using a Pt or boron-doped diamond (BDD) anode and a carbon felt cathode or by the anodic oxidation process with a BDD anode. These processes exhibit great oxidation ability due to the in situ production of hydroxyl radicals ((•)OH), a highly powerful oxidizing species. Both electrochemical processes were shown to be efficient in the removal of dissolved total organic carbon (TOC) from landfill leachates. Regarding the electro-Fenton process, the replacement of the classical anode Pt by the anode BDD allows better performance in terms of dissolved TOC removal. The occurrence and removal yield of 19 polycyclic aromatic hydrocarbons, 15 volatile organic compounds, 7 alkylphenols, 7 polychlorobiphenyls, 5 organochlorine pesticides, and 2 polybrominated diphenyl ethers in landfill leachate were also investigated. Both electrochemical processes allow one to reach a quasicomplete removal (about 98%) of these organic micropollutants.

  20. Vaccine Therapy With or Without Sargramostim in Treating Patients With Advanced or Metastatic Cancer

    ClinicalTrials.gov

    2013-01-24

    Adenocarcinoma of the Colon; Adenocarcinoma of the Gallbladder; Adenocarcinoma of the Pancreas; Adenocarcinoma of the Rectum; Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Gallbladder; Diffuse Adenocarcinoma of the Stomach; Intestinal Adenocarcinoma of the Stomach; Male Breast Cancer; Mixed Adenocarcinoma of the Stomach; Ovarian Endometrioid Adenocarcinoma; Paget Disease of the Breast With Intraductal Carcinoma; Paget Disease of the Breast With Invasive Ductal Carcinoma; Recurrent Adult Primary Liver Cancer; Recurrent Breast Cancer; Recurrent Colon Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Salivary Gland Adenocarcinoma; Stage II Malignant Testicular Germ Cell Tumor; Stage II Pancreatic Cancer; Stage III Colon Cancer; Stage III Gastric Cancer; Stage III Malignant Testicular Germ Cell Tumor; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Salivary Gland Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Gastric Cancer; Stage IV Pancreatic Cancer; Stage IV Rectal Cancer; Stage IV Salivary Gland Cancer; Thyroid Gland Medullary Carcinoma; Unresectable Gallbladder Cancer

  1. What is changing in radiotherapy for the treatment of locally advanced nonsmall cell lung cancer patients? A review.

    PubMed

    Giaj-Levra, Niccoló; Ricchetti, Francesco; Alongi, Filippo

    2016-01-01

    Radiotherapy treatment continues to have a relevant impact in the treatment of nonsmall cell cancer (NSCLC). Use of concurrent chemotherapy and radiotherapy is considered the gold standard in the treatment of locally advanced NSCLC but clinical outcomes are not satisfactory. Introduction of new radiotherapy technology and chemotherapy regimens are under investigation in this setting with the goal to improve unsatisfactory results. We report how radiotherapy is changing in the treatment of locally advanced NSCLC.

  2. Early Toxicity in Patients Treated With Postoperative Proton Therapy for Locally Advanced Breast Cancer

    SciTech Connect

    Cuaron, John J.; Chon, Brian; Tsai, Henry; Goenka, Anuj; DeBlois, David; Ho, Alice; Powell, Simon; Hug, Eugen; Cahlon, Oren

    2015-06-01

    Purpose: To report dosimetry and early toxicity data in breast cancer patients treated with postoperative proton radiation therapy. Methods and Materials: From March 2013 to April 2014, 30 patients with nonmetastatic breast cancer and no history of prior radiation were treated with proton therapy at a single proton center. Patient characteristics and dosimetry were obtained through chart review. Patients were seen weekly while on treatment, at 1 month after radiation therapy completion, and at 3- to 6-month intervals thereafter. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Frequencies of toxicities were tabulated. Results: Median dose delivered was 50.4 Gy (relative biological equivalent [RBE]) in 5 weeks. Target volumes included the breast/chest wall and regional lymph nodes including the internal mammary lymph nodes (in 93%). No patients required a treatment break. Among patients with >3 months of follow-up (n=28), grade 2 dermatitis occurred in 20 patients (71.4%), with 8 (28.6%) experiencing moist desquamation. Grade 2 esophagitis occurred in 8 patients (28.6%). Grade 3 reconstructive complications occurred in 1 patient. The median planning target volume V95 was 96.43% (range, 79.39%-99.60%). The median mean heart dose was 0.88 Gy (RBE) [range, 0.01-3.20 Gy (RBE)] for all patients, and 1.00 Gy (RBE) among patients with left-sided tumors. The median V20 of the ipsilateral lung was 16.50% (range, 6.1%-30.3%). The median contralateral lung V5 was 0.34% (range, 0%-5.30%). The median maximal point dose to the esophagus was 45.65 Gy (RBE) [range, 0-65.4 Gy (RBE)]. The median contralateral breast mean dose was 0.29 Gy (RBE) [range, 0.03-3.50 Gy (RBE)]. Conclusions: Postoperative proton therapy is well tolerated, with acceptable rates of skin toxicity. Proton therapy favorably spares normal tissue without compromising target coverage. Further follow-up is necessary to assess for clinical outcomes and cardiopulmonary

  3. Multi-source recruitment strategies for advancing addiction recovery research beyond treated samples

    PubMed Central

    Subbaraman, Meenakshi Sabina; Laudet, Alexandre B.; Ritter, Lois A.; Stunz, Aina; Kaskutas, Lee Ann

    2014-01-01

    Background The lack of established sampling frames makes reaching individuals in recovery from substance problems difficult. Although general population studies are most generalizable, the low prevalence of individuals in recovery makes this strategy costly and inefficient. Though more efficient, treatment samples are biased. Aims To describe multi-source recruitment for capturing participants from heterogeneous pathways to recovery; assess which sources produced the most respondents within subgroups; and compare treatment and non-treatment samples to address generalizability. Results Family/friends, Craigslist, social media and non-12-step groups produced the most respondents from hard-to-reach groups, such as racial minorities and treatment-naïve individuals. Recovery organizations yielded twice as many African-Americans and more rural dwellers, while social media yielded twice as many young people than other sources. Treatment samples had proportionally fewer females and older individuals compared to non-treated samples. Conclusions Future research on recovery should utilize previously neglected recruiting strategies to maximize the representativeness of samples. PMID:26166909

  4. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy.

    PubMed

    Estilo, Cherry L; Van Poznak, Catherine H; Wiliams, Tijaana; Bohle, George C; Lwin, Phyu T; Zhou, Qin; Riedel, Elyn R; Carlson, Diane L; Schoder, Heiko; Farooki, Azeez; Fornier, Monica; Halpern, Jerry L; Tunick, Steven J; Huryn, Joseph M

    2008-08-01

    Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.

  5. SB-715992 in Treating Patients With Acute Leukemia, Chronic Myelogenous Leukemia, or Advanced Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-01-10

    Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); 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); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  6. Heberprot-P: a novel product for treating advanced diabetic foot ulcer.

    PubMed

    Berlanga, Jorge; Fernández, José I; López, Ernesto; López, Pedro A; del Río, Amaurys; Valenzuela, Carmen; Baldomero, Julio; Muzio, Verena; Raíces, Manuel; Silva, Ricardo; Acevedo, Boris E; Herrera, Luis

    2013-01-01

    Diabetic foot ulcer is a principal diabetic complication. It has been shown that diabetic patients have decreased growth factor concentrations in their tissues, particularly epidermal growth factor. Growth factor shortage impairs wound healing, which leads to chronic nonhealing wounds and sometimes eventual amputation. Ischemic diabetic foot ulcer is the most difficult to treat and confers the highest amputation risk. Injecting epidermal growth factor deep into the wound bottom and contours encourages a more effective pharmacodynamic response in terms of granulation tissue growth and wound closure. Epidermal growth factor injected into the ulcer matrix may also result in association with extracellular matrix proteins, thus enhancing cell proliferation and migration. Heberprot-P is an innovative Cuban product containing recombinant human epidermal growth factor for peri- and intra-lesional infiltration; evidence reveals it accelerates healing of deep and complex ulcers, both ischemic and neuropathic, and reduces diabetes-related amputations. Clinical trials of Heberprot-P in patients with diabetic foot ulcers have shown that repeated local infiltration of this product can enhance healing of chronic wounds safely and efficaciously. As a result, Heberprot-P was registered in Cuba in 2006, and in 2007 was included in the National Basic Medications List and approved for marketing. It has been registered in 15 other countries, enabling treatment of more than 100,000 patients. Heberprot-P is a unique therapy for the most complicated and recalcitrant chronic wounds usually associated with high amputation risk. Local injection in complex diabetic wounds has demonstrated a favorable risk-benefit ratio by speeding healing, reducing recurrences and attenuating amputation risk. Further testing and deployment worldwide of Heberprot-P would provide an opportunity to assess the product's potential to address an important unmet medical need.

  7. Galantamine-loaded PLGA nanoparticles, from nano-emulsion templating, as novel advanced drug delivery systems to treat neurodegenerative diseases

    NASA Astrophysics Data System (ADS)

    Fornaguera, C.; Feiner-Gracia, N.; Calderó, G.; García-Celma, M. J.; Solans, C.

    2015-07-01

    Polymeric nanoparticles could be promising drug delivery systems to treat neurodegenerative diseases. Among the various methods of nanoparticle preparation, nano-emulsion templating was used in the present study to prepare galantamine-loaded nano-emulsions by a low-energy emulsification method followed by solvent evaporation to obtain galantamine-loaded polymeric nanoparticles. This approach was found to be suitable because biocompatible, biodegradable and safe nanoparticles with appropriate features (hydrodynamic radii around 20 nm, negative surface charge and stability higher than 3 months) for their intravenous administration were obtained. Encapsulation efficiencies higher than 90 wt% were obtained with a sustained drug release profile as compared to that from aqueous and micellar solutions. The enzymatic activity of the drug was maintained at 80% after its encapsulation into nanoparticles that were non-cytotoxic at the required therapeutic concentration. Therefore, novel galantamine-loaded polymeric nanoparticles have been designed for the first time using the nano-emulsification approach and showed the appropriate features to become advanced drug delivery systems to treat neurodegenerative diseases.Polymeric nanoparticles could be promising drug delivery systems to treat neurodegenerative diseases. Among the various methods of nanoparticle preparation, nano-emulsion templating was used in the present study to prepare galantamine-loaded nano-emulsions by a low-energy emulsification method followed by solvent evaporation to obtain galantamine-loaded polymeric nanoparticles. This approach was found to be suitable because biocompatible, biodegradable and safe nanoparticles with appropriate features (hydrodynamic radii around 20 nm, negative surface charge and stability higher than 3 months) for their intravenous administration were obtained. Encapsulation efficiencies higher than 90 wt% were obtained with a sustained drug release profile as compared to that from

  8. Comparison of Survival Rate in Primary Non-Small-Cell Lung Cancer Among Elderly Patients Treated With Radiofrequency Ablation, Surgery, or Chemotherapy

    SciTech Connect

    Lee, Heon; Jin, Gong Yong Han, Young Min; Chung, Gyung Ho; Lee, Yong Chul; Kwon, Keun Sang; Lynch, David

    2012-04-15

    Purpose: We retrospectively compared the survival rate in patients with non-small-cell lung cancer (NSCLC) treated with radiofrequency ablation (RFA), surgery, or chemotherapy according to lung cancer staging. Materials and Methods: From 2000 to 2004, 77 NSCLC patients, all of whom had WHO performance status 0-2 and were >60 years old, were enrolled in a cancer registry and retrospectively evaluated. RFA was performed on patients who had medical contraindications to surgery/unsuitability for surgery, such as advanced lung cancer or refusal of surgery. In the RFA group, 40 patients with inoperable NSCLC underwent RFA under computed tomography (CT) guidance. These included 16 patients with stage I to II cancer and 24 patients with stage III to IV cancer who underwent RFA in an adjuvant setting. In the comparison group (n = 37), 13 patients with stage I to II cancer underwent surgery; 18 patients with stage III to IV cancer underwent chemotherapy; and 6 patients with stage III to IV cancer were not actively treated. The survival curves for RFA, surgery, and chemotherapy in these patients were calculated using Kaplan-Meier method. Results: Median survival times for patients treated with (1) surgery alone and (2) RFA alone for stage I to II lung cancer were 33.8 and 28.2 months, respectively (P = 0.426). Median survival times for patients treated with (1) chemotherapy alone and (2) RFA with chemotherapy for stage III to IV cancer were 29 and 42 months, respectively (P = 0.03). Conclusion: RFA can be used as an alternative treatment to surgery for older NSCLC patients with stage I to II inoperable cancer and can play a role as adjuvant therapy with chemotherapy for patients with stage III to IV lung cancer.

  9. Clinical efficacy of CyberKnife combined with chemotherapy and hyperthermia for advanced non-small cell lung cancer.

    PubMed

    Wang, Yuan-Yuan; Lin, Si-Xiang; Yang, Gui-Qing; Liu, Han-Chen; Sun, Dong-Ning; Wang, Yi-Shan

    2013-05-01

    Non-small cell lung cancer (NSCLC) is responsible for at least 80% of all lung tumors and has a poor prognosis, since 75% of NSCLCs are first diagnosed at an advanced stage. This study was conducted to evaluate the therapeutic efficacy of CyberKnife in combination with chemotherapy and hyperthermia for selected patients with advanced non-small cell lung cancer (NSCLC). Clinical charts, imaging and pathology reports of patients with advanced NSCLC who underwent CyberKnife therapy in our Tumor Therapy Center were retrospectively reviewed. Clinical efficacy was evaluated for local control, Karnofsky performance status scale (KPS) and toxicity analysis. A total of 119 patients with 136 target areas were evaluated. A prescribed dose of 24-51 Gy to the gross tumor volume was delivered in 3-6 fractions. The median prescription dose was 35 Gy (mean, 34.73±4.80 Gy), with an average of five fractions. Patients, who voluntarily participated in the study, were assigned to one of three groups, which were as follows: CyberKnife therapy alone, CyberKnife combined with chemotherapy and CyberKnife combined with chemotherapy and hyperthermia. The median follow-up period was 6 months and curative efficiencies were 62.16, 71.79 and 90.70%, respectively, as determined by radiographic and clinical re-examinations. Patients treated by CyberKnife combined with chemotherapy and hyperthermia achieved optimal improvement in the aspect of KPS, which was statistically different compared to the other two groups (P<0.05). In conclusion, our results indicated that CyberKnife combined with chemotherapy and hyperthermia achieved favorable short-term outcomes and may be a more viable option for patients with advanced NSCLC. However, further investigations are required to evaluate long-term outcomes.

  10. Prevention of Hepatitis B Virus Reactivation With Lamivudine in a Patient With Advanced Renal Cell Carcinoma Treated With Everolimus.

    PubMed

    D'Aniello, Carmine; Maruzzo, Marco; Basso, Umberto

    2016-01-01

    Anticancer agents may trigger reactivation of hepatitis B virus infection ensuing in asymptomatic to severe liver damage. Preemptive administration of antiviral agents such as lamivudine to patients receiving cytotoxic chemotherapy has been shown to inhibit viral replication and prevent such events. No data are available so far concerning the coadministration of antiviral agents and everolimus, an oral mammalian target of rapamycin inhibitor recently approved for the treatment of advanced renal cell carcinoma. We present in this study the first case to our knowledge of a hepatitis B surface antigen-positive patient with metastatic renal cell carcinoma who has been successfully treated with prophylactic lamivudine and everolimus. Long-term depletion of viral replication was obtained along with stabilization of lung and bone metastases. Hepatitis B surface antigen positivity may be found in up to 10% of cancer patients but should not be considered a contraindication to treatment with everolimus.

  11. [An advanced metastatic breast cancer patient successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy].

    PubMed

    Sato, Yasushi; Takayama, Tetsuji; Sagawa, Tamotsu; Sato, Tsutomu; Okamoto, Kumiko; Takahashi, Shou; Abe, Seiichiro; Iyama, Satoshi; Murase, Kazuyuki; Kato, Junji; Niitsu, Yoshiro

    2008-03-01

    We reported here a case of advanced breast cancer successfully treated with combination therapy including docetaxel, doxorubicin and cyclophosphamide (TAC) as salvage therapy. A 56-year-old male was referred to our hospital for treatment of recurrent metastatic breast cancer. When he was admitted, his general condition was poor due to massive intraperitoneal metastasis. We administered TAC chemotherapy (docetaxel 75 mg/m(2), doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2), every 3 weeks). During chemotherapy, he showed no major adverse effects except grade 3 neutropenia, which could be easily managed with G-CSF administration. Metastatic lesions almost disappeared after 4 cycles of TAC. TAC therapy was considered to be acceptable as salvage therapy for a metastatic male breast cancer patient.

  12. Simulated flight acoustic investigation of treated ejector effectiveness on advanced mechanical suppresors for high velocity jet noise reduction

    NASA Technical Reports Server (NTRS)

    Brausch, J. F.; Motsinger, R. E.; Hoerst, D. J.

    1986-01-01

    Ten scale-model nozzles were tested in an anechoic free-jet facility to evaluate the acoustic characteristics of a mechanically suppressed inverted-velocity-profile coannular nozzle with an accoustically treated ejector system. The nozzle system used was developed from aerodynamic flow lines evolved in a previous contract, defined to incorporate the restraints imposed by the aerodynamic performance requirements of an Advanced Supersonic Technology/Variable Cycle Engine system through all its mission phases. Accoustic data of 188 test points were obtained, 87 under static and 101 under simulated flight conditions. The tests investigated variables of hardwall ejector application to a coannular nozzle with 20-chute outer annular suppressor, ejector axial positioning, treatment application to ejector and plug surfaces, and treatment design. Laser velocimeter, shadowgraph photograph, aerodynamic static pressure, and temperature measurement were acquired on select models to yield diagnositc information regarding the flow field and aerodynamic performance characteristics of the nozzles.

  13. Imatinib Mesylate in Treating Patients With Advanced Cancer and Liver Dysfunction

    ClinicalTrials.gov

    2013-02-06

    Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Gastrointestinal Stromal Tumor; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Meningeal Chronic Myelogenous Leukemia; Monoclonal Gammopathy of Undetermined Significance; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Central Nervous System Non-Hodgkin Lymphoma; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory

  14. The Modern Role of Radiation Therapy in Treating Advanced-Stage Retinoblastoma: Long-Term Outcomes and Racial Differences

    SciTech Connect

    Orman, Amber; Koru-Sengul, Tulay; Miao, Feng; Markoe, Arnold; Panoff, Joseph E.

    2014-12-01

    Purpose/Objective(s): To evaluate the effects of various patient characteristics and radiation therapy treatment variables on outcomes in advanced-stage retinoblastoma. Methods and Materials: This was a retrospective review of 41 eyes of 30 patients treated with external beam radiation therapy between June 1, 1992, and March 31, 2012, with a median follow-up time of 133 months (11 years). Outcome measures included overall survival, progression-free survival, local control, eye preservation rate, and toxicity. Results: Over 90% of the eyes were stage V. Definitive external beam radiation therapy (EBRT) was delivered in 43.9% of eyes, adjuvant EBRT in 22% of eyes, and second-line/salvage EBRT in 34.1% of eyes. A relative lens sparing (RLS) technique was used in 68.3% of eyes and modified lens sparing (MLS) in 24.4% of eyes. Three eyes were treated with other techniques. Doses ≥45 Gy were used in 68.3% of eyes. Chemotherapy was a component of treatment in 53.7% of eyes. The 10-year overall survival was 87.7%, progression-free survival was 80.5%, and local control was 87.8%. White patients had significantly better overall survival than did African-American patients in univariate analysis (hazard ratio 0.09; 95% confidence interval 0.01-0.84; P=.035). Toxicity was seen in 68.3% of eyes, including 24.3% with isolated acute dermatitis. Conclusions: External beam radiation therapy continues to be an effective treatment modality for advanced retinoblastoma, achieving excellent long-term local control and survival with low rates of treatment-related toxicity and secondary malignancy.

  15. Current management of motor fluctuations in patients with advanced Parkinson's disease treated chronically with levodopa.

    PubMed

    Melamed, E; Zoldan, J; Galili-Mosberg, R; Ziv, I; Djaldetti, R

    1999-01-01

    Motor fluctuations after long-term administration of levodopa may be due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of postsynaptic dopaminergic receptors. Peripheral pharmacokinetic mechanisms may be equally important, particularly in motor fluctuations of the "delayed on" (increased time latencies from dose intake to start-up of clinical benefit) and "no-on" (complete failure of a levodopa dose to exert an "on" response) types. Levodopa itself has a very poor solubility. In addition, there is delayed gastric emptying in many advanced patients. Therefore, an oral dose of levodopa may remain in the stomach for long periods of time before it passes into the duodenum where there is immediate absorption. Consequently, in order to overcome response fluctuations caused by impaired pharmacokinetic mechanisms and to improve its absorption, we recommend that levodopa be taken in multiple small doses, on an empty stomach, preferably crushed and mixed with a lot of liquid. Protein intake should be minimized. Prokinetic drugs such as prepulsid (Cisaprid) could be used to facilitate gastric motility and levodopa transit time. Administration of crushed levodopa through nasoduodenal or gastrojejunostomy tubes may be helpful in certain circumstances. Bypassing the stomach with subcutaneous injections of apomorphine may provide dramatic rescue from difficult "off" situations. Oral and s.c. administration of novel, extremely soluble prodrugs of levodopa, e.g., levodopa ethylester, may offer a new approach to overcome difficulties in levodopa absorption. Addition of dopamine agonists, MAO-B inhibitors, COMT inhibitors and controlled release levodopa preparations may be helpful in prolonging the duration of efficacy of each single levodopa dose. Levodopa, administered orally, usually combined with peripheral dopa decarboxylase inhibitors, continues to be the most widely-used and most

  16. [A Case of Advanced Gastric Cancer with Multiple Liver Metastases Successfully Treated with Capecitabine, Cisplatin, and Trastuzumab].

    PubMed

    Oneda, Yasuo; Tamura, Shigeyuki; Murakami, Kouhei; Takeno, Atsushi; Kuwahara, Ryuichi; Akiyama, Yasuki; Sakamoto, Takuya; Inatome, Junichi; Naito, Atushi; Katsura, Yoshiteru; Ohmura, Yoshiaki; Kagawa, Yoshinori; Egawa, Chiyomi; Takeda, Yutaka; Kato, Takeshi

    2016-11-01

    A 70-year-old-man, whose chief complaint was epigastric pain, was referred to our hospital and diagnosed with advanced gastric cancer with multiple liver metastases. Gastrointestinal endoscopy showed a tumor on the anterior wall of the gastric lower body. Histologically, biopsy specimens indicated adenocarcinoma, and immunohistochemistry showed positive expression of HER2(3+). Chest and abdominal computed tomography showed multiple liver metastases and lymph node metastases. We started chemotherapy with capecitabine, cisplatin, and trastuzumab. Abdominal CT showed the primary tumor and metastases to be reduced after 3 courses, but a ringed enhanced space occupying lesion in the liver had appeared, which was diagnosed as a liver abscess. After administering antibiotics and performing percutaneous transhepatic abscess drainage (PTAD), we continued XPT chemotherapy. The patient received 6 courses of XPT, 15 courses of capecitabine and trastuzumab, and 6 courses of trastuzumab alone, and has remained progression free in the 1 year and 5 months after diagnosis. We experienced a case of advanced gastric cancer with multiple liver metastases successfully treated with capecitabine, cisplatin, and trastuzumab.

  17. Comparison of cost-effectiveness of regorafenib and trifluridine/tipiracil combination tablet for treating advanced and recurrent colorectal cancer

    PubMed Central

    Kimura, Michio; Usami, Eiseki; Iwai, Mina; Go, Makiko; Teramachi, Hitomi; Yoshimura, Tomoaki

    2016-01-01

    Regorafenib and trifluridine/tipiracil combination tablet regimens are standard third-line or later treatments for advanced and recurrent colorectal cancer with no significant difference in efficacy. The present study aimed to compare the cost-effectiveness of using regorafenib vs. the trifluridine/tipiracil combination tablet. The expected cost was calculated based on data from patients with advanced and recurrent colorectal cancer who were treated with regorafenib or trifluridine/tipiracil combination tablet. The median survival time (MST) from the CORRECT and the RECOURSE study was used to evaluate the therapeutic efficacy of the regimens. The cost-effectiveness ratio was calculated from the expected cost and MST for the two regimens. The expected cost per patient for the regorafenib and the trifluridine/tipiracil combination tablet regimen was ¥705,330.3 and ¥371,198.7, respectively, and the cost-effectiveness ratio was ¥110,207.9/MST and ¥52,281.5/MST, respectively. In conclusion, the findings of the present study demonstrated that the trifluridine/tipiracil combination tablet regimen is more cost-effective compared with the regorafenib regimen. PMID:27900102

  18. Copper-transporting P-type adenosine triphosphatase (ATP7A) is associated with platinum-resistance in non-small cell lung cancer (NSCLC)

    PubMed Central

    2012-01-01

    Background Copper export protein ATP7A is important for maintaining copper homeostasis. Recent studies have shown that copper transporters are also involved in the transport of platinum. The goal of this study was to determine the role of ATP7A in the platinum-resistance of non-small cell lung cancer (NSCLC). Methods Sensitivities to platinums were detected by MTT assay and drug-resistance related genes were analyzed by real-time PCR and immunoblotting between DDP-sensitive A549 and the corresponding DDP-resistant cell subline (A549/DDP). ATP7A expression was evaluated by immunohistochemistry in tumor tissues of unresectable NSCLC patients who received cisplatin-basing chemotherapy. Results The expression of ATP7A was significantly higher in A549/DDP cell subline than in A549 cells at both mRNA and protein levels. The silencing of ATP7A expression in A549/DDP by siRNA partially reversed DDP-resistance (29.62%) and increased cell apoptosis. ATP7A expression was detected in 41.6%of NSCLC patients, but not in adjacent stroma nor normal lung tissues. ATP7A-positive patients had a significantly poorer histological grade (p = 0.039) and poorer response to platinum-basing chemotherapy (p = 0.001) compared with ATP7A-negative patients. Cox's proportional hazards analysis showed that ATP7A expression was an independent prognostic factor for overall survival (p = 0.045). Conclusions ATP7A overexpression played an important role in platinum-resistance of NSCLC, and was a negative prognostic factor of NSCLC patients treated with platinum-based chemotherapy. PMID:22304828

  19. MGMT expression levels predict disease stabilisation, progression-free and overall survival in patients with advanced melanomas treated with DTIC.

    PubMed

    Busch, Christian; Geisler, Jürgen; Lillehaug, Johan R; Lønning, Per Eystein

    2010-07-01

    Metastatic melanoma responds poorly to systemic treatment. We report the results of a prospective single institution study evaluating O(6)-methylguanine-DNA methyltransferase (MGMT) status as a potential predictive and/or prognostic marker among patients treated with dacarbazine (DTIC) 800-1000 mg/m(2) monotherapy administered as a 3-weekly schedule for advanced malignant melanomas. The study was approved by the Regional Ethical Committee. Surgical biopsies from metastatic or loco-regional deposits obtained prior to DTIC treatment were snap-frozen immediately upon removal and stored in liquid nitrogen up to processing. Median time from enrolment to end of follow-up was 67 months. MGMT expression levels evaluated by qRT-PCR correlated significantly to DTIC benefit (CR/PR/SD; p=0.005), time to progression (TTP) (p=0.005) and overall survival (OS) (p=0.003). MGMT expression also correlated to Breslow thickness in the primary tumour (p=0.014). While MGMT promoter hypermethylation correlated to MGMT expression, MGMT promoter hypermethylation did not correlate to treatment benefit, TTP or OS, suggesting that other factors may be critical in determining MGMT expression levels in melanomas. In a Cox proportional regression analysis, serum lactate dehydrogenase (LDH, p<0.001), MGMT expression (p=0.022) and p16(INK4a) expression (p=0.037) independently predicted OS, while TTP correlated to DTIC benefit after 6 weeks only (p=0.001). Our data reveal MGMT expression levels to be associated with disease stabilisation and prognosis in patients receiving DTIC monotherapy for advanced melanoma. The role of MGMT expression as a predictor to DTIC sensitivity versus a general prognostic factor in advanced melanomas warrants further evaluation.

  20. Genome-Wide Association Study of Prognosis in Advanced Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy

    PubMed Central

    Hu, Lingmin; Wu, Chen; Zhao, Xueying; Heist, Rebecca; Su, Li; Zhao, Yang; Han, Baohui; Cao, Songyu; Chu, Minjie; Dai, Juncheng; Dong, Jing; Shu, Yongqian; Xu, Lin; Chen, Yijiang; Wang, Yi; Lu, Feng; Jiang, Yue; Yu, Dianke; Chen, Hongyan; Tan, Wen; Ma, Hongxia; Chen, Jiaping; Jin, Guangfu; Wu, Tangchun; Lu, Daru; Christiani, David C.; Lin, Dongxin; Hu, Zhibin; Shen, Hongbing

    2013-01-01

    Purpose Genetic variation may influence chemotherapy response and overall survival in cancer patients. Experimental design We conducted a genome-wide scan in 535 advanced-stage non–small cell lung cancer (NSCLC) patients from two independent cohorts (307 from Nanjing and 228 from Beijing). A replication was carried out on an independent cohort of 340 patients from Southeastern China followed by a second validation on 409 patients from the Massachusetts General Hospital (Boston, MA). Results Consistent associations with NSCLC survival were identified for five single-nucleotide polymorphisms (SNP) in Chinese populations with P values ranging from 3.63 × 10−5 to 4.19 × 10−7 in the additive genetic model. The minor allele of three SNPs (rs7629386 at 3p22.1, rs969088 at 5p14.1, and rs3850370 at 14q24.3) were associated with worse NSCLC survival while 2 (rs41997 at 7q31.31 and rs12000445 at 9p21.3) were associated with better NSCLC survival. In addition, rs7629386 at 3p22.1 (CTNNB1) and rs3850370 at 14q24.3 (SNW1-ALKBH1-NRXN3) were further replicated in the Caucasian population. Conclusion In this three-stage genome-wide association studies, we identified five SNPs as markers for survival of advanced-stage NSCLC patients treated with first-line platinum-based chemotherapy in Chinese Han populations. Two of these SNPs, rs7629386 and rs3850370, could also be markers for survival among Caucasian patients. PMID:22872573

  1. Expression of Nuclear Transcription Factor Kappa B in Locally Advanced Human Cervical Cancer Treated With Definitive Chemoradiation

    SciTech Connect

    Garg, Amit K.; Jhingran, Anuja; Klopp, Ann H.; Aggarwal, Bharat B.; Kunnumakkara, Ajai B.; Broadus, Russell R.; Eifel, Patricia J.; Buchholz, Thomas A.

    2010-12-01

    Purpose: Nuclear factor kappa B (NF-{kappa}B), a transcriptional factor that has been shown to be constitutively active in cervical cancer, is part of an important pathway leading to treatment resistance in many tumor types. The purpose of our study was to determine whether expression of NF-{kappa}B in pretreatment specimens and specimens taken shortly after treatment initiation correlated with outcome in cervical cancer patients treated with definitive chemoradiation. Methods and Materials: Eighteen patients with locally advanced cervical cancer were enrolled in a study in which cervical biopsy specimens were obtained before radiation therapy and 48 h after treatment initiation. Matched biopsy specimens from 16 of these patients were available and evaluated for the nuclear expression of NF-{kappa}B protein by immunohistochemical staining. Results: After a median follow-up of 43 months, there were 9 total treatment failures. Nuclear staining for NF-{kappa}B was positive in 3 of 16 pretreatment biopsy specimens (19%) and 5 of 16 postradiation biopsy specimens (31%). Pretreatment expression of NF-{kappa}B nuclear staining correlated with increased rates of local-regional failure (100% vs. 23%, p = 0.01), distant failure (100% vs. 38%, p = 0.055), disease-specific mortality (100% vs. 31%, p = 0.03), and overall mortality (100% vs. 38%, p = 0.055). Conclusions: Our data suggest that pretreatment nuclear expression of NF-{kappa}B may be associated with a poor outcome for cervical cancer patients treated with chemoradiation. Although these data require validation in a larger group of patients, the results support the continued study of the relationship between NF-{kappa}B and outcome in patients treated for carcinoma of the cervix.

  2. WE-E-17A-02: Predictive Modeling of Outcome Following SABR for NSCLC Based On Radiomics of FDG-PET Images

    SciTech Connect

    Li, R; Aguilera, T; Shultz, D; Rubin, D; Diehn, M; Loo, B

    2014-06-15

    Purpose: This study aims to develop predictive models of patient outcome by extracting advanced imaging features (i.e., Radiomics) from FDG-PET images. Methods: We acquired pre-treatment PET scans for 51 stage I NSCLC patients treated with SABR. We calculated 139 quantitative features from each patient PET image, including 5 morphological features, 8 statistical features, 27 texture features, and 100 features from the intensity-volume histogram. Based on the imaging features, we aim to distinguish between 2 risk groups of patients: those with regional failure or distant metastasis versus those without. We investigated 3 pattern classification algorithms: linear discriminant analysis (LDA), naive Bayes (NB), and logistic regression (LR). To avoid the curse of dimensionality, we performed feature selection by first removing redundant features and then applying sequential forward selection using the wrapper approach. To evaluate the predictive performance, we performed 10-fold cross validation with 1000 random splits of the data and calculated the area under the ROC curve (AUC). Results: Feature selection identified 2 texture features (homogeneity and/or wavelet decompositions) for NB and LR, while for LDA SUVmax and one texture feature (correlation) were identified. All 3 classifiers achieved statistically significant improvements over conventional PET imaging metrics such as tumor volume (AUC = 0.668) and SUVmax (AUC = 0.737). Overall, NB achieved the best predictive performance (AUC = 0.806). This also compares favorably with MTV using the best threshold at an SUV of 11.6 (AUC = 0.746). At a sensitivity of 80%, NB achieved 69% specificity, while SUVmax and tumor volume only had 36% and 47% specificity. Conclusion: Through a systematic analysis of advanced PET imaging features, we are able to build models with improved predictive value over conventional imaging metrics. If validated in a large independent cohort, the proposed techniques could potentially aid in

  3. Basic Fibroblast Growth Factor-2/beta3 Integrin Expression Profile: Signature of Local Progression After Chemoradiotherapy for Patients With Locally Advanced Non-Small-Cell Lung Cancer

    SciTech Connect

    Massabeau, Carole; Rouquette, Isabelle; Lauwers-Cances, Valerie; Mazieres, Julien; Bachaud, Jean-Marc; Armand, Jean-Pierre; Delisle, Marie-Bernadette; Favre, Gilles; Toulas, Christine; Cohen-Jonathan-Moyal, Elizabeth

    2009-11-01

    Purpose: No biologic signature of chemoradiotherapy sensitivity has been reported for patients with locally advanced non-small-cell lung cancer (NSCLC). We have previously demonstrated that basic fibroblast growth factor (FGF-2) and alphavbeta3 integrin pathways control tumor radioresistance. We investigated whether the expression of the proteins involved in these pathways might be associated with the response to treatment and, therefore, the clinical outcome. Methods and Materials: FGF-2, beta3 integrin, angiopoietin-2, and syndecan-1 expression was studied using immunohistochemistry performed on biopsies obtained, before any treatment, from 65 patients exclusively treated with chemoradiotherapy for locally advanced NSCLC. The response to treatment was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria using computed tomography at least 6 weeks after the end of the chemoradiotherapy. Local progression-free survival, metastasis-free survival, and disease-free survival were studied using the log-rank test and Cox proportional hazard analysis. Results: Among this NSCLC biopsy population, 43.7% overexpressed beta3 integrin (beta3{sup +}), 43% FGF-2 (FGF-2{sup +}), 41.5% syndecan-1, and 59.4% angiopoietin-2. Our results showed a strong association between FGF-2 and beta3 integrin expression (p = .001). The adjusted hazard ratio of local recurrence for FGF-2{sup +}/beta3{sup +} tumors compared with FGF-2{sup -}/beta3{sup -} tumors was 6.1 (95% confidence interval, 2.6-14.6, p = .005). However, the risk of local recurrence was not increased when tumors overexpressed beta3 integrin or FGF-2 alone. Moreover, the co-expression of these two proteins was marginally associated with the response to chemoradiotherapy and metastasis-free survival. Conclusion: The results of this study have identified the combined profile FGF-2/beta3 integrin expression as a signature of local control in patients treated with chemoradiotherapy for locally advanced

  4. Efficacy and safety of icotinib in treating non-small cell lung cancer: a systematic evaluation and meta-analysis based on 15 studies

    PubMed Central

    Biaoxue, Rong; Hua, Liu; Wenlong, Gao; Shuanying, Yang

    2016-01-01

    Icotinib is a new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that developed and used in China; this work was to evaluate its efficacy and safety in treating non-small cell lung cancer (NSCLC). Clinical studies evaluating the efficacy and safety of icotinib in treating NSCLC were identified from the databases of Medline, Web of Science, Embase and Cochrance Library. Pooled efficacy and safety of icotinib were calculated through a series of predefined search strategies. A total of 15 studies with 2,304 patients were involved in this study. The overall response rate (ORR) and disease control rate (DCR) of icotinib were 40.99% (95% CI: 33.77% to 48.22%) and 77.16% (95% CI: 51.43% to 82.31%). The pooled progression-free survival (PFS) and overall survival (OS) were 7.34 months (95% CI: 5.60 to 9.07) and 14.98 months (95% CI: 9.78 to 20.18). Patients with EGFR mutations exhibited better ORR (OR = 3.67, p < 0.001), DCR (OR = 1.39, p = 0.001) and PFS (11.0 ± 0.76 vs. 1.97 ± 0.82 months). Moreover, patients with rash had a higher ORR (OR = 2.14, p = 0.001) than those without rash. The common adverse effects (AEs) included skin rash (31.4%), diarrhea (14.2%), pruritus (6.7%) and hepatic toxicity (3.8%) and most of them were well tolerated. In conclusion, Icotinib is an effective and well tolerated regimen for Chinese patients with advanced NSCLC. Further randomized trials with large population are required to provide stronger evidence for icotinib in treating NSCLC. PMID:27893423

  5. Dual targeting of glutaminase 1 and thymidylate synthase elicits death synergistically in NSCLC

    PubMed Central

    Lee, Jae-Seon; Kang, Joon H; Lee, Seon-Hyeong; Hong, Dongwan; Son, Jaekyoung; Hong, Kyeong M; Song, Jaewhan; Kim, Soo-Youl

    2016-01-01

    Glutaminase 1 (GLS1) expression is increased in non-small cell lung cancer (NSCLC). GLS1 knockdown using siRNA or inhibition using bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) induced cell cycle arrest with significant reduction of ATP level while levels of reactive oxygen species or glutathione were not affected in NSCLC cell lines. Recently we found that NSCLC significantly depends on cytosol NADH for ATP production. GLS1 remarkably contributes to ATP production through transferring cytosolic NADH into mitochondria via malate-aspartate shuttle by supply of glutamate in NSCLC. Regulation of malate-aspartate shuttle by knockdown or inhibition of glutamic-oxaloacetic transaminase 2 or malate dehydrogenase 2 mimicked GLS1 knockdown, which induced cell death with ATP reduction in NSCLC. Therefore, GLS1 inhibition induced cell cycle arrest with ATP depletion by glutamate reduction. Dual inhibition with BPTES and thymidylate synthase inhibitor, 5-fluorouracil (5-FU), elicits cell death synergistically through cell cycle arrest in NSCLC. A preclinical xenograft model of NSCLC showed remarkable anti-tumour effect synergistically in the BPTES and 5-FU dual therapy group. PMID:27929535

  6. Phase I study of docetaxel and irinotecan in patients with advanced non-small-cell lung cancer.

    PubMed

    Nogami, Naoyuki; Harita, Shingo; Ueoka, Hiroshi; Yonei, Toshiro; Kiura, Katsuyuki; Kamei, Haruhito; Tabata, Masahiro; Segawa, Yoshihiko; Gemba, Kenichi; Tanimoto, Mitsune

    2004-07-01

    The role of non-platinum combination chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has not yet been clarified. In this phase I study, the dose-limiting toxicity (DLT), the maximum tolerable dose (MTD) and the antitumor activity of a two-drug combination of docetaxel (DCT) and irinotecan (CPT) in patients with advanced NSCLC were evaluated. Previously untreated patients with NSCLC in stage IIIB with malignant pleural effusion or stage IV were eligible. Both drugs were administered by 1-h intravenous infusion on day 1, and repeated every 3 weeks. DCT was given before CPT administration. Five escalating dose levels of DCT/CPT (40/135, 50/135, 50/150, 60/150, and 60/165 mg/m2) were studied. Eighteen patients received 44 courses. The DLT was considered to be neutropenia, because grade 4 neutropenia lasting for 3 days or more was observed in three patients, which was accompanied with three episodes of febrile neutropenia. As a non-hematological toxicity, grade 3 diarrhea occurred in three patients. Since all the three patients treated at the fifth dose level (DCT at 60 mg/m2 and CPT at 165 mg/m2) experienced DLT (grade 4 neutropenia in two patients and grade 3 hepatic toxicity in one), this dose level was determined to be the MTD. The objective response rate was 33.3%, and the median survival time was 13.6 months. To confirm the effectiveness of this combination for advanced NSCLC which was suggested in the present study, a phase II study with the recommended doses (150 mg/m2 for CPT and 50-60 mg/m2 for DCT) is warranted.

  7. Effectiveness of combined (131)I-chTNT and radiofrequency ablation therapy in treating advanced hepatocellular carcinoma.

    PubMed

    Tu, Jianfei; Ji, Jiansong; Wu, Fazong; Wang, Yonghui; Zhang, Dengke; Zhao, Zhongwei; Ying, Xihui

    2015-03-01

    To investigate the effectiveness of monoclonal antibody ((131)I-chTNT) and radiofrequency ablation (RFA) combination therapy in treating middle-advanced stage hepatocellular carcinoma (HCC). Thirty-four patients diagnosed with HCC patients, divided into two groups comprised of 22 and 12 cases were included in this retrospective study. The two groups received RFA with or without ((131)I-chTNT) therapy, respectively. The patients in these groups were followed up for a median of 31 and 35 months, respectively. Patient survival was evaluated using Kaplan-Meier method and safety profiles were determined by analyzing liver, thyroid, and bone marrow toxicities. This retrospective study showed that survival time of the patients who received combination therapy was significantly longer than that of the RFA group (P = 0.052). The median progress-free survival of patients in the two groups was 23 and 7 months, respectively, and the difference was significant (P = 0.04). Tumor recurred in 3.5-8.7 months in four of the combination group patients, among which three had newly developed lesions. The red blood cells and platelets counts were not altered on day 7 and 1 month of the treatment, however, number of white blood cells was significantly increased on day 7 which was reversed back to the normal range in 2 weeks. The ALT and AST were also not significantly altered on day 7 and 1 month of therapy. In middle-advanced stage HCC patients, the combination of (131)I-chTNT and RFA therapy was found to be significantly more effective than the RFA treatment alone as assessed in short-term follow-up. However, the dose we used was insufficient to completely block the local recurrence of the lesions with a diameter of 5 cm or larger.

  8. Chronic myelomonocytic leukemia blast crisis in a patient with advanced non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.

    PubMed

    Ogata, Hiroaki; Okamoto, Isamu; Yoshimoto, Goichi; Obara, Teppei; Ijichi, Kayo; Iwama, Eiji; Harada, Taishi; Akashi, Koichi; Nakanishi, Yoichi

    2017-03-01

    A 59-year-old woman with epidermal growth factor receptor gene (EGFR) mutation-positive advanced lung adenocarcinoma was treated with afatinib after a diagnosis of chronic myelomonocytic leukemia (CMML). Twenty-one weeks later, she developed agranulocytosis, and CMML subsequently progressed to blast crisis. After complete remission of CMML, gefitinib was initiated; however, agranulocytosis recurred. This is the first reported case of both EGFR mutation-positive advanced non-small cell lung cancer with CMML, and of CMML blast crisis. Physicians should be aware of such risks and monitor EGFR-TKI-treated patients with myeloid neoplasms accordingly.

  9. Diagnosis of dissolved organic matter removal by GAC treatment in biologically treated papermill effluents using advanced organic characterisation techniques.

    PubMed

    Antony, Alice; Bassendeh, Mojgan; Richardson, Desmond; Aquilina, Simon; Hodgkinson, Andrew; Law, Ian; Leslie, Greg

    2012-02-01

    Granular activated carbon (GAC) exhaustion rates on pulp and paper effluent from South East Australia were found to be a factor of three higher (3.62cf. 1.47kgm(-3)) on Kraft mills compared to mills using Thermomechanical pulping supplemented by Recycled Fibre (TMP/RCF). Biological waste treatment at both mills resulted in a final effluent COD of 240mgL(-1). The dissolved organic carbon (DOC) was only 1.2 times higher in the Kraft effluent (70 vs. 58mgL(-1)), however, GAC treatment of Kraft and TMP/RCF effluent was largely different on the DOC persisted after biological treatment. The molecular mass (636 vs. 534gmol(-1)) and aromaticity (5.35 vs. 4.67Lmg(-1)m(-1)) of humic substances (HS) were slightly higher in the Kraft effluent. The HS aromaticity was decreased by a factor of 1.0Lmg(-1)m(-1) in both Kraft and TMP/RCF effluent. The molecular mass of the Kraft effluent increased by 50gmol(-1) while the molecular mass of the TMP/RCF effluent was essentially unchanged after GAC treatment; the DOC removal efficiency of the GAC on Kraft effluent was biased towards the low molecular weight humic compounds. The rapid adsorption of this fraction, coupled with the slightly higher aromaticity of the humic components resulted in early breakthrough on the Kraft effluent. Fluorescence excitation-emission matrix analysis of the each GAC treated effluent indicated that the refractory components were higher molecular weight humics on the Kraft effluent and protein-like compounds on the TMP/RCF effluent. Although the GAC exhaustion rates are too high for an effective DOC removal option for biologically treated pulp and paper mill effluents, the study indicates that advanced organic characterisation techniques can be used to diagnose GAC performance on complex effluents with comparable bulk DOC and COD loads.

  10. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study.

    PubMed

    Nakamura, Yasuhiro; Tanaka, Ryota; Asami, Yuri; Teramoto, Yukiko; Imamura, Taichi; Sato, Sayuri; Maruyama, Hiroshi; Fujisawa, Yasuhiro; Matsuya, Taisuke; Fujimoto, Manabu; Yamamoto, Akifumi

    2016-08-11

    Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2-9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression-free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11-0.55 and 0.03-0.79; P = 0.005, and 0.047, respectively). At the 20-week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome.

  11. Prognostic Factors for Survival and Resection in Patients With Initial Nonresectable Locally Advanced Pancreatic Cancer Treated With Chemoradiotherapy

    SciTech Connect

    Bjerregaard, Jon K.; Mortensen, Michael B.; Jensen, Helle A.; Nielsen, Morten; Pfeiffer, Per

    2012-07-01

    Background and Purpose: Controversies regarding the optimal therapy for patients with locally advanced pancreatic cancer (LAPC) exist. Although the prognosis as a whole remains dismal, subgroups are known to benefit from intensive therapy, including chemoradiotherapy (CRT). We describe the results in 178 patients treated from 2001 to 2010 and have developed a prognostic model for both survival and the possibility of a subsequent resection in these patients. Methods and Materials: From 2001 until 2010, 178 consecutive patients with LAPC were treated and included in the present study, with CRT consisting of 50 Gy in 27 fractions combined with tegafur-uracil(UFT)/folinic acid(FA). Results: The median survival from diagnosis was 11.5 months. Adverse events of Grade 3 or above were seen in 36% of the patients. Ninety-three percent of the patients completed all fractions. A Cox regression model for survival demonstrated resection (hazard ratio [HR] 0.12; 95% confidence interval [CI], 0.1-0.3) and pre-CRT gemcitabine-based therapy (HR 0.57; 95% CI, 0.4-0.9) as being associated with a favorable outcome, increasing gross tumor volume (HR 1.14; 95% CI, 1.0-1.3) was associated with shorter survival. A logistic regression model showed Stage III disease (odds ratio [OR] 0.16; 95% CI, 0.0-1.1) and abnormal hemoglobin (OR 0.26; 95% CI, 0.0-1.2) as being associated with lower odds of resection. Conclusion: This study confirms the favorable prognosis for patients receiving gemcitabine therapy before CRT and the poor prognosis associated with increasing tumor volume. In addition, CRT in patients with abnormal hemoglobin and Stage III disease rarely induced tumor shrinkage allowing subsequent resection.

  12. Update on taxanes in the first-line treatment of advanced non-small-cell lung cancer.

    PubMed

    Socinski, M A

    2014-10-01

    Based on demonstrated favourable risk-benefit profiles, taxanes remain a key component in the first-line standard of care for advanced non-small-cell lung cancer (nsclc) and nsclc subtypes. In 2012, a novel taxane, nab-paclitaxel (Abraxane: Celgene Corporation, Summit, NJ, U.S.A.), was approved, in combination with carboplatin, for the first-line treatment of locally advanced or meta-static nsclc. The approval was granted because of demonstrated improved antitumour activity and tolerability compared with solvent-based paclitaxel-carboplatin in a phase iii trial. This review focuses on the evolution of first-line taxane therapy for advanced nsclc and the new options and advances in taxane therapy that might address unmet needs in advanced nsclc.

  13. CYP1B1 G199T Polymorphism Affects Prognosis of NSCLC Patients with the Potential to Be an Indicator and Target for Precise Drug Intervention

    PubMed Central

    Zhang, Shaofeng; Zhang, Qi; Zhao, Shilei

    2017-01-01

    CYP1B1 gene single nucleotide polymorphisms G119T, C432G, and A453G were tested among 164 NSCLC patients treated by Video-Assisted Thoracoscopic Surgery. After a follow-up period of 5 years, it was found that CYP1B1 G119T mutant genotypes were related to a higher risk of tumor recurrence and death after surgical resection. However, C432G and A453G genotypes had no influence on long-term prognosis of the study cohort. Thus, G199T alleles are supposed to be an auxiliary predictor for prognosis of NSCLC patients and a potential target for precise drug intervention, as well as a candidate for further anticancer drug research. PMID:28377924

  14. The Prognostic Value of Baseline Lymphocyte, Neutrophil, and Monocyte Counts in Locally Advanced Cervical Carcinoma Treated with Radiation

    PubMed Central

    Himler, Justin; Nagel, Christa I.; Resnick, Kimberly

    2017-01-01

    Background. To determine the prognostic significance of pretreatment levels of circulating lymphocyte (CLC), neutrophil (CNC), and monocyte (CMC) counts in patients with locally advanced cervical carcinoma (CC) treated with definitive radiation. Methods. A retrospective, dual-institution review of patients with Stage IB2-IVA CC from 2005 to 2015. Progression-free (PFS) and Overall Survival (OS) were determined for high and low CLC, CNC, and CMC groups. Multivariate analysis was used to confirm prognostic value of baseline leukocyte counts. Results. 181 patients were included. Median follow-up time was 26 (3–89) months. CNC had no effect on PFS or OS. PFS was similar between CMC groups; however, OS was significantly improved for patients with low CMC (62.5 versus 45.3 months, p = 0.016). High CLC was associated with improved PFS (48.5 versus 27.8 months, p = 0.048) and OS (58.4 versus 34.9 months, p = 0.048). On multivariate analysis, high CNC was associated with increased relapse risk (HR 1.12, p = 0.006) and low CLC was associated with increased mortality risk (HR 0.67, p = 0.027). Conclusion. This study demonstrates that leukocyte values can provide prognostic information in CC. These hypothesis-generating findings warrant further prospective investigations. PMID:28239396

  15. Achievements and future developments of ALK-TKIs in the management of CNS metastases from ALK-positive NSCLC

    PubMed Central

    Cappuzzo, Federico

    2016-01-01

    Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements being one of the newest and most appealing. Presence of ALK fusions is associated with some particular clinical and pathological features, including a preferential seeding into the central nervous system (CNS). In addition, ALK rearrangements are recognized as the strongest predictor for benefit of anti-ALK therapy. Crizotinib, the first ALK inhibitor (ALK-I) licensed in clinical practice, is the standard of care for newly diagnosed patients. Unfortunately, within the first year of treatment the majority of patients become insensitive to crizotinib, with approximately one third of them developing brain metastases (BMs). Optimal management of BMs is one of the major challenges in treating ALK positive NSCLC. Several novel and highly CNS penetrant ALK-Is are currently under investigation and available data clearly indicated their ability in controlling intracranial disease. PMID:28149753

  16. Identification of a new insertion in exon 20 of EGFR in a woman with NSCLC.

    PubMed

    Zupa, Angela; Vita, Giulia; Landriscina, Matteo; Possidente, Luciana; Aieta, Michele; Tartarone, Alfredo; Improta, Giuseppina

    2012-12-01

    Mutations of epidermal growth factor receptor 1 (EGFR) gene occur in about 15 % of all NSCLCs in Western Europe and are frequently located in exons 19 and 21, being associated with high sensitivity to EGFR tyrosine kinase inhibitors (TKIs). By contrast, exon 20 insertions account for up to 10 % of all EGFR mutations and are correlated to EGFR TKI resistance. Herein, we describe a novel mutation in EGFR exon 20 in a female non-smoker bearing a lung adenocarcinoma, characterized by the insertion of a nucleotide triplet GTT, which translates into a protein with an additional Valine between Proline 772 and Histidine 773 (p.P772_H773insV-c.2316_2317insGTT). The patient was treated with cisplatin/pemetrexed 1st-line and docetaxel 2nd-line chemotherapies, reporting a prolonged disease stabilization of 25 months. The identification and the biological and clinical characterization of novel EGFR mutations represent a prerequisite for their wide use as predictive biomarkers for personalized therapy in NSCLC.

  17. Signaling intermediates (MAPK and PI3K) as therapeutic targets in NSCLC.

    PubMed

    Ciuffreda, Ludovica; Incani, Ursula Cesta; Steelman, Linda S; Abrams, Stephen L; Falcone, Italia; Curatolo, Anais Del; Chappell, William H; Franklin, Richard A; Vari, Sabrina; Cognetti, Francesco; McCubrey, James A; Milella, Michele

    2014-01-01

    The RAS/RAF/MEK/ ERK and the PI3K/AKT/mTOR pathways govern fundamental physiological processes, such as cell proliferation, differentiation, metabolism, cytoskeleton reorganization and cell death and survival. Constitutive activation of these signal transduction pathways is a required hallmark of cancer and dysregulation, on either genetic or epigenetic grounds, of these pathways has been implicated in the initiation, progression and metastastic spread of lung cances. Targeting components of the MAPK and PI3K cascades is thus an attractive strategy in the development of novel therapeutic approaches to treat lung cancer, although the use of single pathway inhibitors has met with limited clinical success so far. Indeed, the presence of intra- and inter-pathway compensatory loops that re-activate the very same cascade, either upstream or downstream the point of pharmacological blockade, or activate the alternate pathway following the blockade of one signaling cascade has been demonstrated, potentially driving preclinical (and possibly clinical) resistance. Therefore, the blockade of both pathways with combinations of signaling inhibitors might result in a more efficient anti-tumor effect, and thus potentially overcome and/or delay clinical resistance, as compared with single agent. The current review aims at summarizing the current status of preclinical and clinical research with regard to pathway crosstalks between the MAPK and PI3K cascades in NSCLC and the rationale for combined therapeutic pathway targeting.

  18. Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion

    PubMed Central

    Lee, Jae-Seon; Nam, Boas; Seong, Tae Wha; Son, Jaekyoung; Jang, Hyonchol; Hong, Kyeong Man; Lee, Cheolju; Kim, Soo-Youl

    2016-01-01

    Among ALDH isoforms, ALDH1L1 in the folate pathway showed highly increased expression in non-small-cell lung cancer cells (NSCLC). Based on the basic mechanism of ALDH converting aldehyde to carboxylic acid with by-product NADH, we suggested that ALDH1L1 may contribute to ATP production using NADH through oxidative phosphorylation. ALDH1L1 knockdown reduced ATP production by up to 60% concomitantly with decrease of NADH in NSCLC. ALDH inhibitor, gossypol, also reduced ATP production in a dose dependent manner together with decrease of NADH level in NSCLC. A combination treatment of gossypol with phenformin, mitochondrial complex I inhibitor, synergized ATP depletion, which efficiently induced cell death. Pre-clinical xenograft model using human NSCLC demonstrated a remarkable therapeutic response to the combined treatment of gossypol and phenformin. PMID:27384481

  19. Degarelix for Treating Advanced Hormone-Dependent Prostate Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

    PubMed

    Uttley, Lesley; Whyte, Sophie; Gomersall, Timothy; Ren, Shijie; Wong, Ruth; Chambers, Duncan; Tappenden, Paul

    2016-12-10

    metastatic disease but could be cost effective for the subgroup with spinal metastases. The company submitted further evidence to NICE following an initial negative Appraisal Committee decision. Further analyses from the Decision Support Unit found that that, whilst some evidence indicated that degarelix could be cost effective for a small subgroup of people with spinal cord compression (SCC), data on the potential size of this subgroup and the rate of SCC were insufficient to estimate an ICER based on the evidence submitted by the company and a separately commissioned systematic review. NICE recommended degarelix as an option for treating advanced hormone-dependent prostate cancer in people with spinal metastases, only if the commissioner can achieve at least the same discounted drug cost as that available to the UK NHS in June 2016.

  20. CA 19-9 as a Predictor for Response and Survival in Advanced Pancreatic Cancer Patients Treated With Chemoradiotherapy

    SciTech Connect

    Koom, Woong Sub; Seong, Jinsil Kim, Yong Bae; Pyun, Hae Ok; Song, Si Young

    2009-03-15

    Purpose: To investigate the significance of carbohydrate antigen 19-9 (CA 19-9) levels for predicting response and survival in pancreatic cancer (PC) treated with concurrent chemoradiotherapy. Methods and Materials: We retrospectively reviewed data from 69 patients with PC between 1999 and 2005. All patients had elevated CA 19-9 levels before treatment. CA 19-9 levels (pre- and posttreatment CA 19-9) and their decline were analyzed for radiologic response and overall survival. Results: Seventeen patients (25%) had a 50% or greater reduction in tumor size within 3 months of chemoradiotherapy (1 complete response, 16 partial responses). CA 19-9 decline was significantly correlated with radiologic response (p = 0.03). The median survival time (MST) was 12 months (range, 4-48 months), and 1-year survival rate was 44%. Pretreatment CA 19-9 > 1,200 U/mL (MST, 13 vs. 8 months; p = 0.002), posttreatment CA 19-9 >100 U/mL (MST, 17 vs. 10 months; p = 0.0003), and CA 19-9 decline {<=}40% (MST, 13 vs. 10 months; p = 0.005) were the strongest and most unfavorable prognostic factors. In addition, patients with multiple unfavorable CA 19-9 levels had significantly worse outcomes than those without. Conclusions: CA 19-9 decline shows a correlation with radiologic response. The combination of pretreatment CA 19-9 >1,200 U/mL, posttreatment CA 19-9 >100 U/mL, and CA 19-9 decline {<=}40% may possibly serve as a surrogate marker for poor survival in advanced PC receiving chemoradiotherapy.

  1. The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent.

    PubMed

    Chung, Ming-Min; Chen, Yen-Lin; Pei, Dee; Cheng, Yi-Chuan; Sun, Binggui; Nicol, Christopher J; Yen, Chia-Hui; Chen, Han-Min; Liang, Yao-Jen; Chiang, Ming-Chang

    2015-05-01

    Diabetic neuronal damage results from hyperglycemia followed by increased formation of advanced glycosylation end products (AGEs), which leads to neurodegeneration, although the molecular mechanisms are still not well understood. Metformin, one of the most widely used anti-diabetic drugs, exerts its effects in part by activation of AMP-activated protein kinase (AMPK). AMPK is a critical evolutionarily conserved enzyme expressed in the liver, skeletal muscle and brain, and promotes cellular energy homeostasis and biogenesis by regulating several metabolic processes. While the mechanisms of AMPK as a metabolic regulator are well established, the neuronal role for AMPK is still unknown. In the present study, human neural stem cells (hNSCs) exposed to AGEs had significantly reduced cell viability, which correlated with decreased AMPK and mitochondria associated gene/protein (PGC1α, NRF-1 and Tfam) expressions, as well as increased activation of caspase 3 and 9 activities. Metformin prevented AGEs induced cytochrome c release from mitochondria into cytosol in the hNSCs. Co-treatment with metformin significantly abrogated the AGE-mediated effects in hNSCs. Metformin also significantly rescued hNSCs from AGE-mediated mitochondrial deficiency (lower ATP, D-loop level, mitochondrial mass, maximal respiratory function, COX activity, and mitochondrial membrane potential). Furthermore, co-treatment of hNSCs with metformin significantly blocked AGE-mediated reductions in the expression levels of several neuroprotective genes (PPARγ, Bcl-2 and CREB). These findings extend our understanding of the molecular mechanisms of both AGE-induced neuronal toxicity, and AMPK-dependent neuroprotection by metformin. This study further suggests that AMPK may be a potential therapeutic target for treating diabetic neurodegeneration.

  2. Electroglottographic Comparison of Voice Outcomes in Patients With Advanced Laryngopharyngeal Cancer Treated by Chemoradiotherapy or Total Laryngectomy

    SciTech Connect

    Kazi, Rehan; Venkitaraman, Ramachandran; Johnson, Catherine; Prasad, Vyas; Clarke, Peter; Rhys-Evans, Peter; Nutting, Christopher M.; Harrington, Kevin J.

    2008-02-01

    Purpose: To conduct prospective electroglottographic analyses of voice outcomes after radical chemoradiotherapy for locally advanced laryngopharyngeal cancers and to compare them with patients who have undergone total laryngectomy (TL). Patients and Methods: Twenty-one patients (19 male, 2 female, median age [range] 65 [50-85] years) with Stage III/IV laryngopharyngeal cancer received induction chemotherapy followed by radical chemoradiotherapy. Electroglottography, using the sustained vowel /i/ and connected speech, was performed before treatment and 1, 6, and 12 months after treatment. In addition, single voice recordings were taken from 21 patients (16 male, 5 female, aged 65 [50-84] years) who had undergone TL and surgical voice restoration and from 21 normal controls (18 male, 3 female, aged 65 [33-80] years). Results: Before treatment the vocal measures for the chemoradiotherapy patients were significantly different from normal controls in jitter (p = 0.02), maximum phonation time (MPT) (p = 0.001), and words per minute (WPM) (p = 0.01). At 12 months after treatment MPT and WPM had normalized, but jitter and normalized noise energy were significantly worse than in normal controls. Comparison of voice outcomes at 12 months for chemoradiotherapy patients revealed superiority over the TL group in all parameters except MPT (18.2 s vs. 10.4 s, p = 0.06). Analysis of the recovery of voice up to 12 months after treatment revealed progressive improvement in most electroglottographic measures. Conclusions: This prospective study demonstrates significantly better outcome for patients treated with chemoradiotherapy as compared with TL. Progressive normalization of many voice parameters occurs over the 12 months following chemoradiotherapy.

  3. Efficacy and safety of nivolumab in Japanese patients with advanced or recurrent squamous non-small cell lung cancer.

    PubMed

    Hida, Toyoaki; Nishio, Makoto; Nogami, Naoyuki; Ohe, Yuichiro; Nokihara, Hiroshi; Sakai, Hiroshi; Satouchi, Miyako; Nakagawa, Kazuhiko; Takenoyama, Mitsuhiro; Isobe, Hiroshi; Fujita, Shiro; Tanaka, Hiroshi; Minato, Koichi; Takahashi, Toshiaki; Maemondo, Makoto; Takeda, Koji; Saka, Hideo; Goto, Koichi; Atagi, Shinji; Hirashima, Tomonori; Sumiyoshi, Naoki; Tamura, Tomohide

    2017-03-07

    Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. This study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3mg/kg, intravenously) every 2 weeks until progressive disease or unacceptable toxicity was seen. The primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). The median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. This article is protected by copyright. All rights reserved.

  4. Can EGFR-TKIs be used in first line treatment for advanced non-small cell lung cancer based on selection according to clinical factors ? -- A literature-based meta-analysis

    PubMed Central

    2012-01-01

    Background In the first line treatment of non-small cell lung cancer (NSCLC), several clinical trials have shown that not all NSCLC patients can benefit from treatment with tyrosine kinase inhibitors (TKIs) than receiving chemotherapy. Some trials treated patients with TKI according to their clinical characteristics. A few studies only chose patients with an epidermal grouth factor receptor (EGFR) mutation for TKI therapy. We aimed to determine whether patients could be treated with TKIs based on clinical factors in the first-line setting. Methods We performed a meta-analysis of randomized trials involving patients with advanced NSCLC treated with chemotherapy or TKIs by different selections. Efficacy outcomes of interest were the objective response rate (ORR), progression-free survival (PFS) and the overall survival (OS) of each treatment arm. Results Four trials enrolled unselected patients, and two trials selected East Asian patients using the clinical factors of gender and smoking history. Five trials chose patients with an EGFR mutation who were randomized for treatment with TKI or chemotherapy. For unselected patients, the risk ratio (RR) of the ORR was 3.52, the hazard ratio (HR) of the PFS was 1.29 and the HR of the OS was 1.35. For the clinically selected patients, the RR of the ORR was 0.64. The HRs of the PFS and OS were 0.83 and 0.92, respectively. The ORR and PFS were better for TKIs than for chemotherapy in patients with an EGFR mutation. The ORR was 0.47, and the HRs of the PFS and OS were 0.36 and 1.00, respectively. Conclusions Advanced NSCLC patients with an EGFR mutation benefit most from TKIs. EGFR-TKI treatment is justified for patients with unknown EGFR status,and those who cannot tolerate chemotherapy owing to age, poor performance status (PS) or other medical conditions, when selected according to clinical factors in the first-line setting. PMID:23050865

  5. Antiangiogenic Agents in Combination with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Ulahannan, Susanna V; Brahmer, Julie R

    2011-01-01

    Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC. PMID:21469981

  6. The role of induction chemotherapy before radiation therapy in non-operative management of stage III NSCLC.

    PubMed

    Green, M R

    1994-11-01

    Radiation therapy alone has been 'standard' management of patients with Stage III non-small cell lung cancer for several decades. Palliative benefits are routinely achieved but significant survival benefits have not been documented. Patterns of failure in Stage III patients emphasize the need to pursue better treatment for both local macroscopic disease and distant micrometastatic sites. Improved control in both areas will be necessary to meaningfully enhance outcome for the universe of Stage III NSCLC patients. Several randomized trials show a significant survival benefit when cisplatin-containing induction chemotherapy is administered prior to locoregional treatment. In the favorable subset of Stage III patients selected for study by CALGB, the surviving fraction at 2-5 years post-therapy was > or = 2-fold larger in the chemoradiation group than in the cohort treated with radiation alone. The French trial documented a significant decrease in distant metastases rate among the chemotherapy treated patients. In all the trials where patterns of failure are discussed, local disease persistence is the overwhelming rule. Future trials must evaluate improved induction chemotherapy approaches. Stage III patients are an ethical population in which to test induction therapy with new drug combinations randomized against already 'active' regimens for comparative efficacy. End points would be initial response rates, patterns of failure, and overall survival. The feasibility of high-dose chemotherapy regimens with growth factor and hematopoietic support followed by aggressive radiation must be tested. If feasible, trials randomizing high dose versus conventional dose induction programs within the context of sequential multimodality therapy should follow. Intensified radiation approaches such as hyperfractionation or CHART should be paired with active concurrent chemotherapy following induction chemotherapy alone. Pursuit of these approaches over the next several years will

  7. Does MRI-detected cranial nerve involvement affect the prognosis of locally advanced nasopharyngeal carcinoma treated with intensity modulated radiotherapy?

    PubMed

    Zong, Jingfeng; Lin, Shaojun; Chen, Yunbin; Wang, Bingyi; Xiao, Youping; Lin, Jin; Li, Rui; Pan, Jianji

    2014-01-01

    Nasopharyngeal carcinoma (NPC) is one of the common cancers in South China. It can easily invade into cranial nerves, especially in patients with local advanced disease. Despite the fact that the magnetic resonance imaging (MRI) findings are not always consistent with the symptoms of CN palsy, MRI is recommended for the detection of CN involvement (CNI). However, the prognostic impact of MRI-detected CNI in NPC patients is still controversial. To investigate the prognostic value of MRI detected CNI, we performed a retrospective analysis on the clinical data of 375 patients with NPC who were initially diagnosed by MRI. All patients had T3-4 disease and received radical intensity modulated radiation therapy (IMRT) as their primary treatment. The incidence of MRI-detected CNI was 60.8%. A higher incidence of MRI-detected CNI was observed in T4 disease compared with T3 disease (96.8% vs. 42.8%, P<0.001), and a higher incidence was also found in patients with Stage IV disease compared with those with Stage III disease (91.5% vs. 42.3%; P<0.001). The local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) of patients with T3 disease, with or without MRI-detected CNI, was superior to that of patients with T4 disease (P<0.05). No significant differences in LRFS, DMFS or OS were observed between T3 patients with or without MRI-detected CNI. The survival of Stage III patients with or without MRI-detected CNI was significantly superior to that of Stage IV patients (P<0.01), but there was no significant difference between Stage III patients with or without MRI-detected CNI for all endpoints. Therefore, when treated with IMRT, MRI-detected CNI in patients with NPC does not appear to affect the prognosis. In patients with clinical T3 disease, the presence of MRI-detected CNI is not sufficient evidence for defining T4 disease.

  8. WEE1 Inhibitor AZD1775 With or Without Cytarabine in Treating Patients With Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2016-09-12

    Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  9. Phase II study of SPI-77 (sterically stabilised liposomal cisplatin) in advanced non-small-cell lung cancer.

    PubMed

    White, S C; Lorigan, P; Margison, G P; Margison, J M; Martin, F; Thatcher, N; Anderson, H; Ranson, M

    2006-10-09

    To determine the efficacy and tolerability of SPI-77 (sterically stabilised liposomal cisplatin) at three dose levels in patients with advanced non-small-cell lung cancer (NSCLC). Patients had Stage IIIB or IV NSCLC and were chemo-naïve, and Eastern Oncology Cooperative Group 0-2. The first cohort received SPI-77 at 100 mg m-2, the second 200 mg m-2 and the final cohort 260 mg m-2. Patients had also pharmacokinetics and analysis of leucocyte platinum (Pt)-DNA adducts performed. Twenty-six patients were treated, with 22 patients being evaluable for response. Only one response occurred at the 200 mg m-2 dose level for an overall response rate of 4.5% (7.1% at >or=200 mg m-2). No significant toxicity was noted including nephrotoxicity or ototoxicity aside from two patients with Grade 3 nausea. No routine antiemetics or hydration was used. The pharmacokinetic profile of SPI-77 was typical for a liposomally formulated drug, and the AUC appeared to be proportional to the dose of SPI-77. Plasma Pt levels and leucocyte DNA adduct levels did not appear to rise with successive doses. SPI-77 demonstrates only modest activity in patients with NSCLC.

  10. Phase II study of SPI-77 (sterically stabilised liposomal cisplatin) in advanced non-small-cell lung cancer

    PubMed Central

    White, S C; Lorigan, P; Margison, G P; Margison, J M; Martin, F; Thatcher, N; Anderson, H; Ranson, M

    2006-01-01

    To determine the efficacy and tolerability of SPI-77 (sterically stabilised liposomal cisplatin) at three dose levels in patients with advanced non-small-cell lung cancer (NSCLC). Patients had Stage IIIB or IV NSCLC and were chemo-naïve, and Eastern Oncology Cooperative Group 0–2. The first cohort received SPI-77 at 100 mg m−2, the second 200 mg m−2 and the final cohort 260 mg m−2. Patients had also pharmacokinetics and analysis of leucocyte platinum (Pt)-DNA adducts performed. Twenty-six patients were treated, with 22 patients being evaluable for response. Only one response occurred at the 200 mg m−2 dose level for an overall response rate of 4.5% (7.1% at ⩾200 mg m−2). No significant toxicity was noted including nephrotoxicity or ototoxicity aside from two patients with Grade 3 nausea. No routine antiemetics or hydration was used. The pharmacokinetic profile of SPI-77 was typical for a liposomally formulated drug, and the AUC appeared to be proportional to the dose of SPI-77. Plasma Pt levels and leucocyte DNA adduct levels did not appear to rise with successive doses. SPI-77 demonstrates only modest activity in patients with NSCLC. PMID:16969346

  11. Protein tyrosine phosphatase PTPRB regulates Src phosphorylation and tumour progression in NSCLC.

    PubMed

    Qi, Yinliang; Dai, Yuanchang; Gui, Shuyu

    2016-10-01

    Protein tyrosine-phosphatases (PTPs) play important roles in various biological processes. Deregulation in PTP function has been implicated in carcinogenesis and tumour progression in many cancer types. However, the role of protein tyrosine phosphatase receptor type B (PTPRB) in non-small-cell lung cancer (NSCLC) tumorigenesis has not been investigated. Lentiviral vector expressing PTPRB cDNA or shRNA was infected into A549 and H1299 cell lines, followed by cell proliferation, colony formation, soft agar and invasion assays. A549 xenograft mouse model was used to evaluate in vivo function of PTPRB. Quantitative polymerase chain reaction (PCR) was used to measure PTPRB expression in NSCLC patient samples. Kaplan Meier analysis was performed to assess association between PTPRB expression and patient overall survival (OS). Multivariate analysis was performed to evaluate prognostic significance of PTPRB. Overexpression of PTPRB reduced cell proliferation rate, colony formation efficiency, soft agar growth and cell invasion in A549 and H1299 cells, as well as tumour growth rate in A549 xenograft. Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2. Additionally, PTPRB was down-regulated in NSCLC patient and was associated with patient OS. PTPRB regulates Src phosphorylation and tumorigenesis in NSCLC. PTPRB may serve as an independent prognostic biomarker for NSCLC patients.

  12. Gene Silencing Associated with SWI/SNF Complex Loss During NSCLC Development

    PubMed Central

    Song, Shujie; Walter, Vonn; Karaca, Mehmet; Li, Ying; Bartlett, Christopher S.; Smiraglia, Dominic J.; Serber, Daniel; Sproul, Christopher D.; Plass, Christoph; Zhang, Jiren; Hayes, D. Neil; Zheng, Yanfang; Weissman, Bernard E.

    2014-01-01

    The SWI/SNF chromatin-remodeling complex regulates gene expression and alters chromatin structures in an ATP-dependent manner. Recent sequencing efforts have shown mutations in BRG1 (SMARCA4), one of two mutually exclusive ATPase subunits in the complex, in a significant number of human lung tumor cell lines and primary non-small cell lung carcinoma (NSCLC) clinical specimens. To determine how BRG1 loss fuels tumor progression in NSCLC, molecular profiling was performed after restoration of BRG1 expression or treatment with an HDAC inhibitor or a DNMT inhibitor in a BRG1-deficient NSCLC cells. Importantly, validation studies from multiple cell lines revealed that BRG1 re-expression led to substantial changes in the expression of CDH1, CDH3, EHF and RRAD that commonly undergo silencing by other epigenetic mechanisms during NSCLC development. Furthermore, treatment with DNMT inhibitors did not restore expression of these transcripts indicating that this common mechanism of gene silencing did not account for their loss of expression. Collectively, BRG1 loss is an important mechanism for the epigenetic silencing of target genes during NSCLC development. PMID:24445599

  13. A small molecule inhibitor of XIAP induces apoptosis and synergises with vinorelbine and cisplatin in NSCLC

    PubMed Central

    Dean, E J; Ward, T; Pinilla, C; Houghten, R; Welsh, K; Makin, G; Ranson, M; Dive, C

    2009-01-01

    Background: Evasion of apoptosis contributes to the pathogenesis of solid tumours including non-small cell lung cancer (NSCLC). Malignant cells resist apoptosis through over-expression of inhibitor of apoptosis proteins (IAPs), such as X-linked IAP (XIAP). Methods: A phenylurea-based small molecule inhibitor of XIAP, XIAP antagonist compound (XAC) 1396-11, was investigated preclincally to determine its ability to sensitise to clinically relevant cytotoxics, potentially allowing dose reduction while maintaining therapeutic efficacy. Results: XIAP protein expression was detected in six NSCLC cell lines examined. The cytotoxicity of XAC 1396-11 against cultured NSCLC cell lines in vitro was concentration- and time-dependent in both short-term and clonogenic assays. XAC 1396-11-induced apoptosis was confirmed by PARP cleavage and characteristic nuclear morphology. XAC 1396-11 synergised with vinorelbine±cisplatin in H460 and A549 NSCLC cells. The mechanism of synergy was enhanced apoptosis, shown by increased cleavage of caspase-3 and PARP and by the reversal of synergy by a pan-caspase inhibitor. Synergy between XAC 1396-11 and vinorelbine was augmented by optimising drug scheduling with superior effects when XAC 1396-11 was administered before vinorelbine. Conclusion: These preclinical data suggest that XIAP inhibition in combination with vinorelbine holds potential as a therapeutic strategy in NSCLC. PMID:19904270

  14. Impact of histological subtype on survival in patients with locally advanced cervical cancer that were treated with definitive radiotherapy: adenocarcinoma/adenosquamous carcinoma versus squamous cell carcinoma

    PubMed Central

    Kuroda, Hiromasa; Kimura, Tadashi

    2017-01-01

    Objective To compare the survival outcomes of patients with cervical squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) among patients with locally advanced cervical cancer that were treated with definitive radiotherapy. Methods The baseline characteristics and outcome data of patients with locally advanced cervical cancer who were treated with definitive radiotherapy between November 1993 and February 2014 were collected and retrospectively reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of AC/ASC histology. Results The patients with AC/ASC of the cervix exhibited significantly shorter overall survival (OS) (p=0.004) and progression-free survival (PFS) (p=0.002) than the patients with SCC of the cervix. Multivariate analysis showed that AC/ASC histology was an independent negative prognostic factor for PFS. Among the patients who displayed AC/ASC histology, larger tumor size, older age, and incomplete response to radiotherapy were found to be independent prognostic factors. PFS was inversely associated with the number of poor prognostic factors the patients exhibited (the estimated 1-year PFS rates; 100.0%, 77.8%, 42.8%, 0.0% for 0, 1, 2, 3 factors, respectively). Conclusion Locally advanced cervical cancer patients with AC/ASC histology experience significantly worse survival outcomes than those with SCC. Further clinical studies are warranted to develop a concurrent chemoradiotherapy (CCRT) protocol that is specifically tailored to locally advanced cervical AC/ASC. PMID:28028992

  15. Sorafenib Tosylate With or Without Doxorubicin Hydrochloride in Treating Patients With Locally Advanced or Metastatic Liver Cancer

    ClinicalTrials.gov

    2016-12-30

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma; BCLC Stage D Adult Hepatocellular Carcinoma; Localized Non-Resectable Adult Liver Carcinoma; Recurrent Adult Liver Carcinoma

  16. KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC: A meta-analysis of 41 studies.

    PubMed

    Pan, Wei; Yang, Yan; Zhu, Hongcheng; Zhang, Youcheng; Zhou, Rongping; Sun, Xinchen

    2016-02-16

    Mutation of oncogene KRAS is common in non-small cell lung cancer (NSCLC), however, its clinical significance is still controversial. Independent studies evaluating its prognostic and predictive value usually drew inconsistent conclusions. Hence, We performed a meta-analysis with 41 relative publications, retrieved from multi-databases, to reconcile these controversial results and to give an overall impression of KRAS mutation in NSCLC. According to our findings, KRAS mutation was significantly associated with worse overall survival (OS) and disease-free survival (DFS) in early stage resected NSCLC (hazard ratio or HR=1.56 and 1.57, 95% CI 1.39-1.76 and 1.17-2.09 respectively), and with inferior outcomes of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment and chemotherapy (relative risk or RR=0.21 and 0.66 for objective response rate or ORR, 95% CI 0.12-0.39 and 0.54-0.81 respectively; HR=1.46 and 1.30 for progression-free survival or PFS, 95%CI 1.23-1.74 and 1.14-1.50 respectively) in advanced NSCLC. When EGFR mutant patients were excluded, KRAS mutation was still significantly associated with worse OS and PFS of EGFR-TKIs (HR=1.40 and 1.35, 95 % CI 1.21-1.61 and 1.11-1.64). Although KRAS mutant patients presented worse DFS and PFS of chemotherapy (HR=1.33 and 1.11, 95% CI 0.97-1.84 and 0.95-1.30), and lower response rate to EGFR-TKIs or chemotherapy (RR=0.55 and 0.88, 95 % CI 0.27-1.11 and 0.76-1.02), statistical differences were not met. In conclusion, KRAS mutation is a weak, but valid predictor for poor prognosis and treatment outcomes in NSCLC. There's a need for developing target therapies for KRAS mutant lung cancer and other tumors.

  17. Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy.

    PubMed

    Wang, Xin Shelley; Shi, Qiuling; Williams, Loretta A; Mao, Li; Cleeland, Charles S; Komaki, Ritsuko R; Mobley, Gary M; Liao, Zhongxing

    2010-08-01

    Elevations in cancer treatment-induced circulating inflammatory cytokines may be partially responsible for the development of significant symptom burden (e.g., pain, fatigue, distress, disturbed sleep) during concurrent chemoradiation therapy (CXRT). Sixty-two patients undergoing CXRT for locally advanced non-small cell lung cancer (NSCLC) reported symptoms weekly for 15 weeks via the M. D. Anderson Symptom Inventory (MDASI). Serum inflammatory cytokines were assessed weekly during therapy via enzyme-linked immunosorbent assay. Dynamic changes in cytokines and associated symptom profiles were estimated using mixed-effect models. MDASI symptom severity increased gradually as CXRT dose accumulated and peaked at week 8. Serum concentrations of interleukin (IL)-6, IL-10, and serum soluble receptor 1 for tumor necrosis factor (sTNF-R1) increased significantly by week 8 (all p<.05). During CXRT, controlled for age, sex, race, body mass index, cancer recurrence, previous treatment status, total radiotherapy dose, and CXRT delivery technique, an increase in sTNF-R1 was significantly related to an increase in the mean score for all 15 MDASI symptoms (estimate, 1.74; SE, 0.69; p<.05) and to a larger radiation dose to normal lung volume (estimate, 1.77; SE, 0.71; p<.01); an increase in serum IL-6 was significantly related to increased mean severity for the five most severe symptoms (pain, fatigue, disturbed sleep, lack of appetite, sore throat) (estimate, 0.32; SE, 0.16; p<.05). These results suggest a role for over-expressed pro-inflammatory cytokines in significant worsening of symptoms in NSCLC patients undergoing CXRT, and warrant further study to identify biological targets for ameliorating treatment-related symptom burden.

  18. MiR-186 Inhibited Migration of NSCLC via Targeting cdc42 and Effecting EMT Process

    PubMed Central

    Dong, Ying; Jin, Xintian; Sun, Zhiqiang; Zhao, Yueming; Song, Xianjing

    2017-01-01

    In this study, qRT-PCR was employed to identify that miR-186 expression level in NSCLC tissues are highly associated with lymph node metastasis. In addition, through the application of western blotting, luciferase assay and qRT-PCR, it was found that miR-186 targeted 3′UTR of cdc42 mRNA and down-regulated cdc42 protein level in a post-transcriptional manner. Transwell assay indicated that cdc42 partially reversed the effect of miR-186 mimics. Besides, miR-186 was proved to regulate EMT by influencing biomarkers of this process and cell adhesion ability. Thus, miR-186 is a potential target for NSCLC therapy. miR-186 is proposed to be one of tumor-suppressors and may serve as a therapeutic target in NSCLC treatment. PMID:28317368

  19. MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells

    PubMed Central

    Presutti, Dario; Santini, Simonetta; Cardinali, Beatrice; Papoff, Giuliana; Lalli, Cristiana; Samperna, Simone; Fustaino, Valentina; Giannini, Giuseppe; Ruberti, Giovina

    2015-01-01

    Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30–40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation

  20. 18F-fludrodeoxyglucose maximal standardized uptake value and metabolic tumor burden are associated with major chemotherapy-related tumor markers in NSCLC patients

    PubMed Central

    Bai, Lu; Guo, Chihua; Wang, Jiansheng; Liu, Xiang; Li, Yang; Li, Miao; Guo, Youmin; Duan, Xiaoyi

    2016-01-01

    Objective Metabolic activity and tumor burden are significant for prognosis and metastasis of non-small cell lung cancer (NSCLC), including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Chemotherapy resistance is a great challenge for treating NSCLC patients and is also closely related with several biomarkers such as epidermal growth factor receptor (EGFR), p53, and excision repair cross-complementing group 1 protein (ERCC1). Our purpose was to determine the correlation between positron emission tomography/computed tomography (PET/CT) parameters and tumor markers-related chemotherapy resistance in NSCLC. Methods Forty-six NSCLC chemotherapy-naïve patients were enrolled. The SUVmax, MTV, and TLG were calculated by PET/CT imaging, and expression of EGFR, p53, and ERCC1 were analyzed by immunohistochemistry on tissues. SUVmax, MTV, and TLG compared for their performance in predicting the expression of EGFR, p53, and ERCC1 were illustrated with statistical analysis. Results SUVmax was significantly correlated with p53 expression (P=0.001), and MTV and TLG were significantly associated with ERCC1 (P=0.000; P=0.000). Furthermore, multiple stepwise regression analysis revealed that SUVmax was the primary predictor for p53, MTV and TLG was the primary predictor for ERCC1. SUVmax had a sensitivity of 91% and specificity of 50% for the detection of p53 positive. The sensitivities of MTV and TLG were 83% and 80%, and specificities were 69% and 75% for the detection of ERCC1 positive, respectively. When we suggested p53 or ERCC1 positive, the cutoff value of SUVmax, MTV, and TLG were 7.68, 23.62, and 129.65 cm3, respectively. Conclusion SUVmax, MTV, and TLG were closely associated with p53 and ERCC1’ expressions. Therefore, 18F-fludrodeoxyglucose PET/CT could be a new way of predicting p53 or ERCC1-related chemotherapy effect in NSCLC patients with more convenience. PMID:27789962

  1. The mechanism involved in the loss of PTEN expression in NSCLC tumor cells

    SciTech Connect

    Li, Gang; Zhao, Jingfeng; Peng, Xianjing; Liang, Jian; Deng, Xin; Chen, Yuxiang

    2012-02-17

    Highlights: Black-Right-Pointing-Pointer Radiation stimulates PTEN reexpression in NSCLC independent of p53 activation. Black-Right-Pointing-Pointer PTEN reexpression is mediated by miR-29b overexpression. Black-Right-Pointing-Pointer miR-29b regulates Dnmts expression in NSCLC tumor cells. Black-Right-Pointing-Pointer Target therapy could be established by overexpressing miR-29b expression. -- Abstract: Loss of PTEN expression is observed in most non-small cell lung cancers (NSCLC). However, the mechanism by which PTEN expression is regulated in NSCLC has not been fully elucidated. In this study, we investigated the role of DNA methyltransferases (Dnmts), microRNA-29b (miR-29b), and anti-miR-29b inhibitor in PTEN promoter methylation and PTEN gene expression in H358 NSCLC cells in vitro and in vivo. PTEN mRNA was measured by RT-PCR. PTEN and Dnmts protein levels were measured by Western blot. miR-29b expression was detected by Northern blot. A xenograft H358 tumor mouse model was established by subcutaneously inoculating H358 cells into the right hind limbs of nude mice. We found that radiation induced cell apoptosis and hypomethylation in PTEN promoter, PTEN and miR-29b expression, and downregulation of Dnmt1, 3a and 3b expression in H358 tumor cells. The effect of radiation on gene expression and apoptosis was blocked by anti-miR-29b inhibitor. In the xenograft H358 tumor model, anti-miR-29b inhibitor reversed radiation-induced tumor growth delay, PTEN reexpression and downregulation of Dnmts expression. Our study suggested that miR-29b is an upstream molecule of PTEN. miR-29b regulates PTEN gene expression through downregulating Dnmts expression and subsequently induces hypomethylation in PTEN promoter. Targeting therapy could be established in NSCLC by upregulating miR-29b expression.

  2. Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

    SciTech Connect

    Jin, Hyeon-Ok; Hong, Sung-Eun; Kim, Chang Soon; Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, Bora; Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun; Park, In-Chul; Lee, Jin Kyung

    2015-08-15

    Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.

  3. Is second-line systemic chemotherapy beneficial in patients with non-small cell lung cancer (NSCLC)? A multicenter data evaluation by the Anatolian Society of Medical Oncology.

    PubMed

    Odabas, Hatice; Ulas, Arife; Aydin, Kubra; Inanc, Mevlude; Aksoy, Asude; Yazilitas, Dogan; Turkeli, Mehmet; Yuksel, Sinemis; Inal, Ali; Ekinci, Ahmet S; Sevinc, Alper; Demirci, Nebi S; Uysal, Mukremin; Alkis, Necati; Dane, Faysal; Aliustaoglu, Mehmet; Gumus, Mahmut

    2015-12-01

    Patients with advanced non-small cell lung cancer (NSCLC) generally require second-line treatment although their prognosis is poor. In this multicenter study, we aimed to detect the characteristics related to patients and disease that can predict the response to second-line treatments in advanced NSCLC. Data of 904 patients who have progressed after receiving first-line platinum-based chemotherapy in 11 centers with the diagnosis of stage IIIB and IV NSCLC and who were evaluated for second-line treatment were retrospectively analyzed. The role of different factors in determining the benefit of second-line treatment was analyzed. Median age of patients was 57 years (range 19-86). Docetaxel was the most commonly used (20.9 %, n = 189) single agent, while gemcitabine-platinum was the most commonly used (6.7 %, n = 61) combination chemotherapy regimen in second-line setting. According to survival analysis, median progression-free survival after first-line treatment (PFS2) was 3.5 months (standard error (SE) 0.2; 95 % confidence interval (CI), 3.2-3.9), median overall survival (OS) was 6.7 months (SE 0.3; 95 % CI, 6.0-7.3). In multivariate analysis, independent factors affecting PFS2 were found to be hemoglobin (Hb) level over 12 g/dl and treatment-free interval (TFI) longer than 3 months (p = 0.006 and 0.003, respectively). Similarly, in OS analysis, Hb level over 12 g/dl and time elapsed after the first-line treatment that is longer than 3 months were found to be independent prognostic factors (p = 0.0001 and 0.045, respectively). In light of these findings, determining and using the parameters for which the treatment will be beneficial prior to second-line treatment can increase success rate.

  4. PET Radiomics in NSCLC: state of the art and a proposal for harmonization of methodology.

    PubMed

    Sollini, M; Cozzi, L; Antunovic, L; Chiti, A; Kirienko, M

    2017-03-23

    Imaging with positron emission tomography (PET)/computed tomography (CT) is crucial in the management of cancer because of its value in tumor staging, response assessment, restaging, prognosis and treatment responsiveness prediction. In the last years, interest has grown in texture analysis which provides an "in-vivo" lesion characterization, and predictive information in several malignances including NSCLC; however several drawbacks and limitations affect these studies, especially because of lack of standardization in features calculation, definitions and methodology reporting. The present paper provides a comprehensive review of literature describing the state-of-the-art of FDG-PET/CT texture analysis in NSCLC, suggesting a proposal for harmonization of methodology.

  5. Water-Exchange-Modified Kinetic Parameters from Dynamic Contrast-Enhanced MRI as Prognostic Biomarkers of Survival in Advanced Hepatocellular Carcinoma Treated with Antiangiogenic Monotherapy

    PubMed Central

    Lee, Sang Ho; Hayano, Koichi; Zhu, Andrew X.; Sahani, Dushyant V.; Yoshida, Hiroyuki

    2015-01-01

    Background To find prognostic biomarkers in pretreatment dynamic contrast-enhanced MRI (DCE-MRI) water-exchange-modified (WX) kinetic parameters for advanced hepatocellular carcinoma (HCC) treated with antiangiogenic monotherapy. Methods Twenty patients with advanced HCC underwent DCE-MRI and were subsequently treated with sunitinib. Pretreatment DCE-MRI data on advanced HCC were analyzed using five different WX kinetic models: the Tofts-Kety (WX-TK), extended TK (WX-ETK), two compartment exchange, adiabatic approximation to tissue homogeneity (WX-AATH), and distributed parameter (WX-DP) models. The total hepatic blood flow, arterial flow fraction (γ), arterial blood flow (BFA), portal blood flow, blood volume, mean transit time, permeability-surface area product, fractional interstitial volume (vI), extraction fraction, mean intracellular water molecule lifetime (τC), and fractional intracellular volume (vC) were calculated. After receiver operating characteristic analysis with leave-one-out cross-validation, individual parameters for each model were assessed in terms of 1-year-survival (1YS) discrimination using Kaplan-Meier analysis, and association with overall survival (OS) using univariate Cox regression analysis with permutation testing. Results The WX-TK-model-derived γ (P = 0.022) and vI (P = 0.010), and WX-ETK-model-derived τC (P = 0.023) and vC (P = 0.042) were statistically significant prognostic biomarkers for 1YS. Increase in the WX-DP-model-derived BFA (P = 0.025) and decrease in the WX-TK, WX-ETK, WX-AATH, and WX-DP-model-derived vC (P = 0.034, P = 0.038, P = 0.028, P = 0.041, respectively) were significantly associated with an increase in OS. Conclusions The WX-ETK-model-derived vC was an effective prognostic biomarker for advanced HCC treated with sunitinib. PMID:26366997

  6. Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy to Treat Advanced/Recurrent Epithelial Ovarian Cancer: Results from a Retrospective Study on Prospectively Established Database1

    PubMed Central

    Sun, Jian-Hua; Ji, Zhong-He; Yu, Yang; Wu, Hai-Tao; Huang, Chao-Qun; Zhang, Qian; Yang, Xiao-Jun; Yonemura, Yutaka; Li, Yan

    2016-01-01

    BACKGROUND: Despite the best standard treatment, optimal cytoreductive surgery (CRS) and platinum/taxane-based chemotherapy, prognosis of advanced epithelial ovarian carcinoma (EOC) remains poor. Recently, CRS plus hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed to treat peritoneal carcinomatosis (PC). This study was to evaluate the efficacy and safety of CRS+HIPEC to treat PC from advanced/recurrent EOC. METHODS: Forty-six PC patients from advanced EOC (group A) or recurrent EOC (group B) were treated by 50 CRS+HIPEC procedures. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoints were safety profiles. RESULTS: The median OS was 74.0 months [95% confidence interval (CI) 8.5-139.5] for group A versus 57.5 months (95% CI 29.8-85.2) for group B (P = .68). The median PFS was not reached for group A versus 8.5 months (95% CI 0-17.5) for group B (P = .034). Better median OS correlated with peritoneal cancer index (PCI) < 20 (76.6 months for PCI ≤ 20 group vs 38.5 months for PCI > 20 group, P = .01), complete cyroreduction (residual disease ≤ 2.5 mm) [79.5 months for completeness of cytoreduction (CC) score 0-1 vs 24.3 months for CC 2-3, P = .00], and sensitivity to platinum (65.3 months for platinum-sensitive group vs 20.0 for platinum-resistant group, P = .05). Serious adverse events occurred in five patients (10.0%). Multivariate analysis identified CC score as the only independent factor for better survival. CONCLUSION: For advanced/recurrent EOC, CRS+HIPEC could improve OS with acceptable safety. PMID:27084429

  7. Personalized Combined Modality Therapy for Locally Advanced Non-small Cell Lung Cancer

    PubMed Central

    Kim, D. Nathan; Nam, Taek-Keun; Choe, Kevin S.

    2012-01-01

    Locally advanced non-small cell lung cancer (NSCLC) is a heterogeneous disease, and we have embarked on an era where patients will benefit from individualized therapeutic strategies based on identifiable molecular characteristics of the tumor. The landmark studies demonstrating the importance of molecular characterization of tumors for NSCLC patients, the promising molecular pathways, and the potential molecular targets/agents for treatment of this disease will be reviewed. Understanding these issues will aid in the development of rationally designed clinical trials, so as to determine best means of appropriately incorporating these molecular strategies, to the current standard of radiation and chemotherapy regimens, for the treatment of locally advanced NSCLC. PMID:22802745

  8. Synergistic antitumor effect of α-pinene and β-pinene with paclitaxel against non-small-cell lung carcinoma (NSCLC).

    PubMed

    Zhang, Z; Guo, S; Liu, X; Gao, X

    2015-04-01

    The objective of the present research work was to evaluate the synergistic interactions between Paclitaxel (PAC) with α-pinene and β-pinene using isobolographic method against non-small-cell lung cancer cells (NSCLC). This type of interaction between an established drug and a new compound is expected to enhance the efficacy of paclitaxel in combination as compared in isolation. Further, cell cycle analysis was carried out using flow cytometric analysis. Phase contrast microscopy was used to assess the effect of paclitaxel, α-pinene and β-pinene alone and in combination with each other in order to evaluate the effect of combination on cell apoptosis. Further, mitochondrial membrane potential was monitored in non-small-cell lung cancer cells (NSCLC) when treated with paclitaxel, α-pinene and β-pinene alone and in combination. The results revealed that the combination of PAC with α-pinene or with β-pinene showed a plotted curve below the straight line, generating a substantial synergistic effect. The effects of the following combinations were examined utilizing isobolograms: PAC and α-pinene and PAC and β-pinene. The combination of PAC and α-pinene as well as of PAC and β-pinene actually generated a synergistic effect. We also examined the effects of these compounds on the cell cycle distributions of A549 cells by flow cytometric analysis. The percentage of sub-G0/G1-phase cells was decreased on the addition of α-pinene to PAC, while the population of G0/G1 cells was increased. The morphological changes characteristic of apoptosis like chromatin condensation and fragmentation of the nucleus were seen in PAC+α-pinene and PAC+β-pinene treated NSCLC cells.

  9. Effect of Amifostine on Response Rates in Locally Advanced Non-Small-Cell Lung Cancer Patients Treated on Randomized Controlled Trials: A Meta-Analysis

    SciTech Connect

    Mell, Loren K. . E-mail: lmell@radonc.uchicago.edu; Malik, Renuka; Komaki, Ritsuko; Movsas, Benjamin; Swann, R. Suzanne; Langer, Corey; Antonadou, Dosia; Koukourakis, Michael

    2007-05-01

    Purpose: Amifostine can reduce the cytotoxic effects of chemotherapy and radiotherapy in patients with locally advanced non-small-cell lung cancer, but concerns remain regarding its possible tumor-protective effects. Studies with sufficient statistical power to address this question are lacking. Methods and Materials: We performed a meta-analysis of all published clinical trials involving locally advanced non-small-cell lung cancer patients treated with radiotherapy with or without chemotherapy, who had been randomized to treatment with amifostine vs. no amifostine or placebo. Random effects estimates of the relative risk of overall, partial, and complete response were obtained. Results: Seven randomized trials involving 601 patients were identified. Response rate data were available for six studies (552 patients). The pooled relative risk (RR) estimate was 1.07 (95% confidence interval, 0.97-1.18; p = 0.18), 1.21 (95% confidence interval, 0.83-1.78; p = 0.33), and 0.99 (95% confidence interval, 0.78-1.26; p = 0.95) for overall, complete, and partial response, respectively (a RR >1 indicates improvement in response with amifostine compared with the control arm). The results were similar after sensitivity analyses. No evidence was found of treatment effect heterogeneity across the studies. Conclusions: Amifostine has no effect on tumor response in patients with locally advanced non-small-cell lung cancer treated with radiotherapy with or without chemotherapy.

  10. Association between Retinoic acid receptor-β hypermethylation and NSCLC risk: a meta-analysis and literature review

    PubMed Central

    Li, Yan; Lu, De-guo; Ma, Ying-mei; Liu, Hongxiang

    2017-01-01

    Emerging evidence indicates that Retinoic acid receptor-β (RARβ) is a tumor suppressor in many types of tumor. However, whether or not RARβ is a risk factor and is correlated to clinicopathological characteristics of non-small cell lung cancer (NSCLC) remains unclear. In this report, we performed a meta-analysis to determine the effects of RARβ hypermethylation on the incidence of NSCLC and clinicopathological characteristics in human NSCLC patients. Final valuation and analysis of 1780 cancer patients from 16 eligible studies was performed. RARβ hypermethylation was found to be significantly higher in NSCLC than in normal lung tissue, the pooled OR from 7 studies including 646 NSCLC and 580 normal lung tissues, OR = 6.05, 95% CI = 3.56-10.25, p<0.00001. RARβ hypermethylation was significantly higher in adenocarcinoma (AC) compared to squamous cell carcinoma (SCC), pooled OR is 0.68 (95% CI = 0.52-0.89, p = 0.005). RARβ hypermethylation was also found to occur significantly higher in smoker (n = 232) than non-smoker (n = 213) (OR = 2.46, 95% CI = 1.54-3.93, p = 0.0002). Our results indicate that RARβ hypermethylation correlates well with an increased risk in NSCLC patients. RARβ geneinactivation caused by RARβ methylation contributes the NSCLC tumorigenesis and may serve as a potential risk factor, diagnostic marker and drug target of NSCLC. PMID:28008143

  11. Pemetrexed for advanced stage nonsquamous non-small cell lung cancer: latest evidence about its extended use and outcomes

    PubMed Central

    Tomasini, Pascale; Barlesi, Fabrice; Mascaux, Celine; Greillier, Laurent

    2016-01-01

    Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related death, and the treatment of advanced NSCLC relies on systemic treatments. During the last decade, pemetrexed, an antifolate agent, gradually became a key component of the treatment for patients with advanced nonsquamous NSCLC. It has indeed been shown to be efficient for first-line, maintenance and second- or third-line treatment in this subgroup of NSCLC. Moreover, it is usually well tolerated, with few grade 3 and 4 toxicities. Several studies have tried to identify predictive biomarkers of pemetrexed efficacy. Due to pemetrexed’s mechanism of action, thymidilate synthase expression predictive value was investigated but could not be demonstrated. Currently, more than 400 trials of pemetrexed for the treatment of nonsquamous NSCLC are ongoing. PMID:27239238

  12. A new frontier for targeted therapy in NSCLC: clinical efficacy of pembrolizumab in the inhibition of programmed cell death 1 (PD-1).

    PubMed

    Addeo, Raffaele

    2017-03-01

    Non-small-cell lung cancer (NSCLC) is the main pathological type among lung cancers, and it is often diagnosed at an advanced stage of the disease when it is no longer amenable to curative treatments. During recent decades, the survival rate for lung cancer patients has improved significantly in only those whose tumours harbour a driver mutation. Immune checkpoint inhibition is a promising therapeutic strategy for lung cancer. The Keynote 024 is randomized, open-label, international, phase III study to evaluate the efficacy of pembrolizumab, an antibody directed to programmed death 1 (PD-1), an immune checkpoint inhibitor, compared with platinum-based chemotherapy in patients with previously untreated advanced NSCLC and PD-L1 expression in at least 50% of the tumour cells. Pembrolizumab treatment achieved statistically significant clinical benefits in terms of progression free survival, overall survival and objective responses. The high quality of data and the novelty of the information obtained created the conditions for a new standard of care driven by the expression of PD-L1.

  13. Therapeutic value of EGFR inhibition in CRC and NSCLC: 15 years of clinical evidence

    PubMed Central

    Troiani, Teresa; Napolitano, Stefania; Della Corte, Carminia Maria; Martini, Giulia; Martinelli, Erika; Morgillo, Floriana; Ciardiello, Fortunato

    2016-01-01

    Epidermal growth factor receptor (EGFR) plays a key role in tumour evolution, proliferation and immune evasion, and is one of the most important targets for biological therapy, especially for non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). In the past 15 years, several EGFR antagonists have been approved for the treatment of NSCLC and metastatic CRC (mCRC). To optimise the use of anti-EGFR agents in clinical practice, various clinical and molecular biomarkers have been investigated, thus moving their indication from unselected to selected populations. Nowadays, anti-EGFR drugs represent a gold-standard therapy for metastatic NSCLC harbouring EGFR activating mutation and for RAS wild-type mCRC. Their clinical efficacy is limited by the presence of intrinsic resistance or the onset of acquired resistance. In this review, we provide an overview of the antitumour activity of EGFR inhibitors in NSCLC and CRC and of mechanisms of resistance, focusing on the development of a personalised approach through 15 years of preclinical and clinical research. PMID:27843640

  14. 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

  15. [A Case of Advanced Esophageal Cancer and Tongue Cancer Treated with Induction DCF Chemotherapy Followed by Radical Surgery].

    PubMed

    Tanaka, Motomu; Koyanagi, Kazuo; Sugiura, Hitoshi; Kakefuda, Toshihiro

    2015-11-01

    A man in his 60s was admitted for the treatment of advanced cervical esophageal cancer with metastasis to the lymph nodes and advanced tongue cancer with metastasis to the lymph nodes. Esophageal cancer was suspected to have invaded the trachea. The tongue cancer was located on the left side and had invaded beyond the median line of the tongue. Both cancers were pathologically diagnosed as squamous cell carcinomas. Therefore, it was determined that pharyngo-laryngo- esophagectomy and total glossectomy were required prior to the treatment. However, after 2 courses of docetaxel/cisplatin/ 5-FU combined induction chemotherapy, both cancers remarkably decreased; consequently, an esophagectomy to preserve laryngeal function and partial glossectomy could be performed simultaneously. The patient is well without recurrence 1 year post-surgery.

  16. A case of severe mandibular retrognathism with bilateral condylar deformities treated with Le Fort I osteotomy and two advancement genioplasty procedures

    PubMed Central

    Nakamura, Masahiro; Matsumura, Tatsushi; Yamashiro, Takashi; Iida, Seiji; Kamioka, Hiroshi

    2016-01-01

    We report a case involving a young female patient with severe mandibular retrognathism accompanied by mandibular condylar deformity that was effectively treated with Le Fort I osteotomy and two genioplasty procedures. At 9 years and 9 months of age, she was diagnosed with Angle Class III malocclusion, a skeletal Class II jaw relationship, an anterior crossbite, congenital absence of some teeth, and a left-sided cleft lip and palate. Although the anterior crossbite and narrow maxillary arch were corrected by interceptive orthodontic treatment, severe mandibular hypogrowth resulted in unexpectedly severe mandibular retrognathism after growth completion. Moreover, bilateral condylar deformities were observed, and we suspected progressive condylar resorption (PCR). There was a high risk of further condylar resorption with mandibular advancement surgery; therefore, Le Fort I osteotomy with two genioplasty procedures was performed to achieve counterclockwise rotation of the mandible and avoid ingravescence of the condylar deformities. The total duration of active treatment was 42 months. The maxilla was impacted by 7.0 mm and 5.0 mm in the incisor and molar regions, respectively, while the pogonion was advanced by 18.0 mm. This significantly resolved both skeletal disharmony and malocclusion. Furthermore, the hyoid bone was advanced, the pharyngeal airway space was increased, and the morphology of the mandibular condyle was maintained. At the 30-month follow-up examination, the patient exhibited a satisfactory facial profile. The findings from our case suggest that severe mandibular retrognathism with condylar deformities can be effectively treated without surgical mandibular advancement, thus decreasing the risk of PCR. PMID:27896214

  17. Advances in cancer immunology and cancer immunotherapy.

    PubMed

    Voena, Claudia; Chiarle, Roberto

    2016-02-01

    After decades of setbacks, cancer immunology is living its Golden Age. Recent advances in cancer immunology have provided new therapeutic approaches to treat cancer. The objective clinical response observed in patients treated with antibodies that block the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) pathways, has led to their FDA approval for the treatment of melanoma in 2011 and in 2014, respectively. The anti-PD-1 antibody nivolumab has received the FDA-approval in March 2015 for squamous lung cancer treatment. In addition, antibodies targeting PD-1 or PD-L1 have demonstrated their efficacy and safety in additional tumors, including non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's lymphoma. Almost at the same time, the field of adoptive cell transfer has exploded. The chimeric antigen receptor (CAR) T technology has provided strong evidence of efficacy in the treatment of B cell malignancies, and different T cell based treatments are currently under investigation for different types of tumors. In this review we will discuss the latest advances in cancer immunology and immunotherapy as well as new treatments now under development in the clinic and potential strategies that have shown promising results in preclinical models.

  18. Targeted nanoconjugate co-delivering siRNA and tyrosine kinase inhibitor to KRAS mutant NSCLC dissociates GAB1-SHP2 post oncogene knockdown

    PubMed Central

    Srikar, R.; Suresh, Dhananjay; Zambre, Ajit; Taylor, Kristen; Chapman, Sarah; Leevy, Matthew; Upendran, Anandhi; Kannan, Raghuraman

    2016-01-01

    A tri-block nanoparticle (TBN) comprising of an enzymatically cleavable porous gelatin nanocore encapsulated with gefitinib (tyrosine kinase inhibitor (TKI)) and surface functionalized with cetuximab-siRNA conjugate has been synthesized. Targeted delivery of siRNA to undruggable KRAS mutated non-small cell lung cancer cells would sensitize the cells to TKI drugs and offers an efficient therapy for treating cancer; however, efficient delivery of siRNA and releasing it in cytoplasm remains a major challenge. We have shown TBN can efficiently deliver siRNA to cytoplasm of KRAS mutant H23 Non-Small Cell Lung Cancer (NSCLC) cells for oncogene knockdown; subsequently, sensitizing it to TKI. In the absence of TKI, the nanoparticle showed minimal toxicity suggesting that the cells adapt a parallel GAB1 mediated survival pathway. In H23 cells, activated ERK results in phosphorylation of GAB1 on serine and threonine residues to form GAB1-p85 PI3K complex. In the absence of TKI, knocking down the oncogene dephosphorylated ERK, and negated the complex formation. This event led to tyrosine phosphorylation at Tyr627 domain of GAB1 that regulated EGFR signaling by recruiting SHP2. In the presence of TKI, GAB1-SHP2 dissociation occurs, leading to cell death. The outcome of this study provides a promising platform for treating NSCLC patients harboring KRAS mutation. PMID:27530552

  19. Targeted nanoconjugate co-delivering siRNA and tyrosine kinase inhibitor to KRAS mutant NSCLC dissociates GAB1-SHP2 post oncogene knockdown

    NASA Astrophysics Data System (ADS)

    Srikar, R.; Suresh, Dhananjay; Zambre, Ajit; Taylor, Kristen; Chapman, Sarah; Leevy, Matthew; Upendran, Anandhi; Kannan, Raghuraman

    2016-08-01

    A tri-block nanoparticle (TBN) comprising of an enzymatically cleavable porous gelatin nanocore encapsulated with gefitinib (tyrosine kinase inhibitor (TKI)) and surface functionalized with cetuximab-siRNA conjugate has been synthesized. Targeted delivery of siRNA to undruggable KRAS mutated non-small cell lung cancer cells would sensitize the cells to TKI drugs and offers an efficient therapy for treating cancer; however, efficient delivery of siRNA and releasing it in cytoplasm remains a major challenge. We have shown TBN can efficiently deliver siRNA to cytoplasm of KRAS mutant H23 Non-Small Cell Lung Cancer (NSCLC) cells for oncogene knockdown; subsequently, sensitizing it to TKI. In the absence of TKI, the nanoparticle showed minimal toxicity suggesting that the cells adapt a parallel GAB1 mediated survival pathway. In H23 cells, activated ERK results in phosphorylation of GAB1 on serine and threonine residues to form GAB1-p85 PI3K complex. In the absence of TKI, knocking down the oncogene dephosphorylated ERK, and negated the complex formation. This event led to tyrosine phosphorylation at Tyr627 domain of GAB1 that regulated EGFR signaling by recruiting SHP2. In the presence of TKI, GAB1-SHP2 dissociation occurs, leading to cell death. The outcome of this study provides a promising platform for treating NSCLC patients harboring KRAS mutation.

  20. CIMAvax-EGF: A New Therapeutic Vaccine for Advanced Non-Small Cell Lung Cancer Patients

    PubMed Central

    Saavedra, Danay; Crombet, Tania

    2017-01-01

    Lung cancer is the common fatal illness with the highest incidence and mortality globally. Epidermal growth factor receptor overexpression by tumor cells is associated with uncontrolled proliferation, angiogenesis, anti-apoptotic signals, metastization, and invasiveness. CIMAvax-EGF vaccine consists of a chemical conjugate of the EGF with the P64 protein derived from the Meningitis B bacteria and Montanide ISA 51, as adjuvant. The vaccine is projected to induce antibodies against EGF that results in EGF withdrawal. CIMAvax-EGF demonstrated to be safe and immunogenic in advanced non-small cell lung cancer (NSCLC) patients. The efficacy study was an open-label, multicentric Phase III clinical trial, which enrolled 405 advanced NSCLC patients. Patients with proven stage IIIB/IV NSCLC, who had completed four to six cycles of chemotherapy (CTP) were randomized to receive CIMAvax-EGF or best supportive care. CIMAvax-EGF resulted in a significantly larger overall survival in patients receiving at least four doses. High EGF concentration at baseline was a good predictive biomarker of the vaccine activity and a poor prognostic biomarker for the non-treated population. The proportion of CD8+CD28− cells, CD4 cells, and the CD4/CD8 ratio after first-line CTP was also associated with CIMAvax-EGF clinical benefit. After completing the Phase III, a Phase IV trial was done where the vaccine was administered in primary care units. Administering the vaccine at primary care institutions granted better access and treatment compliance. Safety was confirmed. Several clinical trials are currently ongoing to validate EGF as a predictive biomarker of CIMAvax-EGF efficacy. PMID:28348561

  1. Prolonged survival in mice with advanced tumors treated with syngeneic or allogeneic intra-bone marrow-bone marrow transplantation plus fetal thymus transplantation.

    PubMed

    Hosaka, Naoki; Cui, Wenhao; Zhang, Yuming; Takaki, Takashi; Inaba, Muneo; Ikehara, Susumu

    2010-07-01

    Thymic function decreases in line with tumor progression in patients with cancer, resulting in immunodeficiency and a poor prognosis. In the present study, we attempted to restore thymic function by BALB/c (H-2(d)) syngeneic (Syn), or B6 (H-2(b)) allogeneic (Allo) bone marrow transplantation (BMT) using intra-bone marrow-bone marrow transplantation (IBM-BMT) plus Syn-, Allo- or C3H (H-2(k)) 3rd-party fetal thymus transplantation (TT). Although the BALB/c mice with advanced tumors (Meth-A sarcoma; H-2(d), >4 cm(2)) treated with either Syn- or Allo-BMT alone showed a slight improvement in survival compared with non-treated controls, the mice treated with BMT + TT showed a longer survival. The mice treated with Allo-BMT + Allo-TT or 3rd-party TT showed the longest survival. Interestingly, although there was no difference in main tumor size among the BMT groups, lung metastasis was significantly inhibited by Allo-BMT + Allo-TT or 3rd-party TT. Numbers of CD4(+) and CD8(+) T cells, Con A response, and IFN-gamma production increased significantly, whereas number of Gr-1(+)/CD11b(+) myeloid suppressor cells and the percentage of FoxP3(+) cells in CD4(+) T cells significantly decreased in these mice. Furthermore, there was a positive correlation between survival days and the number of T cells or T cell function, while there was a negative correlation between survival days and lung metastasis, the number of Gr-1(+)/CD11b(+) cells, or the percentage of FoxP3(+) cells. These results suggest that BMT + TT, particularly Allo-BMT + Allo-TT or 3rd-party TT, is most effective in prolonging survival as a result of the restoration of T cell function in hosts with advanced tumors.

  2. Comparative effectiveness of combined therapy inhibiting EGFR and VEGF pathways in patients with advanced non-small-cell lung cancer: a meta-analysis of 16 phase II/III randomized trials

    PubMed Central

    Cai, Shangli; Wu, Tongwei; Yan, Guangyue; Cheng, Sijin; Cui, Kang; Xi, Ying; Qi, Xiaolong; Zhang, Jie; Ma, Wang

    2017-01-01

    and control therapy in term of OS (including placebo, single EGFR inhibition and single VEGF inhibition) (HR = 0.98, 95% CI = 0.92-1.04, p = 0.41; I2 = 0%). Conclusions Combined inhibition therapy was superior to placebo and single EGFR inhibition in terms of ORR, PFS for advanced NSCLC, however, no statistical difference were found in term of OS. Besides, combined inhibition therapy was not superior to single VEGF inhibition in terms of ORR, PFS and OS. Therefore, combined inhibition therapy is recommended to treat advanced NSCLC patients. PMID:27690345

  3. 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

  4. Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy

    SciTech Connect

    Kim, Jun-Sang . E-mail: k423j@cnu.ac.kr; Kim, Jin-Man; Li, Shengjin; Yoon, Wan-Hee; Song, Kyu-Sang; Kim, Ki-Hwan; Yeo, Seung-Gu; Nam, Ji Sook; Cho, Moon-June

    2006-09-01

    Purpose: To examine retrospectively whether levels of epidermal growth factor receptor (EGFR) expression can predict tumor downstaging after preoperative chemoradiotherapy in patients with locally advanced rectal cancer. Methods and Materials: A total of 183 patients with rectal cancer (cT3-T4 or N+) were enrolled in this study. Preoperative chemoradiotherapy consisted of 50.4 Gy of pelvic radiation with concurrent 5-fluorouracil and leucovorin bolus intravenous chemotherapy in 94 patients or oral capecitabine and leucovorin in 89 patients. EGFR expression in pretreatment paraffin-embedded tumor biopsy specimens was assessed by immunohistochemistry. EGFR expression was determined from the intensity and extent of staining. Tumor downstaging was defined as a reduction of at least one T-stage level. Results: Tumor downstaging occurred in 97 patients (53%), and the tumors showed a pathologic complete response in 27 patients (15%). Positive EGFR expression was observed in 140 (76%) of 183 patients. EGFR expression levels were low in 113 patients (62%) and high in 70 patients (38%). On logistic regression analysis, the significant predictive factor for increased tumor downstaging was a low level of EGFR expression and preoperative chemotherapy using oral capecitabine (odds ratio, 0.437; p 0.012 vs. odds ratio, 3.235; p < 0.001, respectively). Conclusion: A high level of EGFR expression may be a significant predictive molecular marker for decreased tumor downstaging after preoperative chemoradiotherapy in locally advanced rectal cancer.

  5. Synergistic antitumor activity of histone deacetylase inhibitors and anti-ErbB3 antibody in NSCLC primary cultures via modulation of ErbB receptors expression.

    PubMed

    Ciardiello, Chiara; Roca, Maria Serena; Noto, Alessia; Bruzzese, Francesca; Moccia, Tania; Vitagliano, Carlo; Di Gennaro, Elena; Ciliberto, Gennaro; Roscilli, Giuseppe; Aurisicchio, Luigi; Marra, Emanuele; Mancini, Rita; Budillon, Alfredo; Leone, Alessandra

    2016-04-12

    ErbB3, a member of the ErbB family receptors, has a key role in the development and progression of several cancers, including non-small cell lung cancer (NSCLC), and in the establishment of resistance to therapies, leading to the development of anti-ErbB3 therapies.In this study we demonstrated, in a set of malignant pleural effusion-derived cultures of NSCLC, the synergistic antitumor effect of a histone deacetylase inhibitor (HDACi), such as vorinostat or valproic acid (VPA), in combination with the anti-ErbB3 monoclonal antibody (MoAb) A3. Synergistic interaction was observed in 2D and in 3D cultures conditions, both in fully epithelial cells expressing all ErbB receptors, and in cells that had undergone epithelial to mesenchymal transition and expressed low levels of ErbB3. We provided evidences suggesting that differential modulation of ErbB receptors by vorinostat or VPA, also at low doses corresponding to plasma levels easily reached in treated patients, is responsible for the observed synergism. In details, we showed in epithelial cells that both vorinostat and VPA induced time- and dose-dependent down-regulation of all three ErbB receptors and of downstream signaling. On the contrary, in A3-resistant mesenchymal cells, we observed time- and dose-dependent increase of mRNA and protein levels as well as surface expression of ErbB3, paralleled by down-regulation of EGFR and ErbB2. Our results suggest that the combination of a HDACi plus an anti-ErbB3 MoAb represents a viable strategy that warrants further evaluation for the treatment of NSCLC patients.

  6. Synergistic antitumor activity of histone deacetylase inhibitors and anti-ErbB3 antibody in NSCLC primary cultures via modulation of ErbB receptors expression

    PubMed Central

    Noto, Alessia; Bruzzese, Francesca; Moccia, Tania; Vitagliano, Carlo; Gennaro, Elena Di; Ciliberto, Gennaro; Roscilli, Giuseppe; Aurisicchio, Luigi; Marra, Emanuele; Mancini, Rita; Budillon, Alfredo; Leone, Alessandra

    2016-01-01

    ErbB3, a member of the ErbB family receptors, has a key role in the development and progression of several cancers, including non-small cell lung cancer (NSCLC), and in the establishment of resistance to therapies, leading to the development of anti-ErbB3 therapies. In this study we demonstrated, in a set of malignant pleural effusion-derived cultures of NSCLC, the synergistic antitumor effect of a histone deacetylase inhibitor (HDACi), such as vorinostat or valproic acid (VPA), in combination with the anti-ErbB3 monoclonal antibody (MoAb) A3. Synergistic interaction was observed in 2D and in 3D cultures conditions, both in fully epithelial cells expressing all ErbB receptors, and in cells that had undergone epithelial to mesenchymal transition and expressed low levels of ErbB3. We provided evidences suggesting that differential modulation of ErbB receptors by vorinostat or VPA, also at low doses corresponding to plasma levels easily reached in treated patients, is responsible for the observed synergism. In details, we showed in epithelial cells that both vorinostat and VPA induced time- and dose-dependent down-regulation of all three ErbB receptors and of downstream signaling. On the contrary, in A3-resistant mesenchymal cells, we observed time- and dose-dependent increase of mRNA and protein levels as well as surface expression of ErbB3, paralleled by down-regulation of EGFR and ErbB2. Our results suggest that the combination of a HDACi plus an anti-ErbB3 MoAb represents a viable strategy that warrants further evaluation for the treatment of NSCLC patients. PMID:26862736

  7. [A Case of Advanced Seminoma in a 79-Year-Old Man Successfully Treated with Etoposide and Cisplatin].

    PubMed

    Shiga, Masanobu; Kawai, Koji; Kojyo, Kousuke; Kurobe, Masahiro; Ichioka, Daishi; Yoshino, Takayuki; Ikeda, Atsushi; Kojima, Takahiro; Joraku, Akira; Suetomi, Takahiro; Tsutsumi, Masakazu; Miyazaki, Jun; Nishiyama, Hiroyuki

    2015-12-01

    Testicular tumors are representative solid cancers that occur in young men, and the standard multi-drug combination chemotherapy has been established for metastatic tumors. However, they develop rarely in elderly men over 70 years old, and there are few reports about the information of combination chemotherapy for elderly testicular tumor patients. Here, we present a case in a 79-year-old who had right testicular tumors (seminoma, cT2N3M1a, IGCC classification : good prognosis) safely treated with multi-drug combination chemotherapy. To reduce the risk of side effects, we selected 4 courses of etoposide and cisplatin (EP) to the patient. The patient suffered from febrile neutropenia (FN) and oral mucositis during the first cycle of EP. However, no further episodes of oral mucositis and FN were observed after introduction of oral health care by a dentist. The patient received 4 courses of EP without dose reduction or treatment postponement. There was no evidence of recurrence 6 months after chemotherapy. To our knowledge, the present case is the oldest patient with metastatic testicular treated with combination chemotherapy including cisplatin.

  8. [A Case of Advanced Gastric Cancer with Peritoneal Dissemination Effectively Treated with S-1 and Docetaxel Combination Chemotherapy].

    PubMed

    Saito, Hiroyuki; Suematsu, Yuki; Hiratsuka, Miyuki; Suda, Hiroshi; Takahashi, Miyuki; Omori, Keita; Ishibashi, Yuji; Morita, Akihiko; Wakabayashi, Kazuhiko; Ito, Yutaka

    2015-11-01

    A 72-year-old man underwent surgery for advanced gastric cancer. Systemic chemotherapy was started, using a regimen of S-1/CDDP for 4 courses, followed by 8 courses of S-1. Three years and 8 months after the surgery, abdominal CT demonstrated ascites, and the serum CA19-9 level was abnormally high (1,165.1 U/mL). Adenocarcinoma cells were found in the ascites. Treatment with S-1/docetaxel (DOC) was started. After 10 courses, the ascites disappeared and the serum CA19-9 value returned to normal. Four years and 7 months after the operation, the patient has been in good health, with no signs of recurrence.

  9. Efficacy and tolerability of high dose "ethinylestradiol" in post-menopausal advanced breast cancer patients heavily pre-treated with endocrine agents

    PubMed Central

    Agrawal, Amit; Robertson, John FR; Cheung, KL

    2006-01-01

    Background High dose estrogens (HDEs) were frequently used as endocrine agents prior to the introduction of tamoxifen which carries fewer side effects. Due to the development of resistance to available endocrine agents in almost all women with metastatic breast cancer, interest has renewed in the use of HDEs as yet another endocrine option that may have activity. We report our experience with one of the HDEs ("ethinylestradiol" 1 mg daily) in advanced breast cancer (locally advanced and metastatic) in post-menopausal women who had progressed on multiple endocrine agents. Patients and methods According to a database of advanced breast cancer patients seen in our Unit since 1998, those who had complete set of information and fulfilled the following criteria were studied: (1) patients in whom further endocrine therapy was deemed appropriate i.e., patients who have had clinical benefit with previous endocrine agents or were not fit or unwilling to receive chemotherapy in the presence of potentially life-threatening visceral metastases; (2) disease was assessable by UICC criteria; (3) were treated with "ethinylestradiol" until they were withdrawn from treatment due to adverse events or disease progression. Results Twelve patients with a median age of 75.1 years (49.1 – 85 years) were identified. Majority (N = 8) had bony disease. They had ethinylestradiol as 3rd to 7th line endocrine therapy. One patient (8%) came off treatment early due to hepato-renal syndrome. Clinical benefit (objective response or durable stable disease for ≥ 6 months) was seen in 4 patients (33.3%) with a median duration of response of 10+ (7–36) months. The time to treatment failure was 4 (0.5–36) months. Conclusion Yet unreported, high dose "ethinylestradiol" is another viable therapeutic strategy in heavily pre-treated patients when further endocrine therapy is deemed appropriate. Although it tends to carry more side effects, they may not be comparable to those of other HDEs (such as

  10. Early, computer-Aided Design/Computer-Aided Modeling Planned, Le Fort I Advancement With Internal Distractors to Treat Severe Maxillary Hypoplasia in Cleft Lip and Palate.

    PubMed

    Chang, Catherine S; Swanson, Jordan; Yu, Jason; Taylor, Jesse A

    2017-04-11

    Traditionally, maxillary hypoplasia in the setting of cleft lip and palate is treated via orthognathic surgery at skeletal maturity, which condemns these patients to abnormal facial proportions during adolescence. The authors sought to determine the safety profile of computer-aided design/computer-aided modeling (CAD/CAM) planned, Le Fort I distraction osteogenesis with internal distractors in select patients presenting at a young age with severe maxillary retrusion. The authors retrospectively reviewed our "early" Le Fort I distraction osteogenesis experience-patients performed for severe maxillary retrusion (≥12 mm underjet), after canine eruption but prior to skeletal maturity-at a single institution. Patient demographics, cleft characteristics, CAD/CAM operative plans, surgical complications, postoperative imaging, and outcomes were analyzed. Four patients were reviewed, with a median age of 12.8 years at surgery (range 8.6-16.1 years). Overall mean advancement was 17.95 + 2.9 mm (range 13.7-19.9 mm) with mean SNA improved 18.4° to 87.4 ± 5.7°. Similarly, ANB improved 17.7° to a postoperative mean of 2.4 ± 3.1°. Mean follow-up was 100.7 weeks, with 3 of 4 patients in a Class I occlusion with moderate-term follow-up; 1 of 4 will need an additional maxillary advancement due to pseudo-relapse. In conclusion, Le Fort I distraction osteogenesis with internal distractors is a safe procedure to treat severe maxillary hypoplasia after canine eruption but before skeletal maturity. Short-term follow-up demonstrates safety of the procedure and relative stability of the advancement. Pseudo-relapse is a risk of the procedure that must be discussed at length with patients and families.

  11. Efficacy and Patterns of Failure for Locally Advanced Cancer of the Cervix Treated With Celebrex (Celecoxib) and Chemoradiotherapy in RTOG 0128

    SciTech Connect

    Gaffney, David K. Winter, Kathryn; Dicker, Adam P.; Miller, Brigitte; Eifel, Patricia J.; Ryu, Janice; Avizonis, Vilija; Fromm, Mitch; Small, William; Greven, Kathryn

    2007-09-01

    Purpose: To determine the efficacy and patterns of initial failure for oral celecoxib, intravenous cisplatin, and 5-fluorouracil and concurrent pelvic radiotherapy in patients with locally advanced cancer of the cervix. Methods and Materials: Patients were treated with concurrent 5-fluorouracil and cisplatin chemotherapy and pelvic radiotherapy and brachytherapy. Celecoxib was prescribed at a dose of 400 mg twice daily for 1 year beginning on the first day of radiotherapy. The overall and disease-free survival rates were determined. Results: A total of 84 patients were accrued, of whom 78 were eligible. The estimated 2-year disease-free survival and overall survival rate was 69% and 83%, respectively. Of the 78 patients, 24 had treatment failure: 3 with persistent local disease, 9 local only, 2 regional, 4 distant, 1 regional and distant, 1 local and distant, and 2 with local, regional, and distant disease, and 1 had died of cervical cancer without a reported site of first failure and 1 without evidence of disease. Conclusion: At 2 years, the estimated disease-free survival and overall survival rate for patients with advanced cervical cancer who underwent a combination of chemoradiotherapy and celecoxib treatment was 69% and 83%, respectively. Recurrent disease developed in 24 patients, and, of those patients, 18 had a component of locoregional failure as a site of first failure. Thus, locoregional control continues to be problematic after chemoradiotherapy as delivered in our study. The identification of more active biologically targeted therapies is warranted for the treatment of advanced cancer of the cervix.

  12. Archaeal Diversity in Biofilm Technologies Applied to Treat Urban and Industrial Wastewater: Recent Advances and Future Prospects

    PubMed Central

    Calderón, Kadiya; González-Martínez, Alejandro; Gómez-Silván, Cinta; Osorio, Francisco; Rodelas, Belén; González-López, Jesús

    2013-01-01

    Biological wastewater treatment (WWT) frequently relies on biofilms for the removal of anthropogenic contaminants. The use of inert carrier materials to support biofilm development is often required, although under certain operating conditions microorganisms yield structures called granules, dense aggregates of self-immobilized cells with the characteristics of biofilms maintained in suspension. Molecular techniques have been successfully applied in recent years to identify the prokaryotic communities inhabiting biofilms in WWT plants. Although methanogenic Archaea are widely acknowledged as key players for the degradation of organic matter in anaerobic bioreactors, other biotechnological functions fulfilled by Archaea are less explored, and research on their significance and potential for WWT is largely needed. In addition, the occurrence of biofilms in WWT plants can sometimes be a source of operational problems. This is the case for membrane bioreactors (MBR), an advanced technology that combines conventional biological treatment with membrane filtration, which is strongly limited by biofouling, defined as the undesirable accumulation of microbial biofilms and other materials on membrane surfaces. The prevalence and spatial distribution of archaeal communities in biofilm-based WWT as well as their role in biofouling are reviewed here, in order to illustrate the significance of this prokaryotic cellular lineage in engineered environments devoted to WWT. PMID:24022691

  13. Advances with using CRISPR/Cas-mediated gene editing to treat infections with hepatitis B virus and hepatitis C virus.

    PubMed

    Moyo, Buhle; Bloom, Kristie; Scott, Tristan; Ely, Abdullah; Arbuthnot, Patrick

    2017-01-10

    Chronic infections with hepatitis B and hepatitis C viruses (HBV and HCV) account for the majority of cases of cirrhosis and hepatocellular carcinoma. Current therapies for the infections have limitations and improved efficacy is necessary to prevent complications in carriers of the viruses. In the case of HBV persistence, the replication intermediate comprising covalently closed circular DNA (cccDNA) is particularly problematic. Licensed therapies have little effect on cccDNA and HBV replication relapses following treatment withdrawal. Disabling cccDNA is thus key to curing HBV infections and application of gene editing technology, such as harnessing the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system, has curative potential. Several studies have reported good efficacy when employing CRISPR/Cas technologies to disable HBV replication in cultured cells and in hydrodynamically injected mice. Recent advances with HCV drug development have revolutionized treatment of the infection. Nevertheless, individuals may be refractory to treatment. Targeting RNA from HCV with CRISPR/Cas isolated from Francisella novicida may have therapeutic utility. Although preclinical work shows that CRISPR/Cas technology has potential to overcome infection with HBV and HCV, significant challenges need to be met. Ensuring specificity for viral targets and efficient delivery of the gene editing sequences to virus-infected cells are particularly important. The field is at an interesting stage and the future of curative antiviral drug regimens, particularly for treatment of chronic HBV infection, may well entail use of combinations that include derivatives of CRISPR/Cas.

  14. Advanced electro-Fenton degradation of biologically-treated coking wastewater using anthraquinone cathode and Fe-Y catalyst.

    PubMed

    Li, Haitao; Li, Yuping; Cao, Hongbin; Li, Xingang; Zhang, Yi

    2011-01-01

    The electrocatalytic activity of bare and 2-ethyl anthraquinone-modified graphite felt (2-EAQ/GF) toward oxygen reduction was investigated using a cyclic voltammetry technique in a neutral solution. The prepared cathodes were tested for electrogeneration of H2O2 and electro-Fenton oxidation (EFO) treatment of neutral coking wastewater (CW) after biological process, using a graphite anode and Fezeolite Y catalyst. The results showed that (i) H2O2 yield and current efficiency greatly depended on cathodic potential and materials; (ii) hydroxyl radicals, generated from Fe-zeolite Y-catalyzed H2O2 decomposition, played a great role in EFO treatment, while anodic direct and indirect oxidation was insignificant; (iii) chemical oxygen demand, total organic carbon (TOC) and acute toxicity of wastewater decreased by 40-50, 30-40 and 50-60%, respectively, and biodegradability increased after 1 h of EFO treatment. Due to the free-pH adjustment, EFO presents a potential engineering application for advanced treatment of CW.

  15. Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy

    PubMed Central

    Shen, Jinwen; Zhu, Yuan; Wu, Wei; Zhang, Lingnan; Ju, Haixing; Fan, Yongtian; Zhu, Yuping; Luo, Jialin; Liu, Peng; Zhou, Ning; Lu, Ke; Zhang, Na; Li, Dechuan; Liu, Luying

    2017-01-01

    Background Increasing evidence suggests that cancer-associated inflammation is associated with poorer outcomes. The neutrophil-to-lymphocyte ratio (NLR), considered as a systemic inflammation marker, is thought to predict prognoses in colorectal cancer. In this study, we explored the association between the NLR and prognoses following neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). Material/Methods From February 2002 to December 2012, a group of 202 patients diagnosed with LARC and receiving neoadjuvant CRT followed by radical surgery was included in our retrospective study. The associations between the pre-CRT NLR and clinicopathological characteristics, as well as the predictive value of pre-CRT NLR against survival outcomes, were analyzed. Results The average NLR was 2.7±1.5 (median 2.4, range 0.6–12.8). There were 63 (31.2%) patients with NLR ≥3.0, and 139 (68.8%) patients with NLR <3.0. Correlation analyses showed that no clinicopathological characteristics except age were associated with NLR. We did not find an association between NLR and survival outcomes. In multivariate Cox model analyses, the R1/R2 resection, lymph node ratio ≥0.1, and perineural/lymphovascular invasion were independently associated with worse disease-free survival and overall survival. Conclusions In our cohort, the NLR did not correlate with survival outcomes in LARC patients undergoing neoadjuvant CRT. The prognostic value of NLR should be validated in large-scale prospective studies. PMID:28100902

  16. Safety and feasibility of uniportal video-assisted thoracoscopic surgery for locally advanced non-small cell lung cancer

    PubMed Central

    Yao, Jie; Wang, Qi; Chang, Zhibo

    2016-01-01

    Background Conventional video-assisted thoracoscopic surgery (VATS) lobectomy for locally advanced non-small cell lung cancer (NSCLC) is a feasible and safe surgery in high-volume centers with significant VATS experience. Uniportal VATS lobectomy has been recently been reported to be a promising, less invasive approach. The purpose of this study is to explore the safety and feasibility of uniportal video-assisted thoracoscopic surgery (U-VATS) for the treatment of patients with locally advanced NSCLC. Methods From January 2013 to September 2015, a total of 132 patients with locally advanced NSCLC underwent U-VATS or open thoracotomy major pulmonary resections and standard mediastinal lymph node dissection. Patients were divided into two groups: (I) locally advanced NSCLC underwent U-VATS (U-VATS); (II) locally advanced NSCLC underwent open thoracotomy (open). A descriptive and retrospective study was performed, including the operative time, operative blood loss, postoperative chest tube duration, postoperative hospital stay, lymph node dissection, postoperative complications and postoperative recovery. Results A total of 132 patients with locally advanced NSCLC were included in this study: 64 (U-VATS) vs. 68 (open) patients. The patient demographic data was similar in both groups. Median operative time (157.0 vs. 160.6) and median number of lymph nodes (35.5 vs. 32.5) were similar in both groups. Chest tube duration and hospital of stay were statistically shorter in U-VATS group while rate of complications were higher in open thoracotomy group. One patient died on the 55th postoperative day because of tumor metastasis and bronchopleural fistula. A higher percentage of patients who underwent UVATS resections were able to receive adjuvant therapy timely compared to the open group. Conclusions Uniportal VATS major pulmonary resections and mediastinal lymph node dissection is a safe and feasible procedure for the treatment of locally advanced NSCLC. Particularly it is

  17. Targeting EGFR T790M mutation in NSCLC: From biology to evaluation and treatment.

    PubMed

    Passaro, Antonio; Guerini-Rocco, Elena; Pochesci, Alessia; Vacirca, Davide; Spitaleri, Gianluca; Catania, Chiara Matilde; Rappa, Alessandra; Barberis, Massimo; de Marinis, Filippo

    2017-03-01

    The identification of EGFR mutations and their respectively tyrosine kinase inhibitors (TKIs), changed dramatically treatment and survival of patients with EGFR-positive lung cancer. Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. In first-line setting, when comparing with platinum-based chemotherapy, these target drugs improves progression-free survival, response rate and quality of life. Unfortunately, the development of different mechanism of resistance, limits the long term efficacy of these agents. The most clear mechanism of resistance is the development of EGFR Thr790Met mutation. Against this new target, different third-generation EGFR-mutant-selective TKIs, such as osimertinib, rociletinib and olmutinib, showed a great activity. In this review, we summarize the scientific evidences about biology, evaluation and treatment on NSCLC with EGFR T790M mutation.

  18. PPARα activation can help prevent and treat non-small cell lung cancer

    PubMed Central

    Skrypnyk, Nataliya; Chen, Xiwu; Hu, Wen; Su, Yan; Mont, Stacey; Yang, Shilin; Gangadhariah, Mahesha; Wei, Shouzuo; Falck, John R.; Jat, Jawahar Lal; Zent, Roy; Capdevila, Jorge H.; Pozzi, Ambra

    2013-01-01

    Non-small cell lung cancer (NSCLC) not amenable to surgical resection has a high mortality rate, due to the ineffectiveness and toxicity of chemotherapy. Thus, there remains an urgent need of efficacious drugs that can combat this disease. In this study, we show that targeting the formation of pro-angiogenic epoxyeicosatrienoic acids (EETs) by the cytochrome P450 arachidonic acid epoxygenases (Cyp2c) represents a new and safe mechanism to treat NSCLC growth and progression. In the transgenic murine K-Ras model and human orthotopic models of NSCLC, we found that Cyp2c44 could be downregulated by activating the transcription factor PPARα with the ligands bezafibrate and Wyeth-14,643. Notably, both treatments reduced primary and metastatic NSCLC growth, tumor angiogenesis, endothelial Cyp2c44 expression and circulating EET levels. These beneficial effects were independent of the time of administration, whether before or after the onset of primary NSCLC, and they persisted after drug withdrawal, suggesting the benefits were durable. Our findings suggest that strategies to downregulate Cyp2c expression and/or its enzymatic activity may provide a safer and effective strategy to treat NSCLC. Moreover, as bezafibrate is a well-tolerated clinically approved drug used for managing lipidemia, our findings provide an immediate cue for clinical studies to evaluate the utility of PPARα ligands as safe agents for the treatment of lung cancer in humans. PMID:24302581

  19. The Significance of Tumoral ERCC1 Status in Patients With Locally Advanced Cervical Cancer Treated With Chemoradiation Therapy: A Multicenter Clinicopathologic Analysis

    SciTech Connect

    Doll, Corinne M.; Aquino-Parsons, Christina; Pintilie, Melania; Petrillo, Stephanie K.; Milosevic, Michael; Craighead, Peter S.; Clarke, Blaise; Lees-Miller, Susan P.; Fyles, Anthony W.; Magliocco, Anthony M.

    2013-03-01

    Purpose: ERCC1 (excision repair cross-complementation group 1) expression has been shown to be a molecular marker of cisplatin resistance in many tumor sites, but has not been well studied in cervical cancer patients. The purpose of this study was to measure tumoral ERCC1 in patients with locally advanced cervical cancer treated with chemoradiation therapy (CRT) in a large multicenter cohort, and to correlate expression with clinical outcome parameters. Methods and Materials: A total of 264 patients with locally advanced cervical cancer, treated with curative-intent radical CRT from 3 major Canadian cancer centers were evaluated. Pretreatment formalin-fixed, paraffin-embedded tumor specimens were retrieved, and tissue microarrays were constructed. Tumoral ERCC1 (FL297 antibody) was measured using AQUA (R) technology. Statistical analysis was performed to determine the significance of clinical factors and ERCC1 status with progression-free survival (PFS) and overall survival (OS) at 5 years. Results: The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage II disease (n=119, 45%); median tumor size was 5 cm. OS was associated with tumor size (HR 1.16, P=.018), pretreatment hemoglobin status (HR 2.33, P=.00027), and FIGO stage. In addition, tumoral ERCC1 status (nuclear to cytoplasmic ratio) was associated with PFS (HR 2.33 [1.05-5.18], P=.038) and OS (HR 3.13 [1.27-7.71], P=.013). ERCC1 status was not significant on multivariate analysis when the model was adjusted for the clinical factors: for PFS (HR 1.49 [0.61-3.6], P=.38); for OS (HR 2.42 [0.94-6.24] P=.067). Conclusions: In this large multicenter cohort of locally advanced cervical cancer patients treated with radical CRT, stage, tumor size, and pretreatment hemoglobin status were significantly associated with PFS and OS. ERCC1 status appears to have prognostic impact on univariate analysis in these patients, but was not independently associated with outcome on

  20. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer

    PubMed Central

    Liu, Mei-Ching; Lee, Soo Chin; Vanlemmens, Laurence; Ferrero, Jean-Marc; Tabei, Toshio; Pivot, Xavier; Iwata, Hiroji; Aogi, Kenjiro; Lugo-Quintana, Roberto; Harbeck, Nadia; Brickman, Marla J.; Zhang, Ke; Kern, Kenneth A.; Martin, Miguel

    2010-01-01

    This multicenter, randomized, open-label phase III trial (planned enrollment: 700 patients) was conducted to test the hypothesis that single-agent sunitinib improves progression-free survival (PFS) compared with capecitabine as treatment for advanced breast cancer (ABC). Patients with HER2-negative ABC that recurred after anthracycline and taxane therapy were randomized (1:1) to sunitinib 37.5 mg/day or capecitabine 1,250 mg/m2 (1,000 mg/m2 in patients >65 years) BID on days 1–14 q3w. The independent data-monitoring committee (DMC) determined during the first interim analysis (238 patients randomized to sunitinib, 244 to capecitabine) that the trial be terminated due to futility in reaching the primary endpoint. No statistical evidence supported the hypothesis that sunitinib improved PFS compared with capecitabine (one-sided P = 0.999). The data indicated that PFS was shorter with sunitinib than capecitabine (median 2.8 vs. 4.2 months, respectively; HR, 1.47; 95% CI, 1.16–1.87; two-sided P = 0.002). Median overall survival (15.3 vs. 24.6 months; HR, 1.17; two-sided P = 0.350) and objective response rates (11 vs. 16%; odds ratio, 0.65; P = 0.109) were numerically inferior with sunitinib versus capecitabine. While no new or unexpected safety findings were reported, sunitinib treatment was associated with higher frequencies and greater severities of many common adverse events (AEs) compared with capecitabine, resulting in more temporary discontinuations due to AEs with sunitinib (66 vs. 51%). The relative dose intensity was lower with sunitinib than capecitabine (73 vs. 95%). Based on these efficacy and safety results, sunitinib should not be used as monotherapy for patients with ABC. PMID:20339913

  1. Outcomes in a Multi-institutional Cohort of Patients Treated With Intraoperative Radiation Therapy for Advanced or Recurrent Renal Cell Carcinoma

    SciTech Connect

    Paly, Jonathan J.; Hallemeier, Christopher L.; Biggs, Peter J.; Niemierko, Andrzej; Roeder, Falk; Martínez-Monge, Rafael; Whitson, Jared; Calvo, Felipe A.; Fastner, Gerd; Sedlmayer, Felix; Wong, William W.; Ellis, Rodney J.; Haddock, Michael G.; Choo, Richard; Shipley, William U.; Zietman, Anthony L.; Efstathiou, Jason A.

    2014-03-01

    Purpose/Objective(s): This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). Methods and Materials: Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. Results: IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. Conclusions: We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to

  2. Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance

    PubMed Central

    Jotte, Robert M; Spigel, David R

    2015-01-01

    Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance. PMID:26310719

  3. The Changes of Lipid Metabolism in Advanced Renal Cell Carcinoma Patients Treated with Everolimus: A New Pharmacodynamic Marker?

    PubMed Central

    Pantano, Francesco; Santoni, Matteo; Procopio, Giuseppe; Rizzo, Mimma; Iacovelli, Roberto; Porta, Camillo; Conti, Alessandro; Lugini, Antonio; Milella, Michele; Galli, Luca; Ortega, Cinzia; Guida, Francesco Maria; Silletta, Marianna; Schinzari, Giovanni; Verzoni, Elena; Modica, Daniela; Crucitti, Pierfilippo; Rauco, Annamaria; Felici, Alessandra; Ballatore, Valentina; Cascinu, Stefano; Tonini, Giuseppe; Carteni, Giacomo; Russo, Antonio; Santini, Daniele

    2015-01-01

    Background Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC. Methods 177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated. Results Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C,T and C+T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p=0.030), C (8 vs 5, p=0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis. Conclusion C+T raise is an early predictor for everolimus efficacy for patients with mRCC. PMID:25885920

  4. Locoregionally Advanced Head and Neck Cancer Treated With Primary Radiotherapy: A Comparison of the Addition of Cetuximab or Chemotherapy and the Impact of Protocol Treatment

    SciTech Connect

    Caudell, Jimmy J.; Sawrie, Stephen M.; Spencer, Sharon A.; Desmond, Renee A.; Carroll, William R.; Peters, Glenn E.; Nabell, Lisle M.; Meredith, Ruby F.; Bonner, James A.

    2008-07-01

    Purpose: The addition of platinum-based chemotherapy (ChRT) or cetuximab (ExRT) to concurrent radiotherapy (RT) has resulted in improved survival in Phase III studies for locoregionally advanced head and neck cancer (LAHNC). However the optimal treatment regimen has not been defined. A retrospective study was performed to compare outcomes in patients who were treated definitively with ExRT or ChRT. Methods: Cetuximab with concurrent RT was used to treat 29 patients with LAHNC, all of whom had tumors of the oral cavity, oropharynx, or larynx. All patients were T2 to T4 and overall American Joint Committee on Cancer Stage III to IVB, with a Karnofsky Performance Status (KPS) score of 60 or greater. ChRT was used to treat 103 patients with similar characteristics. Patients were evaluated for locoregional control (LRC), distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS). Median follow-up for patients alive at last contact was 83 months for those treated with ExRT and 53 months for those treated with ChRT. Cox proportional hazard models were used to assess independent prognostic factors. Results: The LRC, DMFS, and DSS were not significantly different, with 3-year rates of 70.7%, 92.4%, and 78.6% for ExRT and 74.7%, 86.6%, and 76.5% for ChRT, respectively. The OS was significantly different between the two groups (p = 0.02), with 3-year rates of 75.9% for ExRT and 61.3% for ChRT. OS was not significant when patients who were on protocol treatments of ExRT or ChRT were compared. Also, OS was not significant when multivariate analysis was used to control for potential confounding factors. Conclusion: In our single-institution retrospective review of patients treated with ExRT or ChRT, no significant differences were found in LRC, DMFS, DSS, or OS.

  5. Update on targeted therapies for advanced non-small cell lung cancer: nivolumab in context

    PubMed Central

    Le, Alexander D; Alzghari, Saeed K; Jean, Gary W; La-Beck, Ninh M

    2017-01-01

    While the initial treatment of non-small cell lung cancer (NSCLC) usually relies on surgical resection followed by systemic cytotoxic chemotherapy and/or radiation therapy, recent advances in understanding of NSCLC biology and immunology have spurred the development of numerous targeted therapies. In particular, a class of immune modulatory drugs targeting the immune checkpoint pathways has demonstrated remarkable durable remissions in a select minority of advanced NSCLC patients, potentially heralding the elusive “cancer cure”. This review focuses on the clinical evidence for one of these agents, nivolumab, and clarifies the role of this drug in the context of the other targeted therapies currently available for the treatment of NSCLC. We also discuss the impact of nivolumab on patient quality of life and health economics. PMID:28260909

  6. The role of the epidermal growth factor receptor tyrosine kinase inhibitors as therapy for advanced, metastatic, and recurrent non-small-cell lung cancer: a Canadian national consensus statement

    PubMed Central

    Ellis, P.M.; Morzycki, W.; Melosky, B.; Butts, C.; Hirsh, V.; Krasnoshtein, F.; Murray, N.; Shepherd, F.A.; Soulieres, D.; Tsao, M.S.; Goss, G.

    2009-01-01

    Purpose To provide consensus recommendations on the use of epidermal growth factor receptor tyrosine kinase inhibitors (egfr-tkis) in patients with advanced or meta-static non-small-cell lung cancer (nsclc). Methods Using a systematic literature search, phase ii trials, randomized phase iii trials, and meta-analyses were identified for inclusion. Results A total of forty-six trials were included. Clear evidence is available that egfr-tkis should not be administered concurrently with platinum-based chemotherapy as first-line therapy in advanced or metastatic nsclc. Evidence is currently insufficient to recommend single-agent egfr-tkis as first-line therapy either in unselected populations or in populations selected on the basis of molecular or clinical characteristics. Following failure of platinum-based chemotherapy, the evidence suggests that second-line egfr-tkis or second-line chemotherapy result in similar survival. Quality of life and symptom improvement for patients treated with an egfr-tki appear better than they do for patients treated with second-line docetaxel. Sequence of therapy may not appear to be important, but if survival is the outcome of interest, the goal should be to optimize the number of patients receiving three lines of therapy. Based on available data, molecular markers and clinical characteristics do not appear to be predictive of a differential survival benefit from an egfr-tki and therefore those factors should not be used to select patients for egfr-tki therapy. Conclusions The egfr-tkis represent an additional therapy in the treatment of advanced or metastatic nsclc. The results of ongoing clinical trials may define the optimal role for these agents and the effectiveness of combinations of these agents with other targeted agents. PMID:19229369

  7. The Prognostic Value of Alpha-Fetoprotein Response for Advanced-Stage Hepatocellular Carcinoma Treated with Sorafenib Combined with Transarterial Chemoembolization

    PubMed Central

    Liu, Lei; Zhao, Yan; Jia, Jia; Chen, Hui; Bai, Wei; Yang, Man; Yin, Zhanxin; He, Chuangye; Zhang, Lei; Guo, Wengang; Niu, Jing; Yuan, Jie; Cai, Hongwei; Xia, Jielai; Fan, Daiming; Han, Guohong

    2016-01-01

    This retrospective cohort study aimed to evaluate the prognostic value of the alpha-fetoprotein (AFP) response in advanced-stage hepatocellular carcinoma (HCC) patients treated with sorafenib combined with transarterial chemoembolization. From May 2008 to July 2012, 118 HCC patients with baseline AFP levels >20 ng/ml treated with combination therapy were enrolled. A receiver operating characteristic curve was used to generate a cutoff point for AFP changes for predicting survival. The AFP response was defined as an AFP decrease rate [ΔAFP(%)] greater than the cutoff point. The ΔAFP(%) was defined as the percentage of changes between the baseline and the nadir values within 2 months after therapy. The median follow-up time was 8.8 months (range 1.2–66.9). A level of 46% was chosen as the threshold value for ΔAFP (sensitivity = 53.7%, specificity = 83.3%). The median overall survival was significantly longer in the AFP response group than in the AFP non-response group (12.8 vs. 6.4 months, P = 0.001). Multivariate analysis showed that ECOG ≥ 1 (HR = 1.95; 95% CI 1.24–3.1, P = 0.004) and AFP nonresponse (HR = 1.71; 95% CI 1.15–2.55, P = 0.009) were associated with increased risk of death. In conclusion, AFP response could predict the survival of patients with advanced-stage HCC at an early time point after combination therapy. PMID:26831408

  8. Pregnane X receptors regulate CYP2C8 and P-glycoprotein to impact on the resistance of NSCLC cells to Taxol.

    PubMed

    Chen, Yan; Huang, Wandan; Chen, Feiyu; Hu, Guoping; Li, Fenglei; Li, Jianhua; Xuan, Aiguo

    2016-12-01

    Cytochrome P450 2C8 (CYP2C8) is one of the enzymes that primarily participate in producing metabolisms of medications and P-glycoprotein (P-gp) has been regarded as one of the important molecules in chemotherapeutically induced multidrug resistance (MDR). In addition, the pregnane X receptor (PXR) is involved in regulating both CYP2C8 and P-gp. We aim to research the effect of PXR on Taxol-resistant non-small-cell lung cancer (NSCLC cells) via regulating CYP2C8 and P-gp. NSCLC cells were treated with SR12813, LY335979, or PXR siRNA. Cell counting kit (CCK-8) assay was used to detect cell vitality. Colony formation assay was used to observe cell proliferation. Western blotting, real-time polymerase chain reaction (RT-PCR), and immunofluorescence staining were conducted to analyze the expressions of PXR, CYP2C8, and P-gp. Taxol and its metabolic products were detected by high-performance liquid chromatography (HPLC). The expression of PXR in A549 cell line was higher than that in other cell lines. The accumulation of PXR was observed in the nucleus after cells were treated with SR12813. Besides, SR12813 induced higher expressions of CYP2C8 and P-gp proteins. We also discovered that pretreatment with SR12813 reversed the inhibition of cell viability and proliferation after the Taxol treatment in comparison to the SR12813 untreated group. Furthermore, the hydroxylation products of Taxol analyzed by HPLC were increased in comparison to the SR12813 untreated group, indicating that high expressions of CYP2C8 and P-gp enhanced the resistance of A549 cells to Taxol. For cells treated with PXR siRNA, cell viability, cell proliferation, and Taxol metabolites were significantly reduced after the Taxol treatment in comparison to the siRNA-negative group. The cell viability, cell proliferation, and Taxol metabolites were regulated by the expressions of PXR, P-gp, and CYP2C8. That is, PXR expression has an important effect on the resistance of NSCLC cells to Taxol via

  9. Feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to thoracic radiotherapy in locally advanced unresectable non-small-cell lung cancer: a Phase II trial

    PubMed Central

    Martínez, Enrique; Martínez, Maite; Rico, Mikel; Hernández, Berta; Casas, Francesc; Viñolas, Nuria; Pérez-Casas, Ana; Dómine, Manuel; Mínguez, Julián

    2016-01-01

    Purpose Although many studies have confirmed the synergic effects of combining chemotherapy (CT) and radiotherapy (RT), clinical data evaluating safety and efficacy of erlotinib in combination with RT in locally advanced non-small-cell lung cancer (NSCLC) are limited. The aim of this study was to determine the feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to the standard three-dimensional conformal thoracic RT in patients with unresectable or locally advanced NSCLC who are not candidates for receiving standard CT. Patients and methods Feasibility and tolerability, assessed by evaluating adverse events (AEs), and effectiveness, by calculating progression-free survival (PFS), overall survival (OS), cancer-specific survival (CSS), and objective response rate (ORR), were analyzed in 30 patients receiving RT alone and 60 receiving RT and erlotinib. Results Erlotinib with RT showed an extended CSS and a higher rate of complete responses compared with RT alone. No differences between groups were found regarding OS, PFS, and ORR. AEs were significantly higher in the combined treatment, which mainly included cutaneous toxicity, dyspnea, fatigue, hyporexia, diarrhea, and infection. Erlotinib did not increase the toxicity produced by RT. Conclusion The combination of erlotinib with RT produced, in our study, a scarce clinical benefit in the treatment of unresectable or locally advanced NSCLC, limited to complete responses and longer CSS rate compared with RT alone. Increased toxicity events were associated with combined therapy, which mainly included cutaneous toxicity. In our opinion, further studies in molecularly unselected lung cancer patients treated with EGFR TKIs and RT are not indicated. The use of biomarkers for the identification of patients that are most likely to benefit from this treatment is an essential next step in the research of this condition. PMID:27042098

  10. 125I brachytherapy of locally advanced non-small-cell lung cancer after one cycle of first-line chemotherapy: a comparison with best supportive care

    PubMed Central

    Song, Jingjing; Fan, Xiaoxi; Zhao, Zhongwei; Chen, Minjiang; Chen, Weiqian; Wu, Fazong; Zhang, Dengke; Chen, Li; Tu, Jianfei; Ji, Jiansong

    2017-01-01

    Objectives The objective of this study was to assess the efficacy of computed tomography (CT)-guided 125I brachytherapy alone in improving the survival and quality of life of patients with unresectable locally advanced non-small-cell lung cancer (NSCLC) after one cycle of first-line chemotherapy. Patients and methods Sixteen patients with locally advanced NSCLC were treated with CT-guided 125I brachytherapy after one cycle of first-line chemotherapy (group A). Sixteen patients who received only best supportive care (group B) were matched up with the patients in group A. Primary end point included survival, and secondary end point included assessment of safety, effectiveness of CT-guided 125I brachytherapy, and improvement in the quality of life. Results The two groups were well balanced in terms of age, disease histology, tumor stage, tumor location, and performance status (P>0.05). The median follow-up time was 16 months (range, 3–30). The total tumor response rate was 75.0% in group A, which was significantly higher than that in group B (0.0%) (P<0.01). The median progression-free survival time was 4.80 months for patients in group A and 1.35 months for patients in group B (P<0.001). Kaplan–Meier survival analysis showed that the median survival time of group A was 9.4±0.3 months versus 8.4±0.1 months in group B (P=0.013). Tumor-related symptoms of patients were significantly relieved, and the quality of life was markedly improved in group A than in group B. Conclusion CT-guided 125I brachytherapy improved the survival of patients with locally advanced NSCLC and quality of life after one cycle of first-line chemotherapy compared with best supportive care. PMID:28280369

  11. P73 G4C14‐to‐A4T14 polymorphism is associated with survival in advanced non‐small cell lung cancer patients

    PubMed Central

    Ge, Lei; Yang, Yang; Sun, Yifeng; Xu, Wen

    2017-01-01

    Background p73, a structural and functional homolog of p53, plays an important role in modulating cell cycle arrest. This study investigated the association between p73 G4C14‐to‐A4T14 polymorphism and survival outcomes in a Chinese population of advanced non‐small cell lung cancer (NSCLC) patients treated with platinum agents. Methods The p73 G4C14‐to‐A4T14 polymorphism was genotyped using DNA from blood samples of advanced NSCLC patients (642 in the discovery set and 330 in the replication set). The relationship of the p73 G4C14‐to‐A4T14 polymorphism with clinical outcomes was analyzed. Results Compared with the GC/GC genotype, the genotypes containing AT allele (GC/AT + AT/AT genotypes) were associated with significantly prolonged overall survival (P = 0.040) in the discovery set and after pooling results from the replication set. Stratification analysis revealed that the association was more pronounced in subjects who were older (P = 0.001), male (P = 0.007), smokers (P = 0.006), had a low Eastern Cooperative Oncology Group performance status (P = 0.001), in tumor node metastasis stage IV (P = 0.008), and with adenocarcinoma (P = 0.002). The objective response rates of patients with GC/AT + AT/AT genotypes were statistically higher than those with the GC/GC genotype (P = 0.047). Conclusion Our findings suggest that the p73 G4C14‐to‐A4T14 polymorphism may be related to survival outcome in advanced NSCLC patients. PMID:28134496

  12. A randomized preventive rehabilitation trial in advanced head and neck cancer patients treated with chemoradiotherapy: feasibility, compliance, and short-term effects.

    PubMed

    van der Molen, Lisette; van Rossum, Maya A; Burkhead, Lori M; Smeele, Ludi E; Rasch, Coen R N; Hilgers, Frans J M

    2011-06-01

    The aim of this study was to assess the effect of (preventive) rehabilitation on swallowing and mouth opening after concomitant chemoradiotherapy (CCRT). Forty-nine patients with advanced oral cavity, oropharynx, hypopharynx and larynx, or nasopharynx cancer treated with CCRT were randomized into a standard (S) or an experimental (E) preventive rehabilitation arm. Structured multidimensional assessment (i.e., videofluoroscopy, mouth-opening measurement, structured questionnaires) was performed before and 10 weeks after CCRT. In both S and E arms, feasibility was good (all patients could execute the exercises within a week) and compliance was satisfactory (mean days practiced per week was 4). Nevertheless, mouth opening, oral intake, and weight decreased significantly. Compared to similar CCRT studies at our institute, however, fewer patients were still tube-dependent after CCRT. Furthermore, some functional outcomes seemed less affected than those of studies in the literature that did not incorporate rehabilitation exercises. Patients in the E arm practiced significantly fewer days in total and per week, but they obtained results comparable to the S arm patients. Preventive rehabilitation (regardless of the approach, i.e., experimental or standard) in head and neck cancer patients, despite advanced stage and burdensome treatment, is feasible, and compared with historical controls, it seems helpful in reducing the extent and/or severity of various functional short-term effects of CCRT.

  13. Neutrophil-to-lymphocyte ratio as a prognostic biomarker for patients with locally advanced esophageal squamous cell carcinoma treated with definitive chemoradiotherapy

    PubMed Central

    Zhou, Xi-Lei; Li, Yong-Qiang; Zhu, Wei-Guo; Yu, Chang-Hua; Song, Ya-Qi; Wang, Wan-Wei; He, Dong-Cheng; Tao, Guang-Zhou; Tong, Yu-Suo

    2017-01-01

    The present study evaluated the clinical and prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy (dCRT). A total of 517 patients with ESCC were enrolled and analysed retrospectively. The NLR was calculated at three time points: baseline, post-treatment, and at the time of tumor progression. Elevated NLR was defined as a ratio ≥5. High NLR at baseline was present in 204 (39%) patients and was significantly correlated with larger tumour size, advanced TNM stage, worse ECOG performance status, and dCRT response (p < 0.05). At a median follow-up of 17 months, patients with higher NLR at baseline had poorer progression-free survival (PFS) and overall survival (OS). On multivariate analysis, elevated NLR at baseline was independently associated with PFS and OS (HR = 1.529, p < 0.001 for PFS; HR = 1.856, p < 0.001 for OS). In addition, patients with high pre- and post-treatment NLR demonstrated worse clinical outcomes than other groups. Our results suggest that NLR is an independent prognostic indicator for patients with ESCC undergoing dCRT and changes in NLR level with treatment may indicate therapeutic benefit. PMID:28195186

  14. The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy

    PubMed Central

    Mangia, Anita; Caldarola, Lucia; Dell'Endice, Stefania; Scarpi, Emanuela; Saragoni, Luca; Monti, Manlio; Santini, Daniele; Brunetti, Oronzo; Simone, Giovanni; Silvestris, Nicola

    2015-01-01

    Cellular resistance in advanced gastric cancer (GC) might be related to function of multidrug resistance (MDR) proteins. The adaptor protein NHERF1 (Na+/H+ exchanger regulatory factor) is an important player in cancer progression for a number of solid malignancies, even if its role to develop drug resistance remains uncertain. Herein, we aimed to analyze the potential association between NHERF1 expression and P-gp, sorcin and HIF-1α MDR-related proteins in advanced GC patients treated with epirubicin/oxaliplatin/capecitabine (EOX) chemotherapy regimen, and its relation to response. Total number of 28 untreated patients were included into the study. Expression and subcellular localization of all proteins were assessed by immunohistochemistry on formalin-fixed paraffin embedded tumor samples. We did not found significant association between NHERF1 expression and the MDR-related proteins. A trend was observed between positive cytoplasmic NHERF1 (cNHERF1) expression and negative nuclear HIF-1α (nHIF-1α) expression (68.8% versus 31.3% respectively, P = 0.054). However, cytoplasmic P-gp (cP-gp) expression was positively correlated with both cHIF-1α and sorcin expression (P = 0.011; P = 0.002, respectively). Interestingly, nuclear NHERF1 (nNHERF1) staining was statistically associated with clinical response. In detail, 66.7% of patients with high nNHERF1 expression had a disease control rate, while 84.6% of subjects with negative nuclear expression of the protein showed progressive disease (P = 0.009). Multivariate analysis confirmed a significant correlation between nNHERF1 and clinical response (OR 0.06, P = 0.019). These results suggest that nuclear NHERF1 could be related to resistance to the EOX regimen in advanced GC patients, identifying this marker as a possible independent predictive factor. PMID:26126066

  15. Single nucleotide polymorphisms of the haptoglobin gene in non-small cell lung cancer treated with personalized peptide vaccination

    PubMed Central

    Waki, Kayoko; Yamada, Teppei; Yoshiyama, Koichi; Terazaki, Yasuhiro; Sakamoto, Shinjiro; Sugawara, Shunichi; Takamori, Shinzo; Itoh, Kyogo; Yamada, Akira

    2017-01-01

    The present study analyzed polymorphisms of the 5′ flanking region (from nt −840 to +151) of the haptoglobin gene in 120 patients with advanced non-small cell lung cancer (NSCLC) receiving personalized peptide vaccinations. In the region, six single nucleotide polymorphisms (SNPs) were confirmed, of which two, rs5472 and rs9927981, were completely linked to each other. The minor allele frequencies of rs5472/rs9927981 and rs4788458 were higher than those of the other three SNPs. The genotype frequencies of rs5472 or rs9927981 were A/A or C/C (42.5%, n=51), A/G or C/T (40.8%, n=49), and G/G or T/T (16.7%, n=20), respectively; and those of rs4788458 were T/T (34.2%, n=41), T/C (40.0%, n=48), and C/C (25.8%, n=31). The association between polymorphism rs5472/rs9927981 and prognosis, or between rs4788458 and prognosis, was analyzed further. However, no correlation was found between these SNPs and overall survival, regardless of subgroup analysis of gender, histology or concurrent therapy. These results suggest that the polymorphisms rs5472/rs9927981 and rs4788458 are not useful prognostic tools for patients with NSCLC treated with personalized peptide vaccination. PMID:28356990

  16. [A case of complete response for advanced gastric cancer with liver metastasis treated with combination chemotherapy of weekly paclitaxel and doxifluridine].

    PubMed

    Okabe, Toshio; Ohya, Toshihiro; Matsumoto, Hiroshi; Tago, Ken-Ichi; Totsuka, Osamu; Numaga, Yuki; Higuchi, Toru; Iesato, Hiroshi; Yokomori, Tadahiro; Kawate, Susumu; Takeyoshi, Izumi

    2009-01-01

    A 68-year-old man underwent total gastrectomy for Type 3 gastric cancer with liver metastasis. The final finding was T3(SE), N1, H1, P0, CY0(class IV), Stage IV, Cur C. After surgery, he was treated with combination chemotherapy of weekly paclitaxel(PTX)/doxifluridine(5'-DFUR). Paclitaxel was administered at a dose of 80 mg/m(2) on day 1, 8 and 15, and doxifluridine was orally administered at a dose of 533 mg/m(2) day for five days followed by withdrawal for two days. This regimen was repeated every four weeks. After 2 courses, the tumor marker level normalized, and the size of the liver metastasis was remarkably decreased. After 5 courses, a CT scan revealed the liver metastasis had disappeared, and he has now survived without recurrence after the disappearance of the liver metastasis. No severe adverse reactions were observed, and the man can be treated as an outpatient. This therapy may thus be effective in the treatment of advanced gastric cancer following non-curative operation.

  17. The value of forceps biopsy and core needle biopsy in prediction of pathologic complete remission in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

    PubMed

    Tang, Jing-Hua; An, Xin; Lin, Xi; Gao, Yuan-Hong; Liu, Guo-Chen; Kong, Ling-Heng; Pan, Zhi-Zhong; Ding, Pei-Rong

    2015-10-20

    Patients with pathological complete remission (pCR) after treated with neoadjuvant chemoradiotherapy (nCRT) have better long-term outcome and may receive conservative treatments in locally advanced rectal cancer (LARC). The study aimed to evaluate the value of forceps biopsy and core needle biopsy in prediction of pCR in LARC treated with nCRT. In total, 120 patients entered this study. Sixty-one consecutive patients received preoperative forceps biopsy during endoscopic examination. Ex vivo core needle biopsy was performed in resected specimens of another 43 consecutive patients. The accuracy for ex vivo core needle biopsy was significantly higher than forceps biopsy (76.7% vs. 36.1%; p < 0.001). The sensitivity for ex vivo core needle biopsy was significantly lower in good responder (TRG 3) than poor responder (TRG ≤ 2) (52.9% vs. 94.1%; p = 0.017). In vivo core needle biopsy was further performed in 16 patients with good response. Eleven patients had residual cancer cells in final resected specimens, among whom 4 (36.4%) patients were biopsy positive. In conclusion, routine forceps biopsy was of limited value in identifying pCR after nCRT. Although core needle biopsy might further identify a subset of patients with residual cancer cells, the accuracy was not substantially increased in good responders.

  18. Simultaneous Integrated Boost Using Intensity-Modulated Radiotherapy Compared With Conventional Radiotherapy in Patients Treated With Concurrent Carboplatin and 5-Fluorouracil for Locally Advanced Oropharyngeal Carcinoma

    SciTech Connect

    Clavel, Sebastien; Nguyen, David H.A.; Fortin, Bernard; Despres, Philippe; Khaouam, Nader; Donath, David; Soulieres, Denis; Guertin, Louis; Nguyen-Tan, Phuc Felix

    2012-02-01

    Purpose: To compare, in a retrospective study, the toxicity and efficacy of simultaneous integrated boost using intensity-modulated radiotherapy (IMRT) vs. conventional radiotherapy (CRT) in patients treated with concomitant carboplatin and 5-fluorouracil for locally advanced oropharyngeal cancer. Methods and Materials: Between January 2000 and December 2007, 249 patients were treated with definitive chemoradiation. One hundred patients had 70 Gy in 33 fractions using IMRT, and 149 received CRT at 70 Gy in 35 fractions. Overall survival, disease-free survival, and locoregional control were estimated using the Kaplan-Meier method. Results: Median follow-up was 42 months. Three-year actuarial rates for locoregional control, disease-free survival, and overall survival were 95.1% vs. 84.4% (p = 0.005), 85.3% vs. 69.3% (p = 0.001), and 92.1% vs. 75.2% (p < 0.001) for IMRT and CRT, respectively. The benefit of the radiotherapy regimen on outcomes was also observed with a Cox multivariate analysis. Intensity-modulated radiotherapy was associated with less acute dermatitis and less xerostomia at 6, 12, 24, and 36 months. Conclusions: This study suggests that simultaneous integrated boost using IMRT is associated with favorable locoregional control and survival rates with less xerostomia and acute dermatitis than CRT when both are given concurrently with chemotherapy.

  19. Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

    PubMed Central

    Mangana, Joanna; Cheng, Phil F.; Schindler, Katja; Weide, Benjamin; Held, Ulrike; Frauchiger, Anna L.; Romano, Emanuella; Kähler, Katharina C.; Rozati, Sima; Rechsteiner, Markus; Moch, Holger; Michielin, Olivier; Garbe, Claus; Hauschild, Axel; Hoeller, Christoph; Dummer, Reinhard; Goldinger, Simone M.

    2015-01-01

    Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78–13.2) compared to 8.26 months (95% CI 6.02–19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn’t reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs. PMID:26426340

  20. Clinical value of routine serum squamous cell carcinoma antigen in follow-up of patients with locally advanced cervical cancer treated with radiation or chemoradiation

    PubMed Central

    Oh, Jinju; Lee, Hyun Joo; Lee, Tae Sung; Kim, Ju Hyun; Koh, Suk Bong

    2016-01-01

    Objective The objective of this study was to evaluate the clinical benefits of routine squamous cell carcinoma antigen (SCC-Ag) monitoring of patients with locally advanced cervical squamous cell carcinoma treated with radiation or chemoradiation. Methods A total of 53 patients with recurrent cervical squamous cell carcinoma treated with radiotherapy or chemoradiation were enrolled in this study. A retrospective review of medical records was conducted. The role of routine monitoring of serum SCC-Ag was evaluated in terms of cost effectiveness and effect on survival after diagnosis of recurrence. Results Serum SCC-Ag abnormality (≥2.5 ng/mL) was observed in 62.3% of patients when recurrent disease was diagnosed. The first indicator of relapse was abnormal serum SCC-Ag level in 21 patients (39.6%), 10 of whom had asymptomatic recurrent disease amenable to salvage therapy. Adding SCC-Ag measurement to the basic follow up protocol improved the sensitivity for detecting recurrence (The sensitivity of the basic protocol vs. addition of SCC-Ag: 49.1% vs. 88.7%, P<0.001). Twenty-three patients who were candidates for salvage therapy with curative intent showed better survival compared with those who were not candidates for therapy (5-year survival: 36.6% vs. 0%, P=0.012). Conclusion Surveillance with routine serum SCC-Ag monitoring can better detect asymptomatic recurrent disease that is potentially amenable to salvage therapy with curative intent. Early diagnosis of recurrent disease that can be treated with salvage therapy may lead to better survival. PMID:27462593

  1. Customised, Individualised Treatment of Metastatic Non-Small-Cell Lung Carcinoma (NSCLC)

    PubMed Central

    Furrukh, Muhammad; Al-Moundhri, Mansour; Zahid, Khawaja F.; Kumar, Shiyam; Burney, Ikram

    2013-01-01

    A series of phase II and randomised phase III trials in Asia and Europe have confirmed recently that advanced stage non-small-cell lung carcinoma patients with adenocarcinoma subtypes harbouring specific mutations when subjected to targeted therapy experience equivalent survival outcomes as those treated with chemotherapy and are spared from its side effects. The concept of chemotherapy for all is fading, and therapy optimisation has emerged as a paradigm shift in treatment. This article briefly describes cellular mechanisms involved in lung carcinogenesis which provide a molecular basis for targeted therapy. Advances in molecular biology have improved our understanding of mechanisms involved in primary or secondary drug resistance. Evolving biomarkers of prognostic and predictive importance, and the impact of translational research on outcomes are also covered. A marker is considered prognostic if it predicts the outcome, regardless of the treatment, and predictive if it predicts the outcome of a specific therapy. PMID:23862025

  2. Evaluation of Three Small Molecular Drugs for Targeted Therapy to Treat Nonsmall Cell Lung Cancer

    PubMed Central

    Ni, Jun; Zhang, Li

    2016-01-01

    Objective: To guide the optimal selection among first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in clinical practice. This review attempted to provide a thorough comparison among three first-generation EGFR-TKIs, namely icotinib, erlotinib, and gefitinib, with regard to their molecular structure, pharmacokinetic parameters, clinical data, adverse reactions, and contraindications. Data Sources: An electronic literature search of the PubMed database and Google Scholar for all the available articles regarding gefitinib, icotinib, and erlotinib in the English language from January 2005 to December 2014 was used. Study Selection: The search terms or keywords included but not limited to “lung cancer”, “nonsmall cell lung cancer (NSCLC)”, “epidemiology”, “EGFR”, “TKIs”, and “optimal selection”. Results: As suggested by this review, even though the three first-generation EGFR-TKIs share the quinazoline structure, erlotinib had the strongest apoptosis induction activity because of its use of a different side-chain. The pharmacokinetic parameters indicated that both erlotinib and icotinib are affected by food. The therapeutic window of erlotinib is narrow, and the recommended dosage is close to the maximum tolerable dosage. Icotinib enjoys a wider therapeutic window, and its concentration in the blood is within a safe dosage range even if it is administered with food. Based on multiple large-scale clinical trials, erlotinib is universally applied as the first-line treatment. In marked contrast, icotinib is available only in China as the second- or third-line therapeutic approach for treating advanced lung cancer. In addition, it exhibits a similar efficacy but better safety profile than gefitinib. Conclusions: Although there is a paucity of literature regarding whether icotinib is superior to erlotinib, its superior toxicity profile, noninferior efficacy, and lower cost indicate that it is a better alternative

  3. Advances in treating premature ejaculation

    PubMed Central

    Şerefoğlu, Ege Can

    2014-01-01

    In spite of its high prevalence and long history, the ambiguity regarding the definition, epidemiology and management of premature ejaculation continues. Topical anesthetic creams and daily or on-demand selective serotonin reuptake inhibitor (SSRI) treatment forms the basis of pharmacotherapy for premature ejaculation today, in spite of low adherence by patients. Psychotherapy may improve the outcomes when combined with these treatment modalities. Tramadol and phosphodiesterase type 5 inhibitors have a limited role in the management of premature ejaculation. Further research is required to develop better options for the treatment of this common sexual disorder. PMID:25184045

  4. Advances in treating exposed fractures.

    PubMed

    Nogueira Giglio, Pedro; Fogaça Cristante, Alexandre; Ricardo Pécora, José; Partezani Helito, Camilo; Lei Munhoz Lima, Ana Lucia; Dos Santos Silva, Jorge

    2015-01-01

    The management of exposed fractures has been discussed since ancient times and remains of great interest to present-day orthopedics and traumatology. These injuries are still a challenge. Infection and nonunion are feared complications. Aspects of the diagnosis, classification and initial management are discussed here. Early administration of antibiotics, surgical cleaning and meticulous debridement are essential. The systemic conditions of patients with multiple trauma and the local conditions of the limb affected need to be taken into consideration. Early skeletal stabilization is necessary. Definitive fixation should be considered when possible and provisional fixation methods should be used when necessary. Early closure should be the aim, and flaps can be used for this purpose.

  5. Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus

    PubMed Central

    Liu, Xiaochun; Kambrick, Susan; Fu, Siqing; Naing, Aung; Subbiah, Vivek; Blumenschein, George R.; Glisson, Bonnie S.; Kies, Merrill S.; Tsimberidou, Apostolia M.; Wheler, Jennifer J.; Zinner, Ralph G.; Hong, David S.; Kurzrock, Razelle; Piha-Paul, Sarina A.

    2016-01-01

    BACKGROUND Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab. RESULTS The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)). PATIENTS AND METHODS We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus. CONCLUSION The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development. PMID:26933802

  6. Does Every Necrotizing Granulomatous Inflammation Identified by NSCLC Resection Material Require Treatment?

    PubMed

    Yakar, Fatih; Yakar, Aysun; Büyükpınarbaşılı, Nur; Erelel, Mustafa

    2016-04-11

    BACKGROUND Lung cancer and tuberculosis (TB) are two major public health problems. They can coexist or appear sequentially. In patients with TB, lung cancer risk is increased. However, vice versa is not crystal clear. In this study, we aimed to determine the development of TB in patients with resectabled non-small cell lung cancer (NSCLC) in a 2-year postoperative follow-up period. MATERIAL AND METHODS We conducted a retrospective cohort study at three university hospitals. Patients who had NSCLC surgery between 2009 and 2013 were included and patient records were reviewed for the presence of necrotizing granulomatous inflammation (NGI) in resected specimens. Demographic properties, tumor type, stage, location, type of surgery, tuberculosis history, and thorax CT findings were recorded. We searched for the development of tuberculosis within a 2-year period after surgery. RESULTS A total of 1027 patient cases were reviewed, of which 48 patients had NGI. The median age was 63 years. The most common type of cancer was squamous carcinoma; and lobectomy was the preferred operation (70.8%). Cancer involvement most commonly included the right lung (61.8%) and upper lobes (47,9%). Only 11 patients had anti-TB treatment postoperatively, which was based on radiological findings. Prior tuberculosis or anti-TB history, type, stage or localization of cancer, and adjuvant/neoadjuvant therapy were not found to be related to TB treatment. None of the study population had TB during the two-year follow-up period. Treatment decisions appeared mostly related to physician experience. There was no difference in the risk of developing TB between patients with or without treatment. This finding may change the management of our patients. CONCLUSIONS Every NGI discovered in NSCLC resected material does not always require anti-TB treatment.

  7. Is IMRT Superior or Inferior to 3DCRT in Radiotherapy for NSCLC? A Meta-Analysis

    PubMed Central

    Wen, Shimin; Feng, Xuqin; Fu, Xi; Liu, Yusong; Pu, Ke

    2016-01-01

    Introduction There are no adequate data to determine whether intensity-modulated radiotherapy (IMRT) is superior to three-dimensional conformal radiotherapy (3DCRT) in the treatment of non-small cell lung cancer (NSCLC). This meta-analysis was conducted to compare the clinical outcomes of IMRT and 3DCRT in the treatment of NSCLC. Methods No exclusions were made based on types of study design. We performed a literature search in PubMed, EMBASE and the Cochrane library databases from their inceptions to April 30, 2015. The overall survival (OS) and relative risk (RR) of radiation pneumonitis and radiation oesophagitis were evaluated. Two authors independently assessed the methodological quality and extracted data. Publication bias was evaluated by funnel plot using Egger’s test results. Results From the literature search, 10 retrospective studies were collected, and of those, 5 (12,896 patients) were selected for OS analysis, 4 (981 patients) were selected for radiation pneumonitis analysis, and 4 (1339 patients) were selected for radiation oesophagitis analysis. Cox multivariate proportional hazards models revealed that 3DCRT and IMRT had similar OS (HR = 0.96, P = 0.477) but that IMRT reduced the incidence of grade 2 radiation pneumonitis (RR = 0.74, P = 0.009) and increased the incidence of grade 3 radiation oesophagitis (RR = 2.47, P = 0.000). Conclusions OS of IMRT for NSCLC is not inferior to that of 3DCRT, but IMRT significantly reduces the risk of radiation pneumonitis and increases the risk of radiation oesophagitis compared to 3DCRT. PMID:27100968

  8. Characterization of FGFR1 Locus in sqNSCLC Reveals a Broad and Heterogeneous Amplicon.

    PubMed

    Rooney, Claire; Geh, Catherine; Williams, Victoria; Heuckmann, Johannes M; Menon, Roopika; Schneider, Petra; Al-Kadhimi, Katherine; Dymond, Michael; Smith, Neil R; Baker, Dawn; French, Tim; Smith, Paul D; Harrington, Elizabeth A; Barrett, J Carl; Kilgour, Elaine

    2016-01-01

    FGFR1 amplification occurs in ~20% of sqNSCLC and trials with FGFR inhibitors have selected FGFR1 amplified patients by FISH. Lung cancer cell lines were profiled for sensitivity to AZD4547, a potent, selective inhibitor of FGFRs 1-3. Sensitivity to FGFR inhibition was associated with but not wholly predicted by increased FGFR1 gene copy number. Additional biomarker assays evaluating expression of FGFRs and correlation between amplification and expression in clinical tissues are therefore warranted. We validated nanoString for mRNA expression analysis of 194 genes, including FGFRs, from clinical tumour tissue. In a panel of sqNSCLC tumours 14.4% (13/90) were FGFR1 amplified by FISH. Although mean FGFR1 expression was significantly higher in amplified samples, there was significant overlap in the range of expression levels between the amplified and non-amplified cohorts with several non-amplified samples expressing FGFR1 to levels equivalent to amplified samples. Statistical analysis revealed increased expression of FGFR1 neighboring genes on the 8p12 amplicon (BAG4, LSM1 and WHSC1L1) in FGFR1 amplified tumours, suggesting a broad rather than focal amplicon and raises the potential for codependencies. High resolution aCGH analysis of pre-clinical and clinical samples supported the presence of a broad and heterogeneous amplicon around the FGFR1 locus. In conclusion, the range of FGFR1 expression levels in both FGFR1 amplified and non-amplified NSCLC tissues, together with the breadth and intra-patient heterogeneity of the 8p amplicon highlights the need for gene expression analysis of clinical samples to inform the understanding of determinants of response to FGFR inhibitors. In this respect the nanoString platform provides an attractive option for RNA analysis of FFPE clinical samples.

  9. c-Met Expression Is a Marker of Poor Prognosis in Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma Treated With Chemoradiation

    SciTech Connect

    Baschnagel, Andrew M.; Williams, Lindsay; Hanna, Alaa; Chen, Peter Y.; Krauss, Daniel J.; Pruetz, Barbara L.; Akervall, Jan; Wilson, George D.

    2014-03-01

    Purpose: To examine the prognostic significance of c-Met expression in relation to p16 and epidermal growth factor receptor (EGFR) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with definitive concurrent chemoradiation. Methods and Materials: Archival tissue from 107 HNSCC patients treated with chemoradiation was retrieved, and a tissue microarray was assembled. Immunohistochemical staining of c-Met, p16, and EGFR was performed. c-Met expression was correlated with p16, EGFR, clinical characteristics, and clinical endpoints including locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS). Results: Fifty-one percent of patients were positive for p16, and 53% were positive for EGFR. Both p16-negative (P≤.001) and EGFR-positive (P=.019) status predicted for worse DFS. Ninety-three percent of patients stained positive for c-Met. Patients were divided into low (0, 1, or 2+ intensity) or high (3+ intensity) c-Met expression. On univariate analysis, high c-Met expression predicted for worse LRC (hazard ratio [HR] 2.27; 95% CI, 1.08-4.77; P=.031), DM (HR 4.41; 95% CI, 1.56-12.45; P=.005), DFS (HR 3.00; 95% CI, 1.68-5.38; P<.001), and OS (HR 4.35; 95% CI, 2.13-8.88; P<.001). On multivariate analysis, after adjustment for site, T stage, smoking history, and EGFR status, only high c-Met expression (P=.011) and negative p16 status (P=.003) predicted for worse DFS. High c-Met expression was predictive of worse DFS in both EGFR-positive (P=.032) and -negative (P=.008) patients. In the p16-negative patients, those with high c-Met expression had worse DFS (P=.036) than did those with low c-Met expression. c-Met expression was not associated with any outcome in the p16-positive patients. Conclusions: c-Met is expressed in the majority of locally advanced HNSCC cases, and high c-Met expression predicts for worse clinical outcomes. High c-Met expression predicted for worse DFS in p16

  10. Improvement of Cognitive and Psychomotor Performance in Patients with Mild to Moderate Obstructive Sleep Apnea Treated with Mandibular Advancement Device: A Prospective 1-Year Study

    PubMed Central

    Galic, Tea; Bozic, Josko; Pecotic, Renata; Ivkovic, Natalija; Valic, Maja; Dogas, Zoran

    2016-01-01

    Study Objectives: This study aimed to provide the evidence on effect of mandibular advancement device (MAD) therapy on long-term cognitive and psychomotor performance, excessive daytime sleepiness, and quality of life in patients with mild to moderate obstructive sleep apnea (OSA). Methods: A total of 15 patients with mild to moderate OSA were treated with MAD therapy and they were followed up after 3 mo and 1 y of therapy. The patients were tested on three different tests of cognitive and psychomotor performance using the computer-based system Complex Reactionmeter Drenovac (CRD-series) at baseline and at the time of follow-up, and the 36-Item Short Form Health Survey (SF-36) questionnaire and Epworth Sleepiness Scale were used to assess their quality of life and excessive daytime sleepiness, respectively. Results: The mean apnea-hypopnea index (AHI) decreased significantly from 22.9 ± 5.9 events/h at baseline, to 9.7 ± 4.5 events/h after 1 y of MAD therapy (p < 0.001). There was significant improvement on all three CRD-series tests used after 1 y of MAD therapy, considering total test solving time (TTST) and minimal single task solving time (MinT), whereas total number of errors committed during the tests (TE) remained unchanged. Self-reported measures, excessive daytime sleepiness, and three domains of quality of life, social functioning, general health perception, and health change following MAD therapy showed significant improvements after 1 y of MAD therapy. Conclusions: This study demonstrates significant improvements in cognitive and psychomotor performance, particularly in the domain of perceptive abilities, convergent thinking (constructing and solving simple mathematical tasks) and psychomotor reaction times, excessive daytime sleepiness, and quality of life in patients with mild to moderate OSA following MAD therapy. Citation: Galic T, Bozic J, Pecotic R, Ivkovic N, Valic M, Dogas Z. Improvement of cognitive and psychomotor performance in patients

  11. Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab

    PubMed Central

    Hwu, Wen-Jen; Kefford, Richard; Weber, Jeffrey S.; Daud, Adil; Hamid, Omid; Patnaik, Amita; Ribas, Antoni; Robert, Caroline; Gangadhar, Tara C.; Joshua, Anthony M.; Hersey, Peter; Dronca, Roxana; Joseph, Richard; Hille, Darcy; Xue, Dahai; Li, Xiaoyun Nicole; Kang, S. Peter; Ebbinghaus, Scot; Perrone, Andrea; Wolchok, Jedd D.

    2016-01-01

    Purpose We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827). Patients and Methods Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with ≥ 28 weeks of imaging. Pseudoprogression was defined as ≥ 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Response was assessed centrally per irRC and RECIST v1.1. Results Of the 655 patients with melanoma enrolled, 327 had ≥ 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived ≥ 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177). Conclusion Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment. PMID:26951310

  12. Dendrimer-Based Selective Proteostasis-Inhibition Strategy to Control NSCLC Growth and Progression.

    PubMed

    Walworth, Kyla; Bodas, Manish; Campbell, Ryan John; Swanson, Doug; Sharma, Ajit; Vij, Neeraj

    2016-01-01

    Elevated valosin containing protein (VCP/p97) levels promote the progression of non-small cell lung carcinoma (NSCLC). Although many VCP inhibitors are available, most of these therapeutic compounds have low specificity for targeted tumor cell delivery. Hence, the primary aim of this study was to evaluate the in vitro efficacy of dendrimer-encapsulated potent VCP-inhibitor drug in controlling non-small cell lung carcinoma (NSCLC) progression. The VCP inhibitor(s) (either in their pure form or encapsulated in generation-4 PAMAM-dendrimer with hydroxyl surface) were tested for their in vitro efficacy in modulating H1299 (NSCLC cells) proliferation, migration, invasion, apoptosis and cell cycle progression. Our results show that VCP inhibition by DBeQ was significantly more potent than NMS-873 as evident by decreased cell proliferation (p<0.0001, MTT-assay) and migration (p<0.05; scratch-assay), and increased apoptosis (p<0.05; caspase-3/7-assay) as compared to untreated control cells. Next, we found that dendrimer-encapsulated DBeQ (DDNDBeQ) treatment increased ubiquitinated-protein accumulation in soluble protein-fraction (immunoblotting) of H1299 cells as compared to DDN-control, implying the effectiveness of DBeQ in proteostasis-inhibition. We verified by immunostaining that DDNDBeQ treatment increases accumulation of ubiquitinated-proteins that co-localizes with an ER-marker, KDEL. We observed that proteostasis-inhibition with DDNDBeQ, significantly decreased cell migration rate (scratch-assay and transwell-invasion) as compared to the control-DDN treatment (p<0.05). Moreover, DDNDBeQ treatment showed a significant decrease in cell proliferation (p<0.01, MTT-assay) and increased caspase-3/7 mediated apoptotic cell death (p<0.05) as compared to DDN-control. This was further verified by cell cycle analysis (propidium-iodide-staining) that demonstrated significant cell cycle arrest in the G2/M-phase (p<0.001) by DDNDBeQ treatment as compared to control-DDN. Moreover

  13. Dendrimer-Based Selective Proteostasis-Inhibition Strategy to Control NSCLC Growth and Progression

    PubMed Central

    Walworth, Kyla; Bodas, Manish; Campbell, Ryan John; Swanson, Doug; Sharma, Ajit; Vij, Neeraj

    2016-01-01

    Elevated valosin containing protein (VCP/p97) levels promote the progression of non-small cell lung carcinoma (NSCLC). Although many VCP inhibitors are available, most of these therapeutic compounds have low specificity for targeted tumor cell delivery. Hence, the primary aim of this study was to evaluate the in vitro efficacy of dendrimer-encapsulated potent VCP-inhibitor drug in controlling non-small cell lung carcinoma (NSCLC) progression. The VCP inhibitor(s) (either in their pure form or encapsulated in generation-4 PAMAM-dendrimer with hydroxyl surface) were tested for their in vitro efficacy in modulating H1299 (NSCLC cells) proliferation, migration, invasion, apoptosis and cell cycle progression. Our results show that VCP inhibition by DBeQ was significantly more potent than NMS-873 as evident by decreased cell proliferation (p<0.0001, MTT-assay) and migration (p<0.05; scratch-assay), and increased apoptosis (p<0.05; caspase-3/7-assay) as compared to untreated control cells. Next, we found that dendrimer-encapsulated DBeQ (DDNDBeQ) treatment increased ubiquitinated-protein accumulation in soluble protein-fraction (immunoblotting) of H1299 cells as compared to DDN-control, implying the effectiveness of DBeQ in proteostasis-inhibition. We verified by immunostaining that DDNDBeQ treatment increases accumulation of ubiquitinated-proteins that co-localizes with an ER-marker, KDEL. We observed that proteostasis-inhibition with DDNDBeQ, significantly decreased cell migration rate (scratch-assay and transwell-invasion) as compared to the control-DDN treatment (p<0.05). Moreover, DDNDBeQ treatment showed a significant decrease in cell proliferation (p<0.01, MTT-assay) and increased caspase-3/7 mediated apoptotic cell death (p<0.05) as compared to DDN-control. This was further verified by cell cycle analysis (propidium-iodide-staining) that demonstrated significant cell cycle arrest in the G2/M-phase (p<0.001) by DDNDBeQ treatment as compared to control-DDN. Moreover

  14. Exploiting Tumor-Activated Testes Proteins to Enhance Efficacy of First-Line Chemotherapeutics in NSCLC

    DTIC Science & Technology

    2015-10-01

    Cisplatin (p=0.65, see Figure 3...l) TEX15 HORMAD1 SYCP1 Cisplatin HORMAD1 H1 56 8 H1 15 5 H1 29 9 H5 20 HC C4 4 H2 07 3 H1 57 H1 78 1 Ho p6 2 HC C5 15 A5 49 SK .L U. 1 H3 12 2 Ca lu... Cisplatin Cisplatin Sensitivity (Ranked Low to High) HORMAD1 Expression (green-low Red-high) Cell Line NSCLC Cell Line Vi ab ili ty (R el at iv

  15. Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease.

    PubMed

    Mahmood, Malik Quasir; Ward, Chris; Muller, Hans Konrad; Sohal, Sukhwinder Singh; Walters, Eugene Haydn

    2017-03-01

    NSCLC is a leading cause of morbidity and mortality worldwide. It includes adeno- and squamous cell carcinoma. In the background, COPD and smoking play a vital role in development of NSCLC. Local progression and metastasis of NSCLC has been associated with various mechanisms, but in particular by a process called epithelial mesenchymal transition (EMT), which is implicated in COPD pathogenesis. In this study, we have investigated whether expression of EGFR (activation marker) and S100A4, vimentin and N-cadherin (as EMT) is different both in central and leading edge of NSCLC and to what extent related to EMT activity of both small and large airways, stage and differentiation of NSCLC. We have investigated EMT biomarkers (S100A4, vimentin, and N-cadherin), an epithelial activation marker (EGFR) and a vascularity marker (Type-IV collagen) in surgically resected tissue from patients with NSCLC (adeno- and squamous cell carcinoma), and compared them with expression in the corresponding non-tumorous airways. EGFR, S100A4, vimentin, N-cadherin expression was higher in tumor cells located at the peripheral leading edge of NSCLC when compared with centrally located tumor cells of same subjects (P < 0.01). Type-IV collagen-expressing blood vessels were also more at the leading edge in comparison with central parts of NSCLC. EGFR and S100A4 expression was related to differentiation status (P < 0.05) and TNM stage (P < 0.05) of NSCLC. Moreover, EMT markers in the leading edge were significantly related to airway EMT activity, while peripheral edge vascularity of squamous cell carcinoma only was significantly related to large airway Rbm vascularity (P < 0.05). EGFR- and EMT-related protein expression was markedly high in the peripheral leading edge of NSCLCs and related to tumor characteristics associated with poor prognosis. The relationships between EMT-related tumor biomarker expression and those in the airway epithelium and Rbm provide a background for utility of

  16. Our experiences with erlotinib in second and third line treatment patients with advanced stage IIIB/ IV non-small cell lung cancer.

    PubMed

    Mehić, Bakir; Stanetić, Mirko; Tinjić, Ljuljeta; Smoljanović, Vlatka

    2008-11-01

    HeadHER1/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to 80% of NSCLCs. The study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV open-label, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV) NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H) were selected from two Clinical centres (Sarajevo and Banja Luka). The aim of study was to evaluated efficacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of 14th May 2008 were included in analysis of data (n = 19). This population is defined as the Intent to Treat (ITT) population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. The findings are consistent with the results of the randomized, placebo-controlled BR.21 study. Indicating that erlotinib is an effective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost 84%, and PFS was approximately 24,7 weeks (compared with 44% and 9,7 weeks for erlotinib reported in phase III). Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions. 24% of patients experienced an SAE (most commonly gastrointestinal (GI) disorders).

  17. Plasma cell-free DNA levels and integrity in patients with chest radiological findings: NSCLC versus benign lung nodules.

    PubMed

    Szpechcinski, Adam; Rudzinski, Piotr; Kupis, Wlodzimierz; Langfort, Renata; Orlowski, Tadeusz; Chorostowska-Wynimko, Joanna

    2016-05-01

    Effective discrimination between lung cancer and benign tumours is a common clinical problem in the differential diagnosis of solitary pulmonary nodules. The analysis of cell-free DNA (cfDNA) in blood may greatly aid the early detection of lung cancer by evaluating cancer-related alterations. The plasma cfDNA levels and integrity were analysed in 65 non-small cell lung cancer (NSCLC) patients, 28 subjects with benign lung tumours, and 16 healthy controls using real-time PCR. The NSCLC patients demonstrated significantly higher mean plasma cfDNA levels compared with those with benign tumours (P = 0.0009) and healthy controls (P < 0.0001). The plasma cfDNA integrity in healthy individuals was significantly different than that found in patients with NSCLC or benign lung tumours (P < 0.0003). In ROC curve analysis, plasma cfDNA levels >2.8 ng/ml provided 86.4% sensitivity and 61.4% specificity in discriminating NSCLC from benign lung pathologies and healthy controls. cfDNA integrity showed better discriminatory power (91% sensitivity, 68.2% specificity). These data demonstrate that plasma cfDNA concentration and integrity analyses can significantly differentiate between NSCLC and benign lung tumours. The diagnostic capacity of the quantitative cfDNA assay is comparable to the values presented by conventional imaging modalities used in clinical practice.

  18. ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin - reversal by a chemical chaperone.

    PubMed

    Castilho, Gabriela; Okuda, Ligia S; Pinto, Raphael S; Iborra, Rodgiro T; Nakandakare, Edna R; Santos, Celio X; Laurindo, Francisco R; Passarelli, Marisa

    2012-07-01

    ATP-binding cassette transporter A1 mediates the export of excess cholesterol from macrophages, contributing to the prevention of atherosclerosis. Advanced glycated albumin (AGE-alb) is prevalent in diabetes mellitus and is associated with the development of atherosclerosis. Independently of changes in ABCA-1 mRNA levels, AGE-alb induces oxidative stress and reduces ABCA-1 protein levels, which leads to macrophage lipid accumulation. These metabolic conditions are known to elicit endoplasmic reticulum (ER) stress. We sought to determine if AGE-alb induces ER stress and unfolded protein response (UPR) in macrophages and how disturbances to the ER could affect ABCA-1 content and cholesterol efflux in macrophages. AGE-alb induced a time-dependent increase in ER stress and UPR markers. ABCA-1 content and cellular cholesterol efflux were reduced by 33% and 47%, respectively, in macrophages treated with AGE-alb, and both were restored by treatment with 4-phenyl butyric acid (a chemical chaperone that alleviates ER stress), but not MG132 (a proteasome inhibitor). Tunicamycin, a classical ER stress inductor, also impaired ABCA-1 expression and cholesterol efflux (showing a decrease of 61% and 82%, respectively), confirming the deleterious effect of ER stress in macrophage cholesterol accumulation. Glycoxidation induces macrophage ER stress, which relates to the reduction in ABCA-1 and in reverse cholesterol transport, endorsing the adverse effect of macrophage ER stress in atherosclerosis. Thus, chemical chaperones that alleviate ER stress may represent a useful tool for the prevention and treatment of atherosclerosis in diabetes.

  19. [A Case of Double Cancer of Initially Unresectable Sigmoid Colon Cancer and Advanced Gastric Cancer Treated with Curative Resection after mFOLFOX6 Therapy].

    PubMed

    Yoshikawa, Toru; Aoki, Kazunori; Mitsuhashi, Yuto; Tomiura, Satoko; Suto, Akiko; Miura, Takuya; Ikenaga, Shojirokazunori; Shibasaki, Itaru; Endo, Masaaki

    2016-03-01

    A 61-year-old man was admitted to our hospital because of a complaint of blood in stool. He was diagnosed with advanced colon and gastric cancers. Computed tomography (CT) revealed a sigmoid tumor with invasion to the bladder, a metastatic tumor in the lateral segmental branch of the left hepatic lobe, and ascites. He was diagnosed with initially unresectable double cancer. Ileostomy was performed immediately, and he was treated with modified (m) FOLFOX6 regimen (oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin). After 6 courses of the mFOLFOX6 regimen, CT revealed that the primary lesion of the sigmoid colon and liver metastasis had reduced in size, and the ascites had disappeared. Gastroscopy revealed that the gastric cancer had disappeared. Biopsy results were negative. Accordingly, his gastric cancer was diagnosed as treatment effect Grade 3. After 8 courses of mFOLFOX6 therapy, sigmoidectomy, partial resection of the bladder, and partial resection of the liver were performed. Gastric cancer was not resected in accordance with his will. Although 40 months has passed after the radical resection, neither the sigmoid colon cancer nor the gastric cancer recurred.

  20. A meta-analysis of efficacy and safety of antibodies targeting PD-1/PD-L1 in treatment of advanced nonsmall cell lung cancer

    PubMed Central

    Wang, Cuihua; Yu, Xuetao; Wang, Wei

    2016-01-01

    Abstract Background: Nonsmall cell lung cancer (NSCLC)-patients treated with standard chemotherapy experienced progression rapidly. A novel therapy based on programed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors showed an increasing potential in several malignancies including advanced NSCLC. Objectives: This article is a meta-analysis aiming to systematically evaluate the efficacy and safety profiles of PD-1/PD-L1 agents in patients with NSCLC. Data sources: Data were collected from eligible studies searched from PubMed, ScienceDirect, and Web of Science. Synthesis methods: Pooled hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) was estimated to assess the efficacy of PD-1/PD-L1 inhibitors versus docetaxel, pooled odds ratio (OR) was calculated for objective response rate (ORR). The overall frequency was estimated for 1-year OS, 1-year progression-free survival, and ORR. A subgroup analysis among NSCLC patients tested with different epidermal growth factor receptor (EGFR) status was also performed to figure out the relationship between EGFR status and efficacy of PD-1/PD-L1 therapies. OR for occurrence of any grade and grade 3 to 5 treatment-related adverse effect was calculated for evaluating the safety of PD-1/PD-L1 therapies. Results: Nine studies were included in this analysis. The pooled HRs for OS and PFS were 0.68 (95% confidence interval [CI] 0.61–0.75) and 0.83 (95% CI 0.75–0.91), respectively, the pooled OR for ORR was 1.83 (95% CI 1.41–2.36), indicating a significant improvement in OS, PFS, and ORR. In the results of subgroup analysis, the HR for OS in NSCLC patients was 1.05 (95% CI 0.69–1.59) in patients with mutant EGFR and 0.66 (95% CI 0.57–0.77) in patients with wild-type EGFR status. OR for occurrence was 0.36 (95% CI 0.28–0.46) in any grade treatment-related adverse effect and 0.18 (95% CI 0.14–0.22) in grade 3 to 5 treatment-related adverse effect, suggesting a superior safety profile of

  1. Intratumoral Epiregulin Is a Marker of Advanced Disease in Non–Small Cell Lung Cancer Patients and Confers Invasive Properties on EGFR-Mutant Cells

    PubMed Central

    Zhang, Jie; Iwanaga, Kentaro; Choi, Kuicheon C.; Wislez, Marie; Raso, Maria Gabriela; Wei, Wei; Wistuba, Ignacio I.; Kurie, Jonathan M.

    2012-01-01

    Non–small cell lung cancer (NSCLC) cells with activating epidermal growth factor receptor (EGFR) somatic mutations have unique biological properties, including high expression of the ErbB ligand epiregulin; however, the biological role of epiregulin in these cells has not been elucidated. To examine its role, we used an immunohistochemical approach to detect epiregulin expression in NSCLC biopsy samples and pharmacologic and genetic approaches to inhibit epiregulin in cultured NSCLC cells. In NSCLC biopsy samples, epiregulin was detected in 237 of 366 (64.7%) tumors, which correlated with nodal metastasis and a shorter duration of survival. In EGFR-mutant NSCLC cell lines, treatment with a small-molecule EGFR tyrosine kinase inhibitor diminished mRNA levels of the gene encoding epiregulin (EREG). The ability of EGFR-mutant NSCLC cells to invade through Matrigel in vitro was inhibited by treatment with an anti-epiregulin neutralizing antibody or by transfection with an EREG short hairpin RNA. Collectively, these findings show that epiregulin expression correlated with advanced disease, was EGFR dependent, and conferred invasive properties on NSCLC cells. Additional studies are warranted in NSCLC patients to evaluate whether epiregulin expression predicts the metastatic potential of primary tumors and whether anti-epiregulin treatment strategies are efficacious in the prevention of metastasis. PMID:19138957

  2. The cost-effectiveness of a NSCLC patient assistance program for pemetrexed maintenance therapy in People’s Republic of China

    PubMed Central

    Shi, Qiang; Hu, Shanlian; Furnback, Wesley E; Guzauskas, Gregory F; Shen, Jiejing; Wang, Bruce CM

    2017-01-01

    Background Eli Lilly and the China Primary Health Care Foundation are currently implementing a patient assistance program (PAP) in China, which allows first-line nonsquamous non-small-cell lung cancer (NSCLC) patients who complete four cycles of pemetrexed induction therapy to receive free, continuous pemetrexed maintenance therapy. Objective To estimate the cost-effectiveness of pemetrexed maintenance therapy vs basic standard care (BSC) and the economic impacts of providing a PAP for pemetrexed maintenance therapy to NSCLC patients who have completed pemetrexed induction therapy in a Chinese health care setting. Methods We developed a novel decision-analytic model to evaluate the long-term costs and clinical efficacy of pemetrexed plus BSC vs BSC alone. We utilized a three-state (progression-free survival, progressed disease, and dead) partition survival model for both the clinical and economic aspects of the analysis. Cost and health utility estimates were derived from the literature. We performed a scenario analysis to estimate the real-world impact of introducing the PAP in China by comparing the use of the PAP vs non-PAP. Model uncertainty was evaluated using one-way and multivariate probabilistic sensitivity analysis. Results Compared to BSC, pemetrexed plus BSC resulted in a gain of 0.22 years of life (95% credible range [CR]: 0.04–0.46) and 0.13 quality-adjusted life years (95% CR: 0.04–0.26) per patient, at an increased cost of $28,105 (95% CR: −$22,720 to $48,646) without a PAP and $3,068 (95% CR: −$1,263 to $9,163) with a PAP. The incremental cost-effectiveness ratio for pemetrexed plus BSC vs BSC alone was cost-prohibitive at $222,700 for non-PAP, but cost-effective at $24,319 with a PAP. Conclusion Our study suggests that maintenance pemetrexed therapy following pemetrexed induction for patients with advanced NSCLC is likely to be highly non-cost-effective in the absence of a PAP, but the pending implementation of the PAP promises to make it

  3. Treatment of advanced non-small-cell lung cancer with epidermal growth factor receptor (EGFR) mutation or ALK gene rearrangement: results of an international expert panel meeting of the Italian Association of Thoracic Oncology.

    PubMed

    Gridelli, Cesare; de Marinis, Filippo; Cappuzzo, Federico; Di Maio, Massimo; Hirsch, Fred R; Mok, Tony; Morgillo, Floriana; Rosell, Rafael; Spigel, David R; Yang, James Chih-Hsin; Ciardiello, Fortunato

    2014-05-01

    The availability of targeted drugs has made the assessment of the EGFR mutation and ALK rearrangement critical in choosing the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC). In May 2013, the Italian Association of Thoracic Oncology (AIOT) organized an International Experts Panel Meeting to review strengths and limitations of the available evidence for the diagnosis and treatment of advanced NSCLC with EGFR or anaplastic lymphoma kinase (ALK) alterations and to discuss implications for clinical practice and future clinical research. All patients with advanced NSCLC, with the exclusion of pure squamous cell carcinoma in former or current smokers, should be tested for EGFR mutations and ALK rearrangements before decisions are made on first-line treatment. First-line treatment of EGFR-mutated cases should be with an EGFR tyrosine kinase inhibitor (TKI). Any available agent (gefitinib, erlotinib, or afatinib) can be used, until further data from comparative studies may better guide TKI selection. As general rule, and when clinically feasible, results of EGFR mutational status should be awaited before starting first-line treatment. Panelists agreed that the use of crizotinib is justified in any line of treatment. Although solid evidence supporting the continuation of EGFR TKIs or crizotinib beyond progression is lacking, in some cases (minimal, asymptomatic progression, or oligoprogression manageable by local therapy), treatment continuation beyond progression could be justified. Experimental strategies to target tumor heterogeneity and to treat patients after failure of EGFR TKIs or crizotinib are considered high-priority areas of research. A number of relevant research priorities were identified to optimize available treatment options.

  4. 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

  5. Volumetric CT-based segmentation of NSCLC using 3D-Slicer

    PubMed Central

    Velazquez, Emmanuel Rios; Parmar, Chintan; Jermoumi, Mohammed; Mak, Raymond H.; van Baardwijk, Angela; Fennessy, Fiona M.; Lewis, John H.; De Ruysscher, Dirk; Kikinis, Ron; Lambin, Philippe; Aerts, Hugo J. W. L.

    2013-01-01

    Accurate volumetric assessment in non-small cell lung cancer (NSCLC) is critical for adequately informing treatments. In this study we assessed the clinical relevance of a semiautomatic computed tomography (CT)-based segmentation method using the competitive region-growing based algorithm, implemented in the free and public available 3D-Slicer software platform. We compared the 3D-Slicer segmented volumes by three independent observers, who segmented the primary tumour of 20 NSCLC patients twice, to manual slice-by-slice delineations of five physicians. Furthermore, we compared all tumour contours to the macroscopic diameter of the tumour in pathology, considered as the “gold standard”. The 3D-Slicer segmented volumes demonstrated high agreement (overlap fractions > 0.90), lower volume variability (p = 0.0003) and smaller uncertainty areas (p = 0.0002), compared to manual slice-by-slice delineations. Furthermore, 3D-Slicer segmentations showed a strong correlation to pathology (r = 0.89, 95%CI, 0.81–0.94). Our results show that semiautomatic 3D-Slicer segmentations can be used for accurate contouring and are more stable than manual delineations. Therefore, 3D-Slicer can be employed as a starting point for treatment decisions or for high-throughput data mining research, such as Radiomics, where manual delineating often represent a time-consuming bottleneck. PMID:24346241

  6. Pharmacogenomics of platinum-based chemotherapy response in NSCLC: a genotyping study and a pooled analysis

    PubMed Central

    Chen, Juan; Wang, Zhan; Zou, Ting; Cui, Jiajia; Yin, Jiye; Zheng, Wei; Jiang, Wuzhong; Zhou, Honghao; Liu, Zhaoqian

    2016-01-01

    Published data showed inconsistent results about associations of extensively studied polymorphisms with platinum-based chemotherapy response. Our study aimed to provide reliable conclusions of these associations by detecting genotypes of the SNPs in a larger sample size and summarizing a comprehensive pooled analysis. 13 SNPs in 8 genes were genotyped in 1024 NSCLC patients by SequenomMassARRAY. 39 published studies and our study were included in meta-analysis. Patients with GA or GG genotypes of XRCC1 G1196 had better response than AA genotype carriers (Genotyping study: OR = 0.72, 95%CI: 0.53-0.96, P = 0.028; Meta-analysis: OR = 0.74, 95%CI: 0.62-0.89, P = 0.001). Patients carrying CT or TT genotypes of XRCC1 C580T could be more sensitive to platinum-based chemotherapy compared to patients with CC genotype (OR = 0.54, 95%CI: 0.37-0.80, P = 0.002). CC genotype of XRCC3 C18067T carriers showed more resistance to platinum-based chemotherapy when compared to those with CT or TT genotypes (OR = 0.69, 95%CI: 0.52-0.91, P = 0.009). Our study indicated that XRCC1 G1196A/C580T and XRCC3 C18067T should be paid attention for personalized platinum-based chemotherapy in NSCLC patients. PMID:27248474

  7. Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL

    PubMed Central

    Iaboni, Margherita; Russo, Valentina; Fontanella, Raffaela; Roscigno, Giuseppina; Fiore, Danilo; Donnarumma, Elvira; Esposito, Carla Lucia; Quintavalle, Cristina; Giangrande, Paloma H; de Franciscis, Vittorio; Condorelli, Gerolama

    2016-01-01

    TNF-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent for its remarkable ability to selectively induce apoptosis in cancer cells, without affecting the viability of healthy bystander cells. The TRAIL tumor suppressor pathway is deregulated in many human malignancies including lung cancer. In human non-small cell lung cancer (NSCLC) cells, sensitization to TRAIL therapy can be restored by increasing the expression levels of the tumor suppressor microRNA-212 (miR-212) leading to inhibition of the anti-apoptotic protein PED/PEA-15 implicated in treatment resistance. In this study, we exploited a previously described RNA aptamer inhibitor of the tyrosine kinase receptor Axl (GL21.T) expressed on lung cancer cells, as a means to deliver miR-212 into human NSCLC cells expressing Axl. We demonstrate efficient delivery of miR-212 following conjugation of the miR to GL21.T (GL21.T-miR212 chimera). We show that the chimera downregulates PED and restores TRAIL-mediate cytotoxicity in cancer cells. Importantly, treatment of Axl+ lung cancer cells with the chimera resulted in (i) an increase in caspase activation and (ii) a reduction of cell viability in combination with TRAIL therapy. In conclusion, we demonstrate that the GL21.T-miR212 chimera can be employed as an adjuvant to TRAIL therapy for the treatment of lung cancer. PMID:27111415

  8. MLN4924 suppresses the BRCA1 complex and synergizes with PARP inhibition in NSCLC cells.

    PubMed

    Guo, Zong-Pei; Hu, Ying-Chun; Xie, Yu; Jin, Feng; Song, Zhi-Quan; Liu, Xiao-Dan; Ma, Teng; Zhou, Ping-Kun

    2017-01-29

    Like ubiquitination, several studies have demonstrated that neddylation is implicated to be involved in the double strand break repair. BRCA1 is one of the key repair factors in the homologous recombination repair and may play a downstream role of the neddylation. BRCA1 is also a frequently mutated gene in cancers, which serve as the targets for PARP inhibitors. Here we further investigated the correlation between neddylation and BRCA1 complex using neddylation inhibitor MLN4924. MLN4924 efficiently inhibited the recruitment of components of BRCA1 complex to DNA damage sites. Thus MLN4924 may collaborate with PARP inhibitor to suppress tumor. Our results showed that combination MLN4924 and PARP inhibitor Olaparib impaired the DNA repair process in NSCLC cells. Furthermore, MLN4924 and Olaparib significantly inhibited the cancer cell growth. Kaplan-Meier survival analysis from lung cancer patients showed that high expression of NEDD8, BRCA1 and PARPs correlate with worse overall survival. Thus the combination of MLN4924 and PARP inhibitor may serve as a new strategy for NSCLC treatment.

  9. XIAP inhibits mature Smac-induced apoptosis by degrading it through ubiquitination in NSCLC

    PubMed Central

    Qin, Sida; Yang, Chengcheng; Zhang, Boxiang; Li, Xiang; Sun, Xin; Li, Gang; Zhang, Jing; Xiao, Guodong; Gao, Xiao; Huang, Guanghong; Wang, Peili; Ren, Hong

    2016-01-01

    X-linked inhibitor of apoptosis protein (XIAP) and second mitochondrial-derived activator of caspase (Smac) are two important prognostic biomarkers for cancer. They are negatively correlated in many types of cancer. However, their relationship is still unknown in lung cancer. In the present study, we found that there was a negative correlation between Smac and XIAP at the level of protein but not mRNA in NSCLC patients. However, XIAP overexpression had no effect on degrading endogenous Smac in lung cancer cell lines. Therefore, we constructed plasmids with full length of Smac (fSmac) and mature Smac (mSmac) which located in cytoplasm instead of original mitochondrial location, and was confirmed by immunofluorescence. Subsequently, we found that mSmac rather than fSmac was degraded by XIAP and inhibited cell viability. CHX chase assay and ubiquitin assay were performed to illustrate XIAP degraded mSmac through ubiquitin pathway. Overexpression of XIAP partially reverted apoptotic induction and cell viability inhibition by mSmac, which was due to inhibiting caspase-3 activation. In nude mouse xenograft experiments, mSmac inhibited Ki-67 expression and slowed down lung cancer growth, while XIAP partially reversed the effect of mSmac by degrading it. In conclusion, XIAP inhibits mature Smac-induced apoptosis by degrading it through ubiquitination in NSCLC. PMID:27498621

  10. Volumetric CT-based segmentation of NSCLC using 3D-Slicer

    NASA Astrophysics Data System (ADS)

    Velazquez, Emmanuel Rios; Parmar, Chintan; Jermoumi, Mohammed; Mak, Raymond H.; van Baardwijk, Angela; Fennessy, Fiona M.; Lewis, John H.; de Ruysscher, Dirk; Kikinis, Ron; Lambin, Philippe; Aerts, Hugo J. W. L.

    2013-12-01

    Accurate volumetric assessment in non-small cell lung cancer (NSCLC) is critical for adequately informing treatments. In this study we assessed the clinical relevance of a semiautomatic computed tomography (CT)-based segmentation method using the competitive region-growing based algorithm, implemented in the free and public available 3D-Slicer software platform. We compared the 3D-Slicer segmented volumes by three independent observers, who segmented the primary tumour of 20 NSCLC patients twice, to manual slice-by-slice delineations of five physicians. Furthermore, we compared all tumour contours to the macroscopic diameter of the tumour in pathology, considered as the ``gold standard''. The 3D-Slicer segmented volumes demonstrated high agreement (overlap fractions > 0.90), lower volume variability (p = 0.0003) and smaller uncertainty areas (p = 0.0002), compared to manual slice-by-slice delineations. Furthermore, 3D-Slicer segmentations showed a strong correlation to pathology (r = 0.89, 95%CI, 0.81-0.94). Our results show that semiautomatic 3D-Slicer segmentations can be used for accurate contouring and are more stable than manual delineations. Therefore, 3D-Slicer can be employed as a starting point for treatment decisions or for high-throughput data mining research, such as Radiomics, where manual delineating often represent a time-consuming bottleneck.

  11. Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC.

    PubMed

    Che, Ting-Fang; Lin, Ching-Wen; Wu, Yi-Ying; Chen, Yu-Ju; Han, Chia-Li; Chang, Yih-leong; Wu, Chen-Tu; Hsiao, Tzu-Hung; Hong, Tse-Ming; Yang, Pan-Chyr

    2015-11-10

    Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo. Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics.

  12. Genetic variations in the transforming growth factor-beta pathway as predictors of survival in advanced non-small cell lung cancer

    PubMed Central

    Stewart, David J.; Spitz, Margaret R.; Hildebrandt, Michelle A.T.; Lu, Charles; Lin, Jie; Gu, Jian; Huang, Maosheng; Lippman, Scott M.; Wu, Xifeng

    2011-01-01

    The magnitude of benefit is variable for advanced non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy. The purpose of this study is to determine whether genetic variations in the transforming growth factor-beta (TGF-β) pathway are associated with clinical outcomes in NSCLC patients receiving first-line platinum-based chemotherapy. Five hundred and ninety-eight advanced-stage NSCLC patients who received first-line platinum-based chemotherapy with or without radiotherapy were recruited at the MD Anderson Cancer Center between 1995 and 2007. DNA from blood was genotyped for 227 single nucleotide polymorphisms (SNPs) in 23 TGF-β pathway-related genes to evaluate their associations with overall survival. In individual SNP analysis, 22 variants were significantly associated with overall survival, of which the strongest associations were found for BMP2:rs235756 [hazard ratio (HR) = 1.45; 95% confidence interval (CI), 1.11–1.90] and SMAD3:rs4776342 (HR = 1.25; 95% CI, 1.06–1.47). Fifteen and 18 genetic loci displayed treatment-specific associations for chemotherapy and chemoradiation, respectively, identifying a majority of the cases who would be predicted to respond favorably to a specific treatment regimen. BMP2:rs235753 and a haplotype in SMAD3 were associated with overall survival for both treatment modalities. Cumulative effect analysis showed that multiple risk genotypes had a significant dose-dependent effect on overall survival (Ptrend = 2.44 x 10−15). Survival tree analysis identified subgroups of patients with dramatically different median survival times of 45.39 versus 13.55 months and 18.02 versus 5.89 months for high- and low- risk populations when treated with chemoradiation and chemotherapy, respectively. These results suggest that genetic variations in the TGF-β pathway are potential predictors of overall survival in NSCLC patients treated with platinum-based chemotherapy with or without radiation. PMID:21515830

  13. Isorhamnetin flavonoid synergistically enhances the anticancer activity and apoptosis induction by cis-platin and carboplatin in non-small cell lung carcinoma (NSCLC).

    PubMed

    Zhang, Bao-Yi; Wang, Yan-Ming; Gong, Hai; Zhao, Hui; Lv, Xiao-Yan; Yuan, Guang-Hui; Han, Shao-Rong

    2015-01-01

    The development of novel antitumor drugs for the treatment of non-small cell lung carcinoma NSCLC is imperative in order to improve the efficacy of lung cancer therapy and prognosis. In the current study, we demonstrated the antitumor activity of isorhamnetin and its combinations with cisplatin and carboplatin against A-549 lung cancer cells. In order to assess the anticancer enhancing effect of isorhamnetin on cisplatin and carboplatin, A-549 cells were treated with isorhamnetin, cisplatin, carboplatin and their combinations and cell viability, cell apoptosis, cell cycle arrest as well as loss of mitochondrial membrane potential were evaluated by MTT assay, flow cytometry, confocal microscopy and fluorescence microscopy. The effect of the drugs on cancer cell migration, microtubule depolymerization as well activation of caspases was also studied. The results revealed that, as compared to single drug treatment, the combination of isorhamnetin with cisplatin and carboplatin resulted in greater effect in inhibiting cancer cell growth and inducing apoptosis. Combination of isorhamnetin with cisplatin and carboplatin resulted in more potent apoptosis induction as revealed by fluorescence microscopy using AO/PI double staining. Isorhamnetin and its combinations also triggered microtubule distortion and depolymerization. The combination of isorhamnetin with cisplatin and carboplatin increased the number of cells in G2/M phase dramatically as compared to single drug treatment. Moreover, isorhamnetin and its combinations with known anticancer drugs induced disruption of the mitochondrial membrane potential as well as activation of caspases 3, 9 and poly-(ADP-ribose) polymerase in A-549 cells. Isorhamnetin as well as its combinations with cisplatin and carboplatin resulted in inhibition of cancer cell migration significantly. Results of the current study suggest that isorhamnetin combinations with cisplatin and carboplatin might be a potential clinical chemotherapeutic

  14. Advanced H2O2 oxidation for diethyl phthalate degradation in treated effluents: effect of nitrate on oxidation and a pilot-scale AOP operation.

    PubMed

    Ko, K B; Park, C G; Moon, T H; Ahn, Y H; Lee, J K; Ahn, K H; Park, J H; Yeom, I T

    2008-01-01

    One of the objectives of this study was to delineate the effect of nitrate on diethyl phthalate (DEP) oxidation by conducting a bench-scale ultraviolet (UV)/H2O2 and O3/H2O2 operations as suggested in a previous study. We also aim to investigate DEP oxidation at various UV doses and H2O2 concentrations by performing a pilot-scale advanced oxidation processes (AOP) system, into which a portion of the effluent from a pilot-scale membrane bioreactor (MBR) plant was pumped. In the bench-scale AOP operation, the O3 oxidation alone as well as the UV irradiation without H2O2 addition could be among the desirable alternatives for the efficient removal of DEP dissolved in aqueous solutions at a low DEP concentration range of 85+/-15 microg/L. The adverse effect in the UV/H2O2 process was significantly greater than that in the UV oxidation alone, and its oxidation was almost halved by the nitrate. However, the nitrate clearly enhanced the DEP oxidation in the O3 oxidation and O3/H2O2 process. Especially, the addition of nitrate almost doubled the DEP oxidation efficiency in the O3/H2O2 process. The series of pilot-scale AOP operations confirmed that about 30-50% of DEP dissolved in the treated MBR effluent streams was, at least, oxidized by the O3 oxidation alone as well as the UV irradiation without H2O2 addition. The UV photolysis of H2O2 was most effective for DEP degradation with an H2O2 concentration of 40 mg/L at a UV dose of 500 mJ/cm2.

  15. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.

    PubMed

    Yuan, Jianda; Adamow, Matthew; Ginsberg, Brian A; Rasalan, Teresa S; Ritter, Erika; Gallardo, Humilidad F; Xu, Yinyan; Pogoriler, Evelina; Terzulli, Stephanie L; Kuk, Deborah; Panageas, Katherine S; Ritter, Gerd; Sznol, Mario; Halaban, Ruth; Jungbluth, Achim A; Allison, James P; Old, Lloyd J; Wolchok, Jedd D; Gnjatic, Sacha

    2011-10-04

    Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.

  16. Predictive assessment in pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy

    PubMed Central

    Yuan, Zhengrong; Li, Jiao; Hu, Ruiqi; Jiao, Yang; Han, Yingying; Weng, Qiang

    2015-01-01

    Published data have shown inconsistent results about the pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy. This meta-analysis aimed to summarize published findings and provide more reliable association. A total of 53 eligible studies including 7433 patients were included. Patients bearing the favorable TrpTrp and TrpArg genotypes of Arg194Trp were more likely to better response rates to platinum-based chemotherapy compared to those with the unfavorable ArgArg genotype (TrpTrp+TrpArg vs. ArgArg: odds ratio (OR) = 2.02, 95% CI, 1.66–2.45). The GlnGln and GlnArg genotypes of Arg399Gln were significantly associated with the poorer response rates compared to those with the ArgArg genotype (GlnGln +GlnArg vs. ArgArg: OR = 0.68, 95% CI, 0.54–0.86). The GlnGln genotype might be more closely associated with shorter survival time and higher risks of death for patients (GlnGln vs. ArgArg: hazard ratio (HR) = 1.14, 95% CI, 0.75–1.75). Our cumulative meta-analyses indicated a distinct apparent trend toward a better response rate for Arg194Trp, but a poorer response rate in Arg399Gln. These findings indicate a predictive role of XRCC1 polymorphisms in clinical outcomes. The use of XRCC1 polymorphisms as predictive factor of clinical outcomes in personalized chemotherapy treatment requires further verification from large well-designed pharmacogenetics studies. PMID:26585370

  17. Five Years' Experience Treating Locally Advanced Cervical Cancer With Concurrent Chemoradiotherapy and High-Dose-Rate Brachytherapy: Results From a Single Institution

    SciTech Connect

    Parker, Kate; Gallop-Evans, Eve; Hanna, Louise Adams, Malcolm

    2009-05-01

    Purpose: To assess the clinical outcomes after concurrent cisplatin chemotherapy and radiotherapy (RT) followed by high-dose-rate brachytherapy for locally advanced carcinoma of the cervix and perform a multivariate analysis of the prognostic factors. Methods and Materials: The outcomes were analyzed for all women treated between 1999 and 2004 with concurrent cisplatin chemotherapy and RT followed by high-dose-rate brachytherapy. Kaplan-Meier analysis was used for overall survival (OS), local control (LC), and distant control (DC). The Cox proportional hazards model was used to perform multivariate analysis of the prognostic variables. Results: The standard regimen comprised whole pelvic external RT 45 Gy in 25 fractions with concurrent weekly cisplatin 40 mg/m{sup 2}, followed by four high-dose-rate brachytherapy insertions of 6 Gy. Patients with radiologically enlarged para-aortic lymph nodes underwent extended-field RT. Of 92 patients, the OS rate was 72% at 2 years and 55% at 5 years. The LC rate was 76% at 2 years and 67% at 5 years. The DC rate was 68% at 2 years and 48% at 5 years. The most important prognostic factor for OS, LC, and DC was the pretreatment hemoglobin. For OS, the tumor size and the presence of enlarged lymph nodes were also important. For LC, the number of brachytherapy insertions was important; and for DC, the number of chemotherapy treatments was important. Of the patients, 4% experienced late Grade 3 or 4 toxicity. Conclusion: The results of our study have shown that the regimen is effective, with acceptable long-term side effects. In this cohort, the most important prognostic factor was the pretreatment hemoglobin level, a disease-related factor. However, more effective systemic treatments are needed.

  18. Updated Long-Term Outcomes and Prognostic Factors for Patients With Unresectable Locally Advanced Pancreatic Cancer Treated With Intraoperative Radiotherapy at the Massachusetts General Hospital, 1978 to 2010

    PubMed Central

    Cai, Sophie; Hong, Theodore S.; Goldberg, Saveli I.; Castillo, Carlos Fernandez-del; Thayer, Sarah P.; Ferrone, Cristina R.; Ryan, David P.; Blaszkowsky, Lawrence S.; Kwak, Eunice L.; Willett, Christopher G.; Lillemoe, Keith D.; Warshaw, Andrew L.; Wo, Jennifer Y.

    2014-01-01

    BACKGROUND In the current study, the authors evaluated long-term outcomes, intraoperative radiotherapy (IORT)-related toxicity, and prognostic factors for overall survival (OS) among patients with unresectable locally advanced pancreatic cancer (LAPC) who received IORT as part of their treatment at the Massachusetts General Hospital (MGH). METHODS Medical records were reviewed for 194 consecutive patients with unresectable LAPC who were treated with IORT at MGH between 1978 and 2010. OS was calculated using the Kaplan-Meier method. Prognostic factors were evaluated at the univariate level by the log-rank test and at the multivariate level by the Cox proportional hazards model. Rates of disease progression and treatment toxicity were calculated. RESULTS The 1-year, 2-year, and 3-year survival rates were 49%, 16%, and 6%, respectively. Six patients (3%) survived for > 5 years. The median OS was 12.0 months. Among 183 patients with known post-IORT disease status, the 2-year local progression-free survival and distant metastasis-free survival rates were 41% and 28%, respectively. On multivariate analysis, an IORT applicator diameter ≤ 8 cm (hazards ratio [HR], 0.51; 95% confidence interval [95% CI], 0.30–0.84 [P = .009]), a Charlson age-comorbidity index ≤3 (HR, 0.47; 95% CI, 0.31–0.73 [P = .001]), and receipt of chemotherapy (HR, 0.46; 95% CI, 0.33–0.66 [P < .001]) predicted improved OS. The median OS for patients with all 3 positive prognostic factors was 21.2 months. CONCLUSIONS Well-selected patients with LAPC with small tumors and low Charlson age-comorbidity indices can achieve good long-term survival outcomes with a treatment regimen that incorporates chemotherapy and IORT. PMID:24006012

  19. Inhibition of DNA-PKcs enhances radiosensitivity and increases the levels of ATM and ATR in NSCLC cells exposed to carbon ion irradiation.

    PubMed

    Yang, Lina; Liu, Yuanyuan; Sun, Chao; Yang, Xinrui; Yang, Zhen; Ran, Juntao; Zhang, Qiuning; Zhang, Hong; Wang, Xinyu; Wang, Xiaohu

    2015-11-01

    Non-small cell lung cancer (NSCLC) exhibits radioresistance to conventional rays, due to its DNA damage repair systems. NSCLC may potentially be sensitized to radiation treatment by reducing those factors that continuously enhance the repair of damaged DNA. In the present study, normal lung fibroblast MRC-5 and lung cancer A549 cells were treated with NU7026 and CGK733, which are inhibitors of the DNA-dependent protein kinase catalytic subunit (PKcs) and ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), respectively, followed by exposure to X-rays and carbon ion irradiation. The cytotoxic activity, cell survival rate, DNA damage repair ability, cell cycle arrest and apoptosis rate of the treated cells were analyzed with MTT assay, colony formation assay, immunofluorescence and flow cytometry, respectively. The transcription and translation levels of the ATM, ATR and DNA-PKcs genes were detected by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The results indicated that the radiosensitivity and DNA repair ability of A549 cells were reduced, and the percentages of apoptotic cells and those arrested at the G2/M phase of the cell cycle were significantly increased, following ionizing radiation with inhibitor-pretreatment. The expression levels of ATM, ATR, DNA-PKcs and phosphorylated histone H2AX, a biomarker for DNA double-strand breaks, were all upregulated at the transcriptional or translational level in A549 cells treated with carbon ion irradiation, compared with the control and X-rays-treated cells. In addition, the treatment with 5-50 µM NU7026 or CGK733 did not produce any obvious cytotoxicity in MRC-5 cells, and the effect of the DNA-PKcs-inhibitor on enhancing the radiosensitivity of A549 cells was stronger than that observed for the ATM and ATR-inhibitor. These findings demonstrated a minor role for ATM and ATR in radiation-induced cell death, since the upregulation of

  20. Computed 88% TCP dose for SBRT of NSCLC from tumour hypoxia modelling

    NASA Astrophysics Data System (ADS)

    Ruggieri, Ruggero; Stavreva, Nadejda; Naccarato, Stefania; Stavrev, Pavel

    2013-07-01

    In small NSCLC, 88% local control at three years from SBRT was reported both for schedule (20-22 Gy ×3) (Fakiris et al 2009 Int. J. Radiat. Oncol. Biol. Phys. 75 677-82), actually close to (18-20 Gy ×3) if density correction is properly applied, and for schedules (18 Gy ×3) and (11 Gy ×5) (Palma et al 2012 Int. J. Radiat. Oncol. Biol. Phys. 82 1149-56). Here, we compare our computed iso-TCP = 88% dose per fraction (d88) for three and five fractions (n) with such clinically adopted ones. Our TCP model accounts for tumour repopulation, at rate λ (d-1), reoxygenation of chronic hypoxia (ch-), at rate a (d-1) and fluctuating oxygenation of acute hypoxia (ah-), with hypoxic fraction (C) of the acutely hypoxic fractional volume (AHF). Out of the eight free parameters whose values we had fitted to in vivo animal data (Ruggieri et al 2012 Int. J. Radiat. Oncol. Biol. Phys. 83 1603-8), we here maintained (a(d-1), C, OERch, OERah/OERch, AHF, CHF) = (0.026, 0.17, 1.9, 2.2, 0.033, 0.145) while rescaling the initial total number of clonogens (No) according to the ratio of NSCLC on animal median tumour volumes. From the clinical literature, the usually assumed (αo/βo(Gy), λ(d-1)) = (10, 0.217) for the well-oxygenated (o-)cells were taken. By normal (lognormal) random sampling of all parameter values over their 95% C.I., the uncertainty on present d88(n) computations was estimated. Finally, SBRT intra-tumour dose heterogeneity was simulated by a 1.3 dose boost ratio on 50% of tumour volume. Computed d88(±1σ) were 19.0 (16.3; 21.7) Gy, for n = 3; 10.4 (8.7; 12.1) Gy, for n = 5; 5.8 (5.2; 6.4) Gy, for n = 8; 4.0 (3.6; 4.3) Gy, for n = 12. Furthermore, the iso-TCP = 88% total dose, D88(n) = d88(n)*n, exhibited a relative minimum around n = 8. Computed d88(n = 3, 5) are strictly consistent with the clinically adopted ones, which confirms the validity of LQ-model-based TCP predictions at the doses used in SBRT if a highly radioresistant cell subpopulation is properly

  1. Erlotinib in the treatment of advanced non-small cell lung cancer: an update for clinicians

    PubMed Central

    Wang, Yongsheng; Schmid-Bindert, Gerald

    2012-01-01

    Inhibition of epidermal growth factor receptor (EGFR) has become an important target in the treatment of advanced non-small cell lung cancer (NSCLC). Erlotinib and gefitinib, two small molecular agents that target the tyrosine kinase domain of the EGFR, were approved in many countries for the treatment of locally advanced or metastatic NSCLC as a second- or third-line regimen. Since then, randomized trials have evaluated the role of these two targeted agents alone or combined with chemotherapy in maintenance and first-line settings. This review summarizes the results of recent clinical trials with these tyrosine kinase inhibitors, with a focus on erlotinib, as first-line treatment towards a form of personalized medicine aimed at improving clinical outcome in advanced NSCLC. PMID:22229045

  2. Next-generation sequencing in NSCLC and melanoma patients: a cost and budget impact analysis

    PubMed Central

    van Amerongen, Rosa A; Retèl, Valesca P; Coupé, Veerle MH; Nederlof, Petra M; Vogel, Maartje J; van Harten, Wim H

    2016-01-01

    Next-generation sequencing (NGS) has reached the molecular diagnostic laboratories. Although the NGS technology aims to improve the effectiveness of therapies by selecting the most promising therapy, concerns are that NGS testing is expensive and that the ‘benefits’ are not yet in relation to these costs. In this study, we give an estimation of the costs and an institutional and national budget impact of various types of NGS tests in non-small-cell lung cancer (NSCLC) and melanoma patients within The Netherlands. First, an activity-based costing (ABC) analysis has been conducted on the costs of two examples of NGS panels (small- and medium-targeted gene panel (TGP)) based on data of The Netherlands Cancer Institute (NKI). Second, we performed a budget impact analysis (BIA) to estimate the current (2015) and future (2020) budget impact of NGS on molecular diagnostics for NSCLC and melanoma patients in The Netherlands. Literature, expert opinions, and a data set of patients within the NKI (n = 172) have been included in the BIA. Based on our analysis, we expect that the NGS test cost concerns will be limited. In the current situation, NGS can indeed result in higher diagnostic test costs, which is mainly related to required additional tests besides the small TGP. However, in the future, we expect that the use of whole-genome sequencing (WGS) will increase, for which it is expected that additional tests can be (partly) avoided. Although the current clinical benefits are expected to be limited, the research potentials of NGS are already an important advantage. PMID:27899957

  3. Precision medicine in NSCLC and pathology: how does ALK fit in the pathway?

    PubMed

    Kerr, K M; López-Ríos, F

    2016-09-01

    The evolution of personalised medicine in lung cancer has dramatically impacted diagnostic pathology. Current challenges centre on the growing demands placed on small tissue samples by molecular diagnostic techniques. In this review, expert recommendations are provided regarding successful identification of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Steps to correctly process and conserve tumour tissue during diagnostic testing are essential to ensure tissue availability. For example, storing extra tissue sections ready for molecular diagnostic steps allows faster testing and preserves tissue. Fluorescence in situ hybridisation (FISH) is commonly used to detect ALK rearrangements, with most laboratories favouring screening by immunohistochemistry followed by a confirmatory FISH assay. Reverse transcription-polymerase chain reaction can also identify ALK fusion gene mRNA transcripts but can be limited by the quality of RNA and the risk that rare fusion variants may not be captured. Next-generation sequencing (NGS) technology has recently provided an alternative method for detecting ALK rearrangements. While current experience is limited, NGS is set to become the most efficient approach as an increasing number of genetic abnormalities is required to be tested. Upfront, reflex testing for ALK gene rearrangement should become routine as ALK tyrosine kinase inhibitor therapy moves into the first-line setting. Guidelines recommend that EGFR and ALK tests are carried out in parallel on all confirmed and potential adenocarcinomas, and this is more efficient in terms of tissue usage and testing turnaround time for both of these actionable gene alterations. The practice of sequential testing is not recommended. Identification of ALK rearrangements is now essential for the diagnosis of NSCLC, underpinned by the benefits of ALK inhibitors. As scientific understanding and diagnostic technology develops, ALK testing will continue to be an

  4. MLN0264 in Previously Treated Asian Participants With Advanced Gastrointestinal Carcinoma or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma Expressing Guanylyl Cyclase C

    ClinicalTrials.gov

    2017-02-08

    Advanced Gastrointestinal Carcinoma; Gastroesophageal Junction Adenocarcinoma; Recurrent Gastric Adenocarcinoma; Recurrent Gastroesophageal Junction Adenocarcinoma; Metastatic Gastric Adenocarcinoma; Metastatic Gastroesophageal Junction Adenocarcinoma; Recurrent Gastrointestinal Carcinoma

  5. Metformin Enhances the Therapy Effects of Anti-IGF-1R mAb Figitumumab to NSCLC

    PubMed Central

    Cao, Hongxin; Dong, Wei; Qu, Xiao; Shen, Hongchang; Xu, Jun; Zhu, Linhai; Liu, Qi; Du, Jiajun

    2016-01-01

    The insulin-like growth factor (IGF) signaling system plays a critical role in tumorigenesis, highlighting the potential of targeting IGF-1R as an anti-cancer therapy. Although multiple anti-IGF-1R monoclonal antibody (mAb) drugs have been developed, challenges remain in the validation of the therapeutic effects and understanding the molecular mechanism of these mAbs. Herein, we conducted a study to validate the effect of Figitumumab (CP), an anti-IGF-1R mAb, in a panel of non-small cell lung cancer (NSCLC) cell lines. We found all tested cell lines were sensitive to CP, and CP could block IGF-1R and the downstream PI3K/AKT pathway activation. Unexpectedly, we found CP could activate ERK signaling pathway in IGF-1R kinase independent manner, which we further verified was mainly mediated by β-arrestin2. We also investigated the anti-tumor effect of metformin alone as well as its combination with CP to target NSCLC. Metformin could target IGF-1R signaling pathway by attenuating PI3K/AKT and MEK/ERK signaling pathways and down-regulating IGF-1R. Finally, we found that combining metformin with CP could further induce IGF-1R down-regulation and was more effective to target NSCLC cells. Our data suggests the combining of metformin with CP has additive therapeutic value against NSCLC. PMID:27488947

  6. Kras mutations increase telomerase activity and targeting telomerase is a promising therapeutic strategy for Kras-mutant NSCLC

    PubMed Central

    Shi, Bowen; Zhang, Lianmin; Qian, Dong; Li, Chenguang; Zhang, Hua; Wang, Shengguang; Zhu, Jinfang; Gao, Liuwei; Zhang, Qiang; Jia, Bin; Hao, Ligang; Wang, Changli; Zhang, Bin

    2017-01-01

    As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). MEK inhibition led to reduced TERT expression and telomerase activity. Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant Kras-induced long-term proliferation, colony formation and migration capabilities of BEAS-2B and Calu-3 cells. Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. In addition, higher TERT expression was seen in Kras-mutant NSCLC than that with wild-type Kras. Our data suggest that Kras mutations increase telomerase activity and telomere length by activating the RAS/MEK pathway, which contributes to an aggressive phenotype of NSCLC. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. PMID:27329725

  7. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation.

    PubMed

    Ou, Sai-Hong Ignatius; Weitz, Michael; Jalas, John R; Kelly, Daniel F; Wong, Vanessa; Azada, Michele C; Quines, Oliver; Klempner, Samuel J

    2016-06-01

    Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment.

  8. Management of brain metastasized non-small cell lung cancer (NSCLC) - From local treatment to new systemic therapies.

    PubMed

    Tsakonas, G; De Petris, L; Ekman, S

    2017-03-01

    Lung cancer has the highest frequency of brain dissemination compared to all other solid tumours. Classical treatment options such as brain irradiation have started to be questioned due to lack of survival benefit and risk for severe side effects. Oncogenic driven tumours have the highest frequency of brain dissemination among NSCLC patients and available targeted therapies have shown activity both intra-and extracranially, with an acceptable toxicity profile. The recent approval of immune checkpoint inhibitors for the treatment of NSCLC has complicated treatment selection even more. Data regarding efficacy of immune therapy in the CNS are limited, though promising, and data from larger cohorts are eagerly expected. The purpose of this review is to summarize all available treatment options for brain metastatic NSCLC with an emphasis on oncogenic driven tumours. Treatment selection for brain metastasized NSCLC patients is challenging because of the detrimental effect of potential treatment related CNS side effects in patients' quality of life. Clinical decision making should be done in an individualised way, taking both clinical and molecular factors into consideration.

  9. MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC.

    PubMed

    Ma, Jun; Zhao, Zhenxian; Wu, Kaiming; Xu, Zhe; Liu, Kuanzhi

    2016-08-10

    Cisplatin is one of the most effective chemotherapeutic agents for the treatment of lung cancer. However, the acquired resistance occurred in cancer cells limits the clinical application of cisplatin. MCL-1, which is an important member in the pro-survival Bcl-2 family, plays a critical role in multidrug resistance (MDR). The aim of the present study is to investigate the value of Pan-Bcl-2 inhibitor as sensitizer for the chemotherapy of cisplatin-resistant non-small cell lung cancer (NSCLC) cells. We found the obatoclax but not the ABT-737 significantly decreased the IC50 (half maximal inhibitory concentration) of cisplatin in cisplatin-resistant NSCLC cells. Furthermore, we demonstrated that the mechanism of obatoclax-promoted cell death induced by cisplatin was dependent on the inhibition of MCL-1, which couldn't be inhibited by ABT-737 but is the target of obatoclax. Moreover, inhibition of MCL-1 recovered the function of NOXA and BAK in cisplatin-resistant NSCLC cells, leading to the promotion of mitochondrial apoptosis induced by cisplatin. Interestingly, our date indicated the obatoclax also reversed the cross-resistance in cisplatin-resistant NSCLC cells. Therefore, we demonstrated that the targeted therapy with MCL-1 inhibitors, such as obatoclax, may represent a novel strategy for cancer therapy.

  10. Allyl isothiocyanate induces replication-associated DNA damage response in NSCLC cells and sensitizes to ionizing radiation

    PubMed Central

    Barnett, Reagan; Bachaboina, Lavanya; Scalici, Jennifer; Rocconi, Rodney P.; Owen, Laurie B.; Piazza, Gary A.

    2015-01-01

    Allyl isothiocyanate (AITC), a constituent of many cruciferous vegetables exhibits significant anticancer activities in many cancer models. Our studies provide novel insights into AITC-induced anticancer mechanisms in human A549 and H1299 non-small cell lung cancer (NSCLC) cells. AITC exposure induced replication stress in NSCLC cells as evidenced by γH2AX and FANCD2 foci, ATM/ATR-mediated checkpoint responses and S and G2/M cell cycle arrest. Furthermore, AITC-induced FANCD2 foci displayed co-localization with BrdU foci, indicating stalled or collapsed replication forks in these cells. Although PITC (phenyl isothiocyanate) exhibited concentration-dependent cytotoxic effects, treatment was less effective compared to AITC. Previously, agents that induce cell cycle arrest in S and G2/M phases were shown to sensitize tumor cells to radiation. Similar to these observations, combination therapy involving AITC followed by radiation treatment exhibited increased DDR and cell killing in NSCLC cells compared to single agent treatment. Combination index (CI) analysis revealed synergistic effects at multiple doses of AITC and radiation, resulting in CI values of less than 0.7 at Fa of 0.5 (50% reduction in survival). Collectively, these studies identify an important anticancer mechanism displayed by AITC, and suggest that the combination of AITC and radiation could be an effective therapy for NSCLC. PMID:25742788

  11. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC

    PubMed Central

    Walter, Annette O.; Sjin, Robert Tjin Tham; Haringsma, Henry J.; Ohashi, Kadoaki; Sun, Jing; Lee, Kwangho; Dubrovskiy, Aleksander; Labenski, Matthew; Zhu, Zhendong; Wang, Zhigang; Sheets, Michael; Martin, Thia St; Karp, Russell; van Kalken, Dan; Chaturvedi, Prasoon; Niu, Deqiang; Nacht, Mariana; Petter, Russell C.; Westlin, William; Lin, Kevin; Jaw-Tsai, Sarah; Raponi, Mitch; Dyke, Terry Van; Etter, Jeff; Weaver, Zoe; Pao, William; Singh, Juswinder; Simmons, Andrew D.; Harding, Thomas C.; Allen, Andrew

    2014-01-01

    Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond to first generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR T790M mutation. CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M while exhibiting minimal activity towards the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition (EMT) and demonstrated increased sensitivity to AKT inhibitors. These results suggest CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC. PMID:24065731

  12. Computed Tomography–Guided Interstitial High-Dose-Rate Brachytherapy in Combination With Regional Positive Lymph Node Intensity-Modulated Radiation Therapy in Locally Advanced Peripheral Non–Small Cell Lung Cancer: A Phase 1 Clinical Trial

    SciTech Connect

    Xiang, Li; Zhang, Jian-wen; Lin, Sheng; Luo, Hui-Qun; Wen, Qing-Lian; He, Li-Jia; Shang, Chang-Ling; Ren, Pei-Rong; Yang, Hong-Ru; Pang, Hao-Wen; Yang, Bo; He, Huai-Lin; Chen, Yue; Wu, Jing-Bo

    2015-08-01

    Purpose: To assess the technical safety, adverse events, and efficacy of computed tomography (CT)-guided interstitial high-dose-rate (HDR) brachytherapy in combination with regional positive lymph node intensity modulated radiation therapy in patients with locally advanced peripheral non–small cell lung cancer (NSCLC). Methods and Materials: Twenty-six patients with histologically confirmed NSCLC were enrolled in a prospective, officially approved phase 1 trial. Primary tumors were treated with HDR brachytherapy. A single 30-Gy dose was delivered to the 90% isodose line of the gross lung tumor volume. A total dose of at least 70 Gy was administered to the 95% isodose line of the planning target volume of malignant lymph nodes using 6-MV X-rays. The patients received concurrent or sequential chemotherapy. We assessed treatment efficacy, adverse events, and radiation toxicity. Results: The median follow-up time was 28 months (range, 7-44 months). There were 3 cases of mild pneumothorax but no cases of hemothorax, dyspnea, or pyothorax after the procedure. Grade 3 or 4 acute hematologic toxicity was observed in 5 patients. During follow-up, mild fibrosis around the puncture point was observed on the CT scans of 2 patients, but both patients were asymptomatic. The overall response rates (complete and partial) for the primary mass and positive lymph nodes were 100% and 92.3%, respectively. The 1-year and 2-year overall survival (OS) rates were 90.9% and 67%, respectively, with a median OS of 22.5 months. Conclusion: Our findings suggest that HDR brachytherapy is safe and feasible for peripheral locally advanced NSCLC, justifying a phase 2 clinical trial.

  13. Analysis of Dosimetric Parameters Associated With Acute Gastrointestinal Toxicity and Upper Gastrointestinal Bleeding in Locally Advanced Pancreatic Cancer Patients Treated With Gemcitabine-Based Concurrent Chemoradiotherapy

    SciTech Connect

    Nakamura, Akira; Shibuya, Keiko; Matsuo, Yukinori; Nakamura, Mitsuhiro; Shiinoki, Takehiro; Mizowaki, Takashi; Hiraoka, Masahiro

    2012-10-01

    Purpose: To identify the dosimetric parameters associated with gastrointestinal (GI) toxicity in patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based chemoradiotherapy. Methods and Materials: The data from 40 patients were analyzed retrospectively. Chemoradiotherapy consisted of conventional fractionated three-dimensional radiotherapy and weekly gemcitabine. Treatment-related acute GI toxicity and upper GI bleeding (UGB) were graded according to the Common Toxicity Criteria Adverse Events, version 4.0. The dosimetric parameters (mean dose, maximal absolute dose which covers 2 cm{sup 3} of the organ, and absolute volume receiving 10-50 Gy [V{sub 10-50}]) of the stomach, duodenum, small intestine, and a composite structure of the stomach and duodenum (StoDuo) were obtained. The planning target volume was also obtained. Univariate analyses were performed to identify the predictive factors for the risk of grade 2 or greater acute GI toxicity and grade 3 or greater UGB, respectively. Results: The median follow-up period was 15.7 months (range, 4-37). The actual incidence of acute GI toxicity was 33%. The estimated incidence of UGB at 1 year was 20%. Regarding acute GI toxicity, a V{sub 50} of {>=}16 cm{sup 3} of the stomach was the best predictor, and the actual incidence in patients with V{sub 50} <16 cm{sup 3} of the stomach vs. those with V{sub 50} of {>=}16 cm{sup 3} was 9% vs. 61%, respectively (p = 0.001). Regarding UGB, V{sub 50} of {>=}33 cm{sup 3} of the StoDuo was the best predictor, and the estimated incidence at 1 year in patients with V{sub 50} <33 cm{sup 3} of the StoDuo vs. those with V{sub 50} {>=}33 cm{sup 3} was 0% vs. 44%, respectively (p = 0.002). The dosimetric parameters correlated highly with one another. Conclusion: The irradiated absolute volume of the stomach and duodenum are important for the risk of acute GI toxicity and UGB. These results could be helpful in escalating the radiation doses using novel

  14. TUSC2(FUS1)-erlotinib Induced Vulnerabilities in Epidermal Growth Factor Receptor(EGFR) Wildtype Non-small Cell Lung Cancer(NSCLC) Targeted by the Repurposed Drug Auranofin

    PubMed Central

    Xiaobo, Cao; Majidi, Mourad; Feng, Meng; Shao, Ruping; Wang, Jing; Zhao, Yang; Baladandayuthapani, Veerabhadran; Song, Juhee; Fang, Bingliang; Ji, Lin; Mehran, Reza; Roth, Jack A.

    2016-01-01

    Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy. Addition of the thioredoxin reductase 1 inhibitor (TXNRD1) auranofin (AF) to NSCLC cells treated with combination of TUSC2 forced expression with erlotinib increased tumor cell apoptosis and inhibited colony formation. TXNRD1 overexpression rescued tumors from AF-TUSC2-erlotinib induced apoptosis. Neutralizing ROS with nordihydroguaiaretic acid (NDGA) abrogated cell death induced by AF-TUSC2-erlotinib, indicating a regulatory role for ROS in the efficacy of the three drug combination. Isobologram-based statistical analysis of this combination demonstrated superior synergism, compared with each individual treatment at lower concentrations. In NSCLC tumor xenografts, tumor growth was markedly inhibited and animal survival was prolonged over controls by AF-TUSC2-erlotinib. Microarray mRNA expression analysis uncovered oxidative stress and DNA damage gene signatures significantly upregulated by AF-TUSC2-erlotinib compared to TUSC2-erlotinib. Pathway analysis showed the highest positive z-score for the NRF2-mediated oxidative stress response. Taken together these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with AF. PMID:27845352

  15. Molecular-targeted therapy for elderly patients with advanced non-small cell lung cancer

    PubMed Central

    ANTONELLI, GIOVANNA; LIBRA, MASSIMO; PANEBIANCO, VINCENZO; RUSSO, ALESSIA ERIKA; VITALE, FELICE VITO; COLINA, PAOLO; D'ANGELO, ALESSANDRO; ROSSELLO, ROSALBA; FERRAÙ, FRANCESCO

    2016-01-01

    Lung cancer is the most common cause of cancer-related mortality in men and women. Non-small cell lung cancer (NSCLC) represents close to 90% of all lung cancers. When diagnosed, >50% of patients are >65 years old. Through an improved understanding of the molecular mechanisms involved in lung oncogenesis, molecular-targeted approaches have become an essential element for the treatment of patients with NSCLC. As the toxicity profiles of the techniques are definitely more favorable compared with chemotherapy, they are particularly attractive for use in elderly patients, who are potentially more susceptible to the toxicity of systemic oncological therapies. However, studies on the activity of molecular-targeted agents in this aged patient setting are much more limited compared with those in their younger counterparts. In the present review, the literature on molecular-targeted therapy for elderly patients with advanced NSCLC is discussed. It is concluded that bevacizumab should be reserved only for highly select elderly patients with advanced NSCLC when the clinician deems it useful in the face of acceptable toxicities. In elderly patients with advanced epidermal growth factor receptor mutation-positive NSCLC, erlotinib and gefitinib appear to repeat the same favorable performance as that documented on a larger scale in the overall population of patients with activating mutations. A good toxicity profile is also confirmed for active molecules on different pathways, such as crizotinib. PMID:26870160

  16. Molecular-targeted therapy for elderly patients with advanced non-small cell lung cancer.

    PubMed

    Antonelli, Giovanna; Libra, Massimo; Panebianco, Vincenzo; Russo, Alessia Erika; Vitale, Felice Vito; Colina, Paolo; D'Angelo, Alessandro; Rossello, Rosalba; Ferraù, Francesco

    2016-01-01

    Lung cancer is the most common cause of cancer-related mortality in men and women. Non-small cell lung cancer (NSCLC) represents close to 90% of all lung cancers. When diagnosed, >50% of patients are >65 years old. Through an improved understanding of the molecular mechanisms involved in lung oncogenesis, molecular-targeted approaches have become an essential element for the treatment of patients with NSCLC. As the toxicity profiles of the techniques are definitely more favorable compared with chemotherapy, they are particularly attractive for use in elderly patients, who are potentially more susceptible to the toxicity of systemic oncological therapies. However, studies on the activity of molecular-targeted agents in this aged patient setting are much more limited compared with those in their younger counterparts. In the present review, the literature on molecular-targeted therapy for elderly patients with advanced NSCLC is discussed. It is concluded that bevacizumab should be reserved only for highly select elderly patients with advanced NSCLC when the clinician deems it useful in the face of acceptable toxicities. In elderly patients with advanced epidermal growth factor receptor mutation-positive NSCLC, erlotinib and gefitinib appear to repeat the same favorable performance as that documented on a larger scale in the overall population of patients with activating mutations. A good toxicity profile is also confirmed for active molecules on different pathways, such as crizotinib.

  17. In pursuit of synergy: An investigation of the PI3K/mTOR/MEK co-targeted inhibition strategy in NSCLC

    PubMed Central

    Heavey, Susan; Cuffe, Sinead; Finn, Stephen; Young, Vincent; Ryan, Ronan; Nicholson, Siobhan; Leonard, Niamh; McVeigh, Niall; Barr, Martin; O'Byrne, Kenneth; Gately, Kathy

    2016-01-01

    Clinical PI3K inhibition has been somewhat disappointing, due to both inadequate patient stratification and compensatory cell signalling through bypass mechanisms. As such, investigation of PI3K-MEK co-targeted inhibition has been recommended. With high mortality rates and a clear need for new therapeutic intervention strategies, non-small cell lung cancer (NSCLC) is an important setting to investigate the effectiveness of this approach. Here, 174 NSCLC tumours were screened for 150 mutations by Fluidigm technology, with 15 patients being profiled for phosphoprotein expression. The effects of GDC-0941 (a pan PI3K inhibitor), GDC-0980 (a dual PI3K/mTOR inhibitor) and GDC-0973 (a MEK inhibitor) alone and in combination were assessed in 3 NSCLC cell lines. PIK3CA was mutated in 5.17% of NSCLC patients. GDC-0941 and GDC-0980 treatment induced anti-proliferative and pro-apoptotic responses across all NSCLC cell lines, while GDC-0973 treatment induced only anti-proliferative responses. GDC-0980 and GDC-0973 combined treatment led to significant increases in apoptosis and synergistic reductions in proliferation across the panel of cell lines. This study found that the PI3K/MEK co-targeted inhibition strategy is synergistic in all 3 molecular subtypes of NSCLC investigated. Consequently, we would advocate clinical trials for NSCLC patients combining GDC-0980 and GDC-0973, each of which are separately under clinical investigation currently. PMID:27765909

  18. Drug-resistant CXCR4-positive cells have the molecular characteristics of EMT in NSCLC.

    PubMed

    Yin, Hanlu; Wang, Yi; Chen, Wenping; Zhong, Shanliang; Liu, Zhian; Zhao, Jianhua

    2016-12-05

    High expression of Chemokine receptor 4 (CXCR4) is important in tumor invasion, metastasis, drug-resistance and maintenance of stemness in non-small cell lung cancer (NSCLC). We therefore studied the molecular characteristics of drug-resistant CXCR4-positive cells on epithelial-mesenchymal transition (EMT) for the future identification of the tumor cells with the properties of both EMT and stemness. EMT RT(2) Profier PCR Array was performed to determine the expression levels of mRNA genes in A549 with TGF-β1 induced EMT (A549/TGF-β1) and gefitinib-resistant CXCR4-positive cells (A549/GR). TCGA database on the cBio Cancer Genomics Portal website and Gene Network Central (GNC) Pro Tutorial were used to analyze their clinical relevance and pathway interactions. CXCR4 was up-regulated both in TGF-β induced EMT cells and in gefitinib-resistant cells. In 84 mRNA genes related to EMT, 17 mRNA genes were up-regulated in CXCR4-positive population of A549/GR when compared to those in CXCR4 negative fraction, while 66 mRNA genes were up-regulated during TGF-β induced EMT. ITGA5, BMP7, MMP3, VIM, RGS2, ZEB2, TCF3, SNAI2, VCAN, PLEK2, WNT5A, COL3A1, SPARC and FOXC2 were doubly up-regulated during the two biological processes. Kaplan-Meier analysis indicated that the doubly up-regulated ITGA5, RGS2, SNAI2 and PLEK2 mRNA genes were related to poor overall survival in lung adenocarcinoma patients (P=9.291e-6, 0.0090, 3.81e-7 and 0.0013, respectively). In GNC analysis, SNAI2 mRNA gene but not ITGA5, RGS2 and PLEK2 was dependent on the signaling pathway of CXCR4. The molecular characteristics of drug-resistant CXCR4-positive cells have a crosstalk with EMT, which has the potential to find the marker with prognostic value on multiple signaling pathways in NSCLC.

  19. Altered Transcriptional Control Networks with Trans-Differentiation of Isogenic Mutant-KRas NSCLC Models

    PubMed Central

    Haley, John A.; Haughney, Elizabeth; Ullman, Erica; Bean, James; Haley, John D.; Fink, Marc Y.

    2014-01-01

    Background: The capacity of cancer cells to undergo epithelial mesenchymal trans-differentiation has been implicated as a factor driving metastasis, through the acquisition of enhanced migratory/invasive cell programs and the engagement of anti-apoptotic mechanisms promoting drug and radiation resistance. Our aim was to define molecular signaling changes associated with mesenchymal trans-differentiation in two KRas mutant NSCLC models. We focused on central transcription and epigenetic regulators predicted to be important for mesenchymal cell survival. Experimental design: We have modeled trans-differentiation and cancer stemness in inducible isogenic mutant-KRas H358 and A549 non-small cell lung cell backgrounds. As expected, our models show mesenchymal-like tumor cells acquire novel mechanisms of cellular signaling not apparent in their epithelial counterparts. We employed large-scale quantitative phosphoproteomic, proteomic, protein–protein interaction, RNA-Seq, and network function prediction approaches to dissect the molecular events associated with the establishment and maintenance of the mesenchymal state. Results: Gene-set enrichment and pathway prediction indicated BMI1, KDM5B, RUNX2, MYC/MAX, NFκB, LEF1, and HIF1 target networks were significantly enriched in the trans-differentiation of H358 and A549 NSCLC models. Physical overlaps between multiple networks implicate NR4A1 as an overlapping control between TCF and NFκB pathways. Enrichment correlations also indicated marked decrease in cell cycling, which occurred early in the EMT process. RNA abundance time course studies also indicated early expression of epigenetic and chromatin regulators within 8–24 h, including CITED4, RUNX3, CMBX1, and SIRT4. Conclusion: Multiple transcription and epigenetic pathways where altered between epithelial and mesenchymal tumor cell states, notably the polycomb repressive complex-1, HP1γ, and BAF/Swi-Snf. Network analysis suggests redundancy in the activation

  20. Accelerated second-line or maintenance chemotherapy versus treatment at disease progression in NSCLC.

    PubMed

    Velez, Michel; Belalcazar, Astrid; Domingo, Gelenis; Blaya, Marcelo; Raez, Luis E; Santos, Edgardo S

    2010-04-01

    For many decades, the use of chemotherapy as second-line therapy in non-small-cell lung cancer relied upon disease progression. Several studies have shown that four to six cycles of chemotherapy administered as front-line therapy treatment offers a survival advantage to patients; however, further chemotherapy beyond this initial treatment was more associated with side effects and no benefit in survival. Until 2009, second-line treatment for lung cancer was well established for three therapeutic agents: docetaxel, pemetrexed and erlotinib. Currently, the timeframe to use these agents has been challenged by two large randomized clinical trials in which pemetrexed (JMEN trial) and erlotinib (Sequential Tarceva in Unresectable NSCLC [SATURN] trial) were used as 'maintenance' therapy and shown to impact progression-free survival and overall survival. This review focuses on the actual dilemma that medical oncologists face in clinical practice in terms of when and to whom maintenance therapy should be applied or if the 'watch and wait' approach prior to start second-line therapy is still advisable.

  1. Pretreatment 18F-FDG PET Textural Features in Locally Advanced Non–Small Cell Lung Cancer: Secondary Analysis of ACRIN 6668/RTOG 0235

    PubMed Central

    Ohri, Nitin; Duan, Fenghai; Snyder, Bradley S.; Wei, Bo; Machtay, Mitchell; Alavi, Abass; Siegel, Barry A.; Johnson, Douglas W.; Bradley, Jeffrey D.; DeNittis, Albert; Werner-Wasik, Maria; El Naqa, Issam

    2016-01-01

    In a secondary analysis of American College of Radiology Imaging Network (ACRIN) 6668/RTOG 0235, high pretreatment metabolic tumor volume (MTV) on 18F-FDG PET was found to be a poor prognostic factor for patients treated with chemoradiotherapy for locally advanced non–small cell lung cancer (NSCLC). Here we utilize the same dataset to explore whether heterogeneity metrics based on PET textural features can provide additional prognostic information. Methods Patients with locally advanced NSCLC underwent 18F-FDG PET prior to treatment. A gradient-based segmentation tool was used to contour each patient’s primary tumor. MTV, maximum SUV, and 43 textural features were extracted for each tumor. To address over-fitting and high collinearity among PET features, the least absolute shrinkage and selection operator (LASSO) method was applied to identify features that were independent predictors of overall survival (OS) after adjusting for MTV. Recursive binary partitioning in a conditional inference framework was utilized to identify optimal thresholds. Kaplan–Meier curves and log-rank testing were used to compare outcomes among patient groups. Results Two hundred one patients met inclusion criteria. The LASSO procedure identified 1 textural feature (SumMean) as an independent predictor of OS. The optimal cutpoint for MTV was 93.3 cm3, and the optimal Sum-Mean cutpoint for tumors above 93.3 cm3 was 0.018. This grouped patients into three categories: low tumor MTV (n = 155; median OS, 22.6 mo), high tumor MTV and high SumMean (n = 23; median OS, 20.0 mo), and high tumor MTV and low SumMean (n = 23; median OS, 6.2 mo; log-rank P < 0.001). Conclusion We have described an appropriate methodology to evaluate the prognostic value of textural PET features in the context of established prognostic factors. We have also identified a promising feature that may have prognostic value in locally advanced NSCLC patients with large tumors who are treated with chemoradiotherapy

  2. 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

  3. Factors affecting tumor recurrence after curative surgery for NSCLC: impacts of lymphovascular invasion on early tumor recurrence

    PubMed Central

    Park, Chanyeong; Jang, Seung Hun; Lee, Jae Woong

    2014-01-01

    Background Although surgery is potentially curative treatment for non-small cell lung cancer (NSCLC), the risk of postoperative disease recurrence is still high. This study was conducted to assess the factors associated with postoperative tumor recurrence in patients who underwent curative surgery for NSCLC. Methods One hundred seventy-one patients who underwent curative surgery for NSCLC were included in this study. Clinicopathological factors of histologic type, pathologic TNM stage, T stage, N stage, lymphovascular invasion (LVI), perineural invasion (PNI), surgical procedure, adjuvant chemotherapy and adjuvant radiotherapy were investigated. Gender, age, and clinicopathologic factors were included in univariate and multivariate analyses using the Kaplan-Meier method and Cox proportional hazards model, respectively. Mann-Whitney U and Kruskal-Wallis tests were used to investigate the significance of differences in recurrence-free interval (RFI) according to clinicopathological factors. Results Median RFI was 20 months. Univariate and multivariate analyses for overall recurrence identified T stage, N stage, and LVI as significant factors (P=0.045, 0.044, and <0.001, respectively). Pathologic stage (P=0.005) was the only factor that was significantly associated with locoregional recurrence. T stage (P=0.040) and LVI (P<0.001) were significantly associated with distant recurrence. The difference in 2-year freedom from recurrence between LVI positive and negative groups was significant (14.9% vs. 44.6%, P<0.001). LVI was the only factor that was significantly associated with a shortened mean RFI (P<0.001). Conclusions LVI had a significant effect on both overall and distant recurrence rates as well as on early tumor recurrence after curative surgery for NSCLC. PMID:25364519

  4. Next-Generation Sequencing Workflow for NSCLC Critical Samples Using a Targeted Sequencing Approach by Ion Torrent PGM™ Platform

    PubMed Central

    Vanni, Irene; Coco, Simona; Truini, Anna; Rusmini, Marta; Dal Bello, Maria Giovanna; Alama, Angela; Banelli, Barbara; Mora, Marco; Rijavec, Erika; Barletta, Giulia; Genova, Carlo; Biello, Federica; Maggioni, Claudia; Grossi, Francesco

    2015-01-01

    Next-generation sequencing (NGS) is a cost-effective technology capable of screening several genes simultaneously; however, its application in a clinical context requires an established workflow to acquire reliable sequencing results. Here, we report an optimized NGS workflow analyzing 22 lung cancer-related genes to sequence critical samples such as DNA from formalin-fixed paraffin-embedded (FFPE) blocks and circulating free DNA (cfDNA). Snap frozen and matched FFPE gDNA from 12 non-small cell lung cancer (NSCLC) patients, whose gDNA fragmentation status was previously evaluated using a multiplex PCR-based quality control, were successfully sequenced with Ion Torrent PGM™. The robust bioinformatic pipeline allowed us to correctly call both Single Nucleotide Variants (SNVs) and indels with a detection limit of 5%, achieving 100% specificity and 96% sensitivity. This workflow was also validated in 13 FFPE NSCLC biopsies. Furthermore, a specific protocol for low input gDNA capable of producing good sequencing data with high coverage, high uniformity, and a low error rate was also optimized. In conclusion, we demonstrate the feasibility of obtaining gDNA from FFPE samples suitable for NGS by performing appropriate quality controls. The optimized workflow, capable of screening low input gDNA, highlights NGS as a potential tool in the detection, disease monitoring, and treatment of NSCLC. PMID:26633390

  5. Plasma MiRNA alterations between NSCLC patients harboring Del19 and L858R EGFR mutations

    PubMed Central

    Ma, Yihan; Xu, Peiqi; Mi, Yanjun; Wang, Wenyi; Pan, Xiaoyan; Wu, Xiaoting; He, Qi; Liu, Hongming; Tang, Weiwei; An, Hanxiang

    2016-01-01

    Based on recognition of driver mutations, treatment paradigm for non-small-cell lung cancer (NSCLC) patients has been shifted. However, recently exon 19 deletion mutation (del19) of epidermal growth factor receptor (EGFR) clearly shows better clinical benefit over single-point substitution mutation L858R in exon 21 (L858R). The aim of this study was to investigate the difference by analyzing the expression of plasma microRNAs (miRNAs) of NSCLC patients with EGFR mutation del19 or L858R. MiRNA microarray of plasma from patients' blood identified 79 mapped, network-eligible miRNAs (fold > 5), of which 76 were up regulated and 3 were down regulated. Genetic network was performed with Ingenuity Pathway Analysis (IPA). Among analysis, MYC, Argonaute2 (AGO2), Y-box binding protein 1 (YBX1), cyclin E1 (CCNE1) were involved in organismal abnormalities and cancer. Our findings provide information on the epigenetic signature of the two major sensitive mutations among NSCLC and add to the understanding of mechanisms underlying the different outcomes. PMID:27463019

  6. Second-Line Treatment of NSCLC-The Pan-ErbB Inhibitor Afatinib in Times of Shifting Paradigms.

    PubMed

    Köhler, Jens

    2017-01-01

    In contrast to the established role of epidermal growth factor receptor (EGFR) inhibitors for the first-line treatment of patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR blockade and of EGFR molecular testing in the second-line treatment remains less clear. The irreversible pan-ErbB family inhibitor afatinib (Gi(l)otrif(®)) was recently FDA- and EMA-approved for the second-line treatment of NSCLC with squamous cell histology irrespective of the EGFR mutational status (LUX-Lung 8). Contrariwise, results from the TAILOR and DELTA trials among retrospective biomarker analyses show the predictive value of the EGFR mutational status for efficacy of reversible EGFR inhibitors also as a second-line therapy. This mini review critically summarizes the current role of EGFR-targeting strategies in the second-line treatment of NSCLC with special respect to afatinib in light of emerging T790M-specific EGFR and immune check point inhibitors. The review also emphasizes the urgent need for reliable biomarkers to guide therapeutic decision-making and outlines prospective changes to the second-line landscape with some of the current second-line treatment concepts likely to be moved to the first-line.

  7. Volumetric three-dimensional computed tomographic evaluation of the upper airway in patients with obstructive sleep apnoea syndrome treated by maxillomandibular advancement.

    PubMed

    Bianchi, Alberto; Betti, Enrico; Tarsitano, Achille; Morselli-Labate, Antonio Maria; Lancellotti, Lorenzo; Marchetti, Claudio

    2014-11-01

    Obstructive sleep apnoea syndrome is the periodic reduction or cessation of airflow during sleep together with daytime sleepiness. Its diagnosis requires polysomnographic evidence of 5 or more episodes of apnoea or hypopnoea/hour of sleep (apnoea/hypopnoea index, AHI). Volumetric 3-dimensional computed tomographic (CT) reconstruction enables the accurate measurement of the volume of the airway. Nasal continuous positive airway pressure (CPAP) is the conventional non-surgical treatment for patients with severe disease. Operations on the soft tissues that are currently available give success rates of only 40%-60%. Maxillomandibular advancement is currently the most effective craniofacial surgical technique for the treatment of obstructive sleep apnoea in adults. However, the appropriate distance for advancement has not been established. Expansion of the air-flow column volume did not result in an additional reduction in AHI, which raises the important issue of how much the maxillomandibular complex should be advanced to obtain an adequate reduction in AHI while avoiding the risks of overexpansion or underexpansion. We have shown that there is a significant linear relation between increased absolute upper airway volume after advancement and improvement in the AHI (p=0.013). However, increases in upper airway volume of 70% or more achieved no further reduction in the AHI, which suggests that the clinical improvement in AHI reaches a plateau, and renders further expansion unnecessary. This gives a new perspective to treatment based on the prediction of changes in volume, so the amount of sagittal advancement can be tailored in each case, which replaces the current standard of 1cm.

  8. Synthesis, characterization, in vitro SAR and in vivo evaluation of N,N'bisnaphthylmethyl 2-alkyl substituted imidazolium salts against NSCLC.

    PubMed

    DeBord, Michael A; Southerland, Marie R; Wagers, Patrick O; Tiemann, Kristin M; Robishaw, Nikki K; Whiddon, Kyle T; Konopka, Michael C; Tessier, Claire A; Shriver, Leah P; Paruchuri, Sailaja; Hunstad, David A; Panzner, Matthew J; Youngs, Wiley J

    2017-02-15

    Alkyl- and N,N'-bisnaphthyl-substituted imidazolium salts were tested in vitro for their anti-cancer activity against four non-small cell lung cancer cell lines (NCI-H460, NCI-H1975, HCC827, A549). All compounds had potent anticancer activity with 2 having IC50 values in the nanomolar range for three of the four cell lines, a 17-fold increase in activity against NCI-H1975 cells when compared to cisplatin. Compounds 1-4 also showed high anti-cancer activity against nine NSCLC cell lines in the NCI-60 human tumor cell line screen. In vitro studies performed using the Annexin V and JC-1 assays suggested that NCI-H460 cells treated with 2 undergo an apoptotic cell death pathway and that mitochondria could be the cellular target of 2 with the mechanism of action possibly related to a disruption of the mitochondrial membrane potential. The water solubilities of 1-4 was over 4.4mg/mL using 2-hydroxypropyl-β-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration.

  9. Donor Peripheral Blood Stem Cell Transplant and Pretargeted Radioimmunotherapy in Treating Patients With High-Risk Advanced Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2017-02-27

    Chronic Myelomonocytic Leukemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Cytopenia With Multilineage Dysplasia; Refractory Cytopenia With Multilineage Dysplasia and Ringed Sideroblasts; Secondary Acute Myeloid Leukemia

  10. Molecular Profiling of Circulating Tumour Cells Identifies Notch1 as a Principal Regulator in Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Mariscal, Javier; Alonso-Nocelo, Marta; Muinelo-Romay, Laura; Barbazan, Jorge; Vieito, Maria; Abalo, Alicia; Gomez-Tato, Antonio; Maria de los Angeles, Casares de Cal; Garcia-Caballero, Tomas; Rodriguez, Carmela; Brozos, Elena; Baron, Francisco; Lopez-Lopez, Rafael; Abal, Miguel

    2016-01-01

    Knowledge on the molecular mechanisms underlying metastasis colonization in Non-Small Cell Lung Cancer (NSCLC) remains incomplete. A complete overview integrating driver mutations, primary tumour heterogeneity and overt metastasis lacks the dynamic contribution of disseminating metastatic cells due to the inaccessibility to the molecular profiling of Circulating Tumour Cells (CTCs). By combining immunoisolation and whole genome amplification, we performed a global gene expression analysis of EpCAM positive CTCs from advanced NSCLC patients. We identified an EpCAM+ CTC-specific expression profile in NSCLC patients mostly associated with cellular movement, cell adhesion and cell-to-cell signalling mediated by PI3K/AKT, ERK1/2 and NF-kB pathways. NOTCH1 emerged as a driver connecting active signalling pathways, with a reduced number of related candidate genes (NOTCH1, PTP4A3, LGALS3 and ITGB3) being further validated by RT-qPCR on an independent cohort of NSCLC patients. In addition, these markers demonstrated high prognostic value for Progression-Free Survival (PFS). In conclusion, molecular characterization of EpCAM+ CTCs from advanced NSCLC patients provided with highly specific biomarkers with potential applicability as a “liquid biopsy” for monitoring of NSCLC patients and confirmed NOTCH1 as a potential therapeutic target to block lung cancer dissemination. PMID:27901069

  11. MicroRNA-410 acts as oncogene in NSCLC through downregulating SLC34A2 via activating Wnt/β-catenin pathway

    PubMed Central

    Pu, Qiang; Yuan, Yue; Yang, Weihan; Luo, Xinmei; Jiang, Qianqian; Hu, Xueting; Gong, Yi; Tang, Kui; Su, Xiaolan; Liu, Lunxu; Zhu, Wen; Wei, Yuquan

    2016-01-01

    SLC34A2 had been reported to be down-regulated in human NSCLC cells and patient tissues, and played a significant role in lung cancer. However, the mechanism of its unusual expressionin NSCLC has not been fully elucidated. In present study, we identified SLC34A2 was a direct target of miR-410 and could be inhibited by miR-410 transcriptionally and post-transcriptionally. MiR-410 promoted the growth, invasion and migration of NSCLC cells in vitro. An orthotopic xenograft nude mouse model further affirmed that miR-410 promoted NSCLC cell growth and metastasis in vivo. Moreover, restoring SLC34A2 expression effectively reversed the miR-410-mediated promotion of cell growth, invasion and migration in NSCLC cells. In addition, miR-410high /SLC34A2low expression signature frequently existed in NSCLC cells and tumor tissues. MiR-410 significantly increased the expression of DVL2 and β-catenin protein while decreased that of Gsk3β protein of Wnt/β-catenin signaling pathway, while SLC34A2 partly blocked the effects of miR-410 on those protein expressions. Hence, our data for the first time delineated that unusual expression of SLC34A2 was modulated by miR-410, and miR-410 might positivelycontribute to the tumorigenesis and development of NSCLC by down-regulating SLC34A2 and activating Wnt/β-catenin signaling pathway. MiR-410 might be a new potential therapeutic target for NSCLC. PMID:26910912

  12. p85 protein expression is associated with poor survival in HER2-positive patients with advanced breast cancer treated with trastuzumab.

    PubMed

    Pavlakis, Kitty; Bobos, Mattheos; Batistatou, Anna; Kotoula, Vassiliki; Eleftheraki, Anastasia G; Stofas, Anastasios; Timotheadou, Eleni; Pentheroudakis, George; Psyrri, Amanda; Koutras, Angelos; Pectasides, Dimitrios; Papakostas, Pavlos; Razis, Evangelia; Christodoulou, Christos; Kalogeras, Konstantine T; Fountzilas, George

    2015-04-01

    To investigate the immunohistochemical expression of p85 in a cohort of trastuzumab-treated HER2-positive and HER2-negative metastatic breast cancer patients. The medical records of all patients with metastatic breast cancer treated with trastuzumab-based regimens between 1998 and 2010 were reviewed and clinical information was obtained. Formalin-fixed paraffin-embedded tumor tissue samples with adequate material were retrospectively collected from 183 patients. Samples were evaluated by immunohistochemistry for p85, estrogen receptors (ER), progesterone receptors (PgR), HER2, Ki67, PTEN and phosphorylated Akt (S473 and T308). HER2 status was studied by fluorescence in situ hybridization, as well. PIK3CA mutational status was also evaluated. Median follow-up for all patients was 72 months. Central re-evaluation for HER2 revealed only 111 HER2-positive cases, with the remaining 72 patients being HER2-negative. Median survival was longer in HER2-positive patients (50.7 months) compared to HER2-negative patients (36.6 months) both treated with trastuzumab, but this difference has not reached significance (p = 0.068). In total, 62% of the patients were found positive for p85, however the p85 protein was not found to be differentially expressed in HER2-positive versus HER2-negative cases. There were no significant associations between protein expression of p85 and any of the markers under study, or with time to progression. Positive p85 protein expression was however associated with poor survival in trastuzumab-treated HER2-positive patients. In our cohort of trastuzumab-treated HER2-positive breast cancer patients, positive p85 protein expression appears to be a prognostic factor of poor survival and, if validated, might have important implications in the treatment of such patients.

  13. Selumetinib and Akt Inhibitor MK-2206 in Treating Patients With Refractory or Advanced Gallbladder or Bile Duct Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2014-09-08

    Adenocarcinoma of the Gallbladder; Adenocarcinoma With Squamous Metaplasia of the Gallbladder; Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Localized Unresectable Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Stage II Gallbladder Cancer; Stage IIIA Gallbladder Cancer; Stage IIIB Gallbladder Cancer; Stage IVA Gallbladder Cancer; Stage IVB Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer

  14. Gankyrin promotes epithelial-mesenchymal transition and metastasis in NSCLC through forming a closed circle with IL-6/ STAT3 and TGF-β/SMAD3 signaling pathway

    PubMed Central

    Zhao, Jin-bo; Wang, Xue-jiao; Chen, Zhao; Ni, Yun-feng; Wang, Ju-zheng; Han, Yong; Zhang, Zhi-pei; Yan, Xiao-long; Li, Xiao-fei

    2017-01-01

    Our previous research showed that Gankyrin was overexpressed in NSCLC and significantly associated with clinicopathologic features and poor prognosis. In this study, we will explore potential effect of Gankyrin on EMT and metastasis in NSCLC. The ectopic higher expression of Gankyrin markedly increased the migration and invasion in NSCLC cells. In contrast, silencing Gankyrin inhibit this aggressive behavior in NSCLC cells. Further study demonstrated that overexpression of Gankyrin could decrease E-cadherin expression and increase expression of Vimentin and Twist1 at mRNA and protein levels. These data indicated that Gankyrin could facilitate occurrence and development of EMT. Also IHC analysis showed that Gankyrin expression was negatively correlated with E-cadherin expression, while positively correlated with Vimentin and Twist1 expression in NSCLC tissues. The mechanism study finally suggested that the Gankyrin-driven EMT was partially due to IL-6/p-STAT3 and TGF-β/p-SMAD3 pathways activation. Taken together, our data provided a novel mechanism of Gankyrin promoting EMT and metastasis in NSCLC through forming a closed circle with IL-6/p-STAT3 and TGF-β/p-SMAD3 signaling pathway. PMID:27992365

  15. Human Leukocyte Antigen G Polymorphism and Expression Are Associated with an Increased Risk of Non-Small-Cell Lung Cancer and Advanced Disease Stage

    PubMed Central

    Ben Amor, Amira; Beauchemin, Karine; Faucher, Marie-Claude; Hamzaoui, Agnes; Hamzaoui, Kamel; Roger, Michel

    2016-01-01

    Human leukocyte antigen (HLA)-G acts as negative regulator of the immune responses and its expression may enable tumor cells to escape immunosurveillance. The purpose of this study was to investigate the influence of HLA-G allelic variants and serum soluble HLA-G (sHLA-G) levels on risk of non-small-cell lung cancer (NSCLC). We analyzed 191 Caucasian adults with NSCLC and 191 healthy subjects recruited between January 2009 and March 2014 in Ariana (Tunisia). Serum sHLA-G levels were measured by immunoassay and HLA-G alleles were determined using a direct DNA sequencing procedures. The heterozygous genotypes of HLA-G 010101 and -G 010401 were associated with increased risks of both NSCLC and advanced disease stages. In contrast, the heterozygous genotypes of HLA-G 0105N and -G 0106 were associated with decreased risks of NSCC and clinical disease stage IV, respectively. Serum sHLA-G levels were significantly higher in patients with NSCLC and particularly in those with advanced disease stages compared to healthy subjects. The area under the receiver-operating characteristic (ROC) curves was 0.82 for controls vs patients. Given 100% specificity, the highest sensitivity achieved to detect NSCLC was 52.8% at a cutoff value of 24.9 U/ml. Patients with the sHLA-G above median level (≥ 50 U/ml) had a significantly shorter survival time. This study demonstrates that HLA-G allelic variants are independent risk factors for NSCLC. Serum sHLA-G levels in NSCLC patients could be useful biomarkers for the diagnostic and prognosis of NSCLC. PMID:27517300

  16. Human Leukocyte Antigen G Polymorphism and Expression Are Associated with an Increased Risk of Non-Small-Cell Lung Cancer and Advanced Disease Stage.

    PubMed

    Ben Amor, Amira; Beauchemin, Karine; Faucher, Marie-Claude; Hamzaoui, Agnes; Hamzaoui, Kamel; Roger, Michel

    2016-01-01

    Human leukocyte antigen (HLA)-G acts as negative regulator of the immune responses and its expression may enable tumor cells to escape immunosurveillance. The purpose of this study was to investigate the influence of HLA-G allelic variants and serum soluble HLA-G (sHLA-G) levels on risk of non-small-cell lung cancer (NSCLC). We analyzed 191 Caucasian adults with NSCLC and 191 healthy subjects recruited between January 2009 and March 2014 in Ariana (Tunisia). Serum sHLA-G levels were measured by immunoassay and HLA-G alleles were determined using a direct DNA sequencing procedures. The heterozygous genotypes of HLA-G 010101 and -G 010401 were associated with increased risks of both NSCLC and advanced disease stages. In contrast, the heterozygous genotypes of HLA-G 0105N and -G 0106 were associated with decreased risks of NSCC and clinical disease stage IV, respectively. Serum sHLA-G levels were significantly higher in patients with NSCLC and particularly in those with advanced disease stages compared to healthy subjects. The area under the receiver-operating characteristic (ROC) curves was 0.82 for controls vs patients. Given 100% specificity, the highest sensitivity achieved to detect NSCLC was 52.8% at a cutoff value of 24.9 U/ml. Patients with the sHLA-G above median level (≥ 50 U/ml) had a significantly shorter survival time. This study demonstrates that HLA-G allelic variants are independent risk factors for NSCLC. Serum sHLA-G levels in NSCLC patients could be useful biomarkers for the diagnostic and prognosis of NSCLC.

  17. Clinical retrospective analysis of erlotinib in the treatment of elderly patients with advanced non-small cell lung cancer.

    PubMed

    Platania, Marco; Agustoni, Francesco; Formisano, Barbara; Vitali, Milena; Ducceschi, Monika; Pietrantonio, Filippo; Zilembo, Nicoletta; Gelsomino, Francesco; Pusceddu, Sara; Buzzoni, Roberto

    2011-09-01

    In order to evaluate the clinical efficacy and the safety profile of molecularly targeted therapies as a palliative approach in elderly populations affected by advanced thoracic neoplasms, we retrospectively studied, in terms of effectiveness and toxicities, a group of pretreated elderly metastatic non-small cell lung cancer (NSCLC) patients admitted to our institution and treated with erlotinib at standard daily/dose. Forty-three patients aged 70 years or older who had previously failed on chemotherapy or radiotherapy were treated with oral Eerlotinib (150 mg/d) until disease progression or unacceptable toxicity. Clinical data, pathological types, potential prognostic factors, efficacy and toxicity of erlotinib were included in this analysis. In our series we observed: objective responses in six patients (14%) and stable disease in 15 (35%). Skin rash was the most common side effect (67%). Grade 3-4 adverse events were observed in 16 cases (37%). The median overall survival and the median progression-free survival were 8.4 months (CI 95%: 0.7-43.6) and 3 months (CI 95%: 0.4-28.4), respectively. Patients with adenocarcinoma achieved the best disease control rate (p = 0.027), while not/former smokers showed a better response (p = 0.069). In our experience the use of erlotinib after chemotherapy failure in an unselected elderly population affected by NSCLC showed moderate efficacy and a moderate safety profile. However, erlotinib represents a valid option in this setting, but other factors such as biological information, comorbidities and concomitant medications need to be carefully take into consideration in this particular subset of cancer patients.

  18. [Clinical application value of prognostic nutritional index for predicting survival in patients with advanced non-small cell lung cancer].

    PubMed

    Xu, W J; Kang, Y M; Zhou, L; Chen, F F; Song, Y H; Zhang, C Q

    2017-02-23

    Objective: To explore the clinical application value of prognostic nutritional index(PNI) for predicting overall survival(OS) in patients with advanced non-small cell lung cancer (NSCLC). Methods: 123 patients with histologically confirmed non-small cell lung cancer were enrolled in this study, and their clinical and laboratory data were reviewed. The PNI was calculated as 10×serum albumin value+ 5×total lymphocyte countin peripheral blood.Univariate and multivariate analyses were used to identify the potential prognostic factors for advanced NSCLC. Results: PNI of the 123 NSCLC patients was 46.24±6.56. PNI was significantly associated with age, weight loss and pleural effusion (P<0.05). However, it showed no relationship with sex, smoking, hemoptysis, chest pain, dyspnea, histological type, clinical stage, and administration of chemotherapy (P>0.05). The median OS of the 123 patients was 19.5 months. The median OS in the higher PNI group (PNI≥46.24) and lower PNI group(PNI<46.24) were 25.2 months and 16.4 months, respectively.The 1-year survival rates were 80.6% and 63.9%, and 2-year survival rates were 54.8% and 19.6%, respectively (P<0.01). Univariate analysis showed that PNI, age, dyspnea, and weight loss were related to the OS of the advanced NSCLC patients (P<0.05). Multivariate analysis identified PNI as an independent prognostic factor for OS of advanced NSCLC (P<0.001). Conclusion: PNI can be easily calculated, and may be used as a relatively new prognostic indicator for advanced NSCLC in clinical practice.

  19. The efficacy and safety of platinum plus gemcitabine (PG) chemotherapy with or without molecular targeted agent (MTA) in first-line treatment of non-small cell lung cancer (NSCLC)

    PubMed Central

    Yang, Jiaying; He, Jieyu; Yu, Miao; Li, Taishun; Luo, Li; Liu, Pei

    2016-01-01

    Abstract Background: Trials investigating the efficacy and safety of combining molecular targeted agent (MTA) with platinum–gemcitabine (PG) in first-line treatment of advanced non-small cell lung cancer (NSCLC) have shown inconsistent findings. This meta-analysis aimed to explore whether the addition of MTAs to PG in NSCLC could provide a survival benefit with a tolerable toxicity. Methods: Web of knowledge, PubMed, Ovid, Embase, and Cochrane Library were searched to identify relevant studies and extract data on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and common grade 3 or 4 adverse events. Subgroup analyses were conducted on the basis of race and the type of MTA. Results: Twelve trials with a total of 6143 patients were included in this meta-analysis. Compared with PG chemotherapy, combination therapy of MTA with PG did not improve OS (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.90–1.01) but improved PFS (HR = 0.77, 95% CI = 0.66–0.89) and ORR (risk ratio [RR] = 1.33, 95% CI = 1.11–1.60). Subanalysis indicated that there was more incidence of grade 3 or 4 rash (RR = 11.20, 95% CI = 6.07–20.68), anemia (RR = 1.21, 95% CI = 1.01–1.46), diarrhea (RR = 2.62, 95% CI = 1.21–5.65), and anorexia (RR = 2.08, 95% CI = 1.12–3.88) in combining epidermal growth factor receptor targeted therapy group compared to PG group. An increased risk of grade 3 or 4 rash (RR = 5.08, 95% CI = 1.53–16.79), thrombocytopenia (RR = 1.50, 95% CI = 1.03–2.18), and hypertension (RR = 2.36, 95% CI = 1.05–5.32) was observed in sorafenib combination group. Conclusion: The combination of PG plus MTA was superior to PG alone in terms of PFS and ORR but not in OS. The combination chemotherapy also showed a higher frequency of grade 3 or higher toxic effects in patients with advanced NSCLC than PG chemotherapy. PMID:27977596

  20. Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2017-01-06

    Adult Cholangiocarcinoma; Advanced Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma; BCLC Stage D Adult Hepatocellular Carcinoma; Hilar Cholangiocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Recurrent Adult Liver Carcinoma; Recurrent Childhood Liver Cancer; Recurrent Extrahepatic Bile Duct Carcinoma; Recurrent Gallbladder Carcinoma; Stage II Gallbladder Cancer; Stage III Childhood Hepatocellular Carcinoma; Stage IIIA Gallbladder Cancer; Stage IIIB Gallbladder Cancer; Stage IV Childhood Hepatocellular Carcinoma; Stage IV Distal Bile Duct Cancer; Stage IVA Gallbladder Cancer; Stage IVB Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Carcinoma

  1. First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies

    PubMed Central

    Neidhart, Jeffrey D.; Ramanathan, Ramesh K.; Bassett, Dawn; Neidhart, James A.; Choi, Chung Hang J.; Chow, Warren; Chung, Vincent; Forman, Stephen J.; Garmey, Edward; Hwang, Jungyeon; Kalinoski, D. Lynn; Koczywas, Marianna; Longmate, Jeffrey; Melton, Roger J.; Morgan, Robert; Oliver, Jamie; Peterkin, Joanna J.; Ryan, John L.; Schluep, Thomas; Synold, Timothy W.; Twardowski, Przemyslaw; Davis, Mark E.; Yen, Yun

    2013-01-01

    Summary Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m2 and later bi-weekly at 12, 15, and 18 mg/m2. The maximum tolerated dose (MTD) was determined at 15 mg/m2 bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n=44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing. PMID:23397498

  2. Busulfan, Etoposide, and Intensity-Modulated Radiation Therapy Followed By Donor Stem Cell Transplant in Treating Patients With Advanced Myeloid Cancer

    ClinicalTrials.gov

    2017-04-04

    Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); 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); Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts

  3. Effect of advanced oxidation processes on the micropollutants and the effluent organic matter contained in municipal wastewater previously treated by three different secondary methods.

    PubMed

    Giannakis, Stefanos; Gamarra Vives, Franco Alejandro; Grandjean, Dominique; Magnet, Anoys; De Alencastro, Luiz Felippe; Pulgarin, César

    2015-11-01

    In this study, wastewater from the output of three different secondary treatment facilities (Activated Sludge, Moving Bed Bioreactor and Coagulation-Flocculation) present in the municipal wastewater treatment plant of Vidy, Lausanne (Switzerland), was further treated with various oxidation processes (UV, UV/H2O2, solar irradiation, Fenton, solar photo-Fenton), at laboratory scale. For this assessment, 6 organic micropollutants in agreement with the new environmental legislation requirements in Switzerland were selected (Carbamazepine, Clarithromycin, Diclofenac, Metoprolol, Benzotriazole, Mecoprop) and monitored throughout the treatment. Also, the overall removal of the organic load was assessed. After each secondary treatment, the efficiency of the AOPs increased in the following order: Coagulation-Flocculation < Activated Sludge < Moving Bed Bioreactor, in almost all cases. From the different combinations tested, municipal wastewater subjected to biological treatment followed by UV/H2O2 resulted in the highest elimination levels. Wastewater previously treated by physicochemical treatment demonstrated considerably inhibited micropollutant degradation rates. The degradation kinetics were determined, yielding: k (UV) < k (UV/H2O2) and k (Fenton) < k (solar irradiation) < k (photo-Fenton). Finally, the evolution of global pollution parameters (COD & TOC elimination) was followed and the degradation pathways for the effluent organic matter are discussed.

  4. Patterns of Failure and Treatment-Related Toxicity in Advanced Cervical Cancer Patients Treated Using Extended Field Radiotherapy With Curative Intent

    SciTech Connect

    Rajasooriyar, Chrishanthi; Van Dyk, Sylvia; Bernshaw, David; Kondalsamy-Chennakesavan, Srinivas; Barkati, Maroie; Narayan, Kailash

    2011-06-01

    Purpose: The purpose of this study was to evaluate the patterns of failure and overall survival (OS) and disease-free survival (DFS) rates in cervical cancer patients who had metastatic disease in common iliac or para-aortic lymph nodes and were treated with curative intent, using extended field radiotherapy (EFRT). Methods and Materials: This was a retrospective study involving 39 patients treated from January 1996 to June 2007, using EFRT with concurrent chemotherapy and intracavitary brachytherapy. EFRT consisted of 45 Gy in 1.8-Gy fractions. Radiation to involved nodes was boosted to a total dose of 50.4 to 54 Gy. Primary tumor radiation was boosted to a dose of 80 Gy using brachytherapy. Results: Overall, 30 patients (77%) have relapsed. The 5-year OS rate was 26% (95% confidence interval [CI], 11-44). The 5-year DFS rate was 19.4% (95% CI, 8-35). Only 3 patients (7.5%) experienced treatment failure exclusively within the treatment field, and 2 patients underwent salvage treatment. Grade 3 to 4 acute bone marrow and gastrointestinal toxicities were observed in 10 (26%) and 7 (18%) patients, respectively. Conclusions: Concurrent chemotherapy and EFRT treatment was well tolerated. Most patients showed failure at multiple sites and outside the treatment field. Only 3/39 patients had failures exclusively within the treatment field, and 2 underwent salvage treatment.

  5. [A patient with advanced recurrent breast cancer who firmly resisted hair loss and was then treated by combination therapy with high-dose toremifene and capecitabine].

    PubMed

    Akahane, Tsutomu; Chiba, Tomofumi; Yano, Hideshi; Hashimoto, Yu

    2007-03-01

    The patient was a 36-year-old woman, who found a mass in her right breast around April 2002, visited a physician in June, and was referred to our department because of suspected right breast cancer. It was confirmed that the cancer had metastasized to the right axillary lymph nodes and the skin of the right breast. After undergoing an operation on July 11 (Bt+Ax), the patient was placed on tamoxifen (TAM). Then, the course was followed while the patient was treated with CEF and 5'-DFUR. In April 2004, she had a recurrence manifesting itself as bone metastasis, partly because of poor compliance with the hospital-visit and dosing schedules. After chemotherapy with paclitaxel, etc., combination therapy with docetaxel (DOC), capecitabine, and high-dose (120 mg/day) toremifene (TOR) was started on October 15, 2004. Subsequently, because the patient firmly resisted hair loss, chemotherapy was continued with a double-drug regimen with capecitabine and high-dose TOR. Treatment was temporarily discontinued because the patient developed hand-foot syndrome, which was probably attributable to capecitabine, but the symptoms improved after administration of vitamin B(6). Thereafter,the patient complied well with the dosing schedule, and no new metastatic focus has been detected by any examination as of October 2005. These findings suggest that the double-drug regimen with capecitabine and high-dose TOR is an effective treatment for patients who can not be treated with anthracyclines or taxanes.

  6. Is there a role of nab-paclitaxel in the treatment of advanced non-small cell lung cancer? The data suggest yes

    PubMed Central

    Villaruz, Liza C.; Socinski, Mark A.

    2016-01-01

    Nab-paclitaxel is a novel therapeutic agent, which was approved in combination with carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC) regardless of histologic subtype in the United States of America by the Food and Drug Administration in 2012 and by the European Commission in 2015. This approval was based on the results of a phase III clinical trial showing superior response rates compared with solvent-based paclitaxel in combination with carboplatin. This review will focus on the early development and clinical data to date supporting the use of nab-paclitaxel in advanced NSCLC. The clinical question central to this review is whether nab-paclitaxel has a place in the current therapeutic landscape of advanced NSCLC. PMID:26875112

  7. Expression of paired basic amino acid-cleaving enzyme 4 (PACE4) correlated with prognosis in non-small cell lung cancer (NSCLC) patients

    PubMed Central

    Lin, Yun-En; Wu, Qi-Nian; Lin, Xiao-Dong; Li, Guang-Qiu

    2015-01-01

    Background Paired basic amino acid-cleaving enzyme 4 (PACE4) was shown to enhance tumor cells proliferation and invasive. This study provides the first investigation of PACE4 expression in non-small cell lung cancer (NSCLC) and the correlation with clinicopathologic features, prognostic indicators of 172 cases. Methods Quantitative real-time PCR (RT-PCR) and immunofluorescence (IF) were applied to detect PACE4 expression in NSCLC and 16HBE cell lines, then 172 consecutive NSCLC and 15 normal lung tissues were studied through immunohistochemistry (IHC). The association between PACE4 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of PACE4 expression on survival. Results PACE4 expression in NSCLC were significantly higher than normal lung cell and tissues (P<0.05). PACE4 had cytoplasmic expression and was observed in 111 of the 172 (64.5%) NSCLC patients. Clinicopathologically, PACE4 expression was significantly associated with lymph node metastasis (N stage) (P=0.007), and clinical stage (P=0.024). Multivariable analysis confirmed that PACE4 expression increased the hazard of death after adjusting for other clinicopathological factors [hazards ratio (HR): 1.584; 95% confidence interval (CI): 1.167-2.151; P<0.001]. Overall survival (OS) was significantly prolonged in PACE4 negative group when compared with PACE4 positive group (5-year survival rates, 23.1% vs. 54.5%, log-rank test, χ2=17.717, P<0.001), as was disease-free survival (DFS) (5-year survival rates, 23.4% vs. 55.4%, log-rank test, χ2=20.486, P<0.001). Conclusions Our results suggest that positive expression of PACE4 is an independent factor for NSCLC patients and it might serve as a potential prognostic biomarker for patients with NSCLC. PMID:26101640

  8. Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

    PubMed Central

    Gradishar, William J

    2016-01-01

    Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed. PMID:27468248

  9. Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial.

    PubMed

    Chun, Stephen G; Hu, Chen; Choy, Hak; Komaki, Ritsuko U; Timmerman, Robert D; Schild, Steven E; Bogart, Jeffrey A; Dobelbower, Michael C; Bosch, Walter; Galvin, James M; Kavadi, Vivek S; Narayan, Samir; Iyengar, Puneeth; Robinson, Clifford G; Wynn, Raymond B; Raben, Adam; Augspurger, Mark E; MacRae, Robert M; Paulus, Rebecca; Bradley, Jeffrey D

    2017-01-01

    Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports

  10. Carcinoembryonic Antigen as a Predictor of Pathologic Response and a Prognostic Factor in Locally Advanced Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy and Surgery

    SciTech Connect

    Park, Ji Won; Lim, Seok-Byung Kim, Dae Yong; Jung, Kyung Hae; Hong, Yong Sang; Chang, Hee Jin; Choi, Hyo Seong; Jeong, Seung-Yong

    2009-07-01

    Purpose: To evaluate the role of serum carcinoembryonic antigen (CEA) as a predictor of response to preoperative chemoradiotherapy (CRT) and prognostic factor for rectal cancer. Materials and Methods: The study retrospectively evaluated 352 locally advanced rectal cancer patients who underwent preoperative CRT followed by surgery. Serum CEA levels were determined before CRT administration (pre-CRT CEA) and before surgery (post-CRT CEA). Correlations between pre-CRT CEA levels and rates of good response (Tumor regression grade 3/4) were explored. Patients were categorized into three CEA groups according to their pre-/post-CRT CEA levels (ng/mL) (Group A: pre-CRT CEA {<=} 3; B: pre-CRT CEA >3, post-CRT CEA {<=}3; C: pre- and post-CRT CEA >3 ng/mL), and their oncologic outcomes were compared. Results: Of 352 patients, good responses were achieved in 94 patients (26.7%). The rates of good response decreased significantly as the pre-CRT CEA levels became more elevated (CEA [ng/mL]: {<=}3, 36.4%; 3-6, 23.6%; 6-9, 15.6%; >9, 7.8%; p < 0.001). The rates of good response were significantly higher in Group A than in Groups B and C (36.4% vs. 17.3% and 14.3%, respectively; p < 0.001). The 3-year disease-free survival rate was significantly better in Groups A and B than in Group C (82% and 79% vs. 57%, respectively; p = 0.005); the CEA grouping was identified as an independent prognostic factor (p = 0.025). Conclusions: In locally advanced rectal cancer patients, CEA levels could be of clinical value as a predictor of response to preoperative CRT and as an independent prognostic factor after preoperative CRT and curative surgery.

  11. Clinical effects of autologous dendritic cells combined with cytokine-induced killer cells followed by chemotherapy in treating patients with advanced colorectal cancer: a prospective study.

    PubMed

    Lin, Tao; Song, Chun; Chuo, Dong-Yu; Zhang, Hao; Zhao, Jian

    2016-04-01

    The objective of this study was to evaluate the effects of dendritic cell and cytokine-induced killer (DC-CIK) cell-based immunotherapy combined with chemotherapy on the treatment of patients with advanced colorectal cancer. We prospectively included patients with advanced colorectal cancer and assessed the efficacy of DC-CIK cell-based immunotherapy combined with chemotherapy compared to treatment with chemotherapy alone. T cell subtypes, progression-free survival (PFS), overall survival (OS), and adverse events were evaluated in each group. In total, 134 patients were included in the DC-CIK group and 121 patients were included in the control group. No significant differences were observed in the percentages of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), and NK cells after DC-CIK cell-based immunotherapy compared to before chemotherapy in the DC-CIK group. The median PFS and OS in the DC-CIK treatment group were 8.8 months (95 % CI 8.4-9.1) and 14.7 months (95 % CI 13.9-15.5), respectively, which were significantly improved compared to the PFS and OS in the control group. The frequencies of grade III and IV leukopenia (8.2 vs. 19.0 %, P = 0.011), grade III and IV anemia (3.0 vs. 9.1 %, P = 0.039), and grade III and IV thrombocytopenia (3.7 vs. 10.7 %, P = 0.029) were significantly lower in the DC-CIK group compared to the control group. DC-CIK cell-based immunotherapy could induce an immune response against colorectal cancer and prolong PFS and OS. DC-CIK cell-based immunotherapy combined with chemotherapy had a significant benefit in terms of survival in patients with colorectal cancer compared to chemotherapy alone.

  12. {sup 18}Fluorodeoxyglucose PET Is Prognostic of Progression-Free and Overall Survival in Locally Advanced Pancreas Cancer Treated With Stereotactic Radiotherapy

    SciTech Connect

    Schellenberg, Devin; Quon, Andy; Minn, A. Yuriko; Graves, Edward E.; Kunz, Pamela; Ford, James M.; Fisher, George A.; Goodman, Karyn A.; Koong, Albert C.; Chang, Daniel T.

    2010-08-01

    Purpose: This study analyzed the prognostic value of positron emission tomography (PET) for locally advanced pancreas cancer patients undergoing stereotactic body radiotherapy (SBRT). Patients and Methods: Fifty-five previously untreated, unresectable pancreas cancer patients received a single fraction of 25-Gy SBRT sequentially with gemcitabine-based chemotherapy. On the preradiation PET-CT, the tumor was contoured and the maximum standardized uptake value (SUVmax) and metabolic tumor burden (MTB) were calculated using an in-house software application. High-SUVmax and low-SUVmax subgroups were created by categorizing patients above or below the median SUVmax. The analysis was repeated to form high-MTB and low-MTB subgroups as well as clinically relevant subgroups with SUVmax values of <5, 5-10, or >10. Multivariate analysis analyzing SUVmax, MTB, age, chemotherapy cycles, and pretreatment carbohydrate antigen (CA)19-9 was performed. Results: For the entire population, median survival was 12.7 months. Median survival was 9.8 vs.15.3 months for the high- and low- SUVmax subgroups (p <0.01). Similarly, median survival was 10.1 vs. 18.0 months for the high MTB and low MTB subgroups (p <0.01). When clinical SUVmax cutoffs were used, median survival was 6.4 months in those with SUVmax >10, 9.5 months with SUVmax 5.0-10.0, and 17.7 months in those with SUVmax <5 (p <0.01). On multivariate analysis, clinical SUVmax was an independent predictor for overall survival (p = 0.03) and progression-free survival (p = 0.03). Conclusion: PET scan parameters can predict for length of survival in locally advanced pancreas cancer patients.

  13. S100A9 and ORM1 serve as predictors of therapeutic response and prognostic factors in advanced extranodal NK/T cell lymphoma patients treated with pegaspargase/gemcitabine

    PubMed Central

    Zhou, Zhiyuan; Li, Zhaoming; Sun, Zhenchang; Zhang, Xudong; Lu, Lisha; Wang, Yingjun; Zhang, Mingzhi

    2016-01-01

    Pegaspargase combined with gemcitabine have greatly improved the outcomes of advanced extranodal NK/T cell lymphoma (ENKL). However, patients frequently undergo recurrent disease due to chemoresistance, and few predictive parameters are available. The present study explored potential biomarkers to predict the therapeutic response of advanced ENKL treated with pegaspargase/gemcitabine and evaluate the prognostic significance. Through serum proteomic analysis, we identified 61 upregulated and 22 downregulated proteins in nonresponders compared with responders. We further validated that patients with unfavourable treatment outcomes displayed higher levels of S100A9 and ORM1 via enzyme-linked immunosorbent assay (ELISA). Moreover, the sensitivity and specificity for detecting refractory patients were 81.5% and 71.4% for S100A9 > 62.0 ng/ml, 85.2% and 77.1% for ORM1 > 1436 ug/ml, 100% and 57.1% for S100A9 combined with ORM1. Furthermore, in multivariate analysis elevated levels of S100A9 were associated with poor 2-year OS (40.2% vs. 76.6%, RR = 2.92, p = 0.005) and 2-year PFS (33.1% vs. 61.1%, RR = 2.61 p = 0.011). High ORM1 also predicted inferior 2-year OS (38.7% vs.76.1, RR = 2.46, p = 0.023) and 2-year PFS (18.4% vs. 73.2%, RR = 2.86, p = 0.009). Our results indicated that S100A9 and ORM1 could serve as reliable predictors of therapeutic response and independent prognostic factors of survival in advanced ENKL patients treated with pegaspargase/gemcitabine. PMID:27021626

  14. Gold nanoparticles enhance TRAIL sensitivity through Drp1-mediated apoptotic and autophagic mitochondrial fission in NSCLC cells

    PubMed Central

    Ke, Sunkui; Zhou, Tong; Yang, Peiyan; Wang, Yange; Zhang, Peng; Chen, Keman; Ren, Lei; Ye, Shefang

    2017-01-01

    Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agonistic receptors have been identified as highly promising antitumor agents preferentially eliminating cancer cells with minimal damage, the emergence of TRAIL resistance in most cancers may contribute to therapeutic failure. Thus, there is an urgent need for new approaches to overcome TRAIL resistance. Gold nanoparticles (AuNPs) are one of the most promising nanomaterials that show immense antitumor potential via targeting various cellular and molecular processes; however, the effects of AuNPs on TRAIL sensitivity in cancer cells remain unclear. In this study, we found that AuNPs combined with TRAIL exhibited a greater potency in promoting apoptosis in non-small-cell lung cancer (NSCLC) cells compared with TRAIL alone, suggesting that AuNPs sensitize cancer cells to TRAIL. Further experiments demonstrated that the combination of TRAIL and AuNPs was more effective in causing excessive mitochondrial fragmentation in cancer cells accompanied by a dramatic increase in mitochondrial recruitment of dynamin-related protein 1 (Drp1), mitochondrial dysfunctions, and enhancement of autophagy induction. Small interfering RNA (siRNA) silencing of Drp1 or inhibition of autophagy could effectively alleviate apoptosis in cells exposed to TRAIL combined with AuNPs. In vivo studies revealed that AuNPs augmented TRAIL sensitivity in tumor-bearing mice. Our data indicated that AuNPs potentiate apoptotic response to TRAIL in NSCLC cells through Drp1-dependent mitochondrial fission, and TRAIL combined with AuNPs can be a potential chemotherapeutic strategy for the treatment of NSCLC.

  15. SU-E-J-244: Development and Validation of a Knowledge Based Planning Model for External Beam Radiation Therapy of Locally Advanced Non-Small Cell Lung Cancer

    SciTech Connect

    Liu, Z; Kennedy, A; Larsen, E; Hayes, C; Grow, A; Bahamondes, S.; Zheng, Y; Wu, X; Choi, M; Pai, S; Li, J; Cranford, K

    2015-06-15

    Purpose: The study aims to develop and validate a knowledge based planning (KBP) model for external beam radiation therapy of locally advanced non-small cell lung cancer (LA-NSCLC). Methods: RapidPlan™ technology was used to develop a lung KBP model. Plans from 65 patients with LA-NSCLC were used to train the model. 25 patients were treated with VMAT, and the other patients were treated with IMRT. Organs-at-risk (OARs) included right lung, left lung, heart, esophagus, and spinal cord. DVH and geometric distribution DVH were extracted from the treated plans. The model was trained using principal component analysis and step-wise multiple regression. Box plot and regression plot tools were used to identify geometric outliers and dosimetry outliers and help fine-tune the model. The validation was performed by (a) comparing predicted DVH boundaries to actual DVHs of 63 patients and (b) using an independent set of treatment planning data. Results: 63 out of 65 plans were included in the final KBP model with PTV volume ranging from 102.5cc to 1450.2cc. Total treatment dose prescription varied from 50Gy to 70Gy based on institutional guidelines. One patient was excluded due to geometric outlier where 2.18cc of spinal cord was included in PTV. The other patient was excluded due to dosimetric outlier where the dose sparing to spinal cord was heavily enforced in the clinical plan. Target volume, OAR volume, OAR overlap volume percentage to target, and OAR out-of-field volume were included in the trained model. Lungs and heart had two principal component scores of GEDVH, whereas spinal cord and esophagus had three in the final model. Predicted DVH band (mean ±1 standard deviation) represented 66.2±3.6% of all DVHs. Conclusion: A KBP model was developed and validated for radiotherapy of LA-NSCLC in a commercial treatment planning system. The clinical implementation may improve the consistency of IMRT/VMAT planning.

  16. Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

    ClinicalTrials.gov

    2017-03-27

    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); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

  17. Biomarkers and Targeted Systemic Therapies in Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Kumar, Mukesh; Vinicius, Ernani; Owonikoko, Taofeek K.

    2015-01-01

    The last decade has witnessed significant growth in therapeutic options for patients diagnosed with lung cancer. This is due in major part to our improved technological ability to interrogate the genomics of cancer cells, which has enabled the development of biologically rational anticancer agents. The recognition that lung cancer is not a single disease entity dates back many decades to the histological subclassification of malignant neoplasms of the lung into subcategories of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). While SCLC continues to be regarded as a single histologic and therapeutic category, the NSCLC subset has undergone additional subcategorizations with distinct management algorithms for specific histologic and molecular subtypes. The defining characteristics of these NSCLC subtypes have evolved into important tools for prognosis and for predicting the likelihood of benefit when patients are treated with anticancer agents. PMID:26187108

  18. Beneficial effect of Corni Fructus, a constituent of Hachimi-jio-gan, on advanced glycation end-product-mediated renal injury in Streptozotocin-treated diabetic rats.

    PubMed

    Yamabe, Noriko; Kang, Ki Sung; Goto, Eiko; Tanaka, Takashi; Yokozawa, Takako

    2007-03-01

    Previous investigations have demonstrated that Hachimi-jio-gan, a Chinese prescription consisting of eight crude drugs, has a therapeutic potential in diabetes and diabetic nephropathy, using these model rats. To add to these findings, we performed this study to assess whether one of the crude drugs, Corni Fructus (Cornus officinalis SIEB. et ZUCC.), had an effect on streptozotocin-induced diabetic rats as a major active constituent, compared with an inhibitor of advanced glycation end-product (AGE) formation, aminoguanidine. Diabetic rats were orally administrated Corni Fructus extract (50, 100, 200 mg/kg body weight/d) or aminoguanidine (100 mg/kg body weight/d). Treatment with Corni Fructus for 10 d suppressed hyperglycemia, proteinuria, renal AGE formation, and related protein expressions, i.e., receptor for AGEs, nuclear factor-kappaB, transforming growth factor-beta1, and Nepsilon-(carboxymethyl)lysine, in the same way as with aminoguanidine. However, improvement of renal function, shown via serum creatinine (Cr) and Cr clearance, was superior to aminoguanidine treatment. In conclusion, the present study supported the hypothesis that Corni Fructus plays an important role against diabetic pathogenesis, i.e., reducing glucose toxicities, up-regulating renal function, and consequently ameliorating glycation-associated renal damage; thus, this study may provide a new recognition of crude drugs to clarify the mechanisms of Chinese prescriptions.

  19. Increasing radiation dose improves immunotherapy outcome and prolongation of tumor dormancy in a subgroup of mice treated for advanced intracerebral melanoma.

    PubMed

    Smilowitz, Henry M; Micca, Peggy L; Sasso, Daniel; Wu, Qian; Dyment, Nathanial; Xue, Crystal; Kuo, Lynn

    2016-02-01

    Previously, we developed a clinically relevant therapy model for advanced intracerebral B16 melanomas in syngeneic mice combining radiation and immunotherapies. Here, 7 days after B16-F10-luc2 melanoma cells were implanted intracerebrally (D7), syngeneic mice with bioluminescent tumors that had formed (1E10(5) to 7E10(6) photons per minute (>1E10(6), large; <1E10(6), small) were segregated into large-/small-balanced subgroups. Then, mice received either radiation therapy alone (RT) or radiation therapy plus immunotherapy (RT plus IT) (single injection of mAbPC61 to deplete regulatory T cells followed by multiple injections of irradiated granulocyte macrophage colony stimulating factor transfected B16-F10 cells) (RT plus IT). Radiation dose was varied (15, 18.75 or 22.5 Gy, given on D8), while immunotherapy was provided similarly to all mice. The data support the hypothesis that increasing radiation dose improves the outcome of immunotherapy in a subgroup of mice. The tumors that were greatly delayed in beginning their progressive growth were bioluminescent in vivo-some for many months, indicating prolonged tumor "dormancy," in some cases presaging long-term cures. Mice bearing such tumors had far more likely received radiation plus immunotherapy, rather than RT alone. Radiotherapy is a very important adjunct to immunotherapy; the greater the tumor debulking by RT, the greater should be the benefit to tumor immunotherapy.

  20. Prognostic Value of Neutrophil-Related Factors in Locally Advanced Cervical Squamous Cell Carcinoma Patients Treated with Cisplatin-Based Concurrent Chemoradiotherapy.

    PubMed

    Wang, Yan-Yang; Bai, Zhou-Lan; He, Jian-Li; Yang, Yan; Zhao, Ren; Hai, Ping; Zhe, Hong

    2016-01-01

    The aim of this study was to explore the relationship between neutrophil-related factors, including neutrophil-lymphocyte ratio (NLR) and the responses of neutrophil to granulocyte colony-stimulating factors (RNG), and the prognosis of patients with locally advanced cervical squamous cell carcinoma (LACSCC) undergoing cisplatin-based concurrent chemoradiotherapy (CCCRT). A total of sixty LACSCC patients were enrolled in this study. We analyzed the association of NLR or RNG with clinicopathologic characteristics of these patients. The prognostic factors were evaluated by univariate and multivariate survival analysis. The optimal cut-off value of the NLR was determined to be 2.0 for the overall survival (OS). A higher level of the NLR was associated with younger age (P = 0.017) and higher baseline platelet count (P = 0.040). NLR was identified to be the only independent prognostic factor for OS by multivariate analysis (P = 0.037). The median RNG was 3.01, with a range of 1.19-16.84. RNG level was significantly associated with lymph node metastasis of these patients (P = 0.023). And higher RNG was identified as being a closely independent poor prognostic factor for OS (P = 0.055). This study showed that NLR and RNG may be used as potential biomarkers for survival prediction in patients with LACSCC receiving CCCRT.

  1. Late Consequential Surgical Bed Soft Tissue Necrosis in Advanced Oropharyngeal Squamous Cell Carcinomas Treated With Transoral Robotic Surgery and Postoperative Radiation Therapy

    SciTech Connect

    Lukens, J. Nicholas; Lin, Alexander; Gamerman, Victoria; Mitra, Nandita; Grover, Surbhi; McMenamin, Erin M.; Weinstein, Gregory S.; O'Malley, Bert W.; Cohen, Roger B.; Orisamolu, Abimbola; Ahn, Peter H.; Quon, Harry

    2014-08-01

    Purpose: A subset of patients with oropharyngeal squamous cell carcinoma (OP-SCC) managed with transoral robotic surgery (TORS) and postoperative radiation therapy (PORT) developed soft tissue necrosis (STN) in the surgical bed months after completion of PORT. We investigated the frequency and risk factors. Materials and Methods: This retrospective analysis included 170 consecutive OP-SCC patients treated with TORS and PORT between 2006 and 2012, with >6 months' of follow-up. STN was defined as ulceration of the surgical bed >6 weeks after completion of PORT, requiring opioids, biopsy, or hyperbaric oxygen therapy. Results: A total of 47 of 170 patients (28%) had a diagnosis of STN. Tonsillar patients were more susceptible than base-of-tongue (BOT) patients, 39% (41 of 104) versus 9% (6 of 66), respectively. For patients with STN, median tumor size was 3.0 cm (range 1.0-5.6 cm), and depth of resection was 2.2 cm (range 1.0-5.1 cm). Median radiation dose and dose of fraction to the surgical bed were 6600 cGy and 220 cGy, respectively. Thirty-one patients (66%) received concurrent chemotherapy. Median time to STN was 2.5 months after PORT. All patients had resolution of STN after a median of 3.7 months. Multivariate analysis identified tonsillar primary (odds ratio [OR] 4.73, P=.01), depth of resection (OR 3.12, P=.001), total radiation dose to the resection bed (OR 1.51 per Gy, P<.01), and grade 3 acute mucositis (OR 3.47, P=.02) as risk factors for STN. Beginning May 2011, after implementing aggressive avoidance of delivering >2 Gy/day to the resection bed mucosa, only 8% (2 of 26 patients) experienced STN (all grade 2). Conclusions: A subset of OP-SCC patients treated with TORS and PORT are at risk for developing late consequential surgical bed STN. Risk factors include tonsillar location, depth of resection, radiation dose to the surgical bed, and severe mucositis. STN risk is significantly decreased with carefully avoiding a radiation dosage of >2 Gy/day to the

  2. Dissociation of MIF-rpS3 complex and sequential NF-κB activation is involved in IR-induced metastatic conversion of NSCLC.

    PubMed

    Youn, HyeSook; Son, Beomseok; Kim, Wanyeon; Jun, Se Young; Lee, Jung Sub; Lee, Jae-Myung; Kang, ChulHee; Kim, Joon; Youn, BuHyun

    2015-11-01

    Frequent relapse and spreading of tumors during radiotherapy are principal obstacles to treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to investigate how macrophage migration inhibitory factor (MIF) which is expressed at high levels in metastatic and primary lung cancer cells could regulate NSCLC metastasis in response to ionizing radiation (IR). The results indicated that MIF and ribosomal protein S3 (rpS3) were shown to be connected to inflammation, proliferation, and metastasis of NSCLC via IR-induced activation of the NF-κB pathway. Under unirradiated conditions, MIF physically established a complex with rpS3. MIF-rpS3 dissociation induced by IR activated NF-κB and made the expression of target genes of this factor transactivated in two NSCLC cell lines, A549, and NCI-H358. We also found that IR-induced dissociation of this complex led to increased secretion of pro-inflammatory cytokines and modulated the expression of epithelial-mesenchymal transition marker proteins. Finally, the effects of IR-induced dissociation of the MIF-rpS3 complex on tumor metastasis were confirmed by in vivo xenograft studies. Taken together, the present study revealed that dissociation of the MIF-rpS3 complex and subsequent activation of NF-κB is a critical post-IR exposure event that accounts for IR-induced metastatic conversion of NSCLC.

  3. Contribution of upregulated dipeptidyl peptidase 9 (DPP9) in promoting tumoregenicity, metastasis and the prediction of poor prognosis in non‐small cell lung cancer (NSCLC)

    PubMed Central

    Tang, Zhiyuan; Li, Jun; Shen, Qin; Feng, Jian; Liu, Hua; Wang, Wei; Xu, Liqin; Shi, Guanglin; Ye, Xumei; Ge, Min

    2017-01-01

    Dipeptidyl peptidase 9 (DPP9) is encoded by DPP9, which belongs to the DPP4 gene family. Proteins encoded by these genes have unique peptidase and extra‐enzymatic functions that have been linked to various diseases including cancers. Here, we describe the expression pattern and biological function of DPP9 in non‐small‐cell lung cancer (NSCLC). The repression of DPP9 expression by small interfering RNA inhibited cell proliferation, migration, and invasion. Moreover, we explored the role of DPP9 in regulating epithelial‐mesenchymal transition (EMT). The epithelial markers E‐cadherin and MUC1 were significantly increased, while mesenchymal markers vimentin and S100A4 were markedly decreased in DPP9 knockdown cells. The downregulation of DPP9 in the NSCLC cells induced the expression of apoptosis‐associated proteins both in vitro and in vivo. We investigated the protein expression levels of DPP9 by tissue microarray immunohistochemical assay (TMA‐IHC) (n = 217). Further we found mRNA expression levels of DPP9 in 30 pairs of clinical NSCLC tissues were significantly lower than in the adjacent non‐cancerous tissues. Survival analysis showed that the overexpression of DPP9 was a significant independent factor for poor 5‐year overall survival in patients with NSCLC (p = 0.003). Taken together, DPP9 expression correlates with poor overall survival in NSCLC. PMID:27943262

  4. Reduced miR-3127-5p expression promotes NSCLC proliferation/invasion and contributes to dasatinib sensitivity via the c-Abl/Ras/ERK pathway

    PubMed Central

    Sun, Yifeng; Chen, Chang; Zhang, Peng; Xie, Huikang; Hou, Likun; Hui, Zheng; Xu, Yongjie; Du, Qiaoling; Zhou, Xiao; Su, Bo; Gao, Wen

    2014-01-01

    miR-3127-5p is a primate-specific miRNA which is down-regulated in recurrent NSCLC tissue vs. matched primary tumor tissue (N = 15) and in tumor tissue vs. normal lung tissue (N = 177). Reduced miR-3127-5p expression is associated with a higher Ki-67 proliferation index and unfavorable prognosis in NSCLC. Overexpression of miR-3127-5p significantly reduced NSCLC cells proliferation, migration, and motility in vitro and in vivo. The oncogene ABL1 was a direct miR-3127-5p target, and miR-3127-5p regulated the activation of the Abl/Ras/ERK pathway and transactivated downstream proliferation/metastasis-associated molecules. Overexpression of miR-3127-5p in A549 or H292 cells resulted in enhanced resistance to dasatinib, an Abl/src tyrosine kinase inhibitor. miR-3127-5p expression levels were correlated with dasatinib sensitivity in NSCLC cell lines without K-Ras G12 mutation. In conclusion, miR-3127-5p acts as a tumor suppressor gene and is a potential biomarker for dasatinib sensitivity in the non-mutated Ras subset of NSCLC. PMID:25284075

  5. Advanced treatment of residual nitrogen from biologically treated coke effluent by a microalga-mediated process using volatile fatty acids (VFAs) under stepwise mixotrophic conditions.

    PubMed

    Ryu, Byung-Gon; Kim, Woong; Heo, Sung-Woon; Kim, Donghyun; Choi, Gang-Guk; Yang, Ji-Won

    2015-09-01

    This work describes the development of a microalga-mediated process for simultaneous removal of residual ammonium nitrogen (NH4(+)-N) and production of lipids from biologically treated coke effluent. Four species of green algae were tested using a sequential mixotrophic process. In the first phase-CO2-supplied mixotrophic condition-all microalgae assimilated NH4(+)-N with no evident inhibition. In second phase-volatile fatty acids (VFAs)-supplied mixotrophic condition-removal rates of NH4(+)-N and biomass significantly increased. Among the microalgae used, Arctic Chlorella sp. ArM0029B had the highest rate of NH4(+)-N removal (0.97 mg/L/h) and fatty acid production (24.9 mg/L/d) which were 3.6- and 2.1-fold higher than those observed under the CO2-supplied mixotrophic condition. Redundancy analysis (RDA) indicated that acetate and butyrate were decisive factors for increasing NH4(+)-N removal and fatty acid production. These results demonstrate that microalgae can be used in a sequential process for treatment of residual nitrogen after initial treatment of activated sludge.

  6. Prognostic significance of nestin expression in patients with resected non-small cell lung cancer treated with platinum-based adjuvant chemotherapy; relationship between nestin expression and epithelial to mesenchymal transition related markers

    PubMed Central

    Ryuge, Shinichiro; Sato, Yuichi; Nagashio, Ryo; Hiyoshi, Yasuhiro; Katono, Ken; Igawa, Satoshi; Nakashima, Hiroyasu; Shiomi, Kazu; Ichinoe, Masaaki; Murakumo, Yoshiki; Saegusa, Makoto; Satoh, Yukitoshi; Masuda, Noriyuki

    2017-01-01

    Introduction Although adjuvant platinum-based chemotherapy (AC) has been shown to improve survival of patients with completely resected stage II and stage IIIA non-small cell lung cancer (NSCLC), its effect is limited. Nestin is a class VI intermediate filament protein expressed in neural stem cells and several cancer cells including NSCLC. In the present study, we aimed to determine its prognostic significance concerning survival in NSCLC patients receiving AC. Methods Nestin expression in cancer cells was immunohistochemically studied in 90 patients with completely resected stage II and stage IIIA NSCLC treated with AC and its association with clinicopathologic parameters, including ABCG2, E-cadherin, and vimentin expression, was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of nestin expression on survival. Results Nestin expression was observed in 28 of the 90 (31.1%) NSCLCs. Clinicopathologically, nestin expression was associated with loss of E-cadherin expression (P = 0.006) and vimentin positive expression (P < 0.001). In survival analysis, nestin expression was significantly associated with a poorer prognosis (P = 0.028). Multivariable analysis confirmed that nestin expression is an independent prognostic indicator in NSCLC patients receiving AC (HR = 2.56; 95% CI, 1.23–5.30, P = 0.01). Conclusion The present study reveals that nestin expression is a prognostic indicator of a poorer survival probability in NSCLC patients receiving AC, although its prognostic significance still requires confirmation with larger patient populations. PMID:28358810

  7. A Study of Epacadostat in Combination With a PD-1 Inhibitor and Chemotherapy in Subjects With Advanced or Metastatic Solid Tumors (ECHO-207)

    ClinicalTrials.gov

    2017-03-20

    Advanced or Metastatic Solid Tumors; Advanced or Metastatic Colorectal Cancer (CRC); Pancreatic Ductal Adenocarcinoma (PDAC); Non-Small Cell Lung Cancer (NSCLC; Squamous or Nonsquamous); Advanced or Metastatic Solid Tumor That Progressed on Previous Therapy With a Programmed Cell Death Protein 1 (PD-1) Inhibitor; Advanced or Metastatic Solid Tumor That Progressed on Previous Therapy With a Programmed Cell Death Ligand 1 (PD-L1) Inhibitor

  8. Degradation of diethyl phthalate in treated effluents from an MBR via advanced oxidation processes: effects of nitrate on oxidation and a pilot-scale AOP operation.

    PubMed

    Park, J H; Park, C G; Lee, J W; Ko, K B

    2010-01-01

    The major objective of this study was to delineate the oxidation of diethyl phthalate (DEP) in water, using bench-scale UV/H2O2 and O3/H2O2 processes, and to determine the effects of nitrate (NO(3-)-N, 5 mg L(-1)) on this oxidation. The oxidation of DEP was also investigated through a pilot-scale advanced oxidation process (AOP), into which a portion of the effluent from a pilot-scale membrane bioreactor (MBR) plant was pumped. The bench-scale operation showed that DEP could be oxidized via solely UV oxidation or O3 oxidation. The adverse effect of nitrate on the DEP oxidation was remarkable in the UV/H2O2 process, and the nitrate clearly reduced its oxidation. The adverse effect of nitrate on O3 oxidation was also observed. It was noted, however, that the nitrate clearly enhanced the DEP oxidation in the O3/H2O2 process. A series of pilot-scale AOP operations indicated that the addition of H2O2 enhanced DEP oxidation in both the UV/H2O2 and O3/H2O2 processes. No noticeable adverse effect of nitrate was observed in the NO(3-)-N concentration of about 6.0 mg L(-1), which was naturally contained in the treatment stream. About 52% and 61% of the DEP were oxidized by each of these two oxidation processes in this pilot-scale operation. Both the UV/H2O2 and O3/H2O2 processes appeared to be desirable alternatives for DEP oxidation in treatment effluent streams.

  9. Long-term side effects on the temporomandibular joints and oro-facial function in patients with obstructive sleep apnoea treated with a mandibular advancement device.

    PubMed

    Knappe, S W; Bakke, M; Svanholt, P; Petersson, A; Sonnesen, L

    2017-01-17

    Patients with obstructive sleep apnoea (OSA) in long-term treatment with a mandibular advancement device (MAD) to increase the upper airway space may develop changes in the temporomandibular joint (TMJ) and the oro-facial function due to the protruded jaw position during sleep. The aim was to investigate the influence of long-term MAD treatment on the TMJs, oro-facial function and occlusion. This prospective study included 30 men and 13 women (median age 54) with OSA [Apnoea-Hypopnoea Index (AHI): 7-57]. They were examined with the Nordic Orofacial Test Screening (NOT-S), the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and cone beam computed tomography (CBCT) of the TMJs. The examination was performed before MAD treatment (T0), and 3-6 months (T1, no CBCT), 1 year (T2) and 3 years (T3) after treatment start. The results were analysed as long term (T0-T3, n = 14) and short term (T0-T2, n = 24) by t-test, Fisher's exact test and anova. Both long- and short-term analyses revealed a reduction in AHI (P < 0·002). Significant long term were increased scores in the NOT-S Interview (P < 0·045), reduced vertical overbite (P < 0·031) and increased jaw protrusive movement (P < 0·027). TMJ changes were found as joint sounds in terms of reciprocal clicking and crepitus, short term as a decrease and subsequent recurrence (P < 0·053; P < 0·037). No significant radiological changes were found. In conclusion, MAD treatment is beneficial to some OSA patients, but might induce changes in the TMJs, the oro-facial function and the occlusion. However, these changes seemed to be less harmful than previously reported with careful adaptation, control and follow-ups.

  10. Evaluation of disinfection techniques in the treatment of advanced primary treated wastewater for Ciudad Juárez, México.

    PubMed

    Carrasco, Leirad; Turner, Charles D

    2006-01-01

    The purpose of this study was to develop and evaluate the effectiveness of alternative disinfection techniques at the bench-scale level using wastewater from Ciudad Juarez, Mexico, as model feed. This paper presents findings on the effectiveness of UV radiation, peracetic acid (PAA), chlorine dioxide (ClO2), and hypochlorous acid (HOCl) as disinfectants for advanced primary treatment (APT) plant effluent. Wastewater samples for bench-scale testing were collected from an agua negra ("black water") ditch that is part of the combined sewer system in Ciudad Juarez. Bench-scale simulations of the APT process used in Ciudad Juarez were run using a jar test apparatus and aluminum sulfate [Al2(SO4)3] as the coagulant. Jar test effluent from the bench system was used for disinfection testing. The Mexican discharge quality standard for total coliforms is 10 000/100 mL. Ultraviolet radiation met this standard at a dose of 47.5 mW-s/cm2. Ultraviolet disinfection proved reliable and effective despite the presence of suspended solids, and UV dose effectiveness expressed as a total coliforms survival ratio was best explained by a linear regression model. The ClO2 dose ranged from 10 to 20 mg/L and was only effective under ambient temperature conditions found during the winter months; PAA disinfection never met Mexican standards. Chlorine disinfection was effective at a dose range of 8 to 10 mg/L on samples collected at low temperature conditions. Since the completion of this research, Ciudad Juarez has discontinued the use of chlorine disinfection because of its high cost and ineffectiveness.

  11. Survival analysis of platinum-refractory patients with advanced esophageal cancer treated with docetaxel or best supportive care alone: a retrospective study.

    PubMed

    Moriwaki, T; Kajiwara, T; Matsumoto, T; Suzuki, H; Hiroshima, Y; Matsuda, K; Hirai, S; Yamamoto, Y; Yamada, T; Sugaya, A; Kobayashi, M; Endo, S; Ishige, K; Nishina, T; Hyodo, I

    2014-01-01

    The survival benefit of second-line chemotherapy with docetaxel in platinum-refractory patients with advanced esophageal cancer (AEC) remains unclear. A retrospective analysis of AEC patients with Eastern Cooperative Oncology Group performance status (PS)≤2 was performed, and major organ functions were preserved, who determined to receive docetaxel or best supportive care (BSC) alone after failure of platinum-based chemotherapy. The post-progression survival (PPS), defined as survival time after disease progression following platinum-based chemotherapy, was analyzed by multivariate Cox regression analysis using factors identified as significant in univariate analysis of various 20 characteristics (age, sex, PS, primary tumor location, etc) including Glasgow prognostic score (GPS), which is a well-known prognostic factor in many malignant tumors. Sixty-six and 45 patients were determined to receive docetaxel and BSC between January 2007 and December 2011, respectively. The median PPS was 5.4 months (95% confidence interval [CI] 4.8-6.0) in the docetaxel group and 3.3 months (95% CI 2.5-4.0) in the BSC group (hazard ratio [HR] 0.56, 95% CI 0.38-0.84, P=0.005). Univariate analysis revealed six significant factors: treatment, PS, GPS, number of metastatic organs, liver metastasis, and bone metastasis. Multivariate analysis including these significant factors revealed three independent prognostic factors: docetaxel treatment (HR 0.62, 95% CI 0.39-0.99, P=0.043), better GPS (HR 0.61, 95% CI 0.46-0.81, P=0.001), and no bone metastasis (HR 0.31, 95% CI 0.15-0.68, P=0.003). There was a trend for PPS in favor of the docetaxel group compared with patients who refused docetaxel treatment in the BSC group (adjusted HR 0.61, 95% CI 0.29-1.29, P=0.20). Docetaxel treatment may have prolonged survival in platinum-refractory patients with AEC.

  12. Glufosfamide administered by 1-hour infusion as a second-line treatment for advanced non-small cell lung cancer; a phase II trial of the EORTC-New Drug Development Group.

    PubMed

    Giaccone, G; Smit, E F; de Jonge, M; Dansin, E; Briasoulis, E; Ardizzoni, A; Douillard, J-Y; Spaeth, D; Lacombe, D; Baron, B; Bachmann, P; Fumoleau, P

    2004-03-01

    The activity of glufosfamide (beta-D-glucosylisophosphoramide mustard) was tested in a multicentre phase II clinical trial in patients with advanced non-small cell lung cancer (NSCLC) who had received one prior line of platinum-based chemotherapy. Patients were treated with 5000 mg/m(2) glufosfamide by a 1-h intravenous (i.v.) infusion every 3 weeks following registration at the European Organisation for Research and Treatment of Cancer (EORTC) Data Center. Patients were randomised between hydration and no hydration to evaluate the nephroprotective effects of forced diuresis. Patients experiencing >/= 35 micromol/l increase of serum creatinine compared with baseline values were taken off the treatment. The Response evaluation criteria in solid tumours (RECIST) criteria were applied for the response assessment. Blood sampling was performed for a pharmacokinetic analysis. 39 patients from seven institutions were registered and a median of three cycles was given (range 0-6) cycles; 20 patients were randomised to the hydration arm. Haematological toxicity was mild, but treatment-related metabolic and electrolytic abnormalities and increases of serum creatinine occurred in several patients. Hydration did not have any significant influence on the plasma pharmacokinetics of glufosfamide and did not show any nephroprotective effect. Only one confirmed partial remission was observed (response rate 3%; 95% (Confidence Interval (CI) 0-14) and 18 cases with stable disease (49%) were recorded as assessed by an independent panel. Median survival of all patients treated was 5.8 months (95% CI 4.2-7.9). In conclusion, glufosfamide administered by a 1-h infusion every 3 weeks has modest activity in advanced NSCLC patients after one prior platinum-based chemotherapy.

  13. The study of the relation of DNA repair pathway genes SNPs and the sensitivity to radiotherapy and chemotherapy of NSCLC

    PubMed Central

    Wang, Chunbo; Nie, Huan; Li, Yiqun; Liu, Guiyou; Wang, Xu; Xing, Shijie; Zhang, Liping; Chen, Xin; Chen, Yue; Li, Yu

    2016-01-01

    To analyze the relation between SNPs in DNA repair pathway-related genes and sensitivity of tumor radio-chemotherapy, 26 SNPs in 20 DNA repair genes were genotyped on 176 patients of NSCLC undertaking radio-chemotherapy treatment. In squamous cell carcinoma (SCC), as the rs2228000, rs2228001 (XPC), rs2273953 (TP73), rs2279744 (MDM2), rs2299939 (PTEN) and rs8178085, rs12334811 (DNA-PKcs) affected the sensitivity to chemotherapy, so did the rs8178085, rs12334811 to radiotherapy. Moreover rs344781, rs2273953 and rs12334811 were related with the survival time of SCC. In general, the “good” genotype GG (rs12334811) showed greater efficacy of radio-chemotherapy and MSF (24 months) on SCC. In adenocarcinoma, as the rs2699887 (PIK3), rs12334811 (DNA-PKcs) influenced the sensitivity to chemotherapy, so did the rs2299939, rs2735343 (PTEN) to radiotherapy. And rs402710, rs80270, rs2279744 and rs2909430 impacted the survival time of the adenocarcinoma patients. Both GG (rs2279744) and AG (rs2909430) showed a shorter survival time (MFS = 6). Additionally, some SNPs such as rs2228000, rs2228001 and rs344781 were found to regulate the expression of DNA repair pathway genes through eQTLs dataset analysis. These results indicate that SNPs in DNA repair pathway genes might regulate the expression and affect the DNA damage repair, and thereby impact the efficacy of radio-chemotherapy and the survival time of NSCLC. PMID:27246533

  14. MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC)

    PubMed Central

    Taus, Álvaro; Pijuan, Lara; Arumí, Miriam; Lorenzo, Marta; Menéndez, Silvia; Cañadas, Israel; Albanell, Joan; Serrano, Sergio; Espinet, Blanca; Salido, Marta; Arriola, Edurne

    2015-01-01

    Objective We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation. Methods Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/+3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio ≥ 2.0 and/or MET ≥ 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation. Results Median MET H-score was 140 (range 0–400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cases among different tumor areas, and MET amplification in 25–50%. Cytoplasmic MET staining and positivity for vimentin predicted poor survival (p = 0.042 and 0.047, respectively). Conclusions MET status is highly heterogeneous among different nsNSCLC tumor areas, hindering adequate patient selection for MET-targeted therapies. MET cytoplasmic staining and vimentin might represent surrogate markers for MET activation. PMID:26041880

  15. Gene mutation analysis in EGFR wild type NSCLC responsive to erlotinib: are there features to guide patient selection?

    PubMed

    Ulivi, Paola; Delmonte, Angelo; Chiadini, Elisa; Calistri, Daniele; Papi, Maximilian; Mariotti, Marita; Verlicchi, Alberto; Ragazzini, Angela; Capelli, Laura; Gamboni, Alessandro; Puccetti, Maurizio; Dubini, Alessandra; Burgio, Marco Angelo; Casanova, Claudia; Crinò, Lucio; Amadori, Dino; Dazzi, Claudio

    2014-12-31

    Tyrosine kinase inhibitors (TKIs) are very efficacious in non-small-cell lung cancer (NSCLC) patients harboring activating Epidermal Growth Factor Receptor (EGFR) mutations. However, about 10% of EGFR wild type (wt) patients respond to TKI, with unknown molecular mechanisms of sensitivity. We considered a case series of 34 EGFR wt NSCLC patients responsive to erlotinib after at least one line of therapy. Responsive patients were matched with an equal number of non-responsive EGFR wt patients. A panel of 26 genes, for a total of 214 somatic mutations, was analyzed by MassARRAY® System (Sequenom, San Diego, CA, USA). A 15% KRAS mutation was observed in both groups, with a prevalence of G12C in non-responders (80% vs. 40% in responders). NOTCH1, p53 and EGFR-resistance-related mutations were found more frequently in non-responders, whereas EGFR-sensitizing mutations and alterations in genes involved in proliferation pathways were more frequent in responders. In conclusion, our findings indicate that p53, NOTCH1 and exon 20 EGFR mutations seem to be related to TKI resistance. KRAS mutations do not appear to influence the TKI response, although G12C mutation is more frequent in non-responders. Finally, the use of highly sensitive methodologies could lead to the identification of under-represented EGFR mutations potentially associated with TKI sensitivity.

  16. Post-treatment of biologically treated wastewater containing organic contaminants using a sequence of H2O2 based advanced oxidation processes: photolysis and catalytic wet oxidation.

    PubMed

    Rueda-Márquez, J J; Sillanpää, M; Pocostales, P; Acevedo, A; Manzano, M A

    2015-03-15

    In this paper the feasibility of a multi-barrier treatment (MBT) for the regeneration of synthetic industrial wastewater (SIWW) was evaluated. Industrial pollutants (orange II, phenol, 4-chlorophenol and phenanthrene) were added to the effluent of municipal wastewater treatment plant. The proposed MBT begins with a microfiltration membrane pretreatment (MF), followed by hydrogen peroxide photolysis (H2O2/UVC) and finishing, as a polishing step, with catalytic wet peroxide oxidation (CWPO) using granular activated carbon (GAC) at ambient conditions. During the microfiltration step (0.7 μm) the decrease of suspended solids concentration, turbidity and Escherichia coli in treated water were 88, 94 and 99%, respectively. Also, the effluent's transmittance (254 nm) was increased by 14.7%. Removal of more than 99.9% of all added pollutants, mineralization of 63% of organic compounds and complete disinfection of total coliforms were reached during the H2O2/UVC treatment step (H2O2:TOC w/w ratio = 5 and an UVC average dose accumulated by wastewater 8.80 WUVC s cm(-2)). The power and efficiency of the lamp, the water transmittance and photoreactor geometry are taken into account and a new equation to estimate the accumulated dose in water is suggested. Remaining organic pollutants with a higher oxidation state of carbon atoms (+0.47) and toxic concentration of residual H2O2 were present in the effluent of the H2O2/UVC process. After 2.3 min of contact time with GAC at CWPO step, 90 and 100% of total organic carbon and residual H2O2 were removed, respectively. Also, the wastewater toxicity was studied using Vibrio fischeri and Sparus aurata larvae. The MBT operational and maintenance costs (O&M) was estimated to be 0.59 € m(-3).

  17. Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin

    SciTech Connect

    Zakotnik, Branko . E-mail: bzakotnik@onko-i.si; Budihna, Marjan; Smid, Lojze; Soba, Erika; Strojan, Primoz; Fajdiga, Igor; Zargi, Miha; Oblak, Irena; Lesnicar, Hotimir

    2007-03-01

    Purpose: The long term results and patterns of failure in patients with squamous cell head and neck carcinoma (SCHNC) treated in a prospective randomized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin (CRT) was compared with radiotherapy only (RT), were analyzed. Patients and Methods: Between March 1997 and December 2001, 114 eligible patients with Stage III or IV SCHNC were randomized. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56-70 Gy. Chemotherapy included Mitomycin C 15 mg/m{sup 2} after 10 Gy and 5 mg of Bleomycin twice weekly during irradiation. Median follow-up was 76 months (48-103 months). Results: At 5 years in the RT and CRT arms, the locoregional control was 65% and 88% (p = 0.026), disease-free survival 33% and 53% (p = 0.035), and overall survival 37% and 55% (p = 0.091) respectively. Patients who benefited from chemotherapy were those with high-risk factors. The probability of distant metastases was 22% in RT and 20% in CRT arm (p = 0.913), of grade III or higher late toxicity 19% in RT and 26% in CRT arm (p = 0.52) and of thyroid dysfunction 36% in RT and 56% in CRT arm (p = 0.24). The probability to develop a second primary malignancy (SPM) was 34% in the RT and 8% in the CRT arm (p = 0.023). One third of deaths were due to infection, but there was no difference between the 2 groups. Conclusion: With concomitant radiochemotherapy, locoregional control and disease free survival were significantly improved. Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent. The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation.

  18. MET amplification and epithelial-to-mesenchymal transition exist as parallel resistance mechanisms in erlotinib-resistant, EGFR-mutated, NSCLC HCC827 cells.

    PubMed

    Jakobsen, K R; Demuth, C; Madsen, A T; Hussmann, D; Vad-Nielsen, J; Nielsen, A L; Sorensen, B S

    2017-04-03

    Although many epidermal growth factor receptor (EGFR)-mutated lung cancer patients initially benefit from the EGFR-inhibitor erlotinib, all acquire resistance. So far, several mechanisms implicated in resistance have been identified, but the existence of multiple resistance mechanisms in parallel have only been sparsely investigated. In this study, we investigated parallel resistance mechanisms acquired by HCC827, an EGFR-mutated adenocarcinoma cell line dependent on EGFR activity and sensitive to erlotinib. The cell line was treated with erlotinib by stepwise escalation of the drug-concentration and erlotinib-resistant (HCC827ER) cells created. HCC827ER cells depicted a mixed epithelial and mesenchymal phenotype. To clarify potential parallel resistance mechanisms, 14 resistant subclones were established by limited dilution. Interestingly, all HCC827ER subclones harbored either a MET-amplification (6/14) or underwent EMT (8/14), mechanisms both found in previous studies, but not in co-occurrence. Both subclone-types were resistant to erlotinib, but only MET-subclones responded to the MET-inhibitors crizotinib and capmatinib. EMT-subclones on the other hand had markedly increased FGFR1 expression and responded to the FGFR-inhibitor AZD4547, whereas MET-subclones did not. Monitoring gene expression through the development of HCC827ER revealed upregulation of FGFR1 expression as an early response to erlotinib. In addition, FGFR1 expression increased upon short-term erlotinib treatment (48 h) identifying a physiological role immediately after erlotinib exposure. The high FGFR1 expression seen in EMT-subclones was stable even after five passages without erlotinib. Here we show, that parallel resistance mechanisms appear during erlotinib-resistance development in EGFR-mutated NSCLC cells and highlight a role for FGFR1 expression changes as an early response to erlotinib as well as a bypass-signaling mechanism.

  19. Extracellular ATP a New Player in Cancer Metabolism: NSCLC Cells Internalize ATP In Vitro and In Vivo Using Multiple Endocytic Mechanisms.

    PubMed

    Qian, Yanrong; Wang, Xuan; Li, Yunsheng; Cao, Yanyang; Chen, Xiaozhuo

    2016-11-01

    Intratumoral extracellular ATP concentrations are 1000 times higher than those in normal tissues of the same cell origin. However, whether or not cancer cells use the abundant extracellular ATP was unknown until we recently reported that cancer cells internalize ATP. The internalized ATP was found to substantially increase intracellular ATP concentration and promote cell proliferation and drug resistance in cancer cells. Here, using a nonhydrolyzable fluorescent ATP (NHF-ATP), radioactive and regular ATP, coupled with high and low molecular weight dextrans as endocytosis tracers and fluorescence microscopy and ATP assays, cultured human NSCLC A549 and H1299 cells as well as A549 tumor xenografts were found to internalize extracellular ATP at concentrations within the reported intratumoral extracellular ATP concentration range. In addition to macropinocytosis, both clathrin- and caveolae-mediated endocytosis significantly contribute to the ATP internalization, which led to an approximately 30% (within 45 minutes) or more than 50% (within 4 hours) increase in intracellular ATP levels after ATP incubation. This increase could not be accounted for by either purinergic receptor signaling or increased intracellular ATP synthesis rates in the ATP-treated cancer cells. These new findings significantly deepen our understanding of the Warburg effect by shedding light on how cancer cells in tumors, which are heterogeneous for oxygen and nutrition supplies, take up extracellular ATP and use the internalized ATP to perform multiple previously unrecognized functions of biological importance. They strongly suggest the existence of ATP sharing among cancer and stromal cells in tumors and simultaneously identify multiple new anticancer targets.

  20. Primary Tumor Volume Is an Important Predictor of Clinical Outcomes Among Patients With Locally Advanced Squamous Cell Cancer of the Head and Neck Treated With Definitive Chemoradiotherapy

    SciTech Connect

    Strongin, Anna; Yovino, Susannah; Taylor, Rodney; Wolf, Jeffrey; Cullen, Kevin; Zimrin, Ann; Strome, Scott; Regine, William; Suntharalingam, Mohan

    2012-04-01

    Purpose: The tumor volume has been established as a significant predictor of outcomes among patients with head-and-neck cancer undergoing radiotherapy alone. The present study attempted to add to the existing data on tumor volume as a prognostic factor among patients undergoing chemoradiotherapy. Methods and Materials: A total of 78 patients who had undergone definitive chemoradiotherapy for Stage III-IV squamous cell cancer of the hypopharynx, oropharynx, and larynx were identified. The primary tumor volumes were calculated from the treatment planning computed tomography scans, and these were correlated to the survival and tumor control data obtained from the retrospective analysis. Results: The interval to progression correlated with the primary tumor volume (p = .007). The critical cutoff point for the tumor volume was identified as 35 cm{sup 3}, and patients with a tumor volume <35 cm{sup 3} had a significantly better prognosis than those with a tumor volume >35 cm{sup 3} at 5 years (43% vs. 71%, p = .010). Longer survival was also correlated with smaller primary tumor volumes (p = .022). Similarly, patients with a primary tumor volume <35 cm{sup 3} had a better prognosis in terms of both progression-free survival (61% vs. 33%, p = .004) and overall survival (84% vs. 41%, p = < .001). On multivariate analysis, the primary tumor volume was the best predictor of recurrence (hazard ratio 4.7, 95% confidence interval 1.9-11.6; p = .001) and survival (hazard ratio 10.0, 95% confidence interval 2.9-35.1; p = < .001). In contrast, the T stage and N stage were not significant factors. Analysis of variance revealed that tumors with locoregional failure were on average 21.6 cm{sup 3} larger than tumors without locoregional failure (p = .028) and 27.1-cm{sup 3} larger than tumors that recurred as distant metastases (p = .020). Conclusion: The results of our study have shown that the primary tumor volume is a significant prognostic factor in patients with advanced cancer

  1. TU-CD-BRB-08: Radiomic Analysis of FDG-PET Identifies Novel Prognostic Imaging Biomarkers in Locally Advanced Pancreatic Cancer Patients Treated with SBRT

    SciTech Connect

    Cui, Y; Shirato, H; Song, J; Pollom, E; Chang, D; Koong, A; Li, R

    2015-06-15

    Purpose: This study aims to identify novel prognostic imaging biomarkers in locally advanced pancreatic cancer (LAPC) using quantitative, high-throughput image analysis. Methods: 86 patients with LAPC receiving chemotherapy followed by SBRT were retrospectively studied. All patients had a baseline FDG-PET scan prior to SBRT. For each patient, we extracted 435 PET imaging features of five types: statistical, morphological, textural, histogram, and wavelet. These features went through redundancy checks, robustness analysis, as well as a prescreening process based on their concordance indices with respect to the relevant outcomes. We then performed principle component analysis on the remaining features (number ranged from 10 to 16), and fitted a Cox proportional hazard regression model using the first 3 principle components. Kaplan-Meier analysis was used to assess the ability to distinguish high versus low-risk patients separated by median predicted survival. To avoid overfitting, all evaluations were based on leave-one-out cross validation (LOOCV), in which each holdout patient was assigned to a risk group according to the model obtained from a separate training set. Results: For predicting overall survival (OS), the most dominant imaging features were wavelet coefficients. There was a statistically significant difference in OS between patients with predicted high and low-risk based on LOOCV (hazard ratio: 2.26, p<0.001). Similar imaging features were also strongly associated with local progression-free survival (LPFS) (hazard ratio: 1.53, p=0.026) on LOOCV. In comparison, neither SUVmax nor TLG was associated with LPFS (p=0.103, p=0.433) (Table 1). Results for progression-free survival and distant progression-free survival showed similar trends. Conclusion: Radiomic analysis identified novel imaging features that showed improved prognostic value over conventional methods. These features characterize the degree of intra-tumor heterogeneity reflected on FDG

  2. 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

  3. Increased NDRG1 expression is associated with advanced T stages and poor vascularization in non-small cell lung cancer.

    PubMed

    Fan, Chuifeng; Yu, Juanhan; Liu, Yang; Xu, Hongtao; Wang, Enhua

    2012-07-01

    N-myc downstream regulated gene 1 (NDRG1) is a member of the N-myc downstream regulated gene family which belongs to the alpha/beta hydrolase superfamily. Earlier studies have shown its association with inhibition of tumor metastasis. However, its function in malignant tumors is not fully enunciated. Recently there was increasing evidence that NDRG1 is involved in stress responses. In the current study, we examined the expression of NDRG1 and its correlation with clinicopathological factors and microvessel density (MVD) in non-small cell lung cancer (NSCLC) using immunohistochemistry (IHC). NDRG1 expression in NSCLC (71/115, 61.7%) was higher than that in normal lung tissues (32/115, 27.8%) (p < 0.05). NDRG1 expression in NSCLC cells was found in cytoplasm (63/115, 54.8%), nuclear (24/115, 20.9%) and cell membrane (13/115, 11.3%). NDRG1 expression in NSCLC with advanced T stages (T2-4) (63/84, 75.0%) was significantly higher than that with T1 stage (8/31, 25.8%) (P < 0.05). No other clinicopathological factors including lymph node metastasis were found to be associated with NDRG1 expression (p > 0.05). Moreover increased NDRG1 expression was associated with lower MVD in NSCLC (P < 0.05). MVD in adenocarcinoma (33.4 ± 8.4/HP) was significantly higher than that in squamous cell carcinoma (SCC) (19.3 ± 8.1/HP) (P < 0.05). No other clinicopathological factors were associated with MVD in NSCLC (p > 0.05). The present findings indicate an increase of NDRG1 expression with the progress of tumour extent which may be due to unbalanced tumor oxygenation on account of poor vascularization in NSCLC.

  4. Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells

    PubMed Central

    Wang, Wenchao; Hu, Chen; Ye, Zi; Zhao, Zheng; Wang, Li; Li, Xixiang; Yu, Kailin; Liu, Juan; Wu, Jiaxin; Yan, Xiao-E; Zhao, Peng; Wang, Jinhua; Wang, Chu; Weisberg, Ellen L.; Gray, Nathanael S.; Yun, Cai-Hong; Liu, Jing; Chen, Liang; Liu, Qingsong

    2015-01-01

    Through comprehensive comparison study, we found that ibrutinib, a clinically approved covalent BTK kinase inhibitor, was highly active against EGFR (L858R, del19) mutant driven NSCLC cells, but moderately active to the T790M ‘gatekeeper’ mutant cells and not active to wild-type EGFR NSCLC cells. Ibrutinib strongly affected EGFR mediated signaling pathways and induced apoptosis and cell cycle arrest (G0/G1) in mutant EGFR but not wt EGFR cells. However, ibrutinib only slowed down tumor progression in PC-9 and H1975 xenograft models. MEK kinase inhibitor, GSK1120212, could potentiate ibrutinib's effect against the EGFR (L858R/T790M) mutation in vitro but not in vivo. These results suggest that special drug administration might be required to achieve best clinical response in the ongoing phase I/II clinical trial with ibrutinib for NSCLC. PMID:26375053

  5. 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

  6. Phase II study of the effectiveness and safety of trastuzumab and paclitaxel for taxane‐ and trastuzumab‐naïve patients with HER2‐positive, previously treated, advanced, or recurrent gastric cancer (JFMC45‐1102)

    PubMed Central

    Nishikawa, Kazuhiro; Takahashi, Tsunehiro; Takaishi, Hiromasa; Miki, Akira; Noshiro, Hirokazu; Yoshikawa, Takaki; Nishida, Yasunori; Iwasa, Satoru; Miwa, Hiroto; Masuishi, Toshiki; Boku, Narikazu; Yamada, Yasuhide; Kodera, Yasuhiro; Yoshida, Kazuhiro; Morita, Satoshi; Sakamoto, Junichi; Saji, Shigetoyo

    2016-01-01

    Paclitaxel is a standard second‐line gastric cancer treatment in Japan. Trastuzumab could be active as second‐line chemotherapy for taxane/trastuzumab‐naïve patients with epidermal growth factor 2 (HER2)‐positive advanced gastric cancer. Patients aged ≥20 years with HER2‐positive, previously treated (except for trastuzumab and taxane), unresectable or recurrent gastric adenocarcinoma underwent combined trastuzumab (first and subsequent doses of 8 and 6 mg kg−1, respectively, every 3 weeks) and paclitaxel (days 1, 8, 15, every 4 weeks) treatment. Study endpoints were best overall response, progression‐free survival, overall survival, and safety. From September 2011 to March 2012, 47 Japanese patients were enrolled. Forty patients discontinued treatment after a median of 128.5 (range 4–486) days. Complete and partial responses were obtained in one and 16 patients (response rate of 37% [95% CI 23–52]), respectively. Median progression‐free survival and overall survival were 5.1 (95% CI 3.8–6.5) and 17.1 (95% CI 13.5–18.6) months, respectively. Grade 3/4 adverse events were neutropenia (32.6%), leukopenia (17.4%), anemia (15.2%) and hypoalbuminemia (8.7%). There was no clinically significant cardiotoxicity or cumulative toxicity. Three (disturbed consciousness, pulmonary fibrosis, and rapid disease progression) grade 5 events occurred. In conclusion, trastuzumab combined with paclitaxel was well tolerated and was a promising regimen for patients with HER2‐positive, previously treated, advanced or recurrent gastric cancer. PMID:27521503

  7. Limiting the risk of cardiac toxicity with esophageal-sparing intensity modulated radiotherapy for locally advanced lung cancers

    PubMed Central

    Panettieri, Vanessa; Ruben, Jeremy D.; Senthi, Sashendra

    2016-01-01

    Background Intensity modulated radiotherapy (IMRT) is routinely utilized in the treatment of locally advanced non-small cell lung cancer (NSCLC). RTOG 0617 found that overall survival was impacted by increased low (5 Gy) and intermediate (30 Gy) cardiac doses. We evaluated the impact of esophageal-sparing IMRT on cardiac doses with and without the heart considered in the planning process and predicted toxicity compared to 3D-conventional radiotherapy (3DCRT). Methods Ten consecutive patients with N2 Stage III NSCLC treated to 60 Gy in 30 fractions, between February 2012 and September 2014, were evaluated. For each patient, 3DCRT and esophageal-sparing IMRT plans were generated. IMRT plans were then created with and without the heart considered in the optimization process. To compare plans, the dose delivered to 95% and 99% of the target (D95% and D99%), and doses to the esophagus, lung and heart were compared by determining the volume receiving X dose (VXGy) and the normal tissue complication probability (NTCP) calculated. Results IMRT reduced maximum esophagus dose to below 60 Gy in all patients and produced significant reductions to V50Gy, V40Gy and esophageal NTCP. The cost of this reduction was a non-statistically, non-clinically significant increase in low dose (5 Gy) lung exposure that did not worsen lung NTCP. IMRT plans produced significant cardiac sparing, with the amount of improvement correlating to the amount of heart overlapping with the target. When included in plan optimization, for selected patients further sparing of the heart and improvement in heart NTCP was possible. Conclusions Esophageal-sparing IMRT can significantly spare the heart even if it is not considered in the optimization process. Further sparing can be achieved if plan optimization constrains low and intermediate heart doses, without compromising lung doses. PMID:27162670

  8. Prognostic and Clinicopathological Significance of Downregulated E-Cadherin Expression in Patients with Non-Small Cell Lung Cancer (NSCLC): A Meta-Analysis

    PubMed Central

    Xian, Lei

    2014-01-01

    Background Many studies have investigated the prognostic role of E-cadherin in patients with NSCLC; however, the result still remains inconclusive. An up-to data system review and meta-analysis was necessary to give a comprehensive evaluation of prognostic role of E-cadherin in NSCLC. Methods Eligible studies were searched in Pubmed, Embase and Web of Science databases. The inclusion criteria were studies that assessed the relationship between E-cadherin expression detected by immunohistochemistry (IHC) and the prognosis or clinicopathological features in patients with NSCLC. Subgroup analysis according to race, percentage of reduced/negative E-cadherin expression, histological type, and sample size were also conducted. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were calculated to examine the risk or hazard association. Results A total of 29 studies including 4010 patients were qualified for analysis. The analysis suggested that downregulated E-cadherin expression was significant associated with unfavorable overall survival (OS) and disease-free survival/progression-free survival (DFS/PFS) in patients with NSCLC. Subgroup analysis by race, percentage of reduced/negative E-cadherin expression, sample size also found the significant association in OS. When only the stage I NSCLC were considered, downregulated E-cadherin expression still had an unfavorable impact on OS. Additionally, downregulated E-cadherin expression was significantly associated with differentiation grade, lymphnode metastasis, vascular invasion, and TNM stage. Conclusion Downregulated E-cadherin expression detected by IHC seems to correlate with tumour progression and could serve as an important prognostic factor in patients with NSCLC. PMID:24978478

  9. Clinical outcomes of advanced non-small-cell lung cancer patients with EGFR mutation, ALK rearrangement and EGFR/ALK co-alterations

    PubMed Central

    Chen, Hua-Jun; Zhou, Qing; Yan, Li-Xu; Xie, Zhi; Su, Jian; Chen, Zhi-Hong; Tu, Hai-Yan; Yan, Hong-Hong; Wang, Zhen; Xu, Chong-Rui; Jiang, Ben-Yuan; Wang, Bin-Chao; Bai, Xiao-Yan; Zhong, Wen-Zhao; Wu, Yi-Long; Yang, Jin-Ji

    2016-01-01

    The co-occurrence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular subtype of non-small-cell lung cancer (NSCLC). Herein, we assessed the clinical outcomes and incidence of acquired resistance to tyrosine kinase inhibitors (TKIs) in this subtype. So we enrolled 118 advanced NSCLC treated with TKIs. EGFR mutations and ALK rearrangements were detected by DNA sequencing or Scorpion amplification refractory mutation system and fluorescence in situ hybridization respectively. Immunohistochemistry was used to evaluate the activation of associated proteins. We found that nine in ten patients with EGFR/ALK co-alterations had good response with first-line EGFR TKI, and the objective response rate (ORR) of EGFR TKIs was 80% (8/10) for EGFR/ALK co-altered and 65.5% (55/84) for EGFR-mutant (P = 0.57), with a median progression-free survival (PFS) of 11.2 and 13.2 months, (hazard ratio [HR]=0.95, 95% [CI], 0.49-1.84, P= 0.87). ORR of crizotinib was 40% (2/5) for EGFR/ALK co-altered and 73.9% (17/23) for ALK-rearranged (P= 0.29), with a median PFS of 1.9 and 6.9 months (hazard ratio [HR], 0.40; 95% [CI] 0.15-1.10, P = 0.08). The median overall survival (OS) was 21.3, 23.7, and 18.5 months in EGFR-mutant, ALK-rearranged, and EGFR/ALK co-altered (P= 0.06), and there existed a statistically significant difference in OS between ALK-rearranged and EGFR/ALK co-altered (P=0.03). Taken together, the first-line EGFR-TKI might be the reasonable care for advanced NSCLC harbouring EGFR/ALK co-alterations, whether or nor to use sequential crizotinib should be guided by the status of ALK rearrangement and the relative level of phospho-EGFR and phospho-ALK. PMID:27533086

  10. Prospective Study of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Concurrent With Individualized Radiotherapy for Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

    SciTech Connect

    Wang Jing; Xia Tingyi; Wang Yingjie; Li Hongqi; Li Ping; Wang Jidong; Chang Dongshu; Liu Liyyuan; Di Yupeng; Wang Xuan; Wu Weizhang

    2011-11-01

    Purpose: To establish the safety profile and efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) concurrent with individualized radiotherapy (RT) in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Patients and Methods: Between June 2007 and January 2010, 26 patients with Stage III/IV NSCLC were enrolled in this prospective study. These patients were treated with EGFR-TKIs (gefitinib 250 mg or erlotinib 150 mg, oral daily) concurrent with individualized RT with curative intent. The thoracic RT plans were individually designed on the basis of tumor size and normal tissue volume constraints. All patients were assessed for toxicity, and 25 patients were available for efficacy. The primary endpoints were acute toxicity, overall survival, and median survival time. The secondary endpoints included local control rate, time to tumor progression, and progression-free survival (PFS). Results: Median gross tumor volume, mean lung dose, and lung V20 were 56 cm{sup 3}, 8.6 Gy, and 14%, respectively. Median thoracic radiation dose was 70 Gy at a margin of gross tumor volume (range, 42-82 Gy), and median biological equivalent dose was 105 Gy (range, 60-119 Gy). Acute skin, hematologic, esophageal, and pulmonary toxicities were acceptable and manageable. Severe adverse events included neutropenia (Grade 4, 4%) and thrombocytopenia (Grade 4, 8%), esophagitis (Grade 3, 4%), and pneumonitis (Grade 3, 4%). With a median follow-up of 10.2 months, a local control rate of 96% was achieved for thoracic tumor. Median time to progression, median PFS, and median survival time were 6.3, 10.2, and 21.8 months, respectively. The 1- and 2-year PFS rates were both 42%, and 1-, 2-, and 3-year overall survival rates were 57%, 45%, and 30%, respectively. Conclusion: Concurrent EGFR-TKIs with individualized RT shows a favorable safety profile and promising outcome, therefore serving as a therapeutic option for patients with locally

  11. Risk Factors for Brain Metastases in Locally Advanced Non-Small Cell Lung Cancer With Definitive Chest Radiation

    SciTech Connect

    Ji, Zhe; Bi, Nan; Wang, Jingbo; Hui, Zhouguang; Xiao, Zefen; Feng, Qinfu; Zhou, Zongmei; Chen, Dongfu; Lv, Jima; Liang, Jun; Fan, Chengcheng; Liu, Lipin; Wang, Luhua

    2014-06-01

    Purpose: We intended to identify risk factors that affect brain metastases (BM) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving definitive radiation therapy, which may guide the choice of selective prevention strategies. Methods and Materials: The characteristics of 346 patients with stage III NSCLC treated with thoracic radiation therapy from January 2008 to December 2010 in our institution were retrospectively reviewed. BM rates were analyzed by the Kaplan-Meier method. Multivariate Cox regression analysis was performed to determine independent risk factors for BM. Results: The median follow-up time was 48.3 months in surviving patients. A total of 74 patients (21.4%) experienced BM at the time of analysis, and for 40 (11.7%) of them, the brain was the first site of failure. The 1-year and 3-year brain metastasis rates were 15% and 28.1%, respectively. In univariate analysis, female sex, age ≤60 years, non-squamous cell carcinoma, T3-4, N3, >3 areas of lymph node metastasis, high lactate dehydrogenase and serum levels of tumor markers (CEA, NSE, CA125) before treatment were significantly associated with BM (P<.05). In multivariate analysis, age ≤60 years (P=.004, hazard ratio [HR] = 0.491), non-squamous cell carcinoma (P=.000, HR=3.726), NSE >18 ng/mL (P=.008, HR=1.968) and CA125 ≥ 35 U/mL (P=.002, HR=2.129) were independent risk factors for BM. For patients with 0, 1, 2, and 3 to 4 risk factors, the 3-year BM rates were 7.3%, 18.9%, 35.8%, and 70.3%, respectively (P<.001). Conclusions: Age ≤60 years, non-squamous cell carcinoma, serum NSE >18 ng/mL, and CA125 ≥ 35 U/mL were independent risk factors for brain metastasis. The possibilities of selectively using prophylactic cranial irradiation in higher-risk patients with LA-NSCLC should be further explored in the future.

  12. MiR-146a-5p inhibits cell proliferation and cell cycle progression in NSCLC cell lines by targeting CCND1 and CCND2

    PubMed Central

    Shen, Yu-Qing; Wang, Hui-Min; Ding, Lei; Gu, Yu-Chen; Lou, Jia-Tao; Zhao, Xin-Tai; Ma, Zhong-Liang; Jin, You-Xin

    2016-01-01

    Previous studies have indicated that miR-146a-5p acts as an oncogene in several types of cancer, yet a tumor suppressor gene in others. In non-small cell lung cancer (NSCLC), one report showed that it was downregulated and played the role of tumor suppressor. However, another study showed that miR-146a-5p was overexpressed in the serum of NSCLC patients compared to healthy controls. Therefore, it is obvious that further study of the function of miR-146a-5p in NSCLC is necessary to fully understand its importance. Herein, we have verified that miR- 146a- 5p acts as a tumor suppressor in NSCLC. Our data revealed that the expression level of miR-146a-5p was significantly decreased in several human NSCLC cell lines, and also less abundant in human NSCLC tissues, when compared with controls. Moreover, we observed that miR-146a-5p could suppress cell proliferation, both in vitro and in vivo. Our results also showed that miR-146a-5p directly targeted the 3′-UTR of CCND1 and CCND2 mRNAs as well as decreased their expression at both mRNA and protein levels, causing cell cycle arrest at the G0/G1 phase. Furthermore, siRNA-mediated downregulation of CCND1 or CCND2 yielded the same effects on proliferation and cell cycle arrest as miR-146a-5p upregulation did in the NSCLC cell lines. We confirmed that the expression of miR-146a-5p had negative relationship with CCND1 or CCND2. Besides, we also found that miR-146a-5p could inhibit tumor growth in xengroft mouse models, and CCND1 and CCND2 were downregulated in miR-146a-5p overexpressed xengroft tumor tissues. In summary, our results demonstrated that miR-146a-5p could suppress the proliferation and cell cycle progression in NSCLC cells by inhibiting the expression of CCND1 and CCND2. PMID:27494902

  13. Vitamin D-Related Gene Polymorphisms, Plasma 25-Hydroxy-Vitamin D, Cigarette Smoke and Non-Small Cell Lung Cancer (NSCLC) Risk

    PubMed Central

    Wu, Xiayu; Cheng, Jiaoni; Yang, Kaiyun

    2016-01-01

    Epidemiological studies regarding the relationship between vitamin D, genetic polymorphisms in the vitamin D metabolism, cigarette smoke and non-small cell lung cancer (NSCLC) risk have not been investigated comprehensively. To search for additional evidence, the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique and radioimmunoassay method were utilized to evaluate 5 single-nucleotide polymorphisms (SNPs) in vitamin D receptor (VDR), 6 SNPs in 24-hydroxylase (CYP24A1), 2 SNPs in 1α-hydroxylase (CYP27B1) and 2 SNPs in vitamin D-binding protein (group-specific component, GC) and plasma vitamin D levels in 426 NSCLC cases and 445 controls from China. Exposure to cigarette smoke was ascertained through questionnaire information. Multivariable linear regressions and mixed effects models were used in statistical analysis. The results showed that Reference SNP rs6068816 in CYP24A1, rs1544410 and rs731236 in VDR and rs7041 in GC were statistically significant in relation to reduction in NSCLC risk (p < 0.001–0.05). No significant connection was seen between NSCLC risk and overall plasma 25-hydroxyvitamin D [25(OH)D] concentrations, regardless of smoking status. However, the mutation genotype of CYP24A1 rs6068816 and VDR rs1544410 were also significantly associated with increased 25(OH)D levels only in both the smoker and non-smoker cases (p < 0.01–0.05). Meanwhile, smokers and non-smokers with mutated homozygous rs2181874 in CYP24A1 had significantly increased NSCLC risk (odds ratio (OR) = 2.14, 95% confidence interval (CI) 1.47–3.43; p = 0.031; OR = 3.57, 95% CI 2.66–4.74; p = 0.019, respectively). Smokers with mutated homozygous rs10735810 in VDR had significantly increased NSCLC risk (OR = 1.93, 95% CI 1.41–2.76; p = 0.015). However, smokers with mutated homozygous rs6068816 in CYP24A1 had significantly decreased NSCLC risk (OR = 0.43, 95% CI 0.27–1.02; p = 0.006); and smokers and non-smokers with mutated homozygous rs

  14. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer.

    PubMed

    Wang, Shuhang; Cang, Shundong; Liu, Delong

    2016-04-12

    The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are widely used in patients with non-small cell lung cancer (NSCLC). However, EGFR T790M mutation leads to resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development. These agents include osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. Osimertinib and rociletinib have shown clinical efficacy in phase I/II trials in patients who had acquired resistance to first- or second-generation TKIs. Osimertinib (AZD9291, TAGRISSO) was recently approved by FDA for metastatic EGFR T790M mutation-positive NSCLC. HM61713, ASP8237, EGF816, and PF-06747775 are still in early clinical development. This article reviews the emerging data regarding third-generation agents against EGFR T790M mutation in the treatment of patients with advanced NSCLC.

  15. Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer

    PubMed Central

    Hirsh, V.

    2011-01-01

    Non-small-cell lung cancer (nsclc) has the highest prevalence of all types of lung cancer, which is the second most common cancer and the leading cause of cancer-related mortality in Canada. The need for more effective and less toxic treatment options for nsclc has led to the development of agents targeting the epidermal growth factor receptor (egfr)–mediated signalling pathway, such as egfr tyrosine kinase inhibitors (egfr-tkis). Although egfr-tkis are less toxic than traditional anti-neoplastic agents, they are commonly associated with acneiform-like rash and diarrhea. This review summarizes the clinical presentation and causes of egfr-tki–induced rash and diarrhea, and presents strategies for effective assessment, monitoring, and treatment of these adverse effects. Strategies to improve the management of egfr-tki–related adverse events should improve clinical outcomes, compliance, and quality of life in patients with advanced nsclc. PMID:21655159

  16. Meta-analysis Exploring the Effectiveness of S-1-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer.

    PubMed

    Sun, Xin; Sun, Li; Zhang, Shu-Ling; Xiong, Zhi-Cheng; Ma, Jie-Tao; Han, Cheng-Bo

    2017-01-01

    S-1 is a new oral fluoropyrimidine formulation that comprises tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. S-1 is designed to enhance antitumor activity and to reduce gastrointestinal toxicity. Several studies have demonstrated that both S-1 monotherapy and S-1 combination regimens showed encouraging efficacies and mild toxicities in the treatment of lung squamous cell carcinoma and adenocarcinoma. However, it is unclear whether S-1 can be used as standard care in advanced non-small cell lung cancer (NSCLC). The purpose of this meta-analysis was to assess the efficacy and safety of S-1-based chemotherapy, compared with standard chemotherapy, in patients with locally advanced or metastatic NSCLC. Thirteen randomized controlled trials (RCTs) involving 2,134 patients with a similar ratio of different pathological types were included. In first-line or second-line chemotherapy, compared with standard chemotherapy, S-1-based chemotherapy showed similar efficacy in terms of median overall survival (mOS), median progression free survival (mPFS), and objective response rate (ORR) (all P > 0.1), and significantly reduced the incidence of grade ≥ 3 hematological toxicities. In patients with locally advanced NSCLC receiving concurrent chemoradiotherapy, compared with standard chemoradiotherapy, significantly improved survival in the S-1-based chemotherapy was noted in terms of mOS and mPFS (risk radio [RR] = 1.289, P = 0.009; RR = 1.289, P = 0.000, respectively) with lower incidence of grade ≥ 3 neutropenia (RR = 0.453, P = 0.000). The present meta-analysis demonstrates that S-1-based chemotherapy shows similar benefits in advanced NSCLC and improves survival in locally advanced NSCLC, compared with standard treatment.

  17. Locally Advanced Lung Cancer: An Optimal Setting for Vaccines and Other Immunotherapies

    PubMed Central

    Iyengar, Puneeth; Gerber, David E.

    2013-01-01

    Lung cancer has traditionally been considered relatively resistant to immunotherapies. However, recent advances in the understanding of tumor-associated antigens, anti-tumor immune responses, and tumor immunosuppression mechanisms have resulted in a number of promising immunomodulatory therapies such as vaccines and checkpoint inhibitors. Locally advanced non-small cell lung cancer (NSCLC) is an optimal setting for these treatments because standard therapies such as surgery, radiation, and chemotherapy may enhance anti-tumor immune effects by debulking the tumor, increasing tumor antigen presentation, and promoting T-cell response and trafficking. Clinical trials incorporating immunomodulatory agents into combined modality therapy of locally advanced NSCLC have shown promising results. Future challenges include identifying biomarkers to predict those patients most likely to benefit from this approach, radiographic assessment of treatment effects, the timing and dosing of combined modality treatment including immunotherapies, and avoidance of potentially overlapping toxicities. PMID:23708072

  18. Radiofrequency Ablation of Stage IA NSCLC in Medically Inoperable Patients: Results from the ACOSOG Z4033 (Alliance) Trial

    PubMed Central

    Dupuy, Damian E.; Fernando, Hiran C.; Hillman, Shauna; Ng, Thomas; Tan, Angelina D.; Sharma, Amita; Rilling, William S.; Hong, Kelvin; Putnam, Joe B.

    2015-01-01

    Purpose This study evaluates the two-year overall survival (OS), adverse event rate, local control rate and impact on pulmonary function tests (PFTs) in medically inoperable patients with stage IA NSCLC undergoing CT-guided RFA in a prospective multi-center trial. Methods 54 patients M:F=25:29, median age/range= 76/60–89 were enrolled from 16 US centers 51 patients were eligible (biopsy proven stage IA NSCLC and deemed medically inoperable by board certified thoracic surgeon) for evaluation. PFTs were obtained within 60 days of RFA, 3 and 24 months after RFA. Adverse events were recorded and categorized. Patients were followed by CT and FDG PET. Local control rate and recurrence patterns were analyzed. RESULTS The OS rate was 86.3% at one year and 69.8% at two years. Local tumor recurrence free rate was 68.9% at one year and 59.8% at two years and was worse for tumors >2 cm. In the 19 patients with local recurrence, 11 had retreatment with RFA, nine had radiation and three had chemotherapy. There were 21 grade 3, two grade 4 and one grade 5 AEs in 12 patients within the first 90 days after RFA. None of the grade 4 and 5 AEs were attributed to the RFA. There was no significant change in the FEV1 or DLCO after RFA. Tumor size less than 2.0 cm and performance status of 0–1 were associated with a statistically significant improved survival of 83% and 78% respectively, at two years. CONCLUSIONS RFA is a single minimally invasive procedure, that is well tolerated in medically inoperable patients, does not adversely affect PFTs and gives two year OS that is comparable to that reported following SBRT in similar patients. PMID:26096694

  19. EGFR activating mutations detected by different PCR techniques in Caucasian NSCLC patients with CNS metastases: short report.

    PubMed

    Kamila, Wojas-Krawczyk; Michał, Skroński; Paweł, Krawczyk; Paulina, Jaguś; Tomasz, Kucharczyk; Bożena, Jarosz; Radosław, Mlak; Justyna, Szumiło; Marek, Sawicki; Trojanowski, Tomasz; Janusz, Milanowski; Joanna, Chorostowska-Wynimko

    2013-12-01

    EGFR mutation testing has become an essential determination to decide treatment options for NSCLC. The mutation analysis is often conducted in samples with low percentage of tumour cells from primary tumour biopsies. There is very little evidence that samples from metastatic tissues are suitable for EGFR testing. We had evaluated the frequency of EGFR mutations with three highly sensitive PCR techniques in formalin-fixed, paraffin-embedded samples of 143 NSCLC patients with central nervous system (CNS) metastases. 32 corresponding primary tumours were also examined. We used PCR followed by DNA fragments length analysis (FLA), ASP-PCR and PNA-LNA PCR clamp techniques. We found 9 (6.29 %) EGFR gene mutations in CNS samples: 3 (2.1 %) in exon 19 and 6 (4.2 %) in exon 21. The full concordance between CNS metastases and primary tumour samples was observed. PCR followed by DNA-FLA and PNA-LNA PCR clamp were sensitive enough to detect exon 19 deletions. Two mutations in exon 21 were detected by ASP-PCR only, one L858R substitution was detected only by PNA-LNA PCR clamp. With respect to sensitivity, PCR followed by DNA-FLA achieved a level of detection of at least 10 % of mutated DNA for exon 19 deletion, as for ASP-PCR it was at least 5 % of mutated DNA for L858R substitution. Higher sensitivity of 1 % of mutated DNA was achieved by PNA-LNA PCR clamp technique for both mutations. The use of different methodological techniques authenticates the negative result of molecular tests.

  20. Beams Arrangement in Non-Small Cell Lung Cancer (NSCLC) According to PTV and Dosimetric Parameters Predictive of Pneumonitis

    SciTech Connect

    Ramella, Sara; Trodella, Lucio; Mineo, Tommaso Claudio; Pompeo, Eugenio; Gambacorta, Maria A.; Cellini, Francesco; Ciresa, Marzia; Fiore, Michele; Greco, Carlo; Gaudino, Diego; Stimato, Gerardina; Piermattei, Angelo; Cesario, Alfredo; D'Angelillo, Rolando M.

    2010-10-01

    The aim of this study is to propose and validate an original new class of solutions for three-dimensional conformal radiation therapy (3DCRT) treatment planning for non-small cell lung cancer (NSCLC) according to the different patterns of disease presentation (on the basis of tumor location and volume) and to explore beams arrangement (planar or no-planar solutions) to respect dose constraints to the lung parenchyma. Benchmarks matched to validate the new approach are interuser reproducibility and saving on planning time. Tumor location was explored and specific categories created according to the tumor volume and location. Therefore, by applying planar and no-planar 3D plans, we searched for an optimization of the beams arrangement for each category. Dose-volume histograms (DVHs) were analyzed and a plan comparison performed. Results were then validated (class solution planning confirmation) by applying the same strategy to another group of patients. This has been realized at two dose levels (50.4 and 59.4 Gy). Fifty-nine patients were enrolled in this dosimetric study. In the first 27 patients ('exploratory sample') three main planning target volume location categories were identified according to the pattern of the disease presentation: (1) centrally located; (2) peripheral T and mediastinal N (P+N); and (3) superior sulcus. Original class solutions were proposed for each location category. On the next 32 patients ('validation sample'), the treatment planning started directly with the recommended approach. Mean V{sub 20Gy} value was 18.8% (SD {+-} 7.25); mean V{sub 30Gy}:12% (SD {+-} 4.05); and mean lung dose: 11.6Gy (SD {+-} 5.77). No differences between the two total dose level groups were observed. These results suggest a simple and reproducible tool for treatment planning in NSCLC, allowing interuser reproducibility and cutting down on planning time.

  1. Complex mutations & subpopulations of deletions at exon 19 of EGFR in NSCLC revealed by next generation sequencing: potential clinical implications.

    PubMed

    Marchetti, Antonio; Del Grammastro, Maela; Filice, Giampaolo; Felicioni, Lara; Rossi, Giulio; Graziano, Paolo; Sartori, Giuliana; Leone, Alvaro; Malatesta, Sara; Iacono, Michele; Guetti, Luigi; Viola, Patrizia; Mucilli, Felice; Cuccurullo, Franco; Buttitta, Fiamma

    2012-01-01

    Microdeletions at exon 19 are the most frequent genetic alterations affecting the Epidermal Growth Factor Receptor (EGFR) gene in non-small cell lung cancer (NSCLC) and they are strongly associated with response to treatment with tyrosine kinase inhibitors. A series of 116 NSCLC DNA samples investigated by Sanger Sequencing (SS), including 106 samples carrying exon 19 EGFR deletions and 10 without deletions (control samples), were subjected to deep next generation sequencing (NGS). All samples with deletions at SS showed deletions with NGS. No deletions were seen in control cases. In 93 (88%) cases, deletions detected by NGS were exactly corresponding to those identified by SS. In 13 cases (12%) NGS resolved deletions not accurately characterized by SS. In 21 (20%) cases the NGS showed presence of complex (double/multiple) frameshift deletions producing a net in-frame change. In 5 of these cases the SS could not define the exact sequence of mutant alleles, in the other 16 cases the results obtained by SS were conventionally considered as deletions plus insertions. Different interpretative hypotheses for complex mutations are discussed. In 46 (43%) tumors deep NGS showed, for the first time to our knowledge, subpopulations of DNA molecules carrying EGFR deletions different from the main one. Each of these subpopulations accounted for 0.1% to 17% of the genomic DNA in the different tumors investigated. Our findings suggest that a region in exon 19 is highly unstable in a large proportion of patients carrying EGFR deletions. As a corollary to this study, NGS data were compared with those obtained by immunohistochemistry using the 6B6 anti-mutant EGFR antibody. The immunoreaction was E746-A750del specific. In conclusion, NGS analysis of EGFR exon 19 in NSCLCs allowed us to formulate a new interpretative hypothesis for complex mutations and revealed the presence of subpopulations of deletions with potential pathogenetic and clinical impact.

  2. Cooperative Regulation of NSCLC Angiogenic Potential by Macrophage Migration Inhibitory Factor and its Homolog, D-Dopachrome Tautomerase1

    PubMed Central

    Coleman, Arlixer M.; Rendon, Beatriz E.; Zhao, Ming; Qian, Ming-Wei; Bucala, Richard; Xin, Dan; Mitchell, Robert A.

    2009-01-01

    Tumor-derived growth factors and cytokines stimulate neoangiogenesis from surrounding capillaries in order to support tumor growth. Recent studies reveal that macrophage migration inhibitory factor (MIF) expression is increased in lung cancer, particularly non-small cell lung carcinomas (NSCLC). Because MIF has important autocrine effects on normal and transformed cells, we investigated whether autocrine MIF and its only known family member, D-dopachrome tautomerase (D-DT), promote the expression of pro-angiogenic factors CXCL8 and VEGF in NSCLC cells. Our results demonstrate that the expression of CXCL8 and VEGF are strongly reliant upon both the individual and cooperative activities of the two family members. CXCL8 transcriptional regulation by MIF and D-DT appears to involve a signaling pathway that includes the activation of c-Jun-N-terminal Kinase (JNK), c-jun phosphorylation and subsequent AP-1 transcription factor activity. Importantly, human umbilical vein endothelial cell (HUVEC) migration and tube formation induced by supernatants from lung adenocarcinoma cells lacking either or both MIF and D-DT are substantially reduced when compared to normal supernatants. Finally, we demonstrate that the cognate MIF receptor, CD74, is necessary for both MIF and D-DT-induced JNK activation and CXCL8 expression, suggesting its potential involvement in angiogenic growth factor expression. This is the first demonstration of a biological role for D-DT and its synergism with MIF suggests that the combined therapeutic targeting of both family members may enhance current anti-MIF based therapies. PMID:18684922

  3. Echocardiography and cardiac biomarkers in patients with non-small cell lung cancer treated with platinum-based chemotherapy

    PubMed Central

    Omersa, Daniel; Cufer, Tanja; Marcun, Robert

    2017-01-01

    Abstract Background Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and remains an important cause of cancer death worldwide. Platinum-based chemotherapy (PBC) for NSCLC can modify outcome while the risk of cardiotoxicity remains poorly researched. We aimed to evaluate the incidence and severity of cardiac injury during PBC in patients with NSCLC and to identify patients at risk. Methods This was a single-centre, prospective, observational study of patients with early and advanced stage NSCLC referred for PBC. In addition to standard care, patients were examined and evaluated for cardiotoxicity before the first dose (visit 1), at the last dose (visit 2) and 6 months after the last dose of PBC (visit 3). Cardiotoxicity (at visit 2 and 3) was defined as increase in the ultrasensitive troponin T, N-terminal pro-B type natriuretic peptide or decrease in left ventricular ejection fraction (LVEF). Results Overall, 41 patients (mean age 61 ± 9; 54% men; 68% advanced lung cancer) were included. The median number of PBC cycles was 4. During the study period, there were no incidents of heart failure, and 3 deaths caused by tumour progression were recorded. The mean values of biomarkers and LVEF did not change significantly (p > 0.20). However, 10 (25%) had cardiotoxicity which was independently associated with a history of ischemic heart disease (p = 0.026). Conclusions In NSCLC, cardiac assessment and lifestyle modifications may be pursued in patients with a history of cardiac disease and in patients with longer life expectancy. PMID:28265228

  4. Umbilical cord blood-derived dendritic cells infected by adenovirus for SP17 expression induce antigen-specific cytotoxic T cells against NSCLC cells.

    PubMed

    Liu, Yang; Tian, Xin; Jiang, Shenyi; Ren, Xuemei; Liu, Fengjie; Yang, Jichun; Chen, Yanling; Jiang, Youhong

    2015-01-01

    Sperm protein 17 (SP17), a cancer/testis antigen, is expressed by non-small cell lung cancer (NSCLC). This study examined whether dendritic cells (DC) from human umbilical cord blood (UCB) could be induced for SP17 expression and induce antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) against NSCLC in vitro. We generated recombinant adenovirus of Ad-SP17 and control Ad-null. Infection with Ad-SP17, but not control, induced higher levels of SP17 expression in UCB-derived DC-Ad-SP17. Infection with Ad-SP17 significantly increased the frequency of CD80(+), CD83(+), CD86(+), and HLA-DR(+) DC that produced higher levels of IL-12, but lower IL-10. Co-culture of DC-Ad-SP17 with autologous UCB lymphocytes induced high frequency of IFNγ(+) CD8(+) CTLs, which had selective cytotoxicity against SP17(+) lung cancer CRL-5922 cells in a HLA-I restrictive manner. Thus, UCB-derived DC modulated for SP17 expression induced antigen-specific anti-tumor immunity against SP17(+) NSCLC, and SP17 may be a valuable target for development of immunotherapy against SP17(+) NSCLC.

  5. ERK Signaling Pathway Is Involved in HPV-16 E6 but not E7 Oncoprotein-Induced HIF-1α Protein Accumulation in NSCLC Cells.

    PubMed

    Liu, Fei; Lin, Bihua; Liu, Xin; Zhang, Wenzhang; Zhang, Erying; Hu, Liang; Ma, Yuefan; Li, Xiangyong; Tang, Xudong

    2016-01-01

    Extracellular signal-regulated kinase (ERK)1/2 signaling pathway plays a critical role in regulating tumor angiogenesis. Our previous studies have demonstrated that HPV-16 oncoproteins enhanced hypoxia-inducible factor-1α (HIF-1α) protein accumulation and vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells, thus contributing to angiogenesis. In this study, we further investigated the role of ERK1/2 signaling pathway in HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis in NSCLC cells. Our results showed that HPV-16 E6 and HPV-16 E7 oncoproteins promoted the activation of ERK1/2 signaling pathway in A549 and NCI-H460 cells. Moreover, PD98059, a specific inhibitor of ERK1/2, blocked in vitro angiogenesis stimulated by HPV-16 E6 but not E7 oncoprotein. Additionally, HIF-1α protein accumulation and VEGF and IL-8 expression in NSCLC cells induced by HPV-16 E6 but not E7 oncoprotein were significantly inhibited by PD98059. Taken together, our results suggest that ERK1/2 signaling pathway is involved in HPV-16 E6 but not E7 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression in NSCLC cells, leading to the enhanced angiogenesis in vitro.

  6. Pyroxamide in Treating Patients With Advanced Cancer

    ClinicalTrials.gov

    2013-06-04

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Precancerous Condition; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  7. Long-term results of dose-intensive chemotherapy with G-CSF support (TCC-NHL-91) for advanced intermediate-grade non-Hodgkin's lymphoma: a review of 59 consecutive cases treated at a single institute.

    PubMed

    Akutsu, Miyuki; Tsunoda, Saburo; Izumi, Tohru; Tanaka, Masaru; Katano, Susumu; Inoue, Koichi; Igarashi, Seiji; Hirabayashi, Kaoru; Furukawa, Yusuke; Ohmine, Ken; Sato, Kazuya; Kobayashi, Hiroyuki; Ozawa, Keiya; Kirito, Keita; Nagashima, Takahiro; Teramukai, Satoshi; Fukushima, Masanori; Kano, Yasuhiko

    2008-01-01

    We evaluated the long-term outcome of very dose-intensive chemotherapy (TCC-NHL-91) for advanced intermediate-grade lymphoma, in which an eight-cycle regimen with 11 drugs was given with granulocyte colony-stimulating factor (G-CSF) support (total 18 weeks). Fifty-nine patients were treated during February 1, 1991 and March 31, 2001 (median age: 48 years). Forty-three patients (73%) were in a high-intermediate risk or high-risk group (HI/H) according to the age-adjusted International Prognostic Index (aa-IPI). Forty-six patients received 7 or 8 cycles of therapy. Ten of 15 patients over age 60 stopped before 7 cycles. Forty-three patients with an initial bulky mass or a residual mass received involved-field radiation. Overall, 56 patients (95%) achieved complete remission (CR). Grade 4 hematotoxicity was observed in all patients. With a median follow-up of 128 months, the 10-year overall survival (OS) and progression-free survival (PFS) rates were 76% and 61%, respectively. Neither aa-IPI risk factors nor the index itself was associated with response, OS, or PFS. One patient died of sepsis during the therapy and one died of secondary leukemia. This retrospective study suggests that the TCC-NHL-91 regimen achieves high CR, OS, and PFS in patients with advanced intermediate-grade lymphoma up to 60 years old and may be a valuable asset in the management of this disease. Further evaluation and prospective studies of the TCC-NHL-91 are warranted.

  8. Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy.

    PubMed

    Ha, Hyerim; Nam, Ah-Rong; Bang, Ju-Hee; Park, Ji-Eun; Kim, Tae-Yong; Lee, Kyung-Hun; Han, Sae-Won; Im, Seock-Ah; Kim, Tae-You; Bang, Yung-Jue; Oh, Do-Youn

    2016-11-22

    Programmed death-ligand 1 (PD-L1) expression in tumor tissue is under investigation as a candidate biomarker in immuno-oncology dug development. The soluble form of PD-L1 (sPDL1) is suggested to have immunosuppressive activity. In this study, we measured the serum level of sPDL1 and evaluated its prognostic implication in biliary tract cancer (BTC). Blood was collected from 158 advanced BTC patients (68 intrahepatic cholangiocarcinoma, 56 gallbladder cancer, 22 extrahepatic cholangiocarcinoma and 12 ampulla of vater cancer) before initiation of palliative chemotherapy. Serum sPDL1 was measured using an enzyme-linked immunosorbent assay. Clinical data included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). The patients were assigned to two cohorts (training and validation cohort) using a simple random sampling method to validate the cut-off value of each marker. Validation was performed using a twofold cross-validation method. Overall survival (OS) of all patients was 9.07 months (95% CI: 8.20-11.33). Median sPDL1 was 1.20 ng/mL (range 0.03-7.28, mean 1.50, SD 1.22). Median NLR, PLR and SII were 2.60, 142.85 and 584.93, respectively. Patients with high sPDL1 (≥0.94 ng/mL) showed worse OS than patients with low sPDL1 (7.93 vs. 14.10 months, HR 1.891 (1.35-2.65), p<0.001). In multivariate analysis, high sPDL1 and NLR were independent poor prognostic factors. In conclusion, serum sPDL1 can be measured and has significant role on the prognosis of advanced BTC patients treated with palliative chemotherapy.

  9. Soluble programmed death-ligand 1 (sPDL1) and neutrophil-to-lymphocyte ratio (NLR) predicts survival in advanced biliary tract cancer patients treated with palliative chemotherapy

    PubMed Central

    Ha, Hyerim; Nam, Ah-Rong; Bang, Ju-Hee; Park, Ji-Eun; Kim, Tae-Yong; Lee, Kyung-Hun; Han, Sae-Won; Im, Seock-Ah; Kim, Tae-You; Bang, Yung-Jue; Oh, Do-Youn

    2016-01-01

    Programmed death-ligand 1 (PD-L1) expression in tumor tissue is under investigation as a candidate biomarker in immuno-oncology dug development. The soluble form of PD-L1 (sPDL1) is suggested to have immunosuppressive activity. In this study, we measured the serum level of sPDL1 and evaluated its prognostic implication in biliary tract cancer (BTC). Blood was collected from 158 advanced BTC patients (68 intrahepatic cholangiocarcinoma, 56 gallbladder cancer, 22 extrahepatic cholangiocarcinoma and 12 ampulla of vater cancer) before initiation of palliative chemotherapy. Serum sPDL1 was measured using an enzyme-linked immunosorbent assay. Clinical data included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). The patients were assigned to two cohorts (training and validation cohort) using a simple random sampling method to validate the cut-off value of each marker. Validation was performed using a twofold cross-validation method. Overall survival (OS) of all patients was 9.07 months (95% CI: 8.20-11.33). Median sPDL1 was 1.20 ng/mL (range 0.03-7.28, mean 1.50, SD 1.22). Median NLR, PLR and SII were 2.60, 142.85 and 584.93, respectively. Patients with high sPDL1 (≥0.94 ng/mL) showed worse OS than patients with low sPDL1 (7.93 vs. 14.10 months, HR 1.891 (1.35-2.65), p<0.001). In multivariate analysis, high sPDL1 and NLR were independent poor prognostic factors. In conclusion, serum sPDL1 can be measured and has significant role on the prognosis of advanced BTC patients treated with palliative chemotherapy. PMID:27780932

  10. HER-2, p53, p21 and hormonal receptors proteins expression as predictive factors of response and prognosis in locally advanced breast cancer treated with neoadjuvant docetaxel plus epirubicin combination

    PubMed Central

    Tiezzi, Daniel G; Andrade, Jurandyr M; Ribeiro-Silva, Alfredo; Zola, Fábio E; Marana, Heitor RC; Tiezzi, Marcelo G

    2007-01-01

    Background Neoadjuvant chemotherapy has been considered the standard care in locally advanced breast cancer. However, about 20% of the patients do not benefit from this clinical treatment and, predictive factors of response were not defined yet. This study was designed to evaluate the importance of biological markers to predict response and prognosis in stage II and III breast cancer patients treated with taxane and anthracycline combination as neoadjuvant setting. Methods Sixty patients received preoperative docetaxel (75 mg/m2) in combination with epirubicin (50 mg/m2) in i.v. infusion in D1 every 3 weeks after incisional biopsy. They received adjuvant chemotherapy with CMF or FEC, attaining axillary status following definitive breast surgery. Clinical and pathologic response rates were measured after preoperative therapy. We evaluated the response rate to neoadjuvant chemotherapy and the prognostic significance of clinicopathological and immunohistochemical parameters (ER, PR, p51, p21 and HER-2 protein expression). The median patient age was 50.5 years with a median follow up time 48 months after the time