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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. Clinicopathologic Features of Advanced Squamous NSCLC.

    PubMed

    Socinski, Mark A; Obasaju, Coleman; Gandara, David; Hirsch, Fred R; Bonomi, Philip; Bunn, Paul; Kim, Edward S; Langer, Corey J; Natale, Ronald B; Novello, Silvia; Paz-Ares, Luis; Pérol, Maurice; Reck, Martin; Ramalingam, Suresh S; Reynolds, Craig H; Spigel, David R; Stinchcombe, Thomas E; Wakelee, Heather; Mayo, Carlos; Thatcher, Nick

    2016-09-01

    Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.

  3. Optimal tumor shrinkage predicts long-term outcome in advanced nonsmall cell lung cancer (NSCLC) treated with target therapy: Result from 3 clinical trials of advanced NSCLC by 1 institution.

    PubMed

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

    2016-08-01

    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 (HR, 2.36, 95

  4. A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study.

    PubMed

    Planchard, David; Yokoi, Takashi; McCleod, Michael J; Fischer, Jürgen R; Kim, Young-Chul; Ballas, Marc; Shi, Kelvin; Soria, Jean-Charles

    2016-05-01

    Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-) tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor activity in patients with advanced NSCLC, regardless of PD-L1 tumor status. ARCTIC (NCT02352948) is a global, phase III, randomized, open-label multicenter study in patients with advanced NSCLC assessing the safety and clinical activity of durvalumab versus standard of care (SoC; erlotinib, gemcitabine, or vinorelbine) in patients with PD-L1(+) tumors (≥25% of tumor cells with membrane staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the combination of durvalumab + tremelimumab or either agent as monotherapy versus SoC in patients with PD-L1(-) tumors (Sub-study B). Eligible patients are those with locally advanced or metastatic NSCLC (Stage IIIB/IV), without epidermal growth factor receptor tyrosine kinase activating mutations or anaplastic lymphoma kinase rearrangements, who have received at least 2 prior systemic regimens, including 1 platinum-based chemotherapy regimen. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include the proportion of patients alive at 12 months, objective response rate, duration of response, progression-free survival at 6 and 12 months, safety and tolerability, pharmacokinetics, immunogenicity, and quality of life. The exploratory endpoints will assess potential biomarkers of treatment response. Recruitment started in January 2015 and is ongoing. PMID:27265743

  5. A Phase III Study of Durvalumab (MEDI4736) With or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of the ARCTIC Study.

    PubMed

    Planchard, David; Yokoi, Takashi; McCleod, Michael J; Fischer, Jürgen R; Kim, Young-Chul; Ballas, Marc; Shi, Kelvin; Soria, Jean-Charles

    2016-05-01

    Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-) tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor activity in patients with advanced NSCLC, regardless of PD-L1 tumor status. ARCTIC (NCT02352948) is a global, phase III, randomized, open-label multicenter study in patients with advanced NSCLC assessing the safety and clinical activity of durvalumab versus standard of care (SoC; erlotinib, gemcitabine, or vinorelbine) in patients with PD-L1(+) tumors (≥25% of tumor cells with membrane staining using VENTANA PD-L1 [SP263] CDx Assay) (Sub-study A) and the combination of durvalumab + tremelimumab or either agent as monotherapy versus SoC in patients with PD-L1(-) tumors (Sub-study B). Eligible patients are those with locally advanced or metastatic NSCLC (Stage IIIB/IV), without epidermal growth factor receptor tyrosine kinase activating mutations or anaplastic lymphoma kinase rearrangements, who have received at least 2 prior systemic regimens, including 1 platinum-based chemotherapy regimen. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include the proportion of patients alive at 12 months, objective response rate, duration of response, progression-free survival at 6 and 12 months, safety and tolerability, pharmacokinetics, immunogenicity, and quality of life. The exploratory endpoints will assess potential biomarkers of treatment response. Recruitment started in January 2015 and is ongoing.

  6. PET in the management of locally advanced and metastatic NSCLC.

    PubMed

    Grootjans, Willem; de Geus-Oei, Lioe-Fee; Troost, Esther G C; Visser, Eric P; Oyen, Wim J G; Bussink, Johan

    2015-07-01

    Despite considerable improvements in the treatment options for advanced-stage non-small-cell lung cancer (NSCLC), disease-specific survival remains poor. With the aim of improving patient outcome, the treatment paradigm of locally advanced NSCLC has shifted from solely radiotherapy towards combined and intensified treatment approaches. Also, treatment for patients with stage IV (oligo)metastatic NSCLC has evolved rapidly, with therapeutic options that include a number of targeted agents, surgery, and stereotactic ablative radiotherapy. However, personalizing treatment to the individual patient remains difficult and requires monitoring of biological parameters responsible for treatment resistance to facilitate treatment selection, guidance, and adaptation. PET is a well-established molecular imaging platform that enables non-invasive quantification of many biological parameters that are relevant to both local and systemic therapy. With increasing clinical evidence, PET has gradually evolved from a purely diagnostic tool to a multifunctional imaging modality that can be utilized for treatment selection, adaptation, early response monitoring, and follow up in patients with NSCLC. Herein, we provide a comprehensive overview of the available clinical data on the use of this modality in this setting, and discuss future perspectives of PET imaging for the clinical management of patients with locally advanced and metastatic NSCLC.

  7. The efficacy and safety of immunotherapy in patients with advanced NSCLC: a systematic review and meta-analysis

    PubMed Central

    Zhou, Liang; Wang, Xi-Ling; Deng, Qing-Long; Du, Yan-Qiu; Zhao, Nai-Qing

    2016-01-01

    Immunotherapy is a novel treatment for advanced non-small cell lung cancer (NSCLC) patients. Immunotherapy includes two main broad classes of therapeutic vaccines and immune checkpoint inhibitors, as well as cytokines, biological response modifiers and cellular therapy. The present systematic review and meta-analysis aims to evaluate the efficacy and safety of different classes of immunotherapy in patients with advanced NSCLC. Literature search was done on Medline, Embase and Cochrane Library. The primary endpoints were overall survival (OS) and grade ≥3 adverse events. Twenty randomized controlled trials were finally identified in our study. Efficacy analysis indicated an improvement of OS in advanced NSCLC patients after treating by therapeutic vaccines and immune checkpoint inhibitors, but not for other immunomodulators. Safety analysis showed that immunotherapy was well-tolerated. All kinds of grade ≥3 adverse events were similar between experimental group and control group except that neutropenia and thrombocytopenia had a higher incidence in patients received vaccines. In conclusion, immunotherapy is a promising treatment for advanced NSCLC patients. Our findings will be further confirmed and supplemented by several phase II and phase III RCTs which are going to complete in near future. PMID:27558285

  8. The efficacy and safety of immunotherapy in patients with advanced NSCLC: a systematic review and meta-analysis.

    PubMed

    Zhou, Liang; Wang, Xi-Ling; Deng, Qing-Long; Du, Yan-Qiu; Zhao, Nai-Qing

    2016-01-01

    Immunotherapy is a novel treatment for advanced non-small cell lung cancer (NSCLC) patients. Immunotherapy includes two main broad classes of therapeutic vaccines and immune checkpoint inhibitors, as well as cytokines, biological response modifiers and cellular therapy. The present systematic review and meta-analysis aims to evaluate the efficacy and safety of different classes of immunotherapy in patients with advanced NSCLC. Literature search was done on Medline, Embase and Cochrane Library. The primary endpoints were overall survival (OS) and grade ≥3 adverse events. Twenty randomized controlled trials were finally identified in our study. Efficacy analysis indicated an improvement of OS in advanced NSCLC patients after treating by therapeutic vaccines and immune checkpoint inhibitors, but not for other immunomodulators. Safety analysis showed that immunotherapy was well-tolerated. All kinds of grade ≥3 adverse events were similar between experimental group and control group except that neutropenia and thrombocytopenia had a higher incidence in patients received vaccines. In conclusion, immunotherapy is a promising treatment for advanced NSCLC patients. Our findings will be further confirmed and supplemented by several phase II and phase III RCTs which are going to complete in near future. PMID:27558285

  9. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts

    PubMed Central

    Reck, M.; Barlesi, F.; Crinò, L.; Henschke, C. I.; Isla, D.; Stiebeler, S.; Spigel, D. R.

    2012-01-01

    Background: Bevacizumab is a monoclonal antibody against vascular endothelial growth factor. Severe pulmonary haemorrhage (PH) is a rare but serious potential adverse event associated with bevacizumab therapy for advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: A panel of expert oncologists, pulmonologists and radiologists reviewed the available data to identify predictive factors for PH in order to help guide physicians using bevacizumab in patients with NSCLC. Results: Patients with NSCLC are at an increased risk of PH owing to the underlying disease process. Patients with squamous histology and/or a history of grade ≥2 haemoptysis (≥2.5 ml per event) should not receive bevacizumab. No clinical or radiological features (including cavitation and central tumour location) reliably predict severe PH in bevacizumab-treated patients. Major blood vessel infiltration and bronchial vessel infiltration, encasement and abutting may predict PH; however, standardised radiological criteria for defining infiltration have not been established. Eligibility for bevacizumab is not affected by patient age, performance status or anticoagulation or antiplatelet therapy. Conclusions: An individualised risk–benefit assessment should be undertaken in all patients with NSCLC in whom bevacizumab is being considered. Further research is required to elucidate the mechanisms underlying PH and the clinical risk factors. PMID:22056855

  10. 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.

  11. New radiation techniques for treatment of locally advanced non-small cell lung cancer (NSCLC).

    PubMed

    Silvano, G

    2006-03-01

    Local control is a main step to cure NSCLC because at least 30-40% of patients die for local or regional progression of their disease. Surgery is still the more efficient approach to increase survival but radiation therapy is the only treatment that can cure patients with T1-T2 lesions if they are not suitable for surgery or refuse it. However, doses higher than 60-66 Gy must be given to improve tumor control but doses to the organs at risk (OAR) are the main limit to deliver more than 70 Gy to the planning treatment volume (PTV). The optimal solution would be to 'paint' the dose to the PTV avoiding as possible OARs, but this ballistic precision was not possible till some years ago because of both technology and respiratory movement control. In last ten years many new techniques have been made available for treating NSCLC with radiation more accurately. Some techniques like Intensity Modulated Radiotherapy (IMRT), Image Guided Radiotherapy (IGRT), Stereotactic Radiotherapy can be carried out also with a traditional linear accelerator (LINAC) updated with the new software and hardware, using or not radiopaque markers inside the tumor. On the other hand, a new generation of machines like Cyberknife or Tomotherapy have been especially projected to optimize stereotactic technique and IMRT, respectively, and respiratory gating systems are now disposable from several manufactures. PMID:16608978

  12. Planned FDG PET-CT Scan in Follow-Up Detects Disease Progression in Patients With Locally Advanced NSCLC Receiving Curative Chemoradiotherapy Earlier Than Standard CT

    PubMed Central

    Pan, Yi; Brink, Carsten; Schytte, Tine; Petersen, Henrik; Wu, Yi-long; Hansen, Olfred

    2015-01-01

    Abstract The role of positron emission tomography-computed tomography (PET-CT) in surveillance of patients with nonsmall cell lung cancer (NSCLC) treated with curatively intended chemoradiotherapy remains controversial. However, conventional chest X-ray and computed tomography (CT) are of limited value in discriminating postradiotherapy changes from tumor relapse. The aim of this study was to evaluate the clinical value of PET-CT scan in the follow-up for patients with locally advanced (LA) NSCLC receiving concomitant chemoradiotherapy (CCRT). Between 2009 and 2013, eligible patients with stages IIB–IIIB NSCLC were enrolled in the clinical trial NARLAL and treated in Odense University Hospital (OUH). All patients had a PET-CT scan scheduled 9 months (PET-CT9) after the start of the radiation treatment in addition to standard follow-up (group A). Patients who presented with same clinical stage of NSCLC and received similar treatment, but outside protocol in OUH during this period were selected as control group (group B). Patients in group B were followed in a conventional way without PET-CT9. All patients were treated with induction chemotherapy followed by CCRT. Group A included 37 and group B 55 patients. The median follow-up was 16 months. Sixty-six (72%) patients were diagnosed with progression after treatment. At the time of tumor progression, patients in group A had better performance status (PS) than those in group B (P = 0.02). Because of death (2 patients), poor PS (3) or retreatment of relapse (9), only 23 patients had PET-CT9 in group A. Eleven (48%) patients were firstly diagnosed with progression by PET-CT9 without any clinical symptoms of progression. The median progression-free survival (PFS) was 8.8 months in group A and 12.5 months in group B (P = 0.04). Hazard function PFS showed that patients in group A had higher risk of relapse than in group B. Additional FDG PET-CT scan at 9 months in surveillance increases probability of early

  13. 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

  14. Volumetric tumor growth in advanced NSCLC patients with EGFR mutations during EGFR-TKI therapy: Developing criteria to continue therapy beyond RECIST progression

    PubMed Central

    Nishino, Mizuki; Dahlberg, Suzanne E.; Cardarella, Stephanie; Jackman, David M.; Rabin, Michael S.; Ramaiya, Nikhil H.; Hatabu, Hiroto; Jänne, Pasi A.; Johnson, Bruce E.

    2013-01-01

    Purpose Define volumetric tumor growth rate in advanced NSCLC patients with sensitizing EGFR mutations initially treated with EGFR-TKI therapy beyond progression. Methods The study included 58 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line gefitinib or erlotinib, who had baseline CT showing measurable lung lesion and at least two follow-up CTs while on TKI and experienced volumetric tumor growth. Tumor volume (mm3) of the dominant lung lesion was measured on baseline and follow-up CT scans during therapy. A total of 405 volume measurements were analyzed in a linear mixed effects model, fitting time as a random effect, to define the growth rate of the logarithm of tumor volume (logeV). Results A linear mixed effects model was fitted to predict growth of logeV, adjusting for time in months from baseline. LogeV was estimated as a function of time in months, in patients whose tumors have started growing after nadir: logeV=0.12*time+7.68 In this formula, the regression coefficient for time, 0.12/month, represents the growth rate of logeV (SE: 0.015; p<0.001). When adjusted for baseline volume, logeV0, the growth rate was also 0.12/month (SE: 0.015; p<0.001; logeV =0.12*months+0.72 logeV0+0.61). Conclusion Tumor volume models defined volumetric tumor growth after the nadir in EGFR-mutant advanced NSCLC patients receiving TKI, providing a reference value for the tumor growth rate in patients progressing after the nadir on TKI. The results can be further studied in additional cohorts to develop practical criteria which help to identify patients who are slowly progressing and can safely remain on EGFR-TKIs. PMID:23922022

  15. Advances in treating psoriasis

    PubMed Central

    Belge, Katharina; Brück, Jürgen

    2014-01-01

    Psoriasis is a T helper (Th)17/Th1-mediated autoimmune disease affecting the skin and joints. So far, distinct traditional oral compounds and modern biologics have been approved in most countries for the treatment of patients with moderate to severe psoriasis or psoriatic arthritis. Yet, the anti-psoriatic therapeutic spectrum is to be extended by a number of novel targeted therapies including biologics and modern oral compounds. The next set of anti-psoriatic biologics targets mainly Th17-associated cytokines such as IL-17 or IL-23. In contrast, modern oral anti-psoriatics, such as dimethyl fumarate (DMF), apremilast or Janus kinase (JAK) inhibitors interfere with intracellular proteins and affect signaling pathways. Here we summarize the current systemic therapies for psoriasis and their immunological mechanism. The recent advances in psoriasis therapy will help treat our patients efficiently and complete our understanding of disease pathogenesis. PMID:24592316

  16. Percutaneous CT-guided microwave ablation as maintenance after first-line treatment for patients with advanced NSCLC

    PubMed Central

    Ni, Xiang; Han, Jun-Qing; Ye, Xin; Wei, Zhi-Gang

    2015-01-01

    Background Systemic therapy is recommended for advanced non-small-cell lung cancer (NSCLC). However, conventional first-line treatment has generated a plateau in response rate of 25% to 35%. Few studies have shown patients benefit from microwave ablation (MWA) in combination with radiotherapy and chemotherapy. This study aims to evaluate safety and efficacy of percutaneous computed tomography-guided MWA as maintenance after first-line treatment for patients with advanced NSCLC. Methods Patients with histologically verified NSCLC stage IIIB or IV between January 2010 and March 2014 were involved. After completion of first-line treatment with partial response or stable disease, 35 patients with 39 tumors underwent 39 MWA procedures. Complications, progression-free survival (PFS), overall survival (OS), and correlated predictors were analyzed. Results During a median follow-up of 17.7 months and 10.8 months after initial MWA, local efficacy was 87.2%, median MWA-related local control time was 10.6 months, and tumor size was the only predictor (P=0.002). Median MWA-related PFS, MWA-related OS, PFS, and OS were 5.4, 10.6, 11.8 and 17.7 months, respectively. Local efficacy was significantly correlated with MWA-related PFS (P=0.003), MWA-related OS (P=0.000), and OS (P=0.001). There were no procedure-specific deaths. Total incidence of major complications was 12.8%, including pneumothorax resolved by closed pleural drainage and pneumonia controlled by antibiotics in a short time. Conclusion This study concluded two points, including: 1) patients benefited from MWA as maintenance both in local control and survival; 2) as maintenance MWA was superior to conventional maintenance therapy with improved survival and well-tolerated complications. Therefore, MWA was a safe and effective maintenance after first-line treatment in patients with advanced NSCLC. PMID:26604789

  17. 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. PMID:27479016

  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. Revisiting the relationship between tumour volume and diameter in advanced NSCLC patients: An exercise to maximize the utility of each measure to assess response to therapy

    PubMed Central

    Nishino, M.; Jackman, D.M.; DiPiro, P.J.; Hatabu, H.; Jänne, P.A.; Johnson, B.E.

    2014-01-01

    AIM To revisit the presumed relationship between tumour diameter and volume in advanced non-small-cell lung cancer (NSCLC) patients, and determine whether the measured volume using volume-analysis software and its proportional changes during therapy matches with the calculated volume obtained from the presumed relationship and results in concordant response assessment. MATERIALS AND METHODS Twenty-three patients with stage IIIB/IV NSCLC with a total of 53 measurable lung lesions, treated in a phase II trial of erlotinib, were studied with institutional review board approval. Tumour volume and diameter were measured at baseline and at the first follow-up computed tomography (CT) examination using volume-analysis software. Using the measured diameter (2r) and the equation, calculated volume was obtained as (4/3) πr3 at baseline and at the follow-up. Percent volume change was obtained by comparing to baseline for measured and calculated volumes, and response assessment was assigned. RESULTS The measured volume was significantly smaller than the calculated volume at baseline (median 11,488.9 mm3 versus 17,148.6 mm3; p < 0.0001), with a concordance correlation coefficient (CCC) of 0.7022. At follow-up, the measured volume was once again significantly smaller than the calculated volume (median 6573.5 mm3 versus 9198.1 mm3; p = 0.0022), with a CCC of 0.7408. Response assessment by calculated versus measured volume changes had only moderate agreement (weighted κ = 0.545), with discordant assessment results in 20% (8/40) of lesions. CONCLUSION Calculated volume based on the presumed relationship significantly differed from the measured volume in advanced NSCLC patients, with only moderate concordance in response assessment, indicating the limitations of presumed relationship. PMID:24857677

  20. Specific Safety Profile of Bevacizumab in Asian Patients With Advanced NSCLC: A Meta-Analysis.

    PubMed

    Chen, Zhenguang; Zhong, Beilong; Lun, Xueping; Lai, Yingrong; Bella, Amos Ela; Yang, Weilin; Wu, Jiabin

    2015-06-01

    Randomized studies have obtained varying findings regarding the benefits and toxicities of bevacizumab in the treatment of nonsmall cell lung cancer (NSCLC). It is unclear whether the discrepancies among trials are due to ethnic/racial differences. We therefore performed a meta-analysis of all published, randomized, controlled clinical trials involving bevacizumab in patients with NSCLC to assess its effectiveness and safety in Asian and non-Asian populations. Results from the phase II JO19907 trial, the phase III AVAiL and ECOG 4599 trials, and the phase IV SAiL trials were used to calculate the benefits and toxicities of bevacizumab in Asian and non-Asian patients. Combined statistical estimates, including hazard ratios and odds ratios, were calculated using fixed-effects and random-effects models. A total of 4308 patients were evaluated. Combining bevacizumab with different chemotherapy regimens resulted in similar objective response rates, overall survival, and progression-free survival in Asian and non-Asian populations. Disease control rates, however, were only reported in Asian populations. The rates of severe bleeding (relative risk [RR], 2.17; P = 0.02) and thromboembolism (RR, 3.65; P < 0.0001) were significantly higher, while the rate of severe proteinuria was significantly lower (RR, 0.43; P < 0.0001), in non-Asian than in Asian populations. The rates of severe hypertension (P = 0.71) and hemoptysis (P = 0.66) were similar in Asian and non-Asian populations. Bevacizumab combined with chemotherapy for first-line NSCLC treatment showed similar benefits in Asian and non-Asian populations, but had specific safety profiles in each.

  1. Phase I/II study of bortezomib in combination with carboplatin and bevacizumab as first line therapy in patients with advanced non-small cell lung cancer (NSCLC)

    PubMed Central

    Piperdi, Bilal; Walsh, William V; Bradley, Kendra; Zhou, Zheng; Bathini, Venu; Hanrahan-Boshes, Meredith; Hutchinson, Lloyd; Perez-Soler, Roman

    2013-01-01

    Purpose To establish the maximum tolerated dose (MTD) of weekly bortezomib in combination with fixed standard doses of carboplatin and bevacizumab and to estimate the efficacy (response rate and progression free survival) and safety of combination therapy with carboplatin, bortezomib and bevacizumab as first line therapy in patients with advanced NSCLC. Experimental Design Patients were assigned to three dose levels of weekly bortezomib with the fixed standard doses of carboplatin (AUC 6) and bevacizumab (15 mg/kg) q 3 wks using a standard phase I design. Bortezomib doses were 1.3 mg/m21.6 mg/m2 and 1.8 mg/m2 weekly on D1 and D8 of q 3wk cycle. A maximum of six cycles was administered. Patients with complete, partial response (PR) or stable disease were continued on single agent bevacizumab (15 mg/kg q 3 wks) as maintenance therapy. In phase II, either level III or MTD was administered to evaluate the efficacy and safety of the combination in first line treatment of advanced NSCLC. Results 16 patients were enrolled (3, 4 and 9 pts in dose level I, II and III respectively). There was no pre-defined dose limiting toxicity in cycle 1 in all 16 patients. The recommended phase II dose is bortezomib 1.8 mg/m2 weekly on day 1 and day 8 in combination with carboplatin AUC of 6 and bevacizumab 15 mg/kg on every 21 day cycle. Total of 9 patients were treated at the recommended phase II dose level. The most common treatment related grade 3/4 toxicities during the subsequent cycles were thrombocytopenia (58%), lymphopenia (25%), neutropenia (12%) and diarrhea (25%). The grade 1/2 neuropathy was seen in 7 out of 16 pts (44%). The response rate, PFS and OS in all patients were 37.5% (95%CI 13.8% - 61.2%), 5.0 months (m) (95%CI: 3.1-8.4), 9.9 m (95% CI: 8.2-14.1) and the 9 patients in phase II portion are 44% (95%CI 15.3% - 77.3%), 5.5 m (95%CI: 3.1-12.2) and 10.9 months (95%CI: 8.0-14.1). Conclusion The recommended phase II dose for this combination is: carboplatin AUC 6

  2. A serum microRNA signature as a prognostic factor for patients with advanced NSCLC and its association with tissue microRNA expression profiles

    PubMed Central

    GUO, JING; MENG, RUI; YIN, ZHONGYUAN; LI, PENGCHENG; ZHOU, RUI; ZHANG, SHENG; DONG, XIAORONG; LIU, LI; WU, GANG

    2016-01-01

    The aim of the present study was to detect microRNA (miRNA) signatures in advanced non-small cell lung cancer (NSCLC), and to study the association between miRNA expression levels in serum and tissue. A cohort of patients who had previously been diagnosed with advanced NSCLC was enrolled in the present study. miRNAs associated with prognosis, which had previously been detected in early stage NSCLC samples, were measured in the serum of the patient groups using a cross-validation method. In addition, serum miRNAs associated with progression-free survival (PFS) were detected in paired fresh tissue samples, in order to analyze the correlation between serum and tissue expression levels. A risk-score analysis was used to develop a four-miRNA signature to predict PFS. miR-1, miR-30d, miR-221 and miR-486 were identified as having a significant correlation with PFS in advanced NSCLC. miR-221 and miR-486 exhibited significant positive correlations between serum and tissue expression. Furthermore, overexpression of miR-221 and reduced expression of miR-486 increased cell proliferation, migration and invasion in vitro. In conclusion, the miRNA signature identified in the present study may be considered an independent prognostic factor of PFS in advanced NSCLC. In addition, the expression levels of miR-221 and miR-486 were significantly correlated between serum and tissue. miR-221 was identified as an oncogenic risk factor, whereas miR-486 exerted protective effects against cancer cell proliferation, migration and invasion. PMID:27081922

  3. Stromal Caveolin-1 Is Associated With Response and Survival in a Phase II Trial of nab-Paclitaxel With Carboplatin for Advanced NSCLC Patients

    PubMed Central

    Bertino, Erin M.; Williams, Terence M.; Nana-Sinkam, S. Patrick; Shilo, Konstantin; Chatterjee, Moumita; Mo, Xiaokui; Rahmani, Meliha; Phillips, Gary S.; Villalona-Calero, Miguel A.; Otterson, Gregory A.

    2016-01-01

    In this phase II trial, carboplatin with nanoparticle albumin-bound (nab)-paclitaxel as first-line therapy for advanced non–small-cell lung cancer (NSCLC) was evaluated. Most patients had squamous cell histology. Tumor-associated stromal caveolin-1 (Cav-1) expression was correlated with improved response rate and survival in NSCLC patients who received nab-paclitaxel in this phase II trial. These results suggest Cav-1 might serve as a potential biomarker in this patient population. Background The combination of bevacizumab with platinum-based chemotherapy results in greater response rate (RR) and overall survival (OS) in advanced non–small-cell lung cancer (NSCLC). Bevacizumab is contraindicated in patients with squamous histology or hemoptysis. Nanoparticle albumin-bound (nab)-paclitaxel is a novel formulation of paclitaxel with greater dose tolerance and improved efficacy. We hypothesized that nab-paclitaxel and carboplatin would be superior to alternative doublets in advanced NSCLC patients ineligible for bevacizumab. Patients and Methods We conducted a single-arm phase II trial (NCT00729612) with carboplatin and nab-paclitaxel on day 1 of a 21-day cycle to evaluate RR (primary end point), safety, toxicity, and OS. Eligibility included: squamous histology, hemoptysis, or ongoing anticoagulation. Correlative studies included immunohistochemistry for secreted protein acid rich in cysteine (SPARC) and caveolin-1 (Cav-1). Results Sixty-three patients were enrolled. Most patients had squamous cell carcinoma (n = 48); other reasons for eligibility included hemoptysis (n = 11) and anticoagulation (n = 2). Toxicity Grade ≥ 3/4 included neuropathy, cytopenias, and fatigue. RR was 38% (24 partial response/0 complete response); 20 patients had stable disease (32%). Median progression-free survival was 5 months and median OS was 9.7 months. Immunohistochemistry for SPARC and Cav-1 was performed in 38 and 37 patients respectively. Although no association was found for

  4. 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.

  5. Incidental Prophylactic Nodal Irradiation and Patterns of Nodal Relapse in Inoperable Early Stage NSCLC Patients Treated With SBRT: A Case-Matched Analysis

    SciTech Connect

    Lao, Louis; Hope, Andrew J.; Maganti, Manjula; Brade, Anthony; Bezjak, Andrea; Saibishkumar, Elantholi P.; Giuliani, Meredith; Sun, Alexander; Cho, B. C. John

    2014-09-01

    Purpose: Reported rates of non-small cell lung cancer (NSCLC) nodal failure following stereotactic body radiation therapy (SBRT) are lower than those reported in the surgical series when matched for stage. We hypothesized that this effect was due to incidental prophylactic nodal irradiation. Methods and Materials: A prospectively collected group of medically inoperable early stage NSCLC patients from 2004 to 2010 was used to identify cases with nodal relapses. Controls were matched to cases, 2:1, controlling for tumor volume (ie, same or greater) and tumor location (ie, same lobe). Reference (normalized to equivalent dose for 2-Gy fractions [EQD2]) point doses at the ipsilateral hilum and carina, demographic data, and clinical outcomes were extracted from the medical records. Univariate conditional logistical regression analyses were performed with variables of interest. Results: Cases and controls were well matched except for size. The controls, as expected, had larger gross tumor volumes (P=.02). The mean ipsilateral hilar doses were 9.6 Gy and 22.4 Gy for cases and controls, respectively (P=.014). The mean carinal doses were 7.0 Gy and 9.2 Gy, respectively (P=.13). Mediastinal nodal relapses, with and without ipsilateral hilar relapse, were associated with mean ipsilateral hilar doses of 3.6 Gy and 19.8 Gy, respectively (P=.01). The conditional density plot appears to demonstrate an inverse dose-effect relationship between ipsilateral hilar normalized total dose and risk of ipsilateral hilar relapse. Conclusions: Incidental hilar dose greater than 20 Gy is significantly associated with fewer ipsilateral hilar relapses in inoperable early stage NSCLC patients treated with SBRT.

  6. Evaluation of Circulating Tumor Cells and Related Events as Prognostic Factors and Surrogate Biomarkers in Advanced NSCLC Patients Receiving First-Line Systemic Treatment

    PubMed Central

    Muinelo-Romay, Laura; Vieito, Maria; Abalo, Alicia; Alonso Nocelo, Marta; Barón, Francisco; Anido, Urbano; Brozos, Elena; Vázquez, Francisca; Aguín, Santiago; Abal, Miguel; López López, Rafael

    2014-01-01

    In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC) and their utility for therapy monitoring in non-small cell lung cancer (NSCLC). A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before the 1st, 2nd and 5th cycles of chemotherapy and analyzed using CellSearch technology. Both CTC and CTC-related objects (not morphological standard or broken epithelial cells) were counted. At baseline 18 (41.9%) patients were positive for intact CTC count and 10 (23.2%) of them had ≥5 CTC, while CK positive events were found in 79.1% of patients. The group of patients with CTC ≥5 at baseline presented worse PFS and OS than those with <5 CTC (p = 0.034 and p = 0.008, respectively). Additionally, high levels of total CK positive events were associated with poor prognosis in the group of patients with <5 CTC. Regarding therapy monitoring, patients presenting increased levels of CTC during the treatment demonstrated lower OS and PFS rates. All these data supported the value of CTC as a prognostic biomarker and as a surrogate indicator of chemotherapy effectiveness in advanced NSCLC patients, with the additional value of analyzing other “objects” such as apoptotic CTC or CK fragments to guide the clinical management of these patients. PMID:24452143

  7. Evaluation of Circulating Tumor Cells and Related Events as Prognostic Factors and Surrogate Biomarkers in Advanced NSCLC Patients Receiving First-Line Systemic Treatment.

    PubMed

    Muinelo-Romay, Laura; Vieito, Maria; Abalo, Alicia; Nocelo, Marta Alonso; Barón, Francisco; Anido, Urbano; Brozos, Elena; Vázquez, Francisca; Aguín, Santiago; Abal, Miguel; López, Rafael López

    2014-01-01

    In the present study we investigated the prognostic value of Circulating Tumour Cells (CTC) and their utility for therapy monitoring in non-small cell lung cancer (NSCLC). A total of 43 patients newly diagnosed with NSCLC were prospectively enrolled. Blood samples were obtained before the 1st, 2nd and 5th cycles of chemotherapy and analyzed using CellSearch technology. Both CTC and CTC-related objects (not morphological standard or broken epithelial cells) were counted. At baseline 18 (41.9%) patients were positive for intact CTC count and 10 (23.2%) of them had ≥5 CTC, while CK positive events were found in 79.1% of patients. The group of patients with CTC ³5 at baseline presented worse PFS and OS than those with <5 CTC (p = 0.034 and p = 0.008, respectively). Additionally, high levels of total CK positive events were associated with poor prognosis in the group of patients with <5 CTC. Regarding therapy monitoring, patients presenting increased levels of CTC during the treatment demonstrated lower OS and PFS rates. All these data supported the value of CTC as a prognostic biomarker and as a surrogate indicator of chemotherapy effectiveness in advanced NSCLC patients, with the additional value of analyzing other "objects" such as apoptotic CTC or CK fragments to guide the clinical management of these patients.

  8. 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

  9. The impact of histological types on the efficacy of angiogenesis inhibitors in the treatment of advanced NSCLC: a meta-analysis of randomized controlled trials

    PubMed Central

    Zhang, Jian; Liu, Jie; Chen, Huiguo; Wu, Weibin; Li, Xiaojun; Wu, Yonghui; Zhang, Kai; Gu, Lijia

    2015-01-01

    Purpose We aimed at assessing the overall efficacy of angiogenesis inhibitor (AI)-containing regimens in the treatment of advanced non-small-cell lung cancer (NSCLC) according to histological types. Methods Studies from PubMed and Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) meeting up to October 31, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials (RCTs) evaluating AIs in advanced NSCLC with survival data according to patients’ histologies. The endpoints were overall survival (OS) and progression-free survival (PFS). Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies. Results A total of 10,035 patients with advanced NSCLC from 13 RCTs were identified for analysis. The pooled results demonstrated that AI-containing regimens significantly improved the PFS (HR, 0.84, 95% confidence interval (CI): 0.78–0.91, P<0.001) and OS (HR, 0.92, 95% CI: 0.85–0.99, P=0.017) in lung adenocarcinoma when compared to non-AI-containing regimens. Additionally, there was a significantly improved PFS (HR, 0.87, 95% CI: 0.77–0.98, P=0.027) for AI-containing regimens in squamous cell lung carcinoma, but it did not translated into OS benefit (HR, 1.02, 95% CI: 0.92–1.15, P=0.68). For NSCLC patients with other histological types, the use of AIs did not significantly improve PFS (HR, 0.90, 95% CI: 0.75–1.09, P=0.27) and OS (HR, 0.90, 95% CI: 0.76–1.08, P=0.19). Conclusion The findings of this study suggest that the addition of AIs to the treatment therapies for patients with lung adenocarcinoma offers improved survival benefits. Prospective clinical trials investigating the role of AIs in this setting are recommended. PMID:26366091

  10. 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

  11. Time-to-Progression of NSCLC from Early to Advanced Stages: An Analysis of data from SEER Registry and a Single Institute

    PubMed Central

    Yuan, Ping; Cao, Jin Lin; Rustam, Azmat; Zhang, Chong; Yuan, Xiao Shuai; Bao, Fei Chao; Lv, Wang; Hu, Jian

    2016-01-01

    The average time required for cancers to progress through stages can be reflected in the average age of the patients diagnosed at each stage of disease. To estimate the time it takes for non-small-cell lung cancer (NSCLC) to progress through different tumor, node and metastasis (TNM) stages and sizes, we compared the mean adjusted age of 45904 NSCLC patients with different stages and tumor sizes from Surveillance, Epidemiology and End Results (SEER) cancer registry database and our institute. Multiple-linear-regression models for age were generated adjusting for various factors. Caucasian, African-American and Asian patients with stage IA cancers were on average 0.8, 1.0 and 1.38 adjusted years younger, respectively, than those with stage IIIB cancers (p < 0.001). And these with T1a cancers were on average 0.84, 0.92 and 1.21 adjusted years younger, respectively, than patients with T3 cancers (p < 0.001). Patients with tumors measuring larger than 8 cm in diameter were on average 0.85 adjusted years older than these with tumors smaller than 1 cm (p < 0.001), with Caucasian demonstrating the shortest age span (0.79 years, P < 0.001). In conclusion, the time-to-progression of NSCLC from early to advanced stages varied among ethnicities, Caucasian patients demonstrating a more rapid progression nature of tumor than their African-American and Asian counterparts. PMID:27346236

  12. The efficacy and safety of nivolumab in previously treated advanced non-small-cell lung cancer: a meta-analysis of prospective clinical trials

    PubMed Central

    Huang, Jiaxing; Zhang, Yaxiong; Sheng, Jin; Zhang, Hongyu; Fang, Wenfeng; Zhan, Jianhua; Zhou, Ting; Chen, Ying; Liu, Lin; Zhang, Li

    2016-01-01

    Background Nivolumab (BMS-936558/ONO-4538) was the first monoclonal antibody targeting programmed death (PD)-1. So far, a number of clinical trials on nivolumab have showed satisfactory efficacy in treating non-small-cell lung cancer (NSCLC). Herein, we present a meta-analysis evaluating the efficacy and safety of nivolumab for previously treated advanced NSCLC patients. Methods Electronic databases were searched for eligible literature. Data of objective response rate (ORR), disease control rate, overall survival, progression-free survival, and adverse effects (AEs) were extracted and pooled. Outcomes analyzed and presented in this study were according to the original data from nivolumab 3 mg/kg. Results In general, nine trials with 817 patients were included in this meta-analysis. The pooled ORR, disease control rate, 1-year overall survival rate, and 1-year progression-free survival rate were 20% (95% confidence interval [CI]: 17%–23%), 36% (95% CI: 22%–51%), 47% (95% CI: 40%–53%), 21% (95% CI: 18%–24%), respectively. In addition, the rate of grade 3–4 AEs was only 8% (95% CI: 6%–12%). Subgroup analysis showed no significant difference in terms of ORR between squamous and non-squamous NSCLC (odds ratio 1.23, 95% CI: 0.63–2.39, P=0.51). However, significantly greater ORR was presented in programmed cell death ligand 1 (PD-L1) positive cohort (ORR 31%, 95% CI: 24%–38%), compared to PD-L1 negative cohort (ORR 12%, 95% CI: 9%–17%). The odds ratio for objective response to nivolumab in PD-L1 positive cases relative to negative cases was 3.08 (95% CI: 1.87–5.08, P<0.0001). Conclusion In conclusion, nivolumab is a promising second-line agent for previously treated advanced NSCLC with manageable AEs. Both squamous and non-squamous NSCLC patients showed similar efficacy. In addition, patients with positive PD-L1 expression had better response from nivolumab. Microabstract We present a meta-analysis evaluating the efficacy and safety of nivolumab for

  13. Efficacy of cisplatin/pemetrexed with bevacizumab to treat advanced lung adenocarcinoma with different drive genes: case report and literature review

    PubMed Central

    Wang, Haiyong; Zhu, Hui; Kong, Li; Yu, Jinming

    2016-01-01

    Background Bevacizumab combined with chemotherapy has become the first-line therapy in advanced nonsquamous non-small-cell lung cancer (NSCLC). However, few studies have focused on cisplatin/pemetrexed with bevacizumab as the first-line therapy to treat advanced nonsquamous NSCLC. Importantly, whether the epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements can influence the efficacy of bevacizumab in combination with chemotherapy is very interesting. Herein, we report three cases with different types of gene drives in advanced nonsquamous NSCLC. Case presentation In the first case, a patient presented with wild-type EGFR and negative ALK rearrangement. In the second case, a patient presented with wild-type EGFR and positive ALK rearrangement. In the third case, a patient presented with negative ALK rearrangement and mutated EGFR in exon 19. Conclusion We speculate that bevacizumab in combination with cisplatin/pemetrexed as the first-line therapy is well tolerated and results in a clinically meaningful treatment benefit, irrespective of the gene drive type in advanced nonsquamous NSCLC. However, more data are needed to confirm the relationship. PMID:27555784

  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. Prospective Validation Obtained in a Similar Group of Patients and with Similar High Throughput Biological Tests Failed to Confirm Signatures for Prediction of Response to Chemotherapy and Survival in Advanced NSCLC: A Prospective Study from the European Lung Cancer Working Party

    PubMed Central

    Berghmans, Thierry; Ameye, Lieveke; Lafitte, Jean-Jacques; Colinet, Benoît; Cortot, Alexis; CsToth, Ingrid; Holbrechts, Stéphane; Lecomte, Jacques; Mascaux, Céline; Meert, Anne-Pascale; Paesmans, Marianne; Richez, Michel; Scherpereel, Arnaud; Tulippe, Christian; Willems, Luc; Dernies, Tiffany; Leclercq, Nathalie; Sculier, Jean-Paul

    2014-01-01

    Aim: Cisplatin doublets are standard 1st line treatment for advanced non-small cell lung cancer (NSCLC), without accurate predictor for response and survival, but important toxicity. Our aims were to identify predictive (for response) and prognostic (for survival) biological signatures in patients with NSCLC using messenger RNAs (mRNA) and miRNA expression. Methods: Patients with pathologically proven untreated NSCLC, receiving 1st line cisplatin–vinorelbine and with an assessable lesion were eligible. A bronchial biopsy was lysed into Tripure Isolation Reagent on ice, snap frozen, and stored at −80°C. mRNA expression was analyzed using microarrays Agilent Technologies. miRNA expression was assessed using TaqMan Low Density Arrays (756 human miR panel, Applied Biosystems). Validation was performed by RT-PCR on the selected genes. Survival was measured from the registration date and response assessed by WHO criteria. Results: Biopsies for transcriptomic analyses were obtained from 60 consecutive patients. No statistically significant differences were observed according to the main clinical characteristics, response rate (43 vs. 41%) or survival (median 25 vs. 29 months) between derivation and validation sets. In the derivation set (n = 38 patients), two mRNA and one miRNA predictive signatures for response were obtained. One mRNA and one miRNA prognostic signatures were derived from the first set, allowing an adequate distinction of patients with good and poor overall and progression-free survivals. None of these signatures could be validated in the validation set (n = 22 patients). Conclusion: In this prospective study with advanced NSCLC treated with cisplatin–vinorelbine, we were able to derive with high throughput techniques predictive and prognostic signatures based on transcriptomic analyses. However, these results could not be reproduced in an independent validation set. The role of miRNA and mRNA as predictive or prognostic factors remains a

  16. 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

  17. 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

  18. 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

  19. Complement Factor H Autoantibodies are Associated with Early Stage NSCLC

    PubMed Central

    Amornsiripanitch, Nita; Hong, Shaolin; Campa, Michael J.; Frank, Michael M.; Gottlin, Elizabeth B.; Patz, Edward F.

    2010-01-01

    Purpose In order to discover diagnostic biomarkers associated with early stage non-small cell lung cancer (NSCLC), we searched for autoantibodies preferentially present in stage I patients compared to patients with advanced stage disease. Here we describe an autoantibody against complement factor H (CFH) and its association with early stage NSCLC. Experimental Design Immunoblots were used to detect autoantibodies in the sera of stage I NSCLC patients. An autoantibody recognizing a 150 kDa protein was discovered and the protein was identified by mass spectrometry. The association of the autoantibody with early stage disease was suggested by the results of immunoblot analysis with sera from 28 stage I patients and 28 stage III/IV patients. This association was confirmed by protein microarray of sera from 125 NSCLC patients of all stages as well as 125 age, gender, and smoking history matched controls. Results The immunoreactive protein was identified as CFH. By immunoblot analysis, anti-CFH autoantibody was found in 50% of stage I NSCLC patients and 11% of late stage NSCLC patients (P=0.003). By protein microarray analysis, patients with stage I NSCLC had a significantly higher incidence of anti-CFH antibody than those with late stage NSCLC (P=0.0051). The percentage of sera with a positive level of CFH autoantibody was 30.4% in stage I, 21.1% in stage II, 12.5% in stage III, 7.4% in stage IV and 8.0% in the control group. Conclusions These findings suggest that in patients with NSCLC, CFH autoantibody is a molecular marker associated with early stage disease. PMID:20515868

  20. Comparison of treatment costs of grade 3/4 adverse events associated with erlotinib or pemetrexed maintenance therapy for patients with advanced non-small-cell lung cancer (NSCLC) in Germany, France, Italy, and Spain.

    PubMed

    Banz, Kurt; Bischoff, Helge; Brunner, Matthias; Chouaid, Christos; de Castro Carpeño, Javier; de Marinis, Filippo; Grossi, Francesco; Vergnenègre, Alain; Walzer, Stefan

    2011-12-01

    Objective of this indirect economic comparison was to estimate and compare management costs of grade 3/4 adverse events (AEs) reported for first-line erlotinib or pemetrexed maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC). The economic analysis was performed for Germany, France, Italy and Spain. Types and incidences of reported grade 3/4 AEs observed with erlotinib or pemetrexed maintenance therapy were retrieved from two recently published placebo-controlled trials. Country-specific estimates on standard treatment algorithms and incremental medical resource utilization associated with each of the reported grade 3/4 AEs have been obtained from clinical oncologists practicing in the four countries and co-authoring this article. The resource use items were subsequently assigned country-specific tariffs to estimate total per-patients costs associated with the AE profiles of the two compared maintenance regimens. For the economic analysis a customized economic spreadsheet model was employed. Our comparison shows lower total average per-patient AE management costs for erlotinib than for pemetrexed maintenance therapy in all four studied countries. Total estimated cost savings per patient in favour of erlotinib amount to € 121, € 237, € 106, and € 119 for Germany, France, Italy and Spain, respectively. These AE cost savings for erlotinib when compared to pemetrexed represent a decrease by 80%, 71%, 94%, and 82%, respectively. The study also discovered considerable differences in AE management costs across countries which are primarily due to differences in clinician's estimates of hospitalization referral rates. Erlotinib maintenance therapy in patients with advanced NSCLC causes lower AE management costs than pemetrexed maintenance therapy indicating a potentially superior tolerability profile. PMID:21592611

  1. Initial Evaluation of Treatment-Related Pneumonitis in Advanced-Stage Non-Small-Cell Lung Cancer Patients Treated With Concurrent Chemotherapy and Intensity-Modulated Radiotherapy

    SciTech Connect

    Yom, Sue S.; Liao Zhongxing . E-mail: zliao@mdanderson.org; Liu, H. Helen; Tucker, Susan L.; Hu, C.-S.; Wei Xiong; Wang Xuanming; Wang Shulian; Mohan, Radhe; Cox, James D.; Komaki, Ritsuko

    2007-05-01

    Purpose: To investigate the rate of high-grade treatment-related pneumonitis (TRP) in patients with advanced non-small-cell lung cancer (NSCLC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT). Methods and Materials: From August 2002 to August 2005, 151 NSCLC patients were treated with IMRT. We excluded patients who did not receive concurrent chemotherapy or who had early-stage cancers, a history of major lung surgery, prior chest RT, a dose <50 Gy, or IMRT combined with three-dimensional conformal RT (3D-CRT). Toxicities were graded by Common Terminology Criteria for Adverse Events version 3.0. Grade {>=}3 TRP for 68 eligible IMRT patients was compared with TRP among 222 similar patients treated with 3D-CRT. Results: The median follow-up durations for the IMRT and 3D-CRT patients were 8 months (range, 0-27 months) and 9 months (range, 0-56 months), respectively. The median IMRT and 3D-CRT doses were 63 Gy. The median gross tumor volume was 194 mL (range, 21-911 mL) for IMRT, compared with 142 mL (range, 1.5-1,186 mL) for 3D-CRT (p = 0.002). Despite the IMRT group's larger gross tumor volume, the rate of Grade {>=}3 TRP at 12 months was 8% (95% confidence interval 4%-19%), compared with 32% (95% confidence interval 26%-40%) for 3D-CRT (p = 0.002). Conclusions: In advanced NSCLC patients treated with chemoradiation, IMRT resulted in significantly lower levels of Grade {>=}3 TRP compared with 3D-CRT. Clinical, dosimetric, and patient selection factors that may have influenced rates of TRP require continuing investigation. A randomized trial comparing IMRT with 3D-CRT has been initiated.

  2. 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

  3. Prognostic models to predict survival in patients with advanced non-small cell lung cancer treated with first-line chemo- or targeted therapy

    PubMed Central

    Berardi, Rossana; Rinaldi, Silvia; Santoni, Matteo; Newsom-Davis, Thomas; Tiberi, Michela; Morgese, Francesca; Caramanti, Miriam; Savini, Agnese; Ferrini, Consuelo; Torniai, Mariangela; Fiordoliva, Ilaria; Bower, Marc; Cascinu, Stefano

    2016-01-01

    Background We aimed to assess the prognostic role of neutrophilia, lymphocytopenia and the neutrophil-to-lymphocyte ratio (NLR), and to design models to define the prognosis of patients receiving first-line chemo- or targeted therapy for advanced non-small cell lung cancer (NSCLC). Materials and Methods We retrospectively analysed 401 consecutive patients with advanced NSCLC treated with first line chemo- or targeted therapy. Patients were stratified into two groups with pre-treatment NLR ≥ 3.7 (Group A) vs. < 3.7 (Group B). The best NLR cut-off was identified by ROC curve analysis. Results At baseline 264 patients had NLR≥3.7 (Group A), whilst 137 had lower NLR (Group B). Median OS was 10.8 months and 19.4 months in the two groups (p < 0.001), while median PFS was 3.6 months and 5.6 months, respectively (p = 0.012). At multivariate analysis, ECOG-PS≥2, stage IV cancer, non-adenocarcinoma histology, EGFR wild-type status and NLR were predictors of worse OS. Stage IV cancer, wild type EGFR status and NLR≥3.7 were independent prognostic factors for worse PFS. Patients were stratified according to the presence of 0-1 prognostic factors (8%), 2-3 factors (73%) and 4-5 factors (19%) and median OS in these groups was 33.7 months, 14.6 months and 6.6 months, respectively (p < 0.001). Similarly, patients were stratified for PFS based on the presence of 0-1 prognostic factor (15%), 2 factors (41%) and 3 factors (44%). The median PFS was 8.3 months, 4.6 months and 3.3 months respectively (p < 0.001). Conclusion Pre-treatment NLR is an independent prognostic factor for patients with advanced NSCLC treated with first-line therapies. PMID:27029035

  4. Overall Survival and Long-Term Safety of Nivolumab (Anti–Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non–Small-Cell Lung Cancer

    PubMed Central

    Gettinger, Scott N.; Horn, Leora; Gandhi, Leena; Spigel, David R.; Antonia, Scott J.; Rizvi, Naiyer A.; Powderly, John D.; Heist, Rebecca S.; Carvajal, Richard D.; Jackman, David M.; Sequist, Lecia V.; Smith, David C.; Leming, Philip; Carbone, David P.; Pinder-Schenck, Mary C.; Topalian, Suzanne L.; Hodi, F. Stephen; Sosman, Jeffrey A.; Sznol, Mario; McDermott, David F.; Pardoll, Drew M.; Sankar, Vindira; Ahlers, Christoph M.; Salvati, Mark; Wigginton, Jon M.; Hellmann, Matthew D.; Kollia, Georgia D.; Gupta, Ashok K.; Brahmer, Julie R.

    2015-01-01

    Purpose Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non–small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients and Methods Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Results Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Conclusion Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing. PMID:25897158

  5. Randomized Phase II Study of Docetaxel plus Personalized Peptide Vaccination versus Docetaxel plus Placebo for Patients with Previously Treated Advanced Wild Type EGFR Non-Small-Cell Lung Cancer.

    PubMed

    Takayama, Koichi; Sugawara, Shunichi; Saijo, Yasuo; Maemondo, Makoto; Sato, Atsushi; Takamori, Shinzo; Harada, Taishi; Sasada, Tetsuro; Kakuma, Tatsuyuki; Kishimoto, Junji; Yamada, Akira; Noguchi, Masanori; Itoh, Kyogo; Nakanishi, Yoichi

    2016-01-01

    Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and Methods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m(2) on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS). Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p = 0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder. Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed. PMID:27274999

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

    PubMed Central

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

    2015-01-01

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

  7. 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

  8. Tumor Volume Decrease at 8 weeks is Associated with Longer Survival in EGFR-mutant Advanced Non-Small-Cell Lung Cancer Patients treated with EGFR Tyrosine Kinase Inhibitor

    PubMed Central

    Nishino, Mizuki; Dahlberg, Suzanne E.; Cardarella, Stephanie; Jackman, David M.; Rabin, Michael S.; Hatabu, Hiroto; Jänne, Pasi A.; Johnson, Bruce E.

    2013-01-01

    Background The study investigated if tumor volume changes at 8 weeks of therapy are associated with outcomes in advanced NSCLC patients with sensitizing EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs). Patients and methods In 56 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line erlotinib or gefitinib, tumor volumes of dominant lung lesions were measured on baseline and follow-up CT and were analyzed for association with survival. Results Among 56 eligible patients, the median tumor volume was 17.8 cm3 (range: 1.3-172.7 cm3) on the baseline scans. 49 patients had follow-up CT at approximately 8 weeks; the median tumor volume at 8 weeks was 7.1 cm3 (range: 0.4-62.3 cm3), with the median proportional volume change of -59% (range: -90% to +91%) from baseline. The proportional volume change at 8 weeks was associated with survival (p=0.02). Using the cut-off value of 38% volume decrease (75th percentile) at 8 weeks, patients with volume decrease >38% (n=37) had a median overall survival of 43.5 months compared to 16.3 months among those with volume decrease ≤38% (n=12) (p=0.01). The median progression-free survival for patients with >38% volume decrease was 12.6 months, compared to 5.5 months for those with ≤38% volume decrease (p=0.2). Conclusions The proportional volume change at 8 weeks is associated with overall survival in EGFR-mutant advanced NSCLC patients treated with first-line EGFR-TKIs. The observation of the study, if confirmed in larger study cohorts, indicates that tumor volume analysis at 8 weeks may provide an early marker for survival, and contribute to therapeutic decision making by identifying patients who may benefit from additional anti-cancer therapy after 8 weeks of EGFR-TKI therapy. PMID:23787800

  9. Multiple advanced surgical techniques to treat acquired seminal duct obstruction

    PubMed Central

    Jiang, Hong-Tao; Yuan, Qian; Liu, Yu; Liu, Zeng-Qin; Zhou, Zhen-Yu; Xiao, Ke-Feng; Yang, Jiang-Gen

    2014-01-01

    The aim of this study was to evaluate the outcomes of multiple advanced surgical treatments (i.e. microsurgery, laparoscopic surgery and endoscopic surgery) for acquired obstructive azoospermia. We analyzed the surgical outcomes of 51 patients with suspected acquired obstructive azoospermia consecutively who enrolled at our center between January 2009 and May 2013. Modified vasoepididymostomy, laparoscopically assisted vasovasostomy and transurethral incision of the ejaculatory duct with holmium laser were chosen and performed based on the different obstruction sites. The mean postoperative follow-up time was 22 months (range: 9 months to 52 months). Semen analyses were initiated at four postoperative weeks, followed by trimonthly (months 3, 6, 9 and 12) semen analyses, until no sperm was found at 12 months or until pregnancy was achieved. Patency was defined as >10,000 sperm ml−1 of semen. The obstruction sites, postoperative patency and natural pregnancy rate were recorded. Of 51 patients, 47 underwent bilateral or unilateral surgical reconstruction; the other four patients were unable to be treated with surgical reconstruction because of pelvic vas or intratesticular tubules obstruction. The reconstruction rate was 92.2% (47/51), and the patency rate and natural pregnancy rate were 89.4% (42/47) and 38.1% (16/42), respectively. No severe complications were observed. Using multiple advanced surgical techniques, more extensive range of seminal duct obstruction was accessible and correctable; thus, a favorable patency and pregnancy rate can be achieved. PMID:25337841

  10. Advanced oxidation to treat gasoline-contaminated groundwater

    SciTech Connect

    Singh, R.; Medlar, S.J. )

    1992-04-01

    For 10 to 20 years, an undetermined amount of gasoline leaked from a petroleum terminal at a site in New York State and caused groundwater contamination. Benzene, toluene, ethylbenzene, and xylenes were detected in concentrations of up to 90mg/L in some areas, and high levels of iron and lead were also observed. After discovery, recovery wells were installed to pump the pure product out of the ground. To date, more than 1500m[sup 3] (400,000 gal) of gasoline have been recovered. Wells were also installed to intercept the contaminant plume to prevent its migration. An air stripper with vapor-phase carbon was put on line as an immediate response measure to treat the intercepted groundwater. A site remediation plan was proposed to pump the gasoline-contaminated groundwater, treat it to remove both the metals and toxic organic contaminants, and then recharge it to the aquifer. One of the technologies proposed for the treatability study was the advanced oxidation (AO) process which uses ozone and hydrogen peroxide to destroy organic chemicals. This process involves the formation of free radicals by ozone decomposition; the hydroxyl radical concentration increases and contaminant oxidation and destruction are promoted.

  11. 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

  12. Treating patients with ALK-positive non-small cell lung cancer: latest evidence and management strategy

    PubMed Central

    Liao, Bin-Chi; Shih, Jin-Yuan; Yang, James Chih-Hsin

    2015-01-01

    Rearrangements in anaplastic lymphoma kinase (ALK) gene and echinoderm microtubule-associated protein-like 4 (EML4) gene were first described in a small portion of patients with non-small cell lung cancer (NSCLC) in 2007. Fluorescence in situ hybridization is used as the diagnostic test for detecting an EML4–ALK rearrangement. Crizotinib, an ALK inhibitor, is effective in treating advanced ALK-positive NSCLC, and the US Food and Drug Administration approved it for treating ALK-positive NSCLC in 2011. Several mechanisms of acquired resistance to crizotinib have recently been reported. Second-generation ALK inhibitors were designed to overcome these resistance mechanisms. Two of them, ceritinib and alectinib, were approved in 2014 for advanced ALK-positive NSCLC in the US and Japan, respectively. Heat shock protein 90 (Hsp90) inhibitors also showed activity against ALK-positive NSCLC. Here we review the recent development of crizotinib, ceritinib, alectinib and other second-generation ALK inhibitors as well as Hsp90 inhibitors. We also discuss management strategies for advanced ALK-positive NSCLC. PMID:26327925

  13. 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

  14. 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.

  15. 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.

  16. Pembrolizumab Shows Promise for NSCLC.

    PubMed

    2015-06-01

    Data from the KEYNOTE-001 trial show that pembrolizumab improves clinical outcomes for patients with advanced non-small cell lung cancer, and is well tolerated. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy.

  17. Acute myocardial infarction following erlotinib treatment for NSCLC: A case report

    PubMed Central

    DING, SHANSHAN; LONG, FEI; JIANG, SHUJUAN

    2016-01-01

    Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is an oral targeted anticancer drug that is used to treat non-small cell lung cancer (NSCLC). Previous studies have confirmed that erlotinib is safe and is well-tolerated by patients. The most common adverse reactions observed following erlotinib treatment include a rash and mild diarrhea. In the current study, the first case of acute myocardial infarction following one month of treatment with erlotinib in a 63-year-old male NSCLC patient is presented. The present study highlights the importance of clinicians remaining cautious following erlotinib administration. In elderly NSCLC patients and those with a history of coronary heart disease, cardiac function must be carefully monitored following erlotinib treatment so that serious adverse reactions, such as myocardial infarction, may be identified early and treated quickly. PMID:27313772

  18. Prognostic Potential and Tumor Growth–Inhibiting Effect of Plasma Advanced Glycation End Products in Non–Small Cell Lung Carcinoma

    PubMed Central

    Bartling, Babett; Hofmann, Hans-Stefan; Sohst, Antonia; Hatzky, Yvonne; Somoza, Veronika; Silber, Rolf-Edgar; Simm, Andreas

    2011-01-01

    The plasma fluorescence related to the standard fluorescence of advanced glycation end products (AGEs) is a simple measurable blood parameter for distinct diseases but its importance in human cancer, including non–small cell lung carcinoma (NSCLC), is unknown. Plasma samples of 70 NSCLC patients who underwent resection surgery of the tumor were analyzed for the distinct AGE-related fluorescence at 370 nm excitation/440 nm emission. In a retrospective study, we tested the prognostic relevance of this AGE-related plasma fluorescence. The effect of circulating AGEs on the NSCLC growth was studied experimentally in vitro and in vivo. NSCLC patients with high (> median) AGE-related plasma fluorescence were characterized by a later reoccurrence of the tumor after curative surgery and a higher survival rate compared with patients with low plasma fluorescence (25% versus 47% 5-y survival, P = 0.011). Treating NSCLC cell spheroids with patients’ plasma showed an inverse correlation between the growth of spheroids in vitro and the individual AGE-related fluorescence of each plasma sample. To confirm the impact of circulating AGEs on the NSCLC progression, we studied the NSCLC growth in mice whose circulating AGE level was elevated by AGE-rich diet. In vivo tumorigenicity assays demonstrated that mice with higher levels of circulating AGEs developed smaller tumors than mice with normal AGE levels. The AGE-related plasma fluorescence has prognostic relevance for NSCLC patients in whom the tumor growth-inhibiting effect of circulating AGEs might play a critical role. PMID:21629968

  19. 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.

  20. Molecular advances to treat cancer of the brain.

    PubMed

    Fathallah-Shaykh, H M; Zhao, L J; Mickey, B; Kafrouni, A I

    2000-06-01

    Malignant primary and metastatic brain tumours continue to be associated with poor prognosis. Nevertheless, recent advances in molecular medicine, specifically in the strategies of gene therapy, targeting tumour cells, anti-angiogenesis and immunotherapy, have created novel tools that may be of therapeutic value. To date, gene therapy trials have not yet demonstrated clinical efficacy because of inherent defects in vector design. Despite this, advances in adenoviral technology, namely the helper-dependent adenoviral constructs (gutless) and the uncovering of brain parenchymal cells as effective and necessary targets for antitumour benefits of adenoviral-mediated gene transfer, suggest that developments in vector design may be approaching the point of clinical utility. Targeting tumour cells refers to strategies that destroy malignant but spare normal cells. A new assortment of oncolytic viruses have emerged, capable of specific lysis of cancer tissue while sparing normal cells and propagating until they reach the tumour borders. Furthermore, peptides have been transformed into bullets that specifically seek and destroy cancer cells. The concept of tumour angiogenesis has been challenged by new but still very controversial findings that tumour cells themselves may form blood channels. These results may lead to the redirecting of the molecular targets toward anti-angiogenesis in some tumours including glioblastoma multiform. Unfortunately, our knowledge regarding the immunological ignorance of the tumour is still limited. Even so, newly discovered molecules have shed light on novel pathways leading to the escape of the tumour from the immune system. Finally, significant limitations in our current experimental tumour models may soon be overcome by firstly, the development of models of reproducible organ-specific tumours in non-inbred animals and secondly applying genomics to individualize therapy for a particular tumour in a specific patient.

  1. Looking up: Recent advances in understanding and treating peritoneal carcinomatosis.

    PubMed

    Lambert, Laura A

    2015-01-01

    Until recently, a diagnosis of peritoneal carcinomatosis was uniformly accompanied by a grim prognosis that was typically measured in weeks to months. Consequently, the management of carcinomatosis revolves largely around palliation of symptoms such as bowel obstruction, nausea, pain, fatigue, and cachexia. A prior lack of effective treatment options created the nihilistic view that currently exists and persists despite improvements in the efficacy of systemic therapy and the evolution of multimodality approaches including surgery and intraperitoneal chemotherapy. This article reviews the evolution and current state of treatment options for patients with peritoneal carcinomatosis. In addition, it highlights recent advances in understanding the molecular biology of carcinomatosis and the focus of current and future clinical trials. Finally, this article provides practical management options for the palliation of common complications of carcinomatosis. It is hoped that the reader will recognize that carcinomatosis is no longer an imminent death sentence and that through continued research and therapeutic innovation, clinicians can make an even greater impact on this form of metastatic cancer.

  2. 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.

  3. 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.

  4. Emerging treatments and combinations in the management of NSCLC: clinical potential of nintedanib

    PubMed Central

    Reck, Martin; Mellemgaard, Anders

    2015-01-01

    There remains an unmet need for effective, well-tolerated treatment options in advanced non-small cell lung cancer (NSCLC) to alleviate the disease burden for a broad selection of patients. Nintedanib is a potent, oral, triple angiokinase inhibitor of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, and was recently approved in Europe for use in combination with docetaxel for the treatment of adults with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma tumor histology, following first-line chemotherapy. Nintedanib has been investigated extensively in preclinical research and in a number of clinical studies, the most important of which was the Phase III LUME-Lung 1 study, which investigated nintedanib in combination with docetaxel in patients with advanced NSCLC after failure of first-line chemotherapy. In this study, which led to the approval of nintedanib, addition of nintedanib to docetaxel significantly improved overall survival in patients with adenocarcinoma histology. Nintedanib demonstrated a manageable safety profile in combination with docetaxel. This review focuses on the clinical experience with nintedanib in NSCLC and discusses the clinical potential of this agent for use in combination with chemotherapy. PMID:26170616

  5. 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

  6. LDA-SVM-Based EGFR Mutation Model for NSCLC Brain Metastases

    PubMed Central

    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

    2015-01-01

    Abstract 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

  7. 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

  8. 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

  9. 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

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

    PubMed

    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

    2015-06-22

    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.

  11. Inhibition of JNK-mediated autophagy enhances NSCLC cell sensitivity to mTORC1/2 inhibitors

    PubMed Central

    Jin, Hyeon-Ok; Hong, Sung-Eun; Park, Jin-Ah; Chang, Yoon Hwan; Hong, Young Jun; Park, In-Chul; Lee, Jin Kyung

    2016-01-01

    As the activation of autophagy contributes to the efficacy of many anticancer therapies, deciphering the precise role of autophagy in cancer therapy is critical. Here, we report that the dual mTORC1/2 inhibitors PP242 and OSI-027 decreased cell viability but did not induce apoptosis in the non-small cell lung cancer (NSCLC) cell lines H460 and A549. PP242 induced autophagy in NSCLC cells as demonstrated by the formation of massive vacuoles and acidic vesicular organelles and the accumulation of LC3-II. JNK was activated by PP242, and PP242-induced autophagy was blocked by inhibiting JNK pathway with SP600125 or JNK siRNA, suggesting that JNK activation is required for the mTORC1/2 inhibitor-mediated induction of autophagy in NSCLC cells. Inhibiting JNK or autophagy increased the sensitivity of H460 cells to mTORC1/2 inhibitors, indicating that JNK or autophagy promoted survival in NSCLC cells treated with mTORC1/2 inhibitors. Together, these data suggest that combining mTORC1/2 inhibitors with inhibitors of JNK or autophagy might be an effective approach for improving therapeutic outcomes in NSCLC. PMID:27358039

  12. 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.

  13. [Application of radiofrequency hyperthermia for treating advanced urinary bladder cancer--a case report].

    PubMed

    Kubota, Y; Takebayashi, S; Asakura, K; Oshima, H

    1984-02-01

    A patient with advanced urinary bladder cancer treated with a combination of radiation and hyperthermia, using short-wave radiofrequency (RF) and intravesical irrigation with warm water is reported. The tumor temperature was successfully maintained at 43 degrees to 44.6 degrees by external application of 13.56 MHZ RF when the bladder was irrigated with heated saline (intravesical temperature: 43 degrees) Hyperthermia was performed for 30 min immediately after each course of external bladder irradiation (Linac: 400 rad, twice a week; total 5 weeks exposure of 4000 rad). The tumor disappeared completely (CR) after the completion of the combination therapy. PMID:6200623

  14. 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. PMID:26114268

  15. 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

  16. Advanced adult esthesioneuroblastoma successfully treated with cisplatin and etoposide alternated with doxorubicin, ifosfamide and vincristine.

    PubMed

    Turano, Salvatore; Mastroianni, Candida; Manfredi, Caterina; Biamonte, Rosalbino; Ceniti, Silvia; Liguori, Virginia; De Simone, Rosanna; Conforti, Serafino; Filice, Aldo; Rovito, Antonio; Viscomi, Caterina; Patitucci, Giuseppe; Palazzo, Salvatore

    2010-05-01

    The esthesioneuroblastoma is a rare neuroendocrine tumor that derives from the olfactory cells. In the last 20 years, around 1,000 cases have been described, with an overall survival rate of 60-70% at 5 years. The most common symptoms are nasal bleeding, nasal clogging and, in locally advanced cases, signs/symptoms of intracranic hypertension such as papilla edema, cefalea, and vomiting. The standard treatments are surgery and radiotherapy. Chemotherapy can be used in an adjuvant/neoadjuvant setting and in the metastatic phase, even if its role is still not established with certainty. Here, the case is reported of a young man (38 years old) with a locally advanced esthesioneuroblastoma. Two months before coming to our clinic, he had been treated elsewhere with debulking surgery through bilateral frontal craniotomy. After surgery, MRI showed residual disease in the nasal cavities and in the medial wall of the orbits responsible for blindness and bilateral exophthalmos within a month: a very short time. Octreoscan and whole body CT scan confirmed a locally advanced disease, in the absence of metastases. Chemotherapy was begun with cisplatin and etoposide alternated with doxorubicin, ifosfamide and vincristine with granulocyte colony-stimulating factor (G-CSF) support after every cycle. Soon after the first cycle, an important reduction of pain and decrease of the exophthalmos and vertigos was observed. No improvement in blindness was seen. The patient is still stable after 24 months of follow up.

  17. The hedgehog processing pathway is required for NSCLC growth and survival.

    PubMed

    Rodriguez-Blanco, J; Schilling, N S; Tokhunts, R; Giambelli, C; Long, J; Liang Fei, D; Singh, S; Black, K E; Wang, Z; Galimberti, F; Bejarano, P A; Elliot, S; Glassberg, M K; Nguyen, D M; Lockwood, W W; Lam, W L; Dmitrovsky, E; Capobianco, A J; Robbins, D J

    2013-05-01

    Considerable interest has been generated from the results of recent clinical trials using smoothened (SMO) antagonists to inhibit the growth of hedgehog (HH) signaling-dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH-dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH-processing proteins, skinny hedgehog (SKN) or dispatched-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently overexpressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand-dependent cancers.

  18. 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. PMID:19289275

  19. Variations in serum copper and ceruloplasmin levels in advanced gastrointestinal cancer treated with polychemotherapy.

    PubMed

    Scanni, A; Tomirotti, M; Licciardello, L; Annibali, E; Biraghi, M; Trovato, M; Fittipaldi, M; Adamoli, P; Curtarelli, G

    1979-06-30

    Serum copper and ceruloplasmin levels (SCL, SCeL) in 57 patients with advanced cancer of the stomach (35 cases) or large intestine (22 cases) treated with polychemotherapy were studies. In gastroenteric cancer, SCL, which are already high in untreated patients, have a tendency to increase further in cases of progression of the disease, while they seem to significantly decrease in cases of remission. SCeL during the trial appeared to be correlated to the clinical evolution of the disease only in the case of stomach cancer. In large intestine cancer, SCeL did not show any significant variation in relation to the normal range. These observations, in particular on the behavior of SCL in the neoplasms of the digestive tract, are in accordance with the results of other studies. The authors are inclined to attach a diagnostic and prognostic value to the variation in SCL and SCeL in gastrointestinal cancer.

  20. 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.

  1. 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.

  2. 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.

  3. 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. PMID:20967300

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

    ClinicalTrials.gov

    2016-06-17

    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

  5. Circulating miR-22, miR-24 and miR-34a as novel predictive biomarkers to pemetrexed-based chemotherapy in advanced non-small cell lung cancer.

    PubMed

    Franchina, Tindara; Amodeo, Valeria; Bronte, Giuseppe; Savio, Giuseppina; Ricciardi, Giuseppina R R; Picciotto, Maria; Russo, Antonio; Giordano, Antonio; Adamo, Vincenzo

    2014-01-01

    Pemetrexed has been widely used in patients with advanced non-small cell lung cancer (NSCLC). The clinical relevance of polymorphisms of folate pathway genes for pemetrexed metabolism have not been fully elucidated yet. The aim of this study was to evaluate the expression levels of circulating miR-22, miR-24, and miR-34a, possibly involved in folate pathway, in NSCLC patients treated with pemetrexed compared with healthy controls and to investigate their impact on patient clinical outcomes. A total of 22 consecutive patients with advanced NSCLC, treated with pemetrexed-based chemotherapy and 27 age and sex matched healthy controls were included in this preliminary analysis. miR-22, miR-24, and miR-34a targets were identified by TargetScan 6.2 algorithm, validating the involvement of these microRNAs in folate pathway. MicroRNAs were isolated from whole blood and extracted with miRNAeasy Mini Kit (Qiagen). miRNA profiling was performed using Real-Time PCR. SPSS 17 was used to data analysis. miR-22, miR-24, and miR-34a were found upregulated (P<0.05) in NSCLC patients versus healthy controls. Higher expression levels were recorded for miR-34a. Nevertheless, significantly higher miR-22 expression was observed in patients developing progressive disease (P=0.03). No significant associations with clinical outcome were recorded for miR-24 and miR-34a. Albeit preliminary, these data support the involvement of miR-22, miR-24, and miR-34a in advanced NSCLC. The correlation between high expression of miR-22 in whole blood and the lack of response in pemetrexed treated NSCLC patients indicates that miR-22 could represent a novel predictive biomarker for pemetrexed-based treatment.

  6. 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.

  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. 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.

  9. Neurological Adverse Effects in Patients of Advanced Colorectal Carcinoma Treated with Different Schedules of FOLFOX

    PubMed Central

    Najam, Rahila; Mateen, Ahmed

    2013-01-01

    The study is designed to assess the frequency and severity of few dose limiting neurological adverse effects of four different schedules of FOLFOX. Patients with histologically confirmed advanced colorectal carcinoma (CRC) were included in the study. Toxicity was graded according to CTC v 2.0. The frequency of grade 3 and 4 adverse effects was comparatively assessed in each treatment arm. The difference in the pattern of toxicity between the treatment schedule was evaluated. The most frequent adverse symptom of neurological adverse effect was grade 1 paresthesia in the patients treated with FOLFOX4 schedule. Grade 4 peripheral neuropathy was reported in few patients of FOLFOX7 treatment arm. Frequency and onset of neurological adverse effects like paresthesia, dizziness, and hypoesthesia were significantly different (P < 0.05), whereas frequency and onset of peripheral neuropathy were highly significant (P < 0.01) in each treatment arm of FOLFOX. Peripheral neuropathy was associated with electrolyte imbalance and diabetes in few patients. Frequency of symptoms, for example, paresthesia, is associated with increased number of recurrent exposure to oxaliplatin (increased number of cycles) even at low doses (85 mg/m2), whereas severity of symptoms, for example, peripheral neuropathy, is associated with higher dose (130 mg/m2) after few treatment cycles. PMID:24187619

  10. Neurological Adverse Effects in Patients of Advanced Colorectal Carcinoma Treated with Different Schedules of FOLFOX.

    PubMed

    Bano, Nusrat; Najam, Rahila; Mateen, Ahmed

    2013-01-01

    The study is designed to assess the frequency and severity of few dose limiting neurological adverse effects of four different schedules of FOLFOX. Patients with histologically confirmed advanced colorectal carcinoma (CRC) were included in the study. Toxicity was graded according to CTC v 2.0. The frequency of grade 3 and 4 adverse effects was comparatively assessed in each treatment arm. The difference in the pattern of toxicity between the treatment schedule was evaluated. The most frequent adverse symptom of neurological adverse effect was grade 1 paresthesia in the patients treated with FOLFOX4 schedule. Grade 4 peripheral neuropathy was reported in few patients of FOLFOX7 treatment arm. Frequency and onset of neurological adverse effects like paresthesia, dizziness, and hypoesthesia were significantly different (P < 0.05), whereas frequency and onset of peripheral neuropathy were highly significant (P < 0.01) in each treatment arm of FOLFOX. Peripheral neuropathy was associated with electrolyte imbalance and diabetes in few patients. Frequency of symptoms, for example, paresthesia, is associated with increased number of recurrent exposure to oxaliplatin (increased number of cycles) even at low doses (85 mg/m(2)), whereas severity of symptoms, for example, peripheral neuropathy, is associated with higher dose (130 mg/m(2)) after few treatment cycles.

  11. 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. PMID:19036487

  12. 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

  13. 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.

  14. Impact of metformin use on survival in locally-advanced, inoperable non-small cell lung cancer treated with definitive chemoradiation

    PubMed Central

    Ahmed, Inaya; Ferro, Adam; Cohler, Alan; Langenfeld, John; Surakanti, Sujani G.; Aisner, Joseph; Zou, Wei; Haffty, Bruce G.

    2015-01-01

    Background We investigated survival outcomes in diabetic patients with non-small cell lung cancer (NSCLC) treated with concurrent metformin and definitive chemoradiation. Methods This single-institution, retrospective cohort study included 166 patients with NSCLC who were treated definitively with chemoradiation between 1999 and 2013. Of 40 patients who had type II diabetes, 20 (50%) were on metformin, and 20 (50%) were not on metformin. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS). Kaplan Meier method and log-rank test were performed in survival analysis. Cox regression was utilized in univariate analysis of potential confounders. Results Median follow-up was 17.0 months. Compared with non-diabetic patients, diabetic patients on metformin demonstrated similar OS (16.3 vs. 14.3 mo, P=0.23), PFS (11.6 vs. 9.7 mo, P=0.26), LRRFS (14.1 vs. 11.9 mo, P=0.78), and DMFS (13.4 vs. 10.0 mo, P=0.69). Compared with diabetic patients not on metformin, diabetic patients on metformin also exhibited similar OS (14.3 vs. 19.2 mo, P=0.18), PFS (19.7 vs. 10.1 mo, P=0.38), LRRFS (11.9 vs. 15.5 mo, P=0.69), and DMFS (10.0 vs. 17.4 mo, P=0.12). Identified negative prognostic factors on included squamous cell histology, lower performance status, higher T stage, and non-caucasian ethnicity. Conclusions No statistically significant differences in survival or patterns of failure were found among the three cohorts in this small set of patients. No statistically significant differences in survival or patterns of failure were found between the three cohorts in this small set of patients. Though it is possible that metformin use may in fact have no effect on survival in NSCLC patients treated with definitive RT, larger-scale retrospective and prospective studies are implicated for clarification. PMID:25922712

  15. The role of expression and polymorphism of the BAG-1 gene in response to platinum-based chemotherapeutics in NSCLC

    PubMed Central

    WANG, YA-DI; HA, MIN-WEN; CHENG, JIAN; ZHANG, WEN-LU; CONG, XUE; TONG, CHUN-YAN; SUN, JING

    2012-01-01

    We investigated the correlation between BAG-1 expression and sensitivity to platinum-based chemotherapeutics in patients with non-small cell lung cancer (NSCLC). mRNA and protein expression of BAG-1 in lung tissue of NSCLC postoperative patients (I–IIIA stage) or healthy subjects were detected using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. Cox regression analysis was used to quantify the association of prognostic factors with survival in NSCLC patients. Venous blood samples from patients newly diagnosed with advanced NSCLC (IIIB–IV stage) were collected before chemotherapy to analyze allelic frequency and gene polymorphisms. Compared to healthy controls (11.67%, 14 cases), levels of mRNA and protein of BAG-1 in lung tissues was significantly higher in NSCLC patients (61.67%, 74 cases) (χ2=5.601, P<0.05). Moreover, BAG-1 expression was identified as an independent prognostic factor for survival in NSCLC patients. As time to progression and survival rate was dramatically increased, patients with a positive expression of BAG-1 exhibited a prolonged survival period (TTP, 49.3 months; 5-year survival rat, 16.21%) compared with those without BAG-1 expression (χ2=7.243, P<0.05). Two BAG-1 digestion patterns (CC and CT) were identified and confirmed. Patients (77.46%) had a C/C genotype at BAG-1 codon 324, while 22.54% had the C/T genotype. The T/T genotype was not present in these patients. The progression risk of patients carrying the C/C genotype at Bag-1 codon 324 was 1.87 times higher than that of patients carrying the C/T genotype (P<0.001). Follow-up examination showed that the chemotherapeutic sensitivity of patients carrying the C/C genotype was 2.852 times higher than that of patients carrying the C/T genotype (95% CI, 1.133–7.182; P=0.026). Significant differences were found in the median progression-free survival (PFS) and overall survival (OS) of these two cohorts of patients. Compared to patients

  16. Outcomes After Out-of-Hospital Cardiac Arrest Treated by Basic vs Advanced Life Support

    PubMed Central

    Sanghavi, Prachi; Jena, Anupam B.; Newhouse, Joseph P.; Zaslavsky, Alan M.

    2014-01-01

    IMPORTANCE Most out-of-hospital cardiac arrests receiving emergency medical services in the United States are treated by ambulance service providers trained in advanced life support (ALS), but supporting evidence for the use of ALS over basic life support (BLS) is limited. OBJECTIVE To compare the effects of BLS and ALS on outcomes after out-of-hospital cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS Observational cohort study of a nationally representative sample of traditional Medicare beneficiaries from nonrural counties who experienced out-of-hospital cardiac arrest between January 1, 2009, and October 2, 2011, and for whom ALS or BLS ambulance services were billed to Medicare (31 292 ALS cases and 1643 BLS cases). Propensity score methods were used to compare the effects of ALS and BLS on patient survival, neurological performance, and medical spending after cardiac arrest. MAIN OUTCOMES AND MEASURES Survival to hospital discharge, to 30 days, and to 90 days; neurological performance; and incremental medical spending per additional survivor to 1 year. RESULTS Survival to hospital discharge was greater among patients receiving BLS (13.1% vs 9.2% for ALS; 4.0 [95% CI, 2.3–5.7] percentage point difference), as was survival to 90 days (8.0% vs 5.4% for ALS; 2.6 [95% CI, 1.2–4.0] percentage point difference). Basic life support was associated with better neurological functioning among hospitalized patients (21.8% vs 44.8% with poor neurological functioning for ALS; 23.0 [95% CI, 18.6–27.4] percentage point difference). Incremental medical spending per additional survivor to 1 year for BLS relative to ALS was $154 333. CONCLUSIONS AND RELEVANCE Patients with out-of-hospital cardiac arrest who received BLS had higher survival at hospital discharge and at 90 days compared with those who received ALS and were less likely to experience poor neurological functioning. PMID:25419698

  17. Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines

    PubMed Central

    2012-01-01

    Background The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. Results In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. Conclusion Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib. PMID:23234355

  18. Angiogenesis and lung cancer: ramucirumab prolongs survival in 2(nd)-line metastatic NSCLC.

    PubMed

    Das, Millie; Wakelee, Heather

    2014-12-01

    In the REVEL trial, ramucirumab, a monoclonal antibody to VEGFR-2, improved overall survival in combination with docetaxel compared to docetaxel alone in the second-line setting of non-small cell lung cancer (NSCLC). Along with bevacizumab and nintedanib, ramucirumab is the third anti-angiogenic agent that has yielded positive overall survival results in a phase III trial of patients with advanced NSCLC. Given the lack of effective therapies in the relapsed setting and the disappointing results of many other VEGF-targeted agents in lung cancer, the results from REVEL are encouraging. One of the major remaining hurdles is the identification of reliable predictive biomarkers in order to predict which patients are most likely to benefit from anti-angiogenic therapies. Despite the positive results seen in REVEL, the exact role of ramucirumab in the treatment paradigm of lung cancer remains to be seen given the modest survival benefit of 1.4 months and the lack of predictive biomarkers at this time.

  19. Rationale for targeting VEGF, FGF, and PDGF for the treatment of NSCLC

    PubMed Central

    Ballas, Marc S; Chachoua, Abraham

    2011-01-01

    Lung cancer remains a leading cause of death globally, with the most frequent type, nonsmall cell lung cancer (NSCLC), having a 5-year survival rate of less than 20%. While platinum-based doublet chemotherapy is currently first-line therapy for advanced disease, it is associated with only modest clinical benefits at the cost of significant toxicities. In an effort to overcome these limitations, recent research has focused on targeted therapies, with recently approved agents targeting the epidermal growth factor receptor and vascular endothelial growth factor (VEGF) signaling pathways. However, these agents (gefitinib, erlotinib, and bevacizumab) provide antitumor activity for only a small proportion of patients, and patients whose tumors respond inevitably develop resistance to treatment. As angiogenesis is a crucial step in tumor growth and metastasis, antiangiogenic treatments might be expected to have antitumor activity. Important targets for the development of novel antiangiogenic therapies include VEGF, fibroblast growth factor, platelet-derived growth factor, and their receptors. It is hypothesized that targeting multiple angiogenic pathways may not only improve antitumor activity but also reduce the risk of resistance. Several novel agents, such as BIBF 1120, sorafenib, sunitinib, and cediranib have shown promising preliminary activity and tolerability in Phase II studies, and results of ongoing Phase III randomized studies will be necessary to establish the potential place of these new therapies in the management of individual patients with NSCLC. PMID:21691577

  20. 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.

  1. Glutaminase 1 inhibition reduces thymidine synthesis in NSCLC.

    PubMed

    Lee, Jae-Seon; Kang, Joon H; Lee, Seon-Hyeong; Lee, Chang-Hun; Son, Jaekyoung; Kim, Soo-Youl

    2016-08-26

    We found that non-small cell lung cancer (NSCLC) is remarkably sensitive to the regulation of glutamine supply by testing the metabolic dependency of 11 cancer cell lines against regulation of glycolysis, autophagy, fatty acid synthesis, and glutamine supply. Glutamine is known as a key supplement of cancer cell growth that is converted to α-ketoglutarate for anabolic biogenesis via glutamate by glutaminase 1 (GLS1). GLS1 inhibition using 10 μM of bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) showed about 50% cell growth arrest by SRB assay. By testing the synergistic effects of conventional therapeutics, BPTES combined with 5-fluorouracil (5-FU), an irreversible inhibitor of thymidylate synthase, significant effects were observed on cell growth arrest in NSCLC. We found that GLS1 inhibition using BPTES reduced metabolic intermediates including thymidine and carbamoyl phosphate. Reduction of thymidine and carbamoyl-phosphate synthesis by BPTES treatment exacerbated pyrimidine supply by combination with 5-FU, which induced cell death synergistically in NSCLC. PMID:27338638

  2. Endoscopic vs. open surgery for treating large, locally advanced juvenile angiofibromas: a comparison of local control and morbidity outcomes.

    PubMed

    Bosraty, Hossam; Atef, Ahmed; Aziz, Mossad

    2011-11-01

    Juvenile nasopharyngeal angiofibroma is a combined vascular and fibrous neoplasm that most commonly affects prepubertal and adolescent boys. These tumors have traditionally been managed with open surgery, but interest in endoscopic resection-particularly for small tumors-has increased in recent years. To the best of our knowledge, no comparative study of open and endoscopic approaches for treating large, locally advanced tumors has been previously published in the literature. We conducted a retrospective study of 42 males, aged 6 to 21 years (mean: 13 ± 2.1), who had been treated for histologically proven and locally advanced juvenile nasopharyngeal angiofibroma with either open surgery (n = 29) or endoscopic excision (n = 13). Our two primary outcomes measures were local control and surgical morbidity. We found that the endoscopic approach was as good as or better than open approaches for patients with large tumors.

  3. Systemic inflammatory status at baseline predicts bevacizumab benefit in advanced non-small cell lung cancer patients

    PubMed Central

    Botta, Cirino; Barbieri, Vito; Ciliberto, Domenico; Rossi, Antonio; Rocco, Danilo; Addeo, Raffaele; Staropoli, Nicoletta; Pastina, Pierpaolo; Marvaso, Giulia; Martellucci, Ignazio; Guglielmo, Annamaria; Pirtoli, Luigi; Sperlongano, Pasquale; Gridelli, Cesare; Caraglia, Michele; Tassone, Pierfrancesco; Tagliaferri, Pierosandro; Correale, Pierpaolo

    2013-01-01

    Bevacizumab is a humanized anti-VEGF monoclonal antibody able to produce clinical benefit in advanced non-squamous non-small-cell lung cancer (NSCLC) patients when combined to chemotherapy. At present, while there is a rising attention to bevacizumab-related adverse events and costs, no clinical or biological markers have been identified and validated for baseline patient selection. Preclinical findings suggest an important role for myeloid-derived inflammatory cells, such as neutrophils and monocytes, in the development of VEGF-independent angiogenesis. We conducted a retrospective analysis to investigate the role of peripheral blood cells count and of an inflammatory index, the neutrophil-to-lymphocyte ratio (NLR), as predictors of clinical outcome in NSCLC patients treated with bevacizumab plus chemotherapy. One hundred twelve NSCLC patients treated with chemotherapy ± bevacizumab were retrospectively evaluated for the predictive value of clinical or laboratory parameters correlated with inflammatory status. Univariate analysis revealed that a high number of circulating neutrophils and monocytes as well as a high NLR were associated with shorter progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients only. We have thus developed a model based on the absence or the presence of at least one of the above-mentioned inflammatory parameters. We found that the absence of all variables strongly correlated with longer PFS and OS (9.0 vs. 7.0 mo, HR: 0.39, p = 0.002; and 20.0 vs. 12.0 mo, HR: 0.29, p < 0.001 respectively) only in NSCLC patients treated with bevacizumab plus chemotherapy. Our results suggest that a baseline systemic inflammatory status is marker of resistance to bevacizumab treatment in NSCLC patients. PMID:23760488

  4. 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...

  5. Advanced titration to treat a floppy epiglottis in selective upper airway stimulation.

    PubMed

    Heiser, Clemens

    2016-09-01

    The following report presents a case of a patient with high residual apnea-hypopnea index at 6 months following implantation of an upper airway stimulation device who improved significantly after advanced titration via drug-induced sedated endoscopy by changing the electrode configuration for stimulation from bipolar to monopolar. This case demonstrates the utility of postsurgical advanced titration to optimize programming settings for improved clinical outcomes. Laryngoscope, 126:S22-S24, 2016.

  6. SEOM clinical guidelines for the treatment of non-small cell lung cancer (NSCLC) 2015.

    PubMed

    García-Campelo, R; Bernabé, R; Cobo, M; Corral, J; Coves, J; Dómine, M; Nadal, E; Rodriguez-Abreu, D; Viñolas, N; Massuti, B

    2015-12-01

    Lung cancer is the most common cancer worldwide as well as the leading cause of cancer related deaths as reported by Torre et al (CA Cancer J Clin 65:87-108, 2015]. Non-small cell lung cancer (NSCLC) accounts for up to 85 % of all lung cancers. Multiple advances in the staging, diagnostic procedures, therapeutic options, as well as molecular knowledge have been achieved during the past years, although the overall outlook has not greatly changed for the majority of patients with the overall 5-year survival having marginally increased over the last decade from 15.7 to 17.4 % as reported by Howlader et al. (SEER Cancer Statistics Review 2015).

  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. [Advancement of maggot including living body to treat chronic infected wounds].

    PubMed

    Zhang, Zhen; Wang, Shouyu; Diao, Yunpeng; Zhang, Houli; Huang, Shanshan; Lv, Decheng

    2009-12-01

    Human has used maggot to treat diseases for thousands of years. In recent years, with abuse of antibiotic and the rising incidence of antibiotic resistance, maggot therapy, as a surgical alternative, is mainly applied to treat chronic infected wounds on account of its low cost, efficacy and safety. Its mechanisms are disinfection, bio-debridement and enhancement of tissue regeneration. Maggot therapy which serves as a kind of biological therapy is promising. However, living maggot therapy could result in inevitable complications, so that we should apply traditional Chinese medicine theory to investigate and develop new delivery method of maggot. The review summarizes the past and present of maggot therapy.

  9. Advanced laser heat treatment with respect for the application for Tailored Heat Treated Blanks

    NASA Astrophysics Data System (ADS)

    Merklein, Marion; Nguyen, Hung

    Aluminum alloys offer a great potential for lightweight construction. By application of Tailored Heat Treated Blanks (THTB), the feasibility of complex car parts out of aluminum alloys can be enhanced decisively. To extend the process window for forming of aluminum, a large scale area has to be heat treated. Accordingly, this paper deals with the large scale heat treatment via laser radiation. Thereby, a multi-path heating strategy is developed and discussed. In order to get a sharp transition area, different cooling methods and the influence on the heat distribution is qualified as well. In this context, the temperature and hardness are measured.

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

    ClinicalTrials.gov

    2016-08-10

    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

  11. 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...

  12. miR-143 inhibits NSCLC cell growth and metastasis by targeting Limk1.

    PubMed

    Xia, Hui; Sun, Shengjie; Wang, Bo; Wang, Tao; Liang, Chaoyang; Li, Guo; Huang, Chongbiao; Qi, Daliang; Chu, Xiangyang

    2014-01-01

    MicroRNAs (miRNAs) have essential roles in carcinogenesis and tumor progression. Here, we investigated the roles and mechanisms of miR-143 in non-small cell lung cancer (NSCLC). miR-143 was significantly decreased in NSCLC tissues and cell lines. Overexpression of miR-143 suppressed NSCLC cell proliferation, induced apoptosis, and inhibited migration and invasion in vitro. Integrated analysis identified LIM domain kinase 1 (Limk1) as a direct and functional target of miR-143. Overexpression of Limk1 attenuated the tumor suppressive effects of miR-143 in NSCLC cells. Moreover, miR-143 was inversely correlated with Limk1 expression in NSCLC tissues. Together, our results highlight the significance of miR-143 and Limk1 in the development and progression of NSCLC.

  13. Prospects in cancer immunotherapy: treating advanced stage disease or preventing tumor recurrence?

    PubMed

    Manjili, Masoud H; Payne, Kyle K

    2015-06-01

    Human vaccines against infectious agents are often effective in a prophylactic setting. However, they are usually not effective when used post-exposure. Rabies vaccine is one of the exceptions, which can be used post-exposure, but is effective only when used in combination with other treatments. Similar results have been obtained with cancer vaccines and immunotherapies. Cancer immunotherapies generally prolong patients' survival when they are used during advanced stage disease. The potential of immunotherapy to cure cancer could be revealed when it is applied in a prophylactic setting. This article provides a brief overview of cancer immunotherapeutics and suggests that immunotherapy can cure cancer if used at the right time against the right target; we suggest that targeting cancer during dormancy in order to prevent tumor recurrence as advanced stage disease is potentially curative.

  14. 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

  15. Subretinal Fluid Drainage and Vitrectomy Are Helpful in Diagnosing and Treating Eyes with Advanced Coats' Disease.

    PubMed

    Imaizumi, Ayako; Kusaka, Shunji; Takaesu, Sugie; Sawaguchi, Shoichi; Shimomura, Yoshikazu

    2016-01-01

    Severe forms of Coats' disease are often associated with total retinal detachment, and a differential diagnosis from retinoblastoma is critically important. In such eyes, laser- and/or cryoablation is often ineffective or sometimes impossible to perform. We report a case of advanced Coats' disease in which a rapid pathological examination of subretinal fluid was effective for the diagnosis, and external subretinal drainage combined with vitrectomy was effective in preserving the eye. PMID:27462247

  16. Subretinal Fluid Drainage and Vitrectomy Are Helpful in Diagnosing and Treating Eyes with Advanced Coats' Disease

    PubMed Central

    Imaizumi, Ayako; Kusaka, Shunji; Takaesu, Sugie; Sawaguchi, Shoichi; Shimomura, Yoshikazu

    2016-01-01

    Severe forms of Coats' disease are often associated with total retinal detachment, and a differential diagnosis from retinoblastoma is critically important. In such eyes, laser- and/or cryoablation is often ineffective or sometimes impossible to perform. We report a case of advanced Coats' disease in which a rapid pathological examination of subretinal fluid was effective for the diagnosis, and external subretinal drainage combined with vitrectomy was effective in preserving the eye. PMID:27462247

  17. [Advances in the research of treating refractory diabetic wounds with stem cells].

    PubMed

    Gong, Jiahong; Lu, Shuliang

    2014-12-01

    With the growth of aging society, China has become the country of population with the highest incidence of diabetes in the world. Diabetes leads to pathological changes in vascular and nervous system, rendering the diabetic skin fragile and hard to heal if wounded; in the end most diabetic wounds tend to become chronic skin ulcers. The refractory diabetic wound is the result of various endogenous and exogenous factors. It is a quite complicated pathophysiologic event which lacks an effective and specific therapeutic method in clinic. The use of stem cells could be a new approach of treating diabetic chronic wounds since they have a potential ability of self-renovation and multi-directional differentiation which will promote angiogenesis and wound healing process, thus be beneficial in the care of ischemia diseases of the lower limb. This article reviews basic theory of treating diabetic wound and the changes in microenvironment, and prompts many successful cases in curing refractory diabetic wounds.

  18. Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes.

    PubMed

    Sánchez, Rosa; Esteban, Emilio; Palacio, Isabel; Fernández, Yolanda; Muñiz, Isabel; Vieitez, Jose M; Fra, Joaquin; Blay, Pilar; Villanueva, Noemí; Uña, Esther; Mareque, Beatriz; Estrada, Enrique; Buesa, Jose M; Lacave, Angel J

    2003-11-01

    Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34-71) and a Karnofsky performance status of 60% (60-80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100 mg/m(2) i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1-32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8-24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.

  19. 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. PMID:25336937

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

    PubMed Central

    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. PMID:25336937

  1. 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.

  2. NSCLC tumor shrinkage prediction using quantitative image features.

    PubMed

    Hunter, Luke A; Chen, Yi Pei; Zhang, Lifei; Matney, Jason E; Choi, Haesun; Kry, Stephen F; Martel, Mary K; Stingo, Francesco; Liao, Zhongxing; Gomez, Daniel; Yang, Jinzhong; Court, Laurence E

    2016-04-01

    The objective of this study was to develop a quantitative image feature model to predict non-small cell lung cancer (NSCLC) volume shrinkage from pre-treatment CT images. 64 stage II-IIIB NSCLC patients with similar treatments were all imaged using the same CT scanner and protocol. For each patient, the planning gross tumor volume (GTV) was deformed onto the week 6 treatment image, and tumor shrinkage was quantified as the deformed GTV volume divided by the planning GTV volume. Geometric, intensity histogram, absolute gradient image, co-occurrence matrix, and run-length matrix image features were extracted from each planning GTV. Prediction models were generated using principal component regression with simulated annealing subset selection. Performance was quantified using the mean squared error (MSE) between the predicted and observed tumor shrinkages. Permutation tests were used to validate the results. The optimal prediction model gave a strong correlation between the observed and predicted tumor shrinkages with r=0.81 and MSE=8.60×10(-3). Compared to predictions based on the mean population shrinkage this resulted in a 2.92 fold reduction in MSE. In conclusion, this study indicated that quantitative image features extracted from existing pre-treatment CT images can successfully predict tumor shrinkage and provide additional information for clinical decisions regarding patient risk stratification, treatment, and prognosis. PMID:26878137

  3. 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.

  4. 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.

  5. 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. PMID:25348145

  6. Impact of comorbidity on the outcome in men with advanced prostate cancer treated with docetaxel

    PubMed Central

    Zist, Andrej; Amir, Eitan; Ocana, Alberto F.; Seruga, Bostjan

    2015-01-01

    Background Men with metastatic castrate-resistant prostate cancer (mCRPC) may not receive docetaxel in everyday clinical practice due to comorbidities. Here we explore the impact of comorbidity on outcome in men with mCRPC treated with docetaxel in a population-based outcome study. Methods Men with mCRPC treated with docetaxel at the Institute of Oncology Ljubljana between 2005 and 2012 were eligible. Comorbidity was assessed by the age-adjusted Charlson comorbidity index (aa-CCI) and adult comorbidity evaluation (ACE-27) index. Hospital admissions due to the toxicity and deaths during treatment with docetaxel were used as a measure of tolerability. Association between comorbidity and overall survival (OS) was tested using the Cox proportional hazards analysis. Results Two hundred and eight men were treated with docetaxel. No, mild, moderate and severe comorbidity was present in 2%, 32%, 53% and 13% using aa-CCI and in 27%, 35%, 29% and 8% when assessed by ACE-27. A substantial dose reduction of docetaxel occurred more often in men with moderate or severe comorbidity as compared to those with no or mild comorbidity. At all comorbidity levels about one-third of men required hospitalization or died during treatment with docetaxel. In univariate analysis a higher level of comorbidity was not associated with worse OS (aa-CCI HR 0.99; [95% CI 0.87–1.13], p = 0.93; ACE-27: HR 0.96; [95% CI 0.79–1.17], p = 0.69). Conclusions Men with mCRPC, who have comorbidities may benefit from treatment with docetaxel. PMID:26834528

  7. Advancements in treating subquality natural gas using N-formyl morpholine

    SciTech Connect

    Palla, N.; Lee, A.L.; Gross, M.; Hooper, H.M.; Menzel, J.; Leppin, D.

    1998-12-31

    Process selection for gas treating is a complex phenomenon because processing requirements vary widely, and there are many gas sweetening solvents that are available to meet the requisite specification. Over the past few years, the Institute of Gas Technology (IGT) and Krupp Uhde GmbH (KU) have been conducting research on a physical solvent N-Formyl Morpholine (NFM) for treatment of subquality natural gas because of its advantages of lower energy consumption, higher CO{sub 2}/H{sub 2}S gas loadings, selective absorption of CO{sub 2}/H{sub 2}S, and lower loss of valuable C{sub 1}-C{sub 6} hydrocarbons as compared with other commercial physical solvents. Field experiment studies form the 1 MMscfd pilot plant unit operating at Shell`s Fandango facility confirms NFM as a cost-effective gas treating solvent. To date, a total of 78 tests using Koch`s random, high capacity and high-efficiency structured packing have been completed. These field experiments were conducted at wellhead conditions at 1,000 psig using slipstream from the Shell plant containing sour gas concentrations up to 43 mol % CO{sub 2}. These data, when used in a sophisticated process simulation, predicted a minimum of 40% operating cost savings depending upon sour gas concentration. This paper explains the development of NFM technology with results from laboratory and field tests. This paper also discusses case studies pertaining to NFM application to retrofits, as well as new plants. Furthermore, this paper illustrates the scaling-up calculations from field test investigations. The potential of mixed solvent -- NFM and morpholine additives -- will also be discussed for increased acid gas loading, reduced circulation rate and column size. This emerging technology is the product of extensive research by IGT and is commercially available through KU for gas treating applications.

  8. 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

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

    PubMed Central

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

    2015-01-01

    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. PMID:25954092

  10. 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

  11. New Strategies for Multimodality Therapy in Treating Locally Advanced Cervix Cancer.

    PubMed

    Verma, Jonathan; Monk, Bradley J; Wolfson, Aaron H

    2016-10-01

    Cervical cancer is the fourth most common cause of cancer of women worldwide. In the developing world, it comprises 12% of all cancers of women. Since 1999, the mainstay of treatment for locally advanced cervical cancer (LACC) has been concurrent cisplatin-based chemoradiation. However, outcomes in this disease remain suboptimal, with long-term progression-free survival and overall survival rates of approximately 60%. There are several new strategies of combined modality treatment under evaluation in LACC, including chemotherapy before and after treatment as well as novel agents such as poly-adenosine diphosphate ribose polymerase inhibitors, antiangiogenic blockage, and immunotherapy. We provide a brief overview of these strategies and their potential in the treatment of women with LACC. PMID:27619255

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

    ClinicalTrials.gov

    2016-04-18

    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

  13. Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib

    PubMed Central

    Sosman, Jeffrey A.; Kim, Kevin B.; Schuchter, Lynn; Gonzalez, Rene; Pavlick, Anna C.; Weber, Jeffrey S.; McArthur, Grant A.; Hutson, Thomas E.; Moschos, Stergios J.; Flaherty, Keith T.; Hersey, Peter; Kefford, Richard; Lawrence, Donald; Puzanov, Igor; Lewis, Karl D.; Amaravadi, Ravi K.; Chmielowski, Bartosz; Lawrence, H. Jeffrey; Shyr, Yu; Ye, Fei; Li, Jiang; Nolop, Keith B.; Lee, Richard J.; Joe, Andrew K.; Ribas, Antoni

    2013-01-01

    BACKGROUND Approximately 50% of melanomas harbor activating (V600) mutations in the serine–threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600–mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600–mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600–mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann–La Roche; ClinicalTrials.gov number, NCT00949702.) PMID:22356324

  14. 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

  15. The pathophysiological mechanism of fluid retention in advanced cancer patients treated with docetaxel, but not receiving corticosteroid comedication

    PubMed Central

    Béhar, A.; Pujade-Lauraine, E.; Maurel, A.; Brun, M. D.; Lagrue, G.; Feuilhade De Chauvin, F.; Oulid-Aissa, D.; Hille, D.

    1997-01-01

    Aims Fluid retention is a phenomenon associated with taxoids. The principal objective of this study was to investigate the pathophysiological mechanism of docetaxel-induced fluid retention in advanced cancer patients. Methods Docetaxel was administered as a 1 h intravenous infusion every 3 weeks, for at least 4–6 consecutive cycles, to patients with advanced breast (n=21) or ovarian (n=3) carcinoma, who had received previous chemotherapy, 21 for advanced disease. Phase II clinical trials have shown that 5 day corticosteroid comedication, starting 1 day before docetaxel infusion, significantly reduces the incidence and severity of fluid retention. This prophylactic corticosteroid regimen is currently recommended for patients receiving docetaxel but was not permitted in this study because of its possible interference with the underlying pathophysiology of the fluid retention. Results Fluid retention occurred in 21 of the 24 patients but was mainly mild to moderate, with only five patients experiencing severe fluid retention. Eighteen patients received symptomatic flavonoid treatment, commonly prescribed after the last cycle. Specific investigations for fluid retention confirmed a relationship between cumulative docetaxel dose and development of fluid retention. Capillary filtration test analysis showed a two-step process for fluid retention generation, with progressive congestion of the interstitial space by proteins and water starting between the second and the fourth cycle, followed by insufficient lymphatic drainage. Conclusions A vascular protector such as micronized diosmine hesperidine with recommended corticosteroid premedication and benzopyrones may be useful in preventing and treating docetaxel-induced fluid retention. PMID:9205828

  16. [A case of advanced hepatocellular carcinoma successfully treated by liver resection after complete response induced by sorafenib administration].

    PubMed

    Kim, Yongkook; Hosoda, Yohei; Kakita, Naruyasu; Yamada, Yukinori; Yamasaki, Masaru; Nishino, Masaya; Okano, Miho; Nagai, Kenichi; Yasui, Masayoshi; Tsujinaka, Toshimasa

    2014-11-01

    A 50-year-old man presented to our hospital with the chief complaint of right hypochondriac pain and a palpable tumor. Advanced hepatocellular carcinoma (HCC) and chronic hepatitis B infection were diagnosed and treated by twice-repeated transcatheterarterial chemoembolization (TACE) followed by administration of entecavir. Two months after the last TACE, alpha-fetoprotein(AFP)and protein induced by vitamin K absence or antagonistII (PIVKA-II) levels had elevated, and multiple small early enhancing nodules were detected on computed tomography(CT)scan. Based on his age and liver function (Child-Pugh score A5), a full dose of sorafenib (800 mg/day) was administered. The sorafenib dose was decreased after one month to 400mg/day because of hand-foot syndrome. Following sorafenib administration, the lesions shrank markedly, and complete response (CR) according to modified Response Evaluation Criteria In Solid Tumors(mRECIST)was achieved within 4 months. Six months after sorafenib treatment was begun, recurrent HCC was detected in segment 6, near the previously treated lesion. The decreased size of the main tumor and normalization of AFP levels allowed curative surgical resection. The patient was discharged 5 days after surgery and is currently treated with a half dose of sorafenib. Thirteen months after surgery, a small early enhancing lesion is visible on postoperative CT scan, but AFP and PIVKA-II levels are still keeping in a normal range. This case demonstrates that if sorafenib treatment is effective, then subsequent surgical treatment can be reconsidered in patients with advanced HCC responding to this combined therapy. PMID:25731444

  17. Belinostat and Azacitidine in Treating Patients With Advanced Hematologic Cancers or Other Diseases

    ClinicalTrials.gov

    2014-12-22

    Accelerated Phase of Disease; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndrome; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome

  18. 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

  19. Infused vincristine and adriamycin with high dose methylprednisolone (VAMP) in advanced previously treated multiple myeloma patients.

    PubMed Central

    Forgeson, G. V.; Selby, P.; Lakhani, S.; Zulian, G.; Viner, C.; Maitland, J.; McElwain, T. J.

    1988-01-01

    Forty-five patients with relapsed or refractory multiple myeloma received continuous infusions of vincristine (0.4 mg total dose daily for 4 days) and adriamycin (9 mg m-2 daily for 4 days) with a high dose of methylprednisolone (1 g m-2 i.v. or p.o. daily by 1 h infusion), the VAMP regimen. Sixteen (36%) responded, with a median duration of remission of 11 months and median survival of 20 months. Major toxicities encountered were infective and cardiovascular. Two smaller groups of myeloma patients were treated with high dose methylprednisolone (HDMP) alone, or VAMP plus weekly low dose cyclophosphamide (Cyclo-VAMP). HDMP produced short responses in 25% of patients with less toxicity than VAMP. Cyclo-VAMP was used in a highly selected group of patients who had previously responded to high dose melphalan. It was well tolerated and produced responses in 61% of this group. PMID:3207601

  20. Comprehensive geriatric assessment and traditional Chinese medicine intervention benefit symptom control in elderly patients with advanced non-small cell lung cancer.

    PubMed

    Xue, Dong; Han, Shuyan; Jiang, Shantong; Sun, Hong; Chen, Yanzhi; Li, Yuanqing; Wang, Wei; Feng, Ye; Wang, Ke; Li, Pingping

    2015-04-01

    The aim of this study was to observe the symptom improvement and clinical benefit in elderly patients with advanced non-small cell lung cancer (NSCLC) stratified on the basis of CGA findings after treatment with a combination of traditional Chinese medicine and Western medicine. Twenty-four elderly advanced NSCLC patients with a mean age of 73.0 ± 5.3 (65-83) years were categorized into three stratifications according to CGA results, namely function independent, mildly function impaired, and function dependent. They received standardized therapy, individualized therapy, and best supportive care, respectively. The patients receiving standardized therapy and individualized therapy were randomized into two groups, with or without traditional Chinese medicine for symptom control, while for all the patients receiving best supportive care, traditional Chinese medicine was administered. Nine non-elderly NSCLC patients (<65 years old) were enrolled as control and treated in accordance with NCCN NSCLC treatment guidelines. EORTC QLQ-C30 core scale, LC13 scale, and MDASI-TCM scale were used to assess relevant symptoms before and after treatment. After treatment for 3 weeks, it was shown by QLQ-C30+LC13 scales, for function-dependent patients, that the physical and role performances and the global health status were improved and the symptoms of fatigue and cough were alleviated; by MDASI-TCM scale, the symptoms of fatigue, cough, and expectoration were improved. In function-independent and mildly function-impaired elderly patients, there were no significant changes in functional status and symptoms. But in non-elderly patients, the physical and social performances were lowered, and the symptoms of fatigue, constipation, and poor appetite were aggravated. The elderly patients with advanced NSCLC were categorized on the basis of CGA findings, and traditional Chinese medicine may be beneficial to symptom control of function-dependent patients.

  1. 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

  2. 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.

  3. Hydration with magnesium and mannitol without furosemide prevents the nephrotoxicity induced by cisplatin and pemetrexed in patients with advanced non-small cell lung cancer

    PubMed Central

    Muraki, Keiko; Koyama, Ryo; Honma, Yuichiro; Yagishita, Shigehiro; Shukuya, Takehito; Ohashi, Rina; Takahashi, Fumiyuki; Kido, Kenji; Iwakami, Shin-ichiro; Sasaki, Shinichi; Iwase, Akihiko

    2012-01-01

    Background The aim of this study was to examine the effect of hydration with magnesium and mannitol without furosemide on the nephrotoxocity accompanying combination chemotherapy using cisplatin and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC). Methods Fifty patients with NSCLC who received cisplatin plus pemetrexed, using either old hydration protocol including normal saline with mannitol and furosemide, or a new one including normal saline with magnesium and mannitol without furosemide were retrospectively analyzed. Nephrotoxicity was compared between patients treated using the old protocol and those treated with the new protocol. Univariate and multivariate analyses were performed to identify the independent factors associated with protection against nephrotoxicity in patients with NSCLC who received cisplatin plus pemetrexed. Results Thirty patients received the old hydration protocol, while 20 patients were treated using the new hydration protocol. The patients treated using the new hydration protocol showed a significantly greater increase in creatinine clearance (P=0.0004) and a decrease in the serum creatinine level (P=0.0148) after one course of chemotherapy compared with those treated using the old hydration protocol. There were no differences in the chemotherapeutic response or overall survival between the groups (P=0.572). The new hydration protocol with supplemented magnesium with mannitol without furosemide was an independent factor for the protection against nephrotoxicity induced by cisplatin and pemetrexed in patients with advanced NSCLC [HR 0.232 (95% CI: 0.055-0.986), P=0.039]. Conclusions These results demonstrate that the new hydration protocol comprising supplementation with magnesium without furosemide could prevent the nephrotoxicity induced by cisplatin and pemetrexed without affecting the treatment outcome. PMID:23205279

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

    PubMed Central

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

    2016-01-01

    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

  5. 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

  6. 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.

  7. Potential Therapeutic Benefit of Combining Gefitinib and Tamoxifen for Treating Advanced Lung Adenocarcinoma

    PubMed Central

    Chiu, Kuo-Liang; Chen, Tzu-Sheng; Chang, Shang-Miao; Yang, Shu-Yun; Chen, Li-Hsiou; Ni, Yung-Lun

    2015-01-01

    Introduction. Epidermal growth factor receptor (EGFR) mutations are known as oncogene driver mutations and with EGFR mutations exhibit good response to the EGFR tyrosine kinase inhibitor Gefitinib. Some studies have shown that activation of estrogen and estrogen receptor α or β (ERα/β) promote adenocarcinoma. We evaluated the relationship between the two receptors and the potential therapeutic benefit with Gefitinib and Tamoxifen. Methods. We assessed the association between EGFR mutations as well as ERα/β expression/location and overall survival in a cohort of 55 patients with LAC from a single hospital. PC9 (EGFR exon 19 deletion mutant; Gefitinib-vulnerable cells) and A549 (EGFR wild type; Gefitinib-resistant cells) cancer cells were used to evaluate the in vitro therapeutic benefits of combining Gefitinib and Tamoxifen. Results. We found that the cytosolic but not the nuclear expression of ERβ was associated with better OS in LAC tumors but not associated with EGFR mutation. The in vitro study showed that combined Gefitinib and Tamoxifen resulted in increased apoptosis and cytosolic expression of ERβ. In addition, combining both medications resulted in reduced cell growth and increased the cytotoxic effect of Gefitinib. Conclusion. Tamoxifen enhanced advanced LAC cytotoxic effect induced by Gefitinib by arresting ERβ in cytosol. PMID:25692143

  8. 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

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

    ClinicalTrials.gov

    2016-07-05

    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

  10. Role of mixing on microwave-enhanced advanced oxidation process in treating sewage sludge.

    PubMed

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

    2008-10-01

    The microwave enhanced advanced oxidation process (MW/H2O2-AOP) was used for the release of nutrients and the disintegration of suspended solids from both anaerobic sludge and aerobic sludge. The purpose of this study was to determine the effects of mixing on the performance of the process, in terms of soluble ammonia, orthophosphate and soluble chemical oxygen demands. Experiments were conducted on sludge samples with various total solids concentrations (1.1-3.7%) and hydrogen peroxide dosage (1% per 1% of total solids) at 80 degrees C of microwave temperature and five minutes of heating time. The results indicated that mixing affected solids disintegration and nutrient solubilization of sewage sludge, regardless of the sludge used, anaerobic or aerobic. However, the effects of mixing on the MW/H2O2-AOP were dependent on the total solids concentration of the sludge. A paired t-test was performed on data for aerobic sludge: at 2.9% of total solids (TS), the difference for solubilization of nutrients and solids disintegration was statistically significant at a 95% confidence level between mixing and non-mixing samples. At a lower TS of 1.7% only soluble chemical oxygen demand showed significant difference between mixing and non-mixing. The results suggest that, for sludge with higher solids content, the MW/H2O2-AOP can be more effective if a mixing device is implemented.

  11. 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

  12. Characterization of aquatic humic substances to DBPs formation in advanced treatment processes for conventionally treated water.

    PubMed

    Kim, Hyun-Chul; Yu, Myong-Jin

    2007-05-01

    An advanced water treatment demonstration plant consisted of ozone/granular activated carbon processes was operated to study feasibility of the processes. Natural organic matter (NOM) from raw and process waters at the demonstration plant was isolated into humic and non-humic fractions by physicochemical fractionation method to investigate characteristics of humic fraction (i.e., humic substances, HS) as a predominant haloform reactant. Ozone did not significantly oxidize the carboxylic fraction (from 39.1 to 35.9%), while GAC removed some of the carboxylic fraction (from 35.9 to 29.1%). Formation potential of trihalomethanes (THMs) as compared to haloacetic acids formation potential (HAAFP) was highly influenced by HS. Higher yields of THMs resulted from chlorination of HS with a higher phenolic content and phenolic fraction in the HS gradually decreased from 60.5% to 15.8% through the water treatment. The structural and functional changes of HS were identified by elemental, Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance ((1)H NMR) analyses, and these results were mutually consistent. The functional distribution data obtained by using A-21 resin could be used to support the interpretation of data obtained from the spectroscopic analyses. Decreases in ratio of UV absorbance at 253 nm and 203 nm (A(253)/A(203)) and DBPFPs/DOC showed consistent trends, therefore, A(253)/A(203) ratio may be a good indicator for the disinfection by-product formation potentials (DBPFPs).

  13. 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.

  14. [A case of advanced esophageal cancer with direct bronchial invasion successfully treated by multidisciplinary therapy].

    PubMed

    Haba, Yusuke; Okamoto, Koichi; Watanabe, Toshifumi; Tsukada, Tomoya; Kinoshita, Jun; Makino, Isamu; Nakamura, Keishi; Oyama, Katsunobu; Ninomiya, Itasu; Fushida, Sachio; Fujimura, Takashi; Ohta, Tetsuo

    2014-11-01

    A 66-year-old man with advanced esophageal cancer (staging Mt, 6.0 cm, cT3N0M0, cStage II) was administered neoadjuvant chemotherapy (NAC: 5-fluorouracil and cisplatin). As the tumor continued to grow after one course of NAC, video-assisted thoracoscopic surgery(VATS) was used to perform an esophagectomy along with 3-field lymph node dissection and retrosternal route reconstruction using a gastric tube. The second course of NAC was not administered. Intraoperative findings showed the direct invasion of the primary esophageal cancer into the membranous portion of the left bronchus. The maximum possible tumor tissue was resected and removed. The tumor tissue was exposed extensively to the surface of the esophageal adventitia and a residual tumor at the surface of the left bronchus was suspected. It was diagnosed as CT-pT4 (left bronchus), N0, M0, CT-pStage III. Subsequently, we administered chemoradiotherapy consisting of weekly low-dose docetaxel with radiation for the residual tumor (60 Gy/30 Fr). The patient is still alive 40 months after surgery without any signs of recurrence.

  15. [A case of advanced esophageal cancer with direct bronchial invasion successfully treated by multidisciplinary therapy].

    PubMed

    Haba, Yusuke; Okamoto, Koichi; Watanabe, Toshifumi; Tsukada, Tomoya; Kinoshita, Jun; Makino, Isamu; Nakamura, Keishi; Oyama, Katsunobu; Ninomiya, Itasu; Fushida, Sachio; Fujimura, Takashi; Ohta, Tetsuo

    2014-11-01

    A 66-year-old man with advanced esophageal cancer (staging Mt, 6.0 cm, cT3N0M0, cStage II) was administered neoadjuvant chemotherapy (NAC: 5-fluorouracil and cisplatin). As the tumor continued to grow after one course of NAC, video-assisted thoracoscopic surgery(VATS) was used to perform an esophagectomy along with 3-field lymph node dissection and retrosternal route reconstruction using a gastric tube. The second course of NAC was not administered. Intraoperative findings showed the direct invasion of the primary esophageal cancer into the membranous portion of the left bronchus. The maximum possible tumor tissue was resected and removed. The tumor tissue was exposed extensively to the surface of the esophageal adventitia and a residual tumor at the surface of the left bronchus was suspected. It was diagnosed as CT-pT4 (left bronchus), N0, M0, CT-pStage III. Subsequently, we administered chemoradiotherapy consisting of weekly low-dose docetaxel with radiation for the residual tumor (60 Gy/30 Fr). The patient is still alive 40 months after surgery without any signs of recurrence. PMID:25731408

  16. 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. PMID:26378656

  17. Treating Elderly Patients With Hormone Receptor–Positive Advanced Breast Cancer

    PubMed Central

    Riseberg, David

    2015-01-01

    As the overall population ages, the proportion of elderly patients (aged ≥65 years) with breast cancer also increases. Studies have shown that elderly patients with hormone receptor–positive breast cancer can derive as much benefit from treatment as do younger patients, yet they remain underrepresented in clinical trials and are often undertreated in clinical practice. Treatment decisions for older patients should not be based solely on chronologic age; a patient’s physiologic functioning and comorbidities must also be taken into consideration. For recurrent or metastatic disease, systemic treatment with endocrine therapies or chemotherapy may prolong a patient’s life and alleviate troublesome symptoms. Resistance to therapy remains a problem in the advanced breast cancer setting, with most patients eventually becoming resistant to additional treatment. New combination regimens that target multiple pathways, such as everolimus plus exemestane, have shown efficacy in elderly patients previously resistant to endocrine therapies, and future research may need to focus on such combinations in order to improve outcomes in this patient group. A number of investigational agents are in clinical development, although few studies identify their effects in the elderly patient population. Optimizing effective yet tolerable therapeutic regimens for elderly patients could improve their outcomes while ensuring that the goals of improved survival and quality of life are considered. PMID:26339192

  18. EGFR, KRAS, BRAF, and HER-2 molecular status in brain metastases from 77 NSCLC patients

    PubMed Central

    Villalva, Claire; Duranton-Tanneur, Valérie; Guilloteau, Karline; Burel-Vandenbos, Fanny; Wager, Michel; Doyen, Jérôme; Levillain, Pierre Marie; Fontaine, Denys; Blons, Hélène; Pedeutour, Florence; Karayan-Tapon, Lucie

    2013-01-01

    The aim of this study was to determine the frequency of EGFR, KRAS, BRAF, and HER-2 mutations in brain metastases from non-small cell lung carcinomas (BM-NSCLC). A total of 77 samples of BM-NSCLC were included and 19 samples of BM from breast, kidney, and colorectal tumors were also studied as controls. These samples were collected from patients followed between 2008 and 2011 at Poitiers and Nice University Hospitals in France. The frequencies of EGFR, KRAS, BRAF, and HER-2 mutations in BM-NSCLC were 2.6, 38.5, 0, and 0% respectively. The incidence of KRAS mutation was significantly higher in female and younger patients (P < 0.05). No mutations of the four genes were found in BM from breast or kidney. However, among six BM from colorectal tumors, we identified KRAS mutations in three cases and BRAF mutations in two other cases. This study is the largest analysis on genetic alterations in BM-NSCLC performed to date. Our results suggest a low frequency of EGFR mutations in BM-NSCLC whereas KRAS mutations are as frequent in BM-NSCLC as in primitive NSCLC. These results raise the question of the variability of the brain metastatic potential of NSCLC cells in relation to the mutation pattern. PMID:23930206

  19. 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

  20. 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

  1. Selective laser trabeculoplasty in treating post-trabeculectomy advanced primary open-angle glaucoma

    PubMed Central

    ZHANG, HONGYANG; YANG, YANGFAN; XU, JIANGANG; YU, MINBIN

    2016-01-01

    The aim of this study was to investigate the safety and efficacy of selective laser trabeculoplasty (SLT) treatment of patients with primary open-angle glaucoma (POAG) who could not obtain target intraocular pressure (IOP) through post-trabeculectomy medication. Sixteen patients with POAG (18 eyes), who could not obtain target IOP following medication and surgery, were treated with 360° SLT. The IOP, anterior chamber inflammation, and daytime and long-term IOP fluctuations before and 2 h, 1 day, 7 days, 1 month, 3 months, 6 months and 9 months after SLT were documented. SLT treatment success was defined as >20% IOP reduction compared with the baseline IOP at 6 and 9 months after the laser treatment date. Prior to SLT, the patients were administered different types (average, 2.8±0.8) of anti-glaucoma drugs and had an average IOP of 21.3±3.4 mmHg. Following SLT, the average IOP decreased to 16.2±3.0 mmHg and the success rate was 77.7%. The pre-SLT daytime IOP fluctuation was 4.1±1.4 mmHg, which decreased to 2.6±1.1 mmHg following the laser treatment (P<0.05). In conclusion, this study demonstrated that SLT could reduce the IOP in post-trabeculectomy patients with POAG, and reduce the daytime IOP fluctuations. PMID:26998042

  2. Recent advances in treating multiple sclerosis: efficacy, risks and place in therapy.

    PubMed

    Jeffery, Douglas R

    2013-01-01

    The development of new pharmacologic agents for the treatment of multiple sclerosis (MS) and advances in testing for exposure to the JC virus have led to changes in the treatment of MS. In addition several new agents are in late stage development for MS and their entry onto the market will provide additional treatment options. In 2012 and in early 2013, it is likely that both terifunomide and BG-12 will be approved by the United States Food and Drug Administration (FDA) for the treatment of relapsing forms of MS. The therapeutic environment has already changed and is likely to change rapidly over the next several years. Fingolimod was the first oral agent approved for the treatment of MS and this agent is now widely used in patients intolerant of injections and the side effects associated with the older platform therapies. In many settings it is also used a first-line agent. Owing to the risk of progressive multifocal leukoencephalopathy, natalizumab had previously been reserved for patients with active disease who were intolerant of first-line agents or patients who were worsening despite standard therapy. With the availability of JC virus antibody testing, natalizumab is now being used as a first-line agent in patients negative for JC virus antibodies. Teriflunomide and BG-12 will become available in the next year. Both agents have suitable efficacy and a favorable safety and tolerability profile. There are advantages and disadvantages associated with all of the oral agents. In this article we summarize the clinical trial results regarding the efficacy and safety of the oral agents and discuss the changes that are already taking place in the therapeutic landscape for MS. PMID:23342246

  3. MiRNA-10a is upregulated in NSCLC and may promote cancer by targeting PTEN

    PubMed Central

    Yu, Tao; Liu, Lei; Li, Jing; Yan, Mingxia; Lin, Hechun; Liu, Ying; Chu, Dandan; Tu, Hong; Gu, Aiqin; Yao, Ming

    2015-01-01

    MicroRNAs (miRNAs) are involved in human cancer including non-small cell lung cancer (NSCLC). In this study, we compared miRNA expression microarray of SPC-A-1sci (high metastatic) and SPC-A-1 (weakly metastatic) cells. We found that miRNA-10a was up-regulated in NSCLC compared with corresponding normal tissues. High expression of miR-10a was associated with tumor node metastasis and lymph node metastasis. Furthermore, overexpression of miR-10a promoted NSCLC cell proliferation, migration and invasion in vitro. We found that PTEN was a direct target of miR-10a in NSCLC. Also miR-10a activated the PTEN/AKT/ERK pathway. We suggest that miR-10a contributes to NSCLC by targeting PTEN. PMID:26317552

  4. 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

  5. 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.

  6. [A Case of HER2-Positive Stage IV Advanced Gastric Cancer Treated with Chemotherapy Combined with Trastuzumab].

    PubMed

    Takaya, Kai; Takahashi, Ryosuke; Honma, Satoru; Horii, Shinichiro; Takahashi, Hirokazu; Hagiwara, Motohisa; Chin, Masahiro; Hashizume, Eiji

    2016-09-01

    We report a case of human epidermal growth factor receptor(HER)2 positive stage IV advanced gastric cancer successfully treated with chemotherapy combined with trastuzumab. A 50-year-old man was diagnosed with type 3 gastric cancer complicated by liver and lymph node metastases. Owing to a HER2 immunohistochemistry tumor score of 3+, we initiated capecitabine plus CDDP plus trastuzumab chemotherapy. After 6 chemotherapy courses, computed tomography showed the liver metastasis had disappeared and the paraaortic lymph nodes had shrunk. We continued the capecitabine plus trastuzumab chemotherapy, which resulted in a progression free survival of 31 months. After 38 chemotherapy courses, the primary tumor progressed; therefore, the patient underwent surgery. Chemotherapy combined with trastuzumab can allow for resec- tion of the primary tumor. PMID:27628555

  7. 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.

  8. 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.

  9. 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

  10. Prognostic and Predictive Value of Baseline and Posttreatment Molecular Marker Expression in Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiotherapy

    SciTech Connect

    Bertolini, Federica . E-mail: bertolini.federica@policlinico.mo.it; Bengala, Carmelo; Losi, Luisa; Pagano, Maria; Iachetta, Francesco; Dealis, Cristina; Jovic, Gordana; Depenni, Roberta; Zironi, Sandra; Falchi, Anna Maria; Luppi, Gabriele; Conte, Pier Franco

    2007-08-01

    Purpose: To evaluate expression of a panel of molecular markers, including p53, p21, MLH1, MSH2, MIB-1, thymidylate synthase, epidermal growth factor receptor (EGFR), and tissue vascular endothelial growth factor (VEGF), before and after treatment in patients treated with neoadjuvant chemoradiotherapy for locally advanced rectal cancer, to correlate the constitutive profile and dynamics of expression with pathologic response and outcome. Methods and Materials: Expression of biomarkers was evaluated by immunohistochemistry in tumor samples from 91 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy (50 Gy) plus concurrent 5-fluorouracil by continuous intravenous infusion. Results: A pathologic complete remission was observed in 14 patients (15.4%). Patients with MLH1-positive tumors had a higher pathologic complete response rate (24.3% vs. 9.4%; p = 0.055). Low expression of constitutive p21, absence of EGFR expression after chemoradiotherapy, and high Dworak's tumor regression grade (TRG) were significantly associated with improved disease-free survival and overall survival. A high MIB-1 value after chemoradiotherapy was significantly associated with worse overall survival. Multivariate analysis confirmed the prognostic value of constitutive p21 expression as well as EGFR expression and MIB-1 value after chemoradiotherapy among patients not achieving TRG 3-4. Conclusions: In our study, we observed the independent prognostic value of EGFR expression after chemoradiotherapy on disease-free survival. Moreover, our study suggests that a constitutive high p21 expression and a high MIB-1 value after neoadjuvant chemoradiotherapy treatment could predict worse outcome in locally advanced rectal cancer.

  11. Modulation of Inflammatory and Hemostatic Markers in Obstructive Sleep Apnea Patients Treated with Mandibular Advancement Splints: A Parallel, Controlled Trial

    PubMed Central

    Niżankowska-Jędrzejczyk, Agata; Almeida, Fernanda R.; Lowe, Alan A.; Kania, Aleksander; Nastałek, Paweł; Mejza, Filip; Foley, Jonathan H.; Niżankowska-Mogilnicka, Ewa; Undas, Anetta

    2014-01-01

    Study Objective: Obstructive sleep apnea (OSA) is associated with systemic inflammation and a hypercoagulable state. The current study aim was to investigate whether mandibular advancement splint (MAS) therapy affects inflammatory and hemostatic parameters in patients with mild-to-moderate OSA. Methods: Twenty-two patients with mild-to-moderate OSA and 16 control subjects were studied. OSA subjects were treated with a titratable MAS for 6 months. Baseline plasma C-reactive protein, interleukin-1β, interleukin-10, interleukin-6, P-selectin, fibrinogen, D-dimer, plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex, activated thrombin-activatable fibrinolysis inhibitor (TAFIa), 6-keto-PGF1α, glucose, and fibrin clot lysis time (CLT) were measured in all subjects. After 3 months of MAS therapy, measurements were repeated for the 22 patients, and after 6 months all measurements were repeated for all study subjects. Results: MAS treatment reduced significantly AHI at 3 months (24 vs 13.1/h) and further improved it at 6 months (13.1 vs 7.05/h). Compared with controls, OSA subjects had a significant higher baseline mean levels of fibrinogen, TAFIa, 6-keto-PGF1α, and glucose. MAS treatment significantly improved levels of IL-1β, D-dimer, TAFIa, and CLT. Despite residual apneas, MAS treatment group presented similar measured homeostatic and inflammatory levels to controls except for glucose. Conclusion: Treatment with MAS in mild-to-moderate OSA subjects improves the inflammatory profile and homeostatic markers. Citation: Niżankowska-Jędrzejczyk A; Almeida FR; Lowe AA; Kania A; Nastałek P; Mejza F; Foley JH; Niżankowska-Mogilnicka E; Undas A. Modulation of inflammatory and hemostatic markers in obstructive sleep apnea patients treated with mandibular advancement splints: a parallel, controlled trial. J Clin Sleep Med 2014;10(3):255-262. PMID:24634622

  12. 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.

  13. Long-term follow-up of patients with advanced ovarian cancer treated in randomised clinical trials.

    PubMed Central

    Warwick, J.; Kehoe, S.; Earl, H.; Luesley, D.; Redman, C.; Chan, K. K.

    1995-01-01

    The data from two prospective randomised phase III trials that were initiated by the West Midlands Ovarian Cancer Study Group (WMOCSG) in 1981 and 1986, recruiting 167 and 195 patients respectively, have been pooled and the survival patterns of the 362 patients treated for advanced epithelial ovarian cancer within clinical trials in the West Midlands over the 10 year period (1981-91) have been explored. All patients had histologically proven epithelial ovarian cancer and all had residual disease after primary surgery, with the majority having stage III/IV disease. The primary treatment for all patients was debulking surgery followed by platinum-based chemotherapy. Eligible patients were further randomised to undergo a second debulking operation. The main end point, survival, was assessed using Kaplan-Meier curves and the log-rank test. A Cox proportional hazards model identified performance status (P = 0.002), residual disease (P = 0.005) and albumin level (P = 0.04) as independent prognostic factors. A multivariate model to predict survival curves for patients with the best and worst prognoses was developed with predicted 5 year survival of 30% and 3% for those in the best and worst prognostic groups respectively. The identification of clinical interventions to improve outcome is an urgent matter since the prognosis for patients with advanced ovarian cancer remains poor. PMID:8519669

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

    PubMed

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

    2015-07-28

    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. PMID:26118655

  15. 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

  16. 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.

  17. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC

    PubMed Central

    Amato, Katherine R.; Wang, Shan; Hastings, Andrew K.; Youngblood, Victoria M.; Santapuram, Pranav R.; Chen, Haiying; Cates, Justin M.; Colvin, Daniel C.; Ye, Fei; Brantley-Sieders, Dana M.; Cook, Rebecca S.; Tan, Li; Gray, Nathanael S.; Chen, Jin

    2014-01-01

    Genome-wide analyses determined previously that the receptor tyrosine kinase (RTK) EPHA2 is commonly overexpressed in non–small cell lung cancers (NSCLCs). EPHA2 overexpression is associated with poor clinical outcomes; therefore, EPHA2 may represent a promising therapeutic target for patients with NSCLC. In support of this hypothesis, here we have shown that targeted disruption of EphA2 in a murine model of aggressive Kras-mutant NSCLC impairs tumor growth. Knockdown of EPHA2 in human NSCLC cell lines reduced cell growth and viability, confirming the epithelial cell autonomous requirements for EPHA2 in NSCLCs. Targeting EPHA2 in NSCLCs decreased S6K1-mediated phosphorylation of cell death agonist BAD and induced apoptosis. Induction of EPHA2 knockdown within established NSCLC tumors in a subcutaneous murine model reduced tumor volume and induced tumor cell death. Furthermore, an ATP-competitive EPHA2 RTK inhibitor, ALW-II-41-27, reduced the number of viable NSCLC cells in a time-dependent and dose-dependent manner in vitro and induced tumor regression in human NSCLC xenografts in vivo. Collectively, these data demonstrate a role for EPHA2 in the maintenance and progression of NSCLCs and provide evidence that ALW-II-41-27 effectively inhibits EPHA2-mediated tumor growth in preclinical models of NSCLC. PMID:24713656

  18. Heavy Metal Content in Thoracic Tissue Samples from Patients with and without NSCLC.

    PubMed

    Tran, Jessica Q; Dranikov, Alexandra; Iannucci, Anita; Wagner, Walter P; LoBello, Janine; Allen, Jeffrey; Weiss, Glen J

    2014-01-01

    Objectives. Environmental factors expose an individual to heavy metals that may stimulate cancer growth preclinically including non-small cell lung cancer (NSCLC) cells. Here, we examine the prevalence of four heavy metals present in postsurgical tissues from individuals with and without NSCLC. Materials and Methods. Thoracic tissue samples from two separate sample sets were analyzed for cadmium (Cd), arsenic (As), mercury (Hg), and lead (Pb) content. Results. In the first sample set, there was no significant measurable amount of Pb and Hg found in either NSCLC tissue or nonmalignant lung tissue samples. Cd was the most prevalent heavy metal and As was present in moderate amounts. In the second sample set, Cd was measurable across all tissue types taken from 28 NSCLC patients and significantly higher Cd was measurable in noncancer benign lung (n = 9). In the NSCLC samples, As was measurable in moderate amounts, while Hg and Pb amounts were negligible. Conclusion. Cd and As are present in lung tissues for patients with NSCLC. With existing preclinical evidence of their tumorigenecity, it is plausible that Cd and/or As may have an impact on NSCLC development. Additional studies examining the prevalence and association between smokers and nonsmokers are suggested. PMID:26316947

  19. Cyproheptadine significantly improves the overall and progression-free survival of sorafenib-treated advanced HCC patients

    PubMed Central

    Feng, Yu-Min; Feng, Chin-Wen; Lu, Chin-Li; Lee, Ming-Yang; Chen, Chi-Yi; Chen, Solomon Chih-Cheng

    2015-01-01

    Objective Sorafenib is a recommended treatment for advanced hepatocellular carcinoma. The study is to evaluate the efficacy of sorafenib plus cyproheptadine compared with sorafenib alone in patients with advanced hepatocellular carcinoma. Methods A retrospective cohort study reviewed all consecutive advanced hepatocellular carcinoma cases with Child-Pugh Class A disease starting sorafenib treatment at our hospital from August 2012 to March 2013. They were followed up until 31 December 2013. A total of 52 patients were enrolled: 32 patients in the combination (sorafenib–cyproheptadine) group and 20 patients in the control (sorafenib alone) group. The response to treatment, overall survival and progression-free survival were compared. Results The median overall survival was 11.0 months (95% confidence interval: 6.8–15.1 months) in the combination group compared with 4.8 months (95% confidence interval: 3.1–6.6 months) in the control group (crude hazard ratio = 0.45, 95% confidence interval: 0.22–0.82). The median progression-free survival time was 7.5 months (95% confidence interval: 5.1–10.0 months) in the combination group compared with 1.7 months (95% confidence interval: 1.4–2.1 months) in the control group (crude hazard ratio = 0.43, 95% confidence interval: 0.22–0.86). Kaplan–Meier survival analysis revealed that both overall survival and progression-free survival in the combination group were significantly longer than that in the control group. The multivariate model found patients in the combination group were 76% less likely to die (adjusted hazard ratio = 0.24, 95% confidence interval: 0.10–0.58) and 82% less likely to have progression (adjusted hazard ratio = 0.18, 95% confidence interval: 0.08–0.44) during the 17 months of follow-up. Conclusion Cyproheptadine may significantly improve survival outcomes of sorafenib-treated advanced hepatocellular carcinoma patients. PMID:25646358

  20. A novel acquired ALK F1245C mutation confers resistance to crizotinib in ALK-positive NSCLC but is sensitive to ceritinib.

    PubMed

    Kodityal, Sandeep; Elvin, Julia A; Squillace, Rachel; Agarwal, Nikita; Miller, Vincent A; Ali, Siraj M; Klempner, Samuel J; Ou, Sai-Hong Ignatius

    2016-02-01

    The emergence of acquired anaplastic lymphoma kinase (ALK) resistant mutations is a common molecular mechanism underpinning disease progression during crizotinib treatment of ALK-positive (ALK+) non-small cell lung cancer (NSCLC) patients. Identifying acquired resistance mutations in ALK is paramount for tailoring future therapy with second generation ALK inhibitors and beyond. Comprehensive genomic profiling using hybrid-capture next generation sequencing has been successful in identifying acquired ALK resistance mutations. Here we described the emergence of an ALK F1245C mutation in an advanced ALK+ NSCLC patient (EML4-ALK variant 3a/b) who developed slow disease progression after a durable response to crizotinib. The patient was eventually switched to ceritinib with on-going clinical response. This is the first patient report that ALK F1245C is an acquired resistance mutation to crizotinib that can be overcome by ceritinib. PMID:26775591

  1. Pharmacogenomics of platinum-based chemotherapy sensitivity in NSCLC: toward precision medicine.

    PubMed

    Yin, Ji-Ye; Li, Xi; Zhou, Hong-Hao; Liu, Zhao-Qian

    2016-08-01

    Lung cancer is one of the leading causes of cancer-related death in the world. Platinum-based chemotherapy is the first-line treatment for non-small-cell lung cancer (NSCLC), however, the therapeutic efficiency varies remarkably among individuals. A large number of pharmacogenomics studies aimed to identify genetic variations which can be used to predict platinum response. Those studies are leading NSCLC treatment to the new era of precision medicine. In the current review, we provided a comprehensive update on the main recent findings of genetic variations which can be used to predict platinum sensitivity in the NSCLC patients.

  2. Pharmacogenomics of platinum-based chemotherapy sensitivity in NSCLC: toward precision medicine.

    PubMed

    Yin, Ji-Ye; Li, Xi; Zhou, Hong-Hao; Liu, Zhao-Qian

    2016-08-01

    Lung cancer is one of the leading causes of cancer-related death in the world. Platinum-based chemotherapy is the first-line treatment for non-small-cell lung cancer (NSCLC), however, the therapeutic efficiency varies remarkably among individuals. A large number of pharmacogenomics studies aimed to identify genetic variations which can be used to predict platinum response. Those studies are leading NSCLC treatment to the new era of precision medicine. In the current review, we provided a comprehensive update on the main recent findings of genetic variations which can be used to predict platinum sensitivity in the NSCLC patients. PMID:27462924

  3. Advances in treating glioblastoma

    PubMed Central

    Weathers, Shiao-Pei

    2014-01-01

    Glioblastoma is the most common and most aggressive primary brain tumor in adults. Optimized standard treatment only confers a modest improvement in progression and overall survival, underscoring the pressing need for the development of novel therapies. Our understanding of glioblastoma (a molecularly heterogeneous disorder) has been accelerated in the setting of large scale genomic analyses, lending insight into potential actionable targets. Antiangiogenic therapies have been used in the treatment of glioblastoma, and our understanding of the means to optimize the role of these agents is continuing to evolve. Recently, immunotherapy has garnered increasing attention as a therapeutic approach in the treatment of gliomas. Promising novel approaches are under active development in the treatment of glioblastoma. PMID:24991423

  4. A clinical comparison of cefepime and metronidazole versus gentamicin and clindamycin in the antibiotic management of surgically treated advanced appendicitis.

    PubMed

    Berne, T V; Yellin, A E; Appleman, M D; Heseltine, P N; Gill, M A

    1993-01-01

    Many antibiotics and antibiotic combinations are used for the treatment of peritonitis because of advanced (gangrenous or perforated) appendicitis. An aminoglycoside combined with an antianaerobe antibiotic is one standard treatment, but there is concern about the potential nephrotoxicity of the aminoglycoside and the necessity for monitoring aminoglycoside blood levels. Cefepime, a new broad-spectrum cephalosporin with a prolonged serum half-life, has excellent activity against gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa. Its spectrum of activity is similar to the aminoglycosides, but it has less potential for inducing renal injury. A double-blind, randomized study compared cefepime, 2 grams every 12 hours IVPB plus metronidazole 0.5 grams every eight hours IVPB (C/M) with gentamicin 1.5 milligrams per kilograms of IVPB plus clindamycin 0.9 grams q eight hours IVPB (G/C), administered up to 14 days, in 96 surgically treated patients with gangrenous or perforated appendicitis. Fifty patients had advanced appendicitis (nine gangrenous and 41 perforated) in the C/M group and 46 patients (six gangrenous and 40 perforated) in the G/C group. The mean number of days of postoperative fever (C/M, 4.4 +/- 2.7 versus G/C, 5.0 +/- 2.2), postoperative hospitalization (C/M, 2.0 +/- 1.9 versus G/C, 2.0 +/- 2.1) and antibiotic therapy (C/M, 6.3 +/- 1.9 versus G/C, 6.9 +/- 1.9) was similar in the two treatment groups. There were 11 treatment failures (C/M, three; G/C, eight; p = 0.13), six of which were probably a result of enterococci. No deaths occurred. Our study results show that the efficacy of cefepime plus metronidazole is equivalent to that of clindamycin plus gentamicin.

  5. 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.

  6. The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy

    PubMed Central

    Faloppi, Luca; Del Prete, Michela; Gardini, Andrea Casadei; Santini, Daniele; Silvestris, Nicola; Bianconi, Maristella; Giampieri, Riccardo; Valgiusti, Martina; Brunetti, Oronzo; Bittoni, Alessandro; Andrikou, Kalliopi; Lai, Eleonora; Dessì, Alessandra; Cascinu, Stefano; Scartozzi, Mario

    2016-01-01

    LDH may represent an indirect marker of neo-angiogenesis and worse prognosis in many tumour types. We assessed the correlation between LDH and clinical outcome for biliary tract cancer (BTC) patients treated with first-line chemotherapy. Overall, 114 advanced BTC patients treated with first-line gemcitabine and cisplatin were included. Patients were divided into two groups (low vs. high LDH), according to pre-treatment LDH values. Patients were also classified according to pre- and post-treatment variation in LDH serum levels (increased vs. decreased). Median progression free survival (PFS) was 5.0 and 2.6 months respectively in patients with low and high pre-treatment LDH levels (p = 0.0042, HR = 0.56, 95% CI: 0.37–0.87). Median overall survival (OS) was 7.7 and 5.6 months (low vs. high LDH) (p = 0.324, HR = 0.81, 95% CI: 0.54–1.24). DCR was 71% vs. 43% (low vs. high LDH) (p = 0.002). In 38 patients with decreased LDH values after treatment, PFS and OS were respectively 6.2 and 12.1 months, whereas in 76 patients with post-treatment increased LDH levels, PFS and OS were respectively 3.0 and 5.1 months (PFS: p = 0.0009; HR = 0.49; 95% IC: 0.33–0.74; OS: p < 0.0001; HR = 0.42; 95% IC: 0.27–0.63). Our data seem to suggest that LDH serum level may predict clinical outcome in BTC patients receiving first-line chemotherapy. PMID:27063994

  7. Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population*

    PubMed Central

    Hong, Wei; Wang, Kai; Zhang, Yi-ping; Kou, Jun-yan; Hong, Dan; Su, Dan; Mao, Wei-min; Yu, Xin-min; Xie, Fa-jun; Wang, Xiao-jian

    2013-01-01

    Objective: The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C677T excision repair cross-complementation group 1 (ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Methods: A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 C118T were genotyped using the TaqMan methods. Results: The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype (TT or CT) (41.2% versus 19.1%, P=0.01). Median time to progression (TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype (7.6 months versus 5.0 months, P=0.003). No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival. Conclusions: Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum. PMID:23463763

  8. 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

  9. Treatment of advanced non-small-cell lung cancer in the elderly.

    PubMed

    Gridelli, Cesare; Maione, Paolo; Rossi, Antonio; Ferrara, Marianna Luciana; Castaldo, Vincenzo; Palazzolo, Giovanni; Mazzeo, Nicole

    2009-12-01

    Lung cancer in the older individual is an increasingly common problem faced by the oncologist. Elderly patients have more co-morbidities and tend to tolerate toxic medical treatments more poorly than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of non-selected elderly patients with non-small-cell lung cancer (NSCLC). The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients comes from studies in advanced disease. In elderly advanced NSCLC patients single-agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered as the standard treatment for unselected patients, based on several phase II and III trials specifically designed for this special population. Retrospective analyses found no differences in survival between elderly and younger patients treated with cisplatin-based chemotherapy, with a small but significant increase in toxicity in the elderly. Cisplatin-based chemotherapy with cisplatin at attenuated doses has demonstrated to be an active and feasible option in phase II trials and deserves prospective phase III comparison against monochemotherapy. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib are the most promising agents and have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the anti-vascular endothelial growth factor monoclonal antibody bevacizumab, particular care must be taken for elderly patients because of a possible higher incidence of cardiovascular co-morbidities. However its role in this population remains controversial and specific prospective studies are warranted to clarify this topic. Further specifically designed phase III randomized trials are needed to optimize medical treatment of NSCLC in

  10. Safflower polysaccharide induces NSCLC cell apoptosis by inhibition of the Akt pathway.

    PubMed

    Li, Jian-Ying; Yu, Jun; Du, Xu-Sheng; Zhang, Hui-Min; Wang, Bo; Guo, Hua; Bai, Jie; Wang, Juan-Hong; Liu, An; Wang, Yi-Li

    2016-07-01

    Lung cancer is the leading cause of cancer death in the world. Safflower polysaccharide (SPS) has been used for the improvement of immunomodulatory activities and treatment of cancers. However, studies on the effect of SPS on the progression of lung cancer have rarely been reported. To study the antitumor effect of SPS on human lung cancer and its potential mechanism, non-small cell lung cancer cell lines (NSCLC), A549 and YTMLC-90 were treated with SPS at various concentrations ranging from 0.04 to 2.56 mg/ml and BALB/c nude tumor-bearing mice were injected intraperitoneally with SPS at concentrations ranging from 15 to 135 mg/kg. Results showed that SPS suppressed the proliferation of A549 and YTMLC-90 cells and induced apoptosis by increasing mRNA levels of bax and caspase-3, and inhibited tumor growth in vivo. SPS induced cell cycle arrest in the G2/M phase by decreasing the expression of cdc25B and cyclin B1. Moreover, SPS decreased the expression of Akt, p-Akt and PI3K. In mice, SPS injection enhanced immunomodulatory activities by increasing levels of TNF-α and IL-6 in tumor-bearing mice. Our findings suggest that SPS suppresses tumor growth by enhancing immunomodulatory activities and blocking the PI3K/Akt pathway. This study provides new insight into the anticancer mechanism of SPS. PMID:27177149

  11. Elimination of pharmaceutical residues in biologically pre-treated hospital wastewater using advanced UV irradiation technology: a comparative assessment.

    PubMed

    Köhler, C; Venditti, S; Igos, E; Klepiszewski, K; Benetto, E; Cornelissen, A

    2012-11-15

    UV irradiation technology as a membrane bioreactor (MBR) post-treatment was investigated and assessed. Both UV low pressure (LP) and medium pressure (MP) lamps were examined. The technology was installed in a pilot plant treating hospital wastewater to provide the study with adequate field data. The effect of the UV irradiation was enhanced with varying dosages of H2O2 to establish an advanced oxidation process (AOP). The efficiency of the pharmaceutical removal process was assessed by examining 14 micropollutants (antibiotics, analgesics, anticonvulsants, beta-blockers, cytostatics and X-ray contrast media) which are typically released by hospitals and detected with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS). While the MBR treatment generally showed only a low degradation capacity for persistent pharmaceuticals, much better degradation was obtained by applying UV irradiation and H2O2 as AOP. The "conventional" cost-benefit analysis of the different technology options taking into account both electrical energy consumption and pharmaceutical removal efficiency, revealed clearly better performance of low pressure UV lamps as AOP. However, a holistic comparison between the different scenarios was carried out by evaluating their environmental impacts using the life cycle assessment (LCA) methodology. Decisive advantages were highlighted to include this approach in the decision making process.

  12. Elimination of pharmaceutical residues in biologically pre-treated hospital wastewater using advanced UV irradiation technology: a comparative assessment.

    PubMed

    Köhler, C; Venditti, S; Igos, E; Klepiszewski, K; Benetto, E; Cornelissen, A

    2012-11-15

    UV irradiation technology as a membrane bioreactor (MBR) post-treatment was investigated and assessed. Both UV low pressure (LP) and medium pressure (MP) lamps were examined. The technology was installed in a pilot plant treating hospital wastewater to provide the study with adequate field data. The effect of the UV irradiation was enhanced with varying dosages of H2O2 to establish an advanced oxidation process (AOP). The efficiency of the pharmaceutical removal process was assessed by examining 14 micropollutants (antibiotics, analgesics, anticonvulsants, beta-blockers, cytostatics and X-ray contrast media) which are typically released by hospitals and detected with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS). While the MBR treatment generally showed only a low degradation capacity for persistent pharmaceuticals, much better degradation was obtained by applying UV irradiation and H2O2 as AOP. The "conventional" cost-benefit analysis of the different technology options taking into account both electrical energy consumption and pharmaceutical removal efficiency, revealed clearly better performance of low pressure UV lamps as AOP. However, a holistic comparison between the different scenarios was carried out by evaluating their environmental impacts using the life cycle assessment (LCA) methodology. Decisive advantages were highlighted to include this approach in the decision making process. PMID:22748974

  13. Blood neutrophil-lymphocyte ratio predicts survival in locally advanced cancer stomach treated with neoadjuvant chemotherapy FOLFOX 4.

    PubMed

    el Aziz, Lamiss Mohamed Abd

    2014-12-01

    Accurate predictors of survival for patients with advanced gastric cancer treated with neoadjuvant chemotherapy are currently lacking. In this study, we aimed to evaluate the prognostic significance of the neutrophil-lymphocyte ratio (NLR) in patients with stage III-IV gastric cancer who received neoadjuvant chemotherapy FOLFOX 4 as neoadjuvant chemotherapy. We enrolled 70 patients with stage III-IV cancer stomach in this study. Patients received FOLFOX 4 as neoadjuvant chemotherapy. Blood sample was collected before chemotherapy. The NLR was divided into two groups: high (>3) and low (≤ 3). Univariate analysis on progression-free survival (PFS) and overall survival (OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model. The toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria. The univariate analysis showed that PFS and OS were both worse for patients with high NLR than for those with low NLR before chemotherapy (median PFS 28 and 44 months, respectively, P = 0.001; median OS 30 and 48 months, P = 0.001). Multivariate analysis showed that NLRs before chemotherapy were independent prognostic factors of OS but not for progression-free survival. NLR may serve as a potential biomarker for survival prognosis in patients with stage III-IV gastric cancer receiving neoadjuvant chemotherapy. The FOLFOX 4 demonstrated an acceptable toxicity.

  14. [Analysis of the risk factors for severe neutropenia in advanced non-small cell lung cancer after the first course of chemotherapy with third-generation agents].

    PubMed

    Shibuya, Midori; Kogo, Mari; Kurihara, Tatsuya; Shikama, Yusuke; Nakajima, Hiroaki; Yoneyama, Keiichiro; Kiuchi, Yuji

    2013-01-01

      We retrospectively evaluated clinical data before therapy to determine the risk factors for severe neutropenia in advanced non-small-cell lung cancer (NSCLC) patients treated with third-generation agents. We analyzed 100 patients who received such agents (paclitaxel, docetaxel, gemcitabine, irinotecan, or vinorelbine) for advanced NSCLC. The endpoint of the survey was the occurrence of severe neutropenia (grade 4). Risk factors significantly related to severe neutropenia were identified using logistic regression analysis. Of the 100 patients studied, the median age was 62.0 (32-81 years), and 77 (77.0%) were male. CEA 6.6 (0-2220) ng/dL and cytokeratin 19 fragment 21-1 (CYFRA) 4.8 (0.2-173.8) ng/dL before chemotherapy were higher than normal range. Severe neutropenia occurred in 36.0%, the incidence being highest in the first cycle (61.1%). In the univariate analysis, variables associated with severe neutropenia were sex, chest pain, absolute neutrophil count (ANC), Cr, CRP, and CYFRA. In the multivariate analysis, low CYFRA level was identified as a significant risk factor that contributed independently to chemotherapy-induced severe neutropenia (p<0.05). Our analysis suggests that low CYFRA level is the most important risk factor for severe neutropenia in advanced NSCLC patients after the first course of chemotherapy with third-generation agents. PMID:23728094

  15. Mitophagy switches cell death from apoptosis to necrosis in NSCLC cells treated with oncolytic measles virus.

    PubMed

    Xia, Mao; Meng, Gang; Jiang, Aiqin; Chen, Aiping; Dahlhaus, Meike; Gonzalez, Patrick; Beltinger, Christian; Wei, Jiwu

    2014-06-15

    Although apoptotic phenomena have been observed in malignant cells infected by measles virus vaccine strain Edmonston B (MV-Edm), the precise oncolytic mechanisms are poorly defined. In this study we found that MV-Edm induced autophagy and sequestosome 1-mediated mitophagy leading to decreased cytochrome c release, which blocked the pro-apoptotic cascade in non-small cell lung cancer cells (NSCLCs). The decrease of apoptosis by mitophagy favored viral replication. Persistent viral replication sustained by autophagy ultimately resulted in necrotic cell death due to ATP depletion. Importantly, when autophagy was impaired in NSCLCs MV-Edm-induced cell death was significantly abrogated despite of increased apoptosis. Taken together, our results define a novel oncolytic mechanism by which mitophagy switches cell death from apoptosis to more efficient necrosis in NSCLCs following MV-Edm infection. This provides a foundation for future improvement of oncolytic virotherapy or antiviral therapy.

  16. Efficacy of tamoxifen in combination with docetaxel in patients with advanced non-small-cell lung cancer pretreated with platinum-based chemotherapy.

    PubMed

    Wen, Shimin; Fu, Xi; Li, Guangming; He, Lang; Zhao, Caixia; Hu, Xin; Pan, Rongqiang; Guo, Cuihua; Zhang, Xinping; Hu, Xingsheng

    2016-06-01

    The aim of this study was to evaluate the efficacy and safety of the combination of docetaxel (TXT) plus tamoxifen (TAM) in advanced non-small-cell lung cancer (NSCLC) patients who had received platinum-based first-line chemotherapy. A total of 120 advanced NSCLC patients pretreated with platinum-based chemotherapy were randomized into two treatment groups (the TXT and TXT+TAM groups) in a 1 : 1 ratio. Reversal of P-glycoprotein (P-gp) expression, tumor response, progression-free survival, overall survival, and safety were evaluated on an intention-to-treat basis. The median number of cycles of allocated chemotherapy was four in each treatment group (range: 2-6 cycles). The overall response rate and disease control rate in the TXT+TAM group were significantly higher than those in the TXT group (36.7 vs. 15.0% for overall response rate, P=0.007; 85.0 vs. 68.3% for disease control rate, P=0.031). The combination of TXT and TAM could effectively reverse P-gp expression in tumor tissues and provide a significant survival benefit for advanced NSCLC patients compared with TXT alone (11.6 vs. 9.1 months, P=0.030). In addition, in the TXT+TAM group, patients achieving P-gp reversal had a significantly greater median progression-free survival and overall survival than nonreversal patients. Furthermore, the combined therapy showed a safety profile comparable to that of TXT. The combination of TXT and TAM may be an effective and safe treatment option for advanced NSCLC patients who have already developed P-gp-mediated multidrug resistance. PMID:26882453

  17. Functional role of eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) in NSCLC

    PubMed Central

    Cao, Yueyu; Wei, Mengdan; Li, Bing; Liu, Yali; Lu, Ying; Tang, Zhipeng; Lu, Tianbao; Yin, Yujiao; Qin, Zhiqiang; Xu, Zengguang

    2016-01-01

    Eukaryotic translation initiation factor 4 gamma 1(EIF4G1) is related to tumorigenesis and tumor progression. However, its role and the underlying mechanisms in the regulation of tumor development in non–small cell lung cancers (NSCLC) remain largely unknown. Here we report that the levels of EIF4G1 expression are much higher in NSCLC cell lines and tumor tissues than those in the normal lung cells and adjacent normal tissues from the same patients. Using shRNA to knock down EIF4G1 expression stably, we found EIF4G1 required for NSCLC cell proliferation, anchorage-independent growth, migration and invasion. Furthermore, silencing of EIF4G1 induces NSCLC cell apoptosis and causes G0/G1 cell cycle arrest. To identify the partner protein network of EIF4G1 in NSCLC cells, we found that Ubiquitin-specific protease 10 (USP10) can directly interacts with EIF4G1, while acting as a negative regulator for EIF4G1-mediated functions. Together, our results indicate that EIF4G1 functions as an oncoprotein during NSCLC development, which may represent a novel and promising therapeutic target in lung cancer. PMID:27003362

  18. Functional role of eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) in NSCLC.

    PubMed

    Cao, Yueyu; Wei, Mengdan; Li, Bing; Liu, Yali; Lu, Ying; Tang, Zhipeng; Lu, Tianbao; Yin, Yujiao; Qin, Zhiqiang; Xu, Zengguang

    2016-04-26

    Eukaryotic translation initiation factor 4 gamma 1(EIF4G1) is related to tumorigenesis and tumor progression. However, its role and the underlying mechanisms in the regulation of tumor development in non-small cell lung cancers (NSCLC) remain largely unknown. Here we report that the levels of EIF4G1 expression are much higher in NSCLC cell lines and tumor tissues than those in the normal lung cells and adjacent normal tissues from the same patients. Using shRNA to knock down EIF4G1 expression stably, we found EIF4G1 required for NSCLC cell proliferation, anchorage-independent growth, migration and invasion. Furthermore, silencing of EIF4G1 induces NSCLC cell apoptosis and causes G0/G1 cell cycle arrest. To identify the partner protein network of EIF4G1 in NSCLC cells, we found that Ubiquitin-specific protease 10 (USP10) can directly interacts with EIF4G1, while acting as a negative regulator for EIF4G1-mediated functions. Together, our results indicate that EIF4G1 functions as an oncoprotein during NSCLC development, which may represent a novel and promising therapeutic target in lung cancer.

  19. Optimal pharmacotherapeutic strategies for elderly patients with advanced non-small cell lung cancer.

    PubMed

    Quoix, Elisabeth

    2011-11-01

    carboplatin with weekly paclitaxel. While there have been no trials of second-line therapy for NSCLC specifically in elderly patients, exploratory subgroup analyses indicate that docetaxel, pemetrexed and erlotinib may provide outcomes in elderly patients similar to those reported in younger patients. However, specific second-line therapy trials in elderly patients are required as the elderly patients in trials conducted to date were probably highly selected to fit the inclusion criteria. There is no more room for nihilism in the treatment of elderly patients with advanced NSCLC. Such patients should be evaluated carefully by geriatric indexes and, if they have a PS score of 0-2, may be treated with platinum-based (mostly carboplatin) doublet therapy in the same manner as their younger counterparts. The optimal second line treatment remains to be determined. PMID:22054229

  20. Survival Outcome Assessed According to Tumor Response and Shrinkage Pattern in Patients with EGFR Mutation–Positive Non–Small-Cell Lung Cancer Treated with Gefitinib or Erlotinib

    PubMed Central

    Takeda, Masayuki; Nakagawa, Kazuhiko

    2014-01-01

    Introduction: Somatic mutations in the epidermal growth factor receptor gene (EGFR) are associated with a marked therapeutic response to EGFR–tyrosine kinase inhibitors (TKIs) in patients with advanced non–small cell lung cancer (NSCLC). Clinical indicators of the likely survival benefit of EGFR-TKI treatment in NSCLC patients with EGFR mutations have not been identified, however. We therefore evaluated progression-free survival (PFS) and overall survival (OS) according to tumor response and tumor shrinkage pattern in such patients. Methods: Among 145 EGFR mutation–positive NSCLC patients treated with EGFR-TKIs, 68 individuals were selected for analysis. Results: Of the 68 selected patients, 6 achieved a complete response (CR), 42 a partial response (PR), and 14 stable disease (SD). Both PFS and OS were significantly longer in patients who achieved a CR or PR than in those who experienced SD. Multivariate analysis showed that a response (CR or PR) to EGFR-TKIs was significantly associated with both PFS and OS. Among the CR/PR group, the median maximal tumor shrinkage relative to baseline was 56%, and the median time to response (TTR) was 4.2 weeks. The subsets of these patients who experienced rapid tumor regression (TTR of ≤4.2 weeks) or a high degree of tumor shrinkage (≥56%) did not show a more favorable PFS or OS compared with those who experienced slow tumor regression or a low degree of tumor shrinkage. Conclusion: Response (CR or PR) may represent the optimal surrogate for efficacy among EGFR mutation–positive NSCLC patients treated with EGFR-TKIs. PMID:24419417

  1. 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.

  2. miR-143 suppresses the proliferation of NSCLC cells by inhibiting the epidermal growth factor receptor

    PubMed Central

    Zhang, Hong-Bo; Sun, Li-Chao; Ling, Lan; Cong, Lu-Hong; Lian, Rui

    2016-01-01

    MicroRNAs (miRs) regulate the proliferation and metastasis of numerous cancer cell types. It was previously reported that miR-143 levels were downregulated in non-small cell lung cancer (NSCLC) tissues and cell lines, and that the migration and invasion of NSCLC cells was inhibited upon suppression of cell proliferation and colony formation by the upregulation of miR-143. Epidermal growth factor receptor (EGFR), which is a vital factor in the promotion of cancer cell proliferation and has been investigated as a potential focus in cancer therapy, has been reported to be a possible target of miR-143. The present study aimed to investigate the role of miR-143 in NSCLC using NSCLC cell lines and primary cells from NSCLC patients. NSCLC cells were co-transfected with EGFR and miR-143, and the mRNA and protein expression of EGFR were analyzed. Furthermore, the activity of the transfected cancer cells with regard to colony formation, migration, invasion and apoptosis were evaluated. The levels of miR-143 were decreased in the NSCLC cell lines and primary cells from patients with NSCLC compared with the controls. Following transfection with miR-143, the ability of NSCLC cells to proliferate, form colonies, migrate and invade was inhibited. Similarly, knockdown of EGFR led to the suppression of NSCLC cell proliferation. The mRNA and protein expression levels of EGFR were significantly reduced following miR-143 overexpression, and the level of miR-143 was inversely correlated with that of EGFR in NSCLC cells. The results of the present study demonstrated that miR-143 was able to suppress NSCLC cell proliferation and invasion by inhibiting the effects of EGFR, suggesting that EGFR may be considered a potential target for NSCLC therapy. PMID:27602093

  3. miR-143 suppresses the proliferation of NSCLC cells by inhibiting the epidermal growth factor receptor

    PubMed Central

    Zhang, Hong-Bo; Sun, Li-Chao; Ling, Lan; Cong, Lu-Hong; Lian, Rui

    2016-01-01

    MicroRNAs (miRs) regulate the proliferation and metastasis of numerous cancer cell types. It was previously reported that miR-143 levels were downregulated in non-small cell lung cancer (NSCLC) tissues and cell lines, and that the migration and invasion of NSCLC cells was inhibited upon suppression of cell proliferation and colony formation by the upregulation of miR-143. Epidermal growth factor receptor (EGFR), which is a vital factor in the promotion of cancer cell proliferation and has been investigated as a potential focus in cancer therapy, has been reported to be a possible target of miR-143. The present study aimed to investigate the role of miR-143 in NSCLC using NSCLC cell lines and primary cells from NSCLC patients. NSCLC cells were co-transfected with EGFR and miR-143, and the mRNA and protein expression of EGFR were analyzed. Furthermore, the activity of the transfected cancer cells with regard to colony formation, migration, invasion and apoptosis were evaluated. The levels of miR-143 were decreased in the NSCLC cell lines and primary cells from patients with NSCLC compared with the controls. Following transfection with miR-143, the ability of NSCLC cells to proliferate, form colonies, migrate and invade was inhibited. Similarly, knockdown of EGFR led to the suppression of NSCLC cell proliferation. The mRNA and protein expression levels of EGFR were significantly reduced following miR-143 overexpression, and the level of miR-143 was inversely correlated with that of EGFR in NSCLC cells. The results of the present study demonstrated that miR-143 was able to suppress NSCLC cell proliferation and invasion by inhibiting the effects of EGFR, suggesting that EGFR may be considered a potential target for NSCLC therapy.

  4. 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

  5. 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

  6. Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation.

    PubMed

    Dumoff, Kimberly L; Chu, Christina S; Harris, Eleanor E; Holtz, David; Xu, Xiaowei; Zhang, Paul J; Acs, Geza

    2006-05-01

    Lymphatic invasion and nodal metastasis are predictors of poor outcome in cervix carcinoma. We have recently found that low podoplanin immunoreactivity in cervix carcinoma correlated with the presence of lymphatic invasion and nodal metastasis. In the current study, we examined whether podoplanin expression in pretreatment cervical biopsies can predict the presence lymphatic invasion, nodal metastasis, and outcome in advanced-stage tumors treated by nonsurgical means. Podoplanin expression was analyzed by immunohistochemistry in 48 cervical biopsies and corresponding hysterectomy specimens of early-stage invasive squamous cell carcinoma and in 74 pretreatment biopsies from advanced-stage tumors treated with primary radiation. We found a highly significant correlation between podoplanin expression obtained in biopsy and corresponding hysterectomy materials (r = 0.8962, P < 0.0001). Low podoplanin expression showed a significant correlation with lymphatic invasion (P < 0.0001) and nodal metastasis (P = 0.0058). Low podoplanin expression in pretreatment biopsy material showed a significant correlation with poor disease-free (P = 0.0009) and overall (P = 0.0002) survival in advanced-stage tumors. Our results suggest that in advanced-stage cervix carcinomas treated by radiation, when traditional prognostic indicators are not available and treatment decisions are based on biopsy material and clinical staging parameters, examination of podoplanin expression in pretreatment biopsy material may be a useful marker to predict lymphatic metastasis and patient outcome. Prospective studies involving larger numbers of patients are needed to further evaluate the clinical utility of examination of podoplanin expression in patients with cervix carcinoma.

  7. Maintenance monotherapy with Gemcitabine following cisplatin-based primary combination chemotherapy in surgically treated advanced urothelial carcinoma: A matched-pair single institution analysis

    PubMed Central

    KALOGIROU, CHARIS; SVISTUNOV, ANDREY; KREBS, MARKUS; LAUSENMEYER, EVA MARIA; VERGHO, DANIEL; RIEDMILLER, HUBERTUS; KOCOT, ARKADIUS

    2016-01-01

    The role of maintenance therapy with Gemcitabine (GEM) following cisplatin-based combination chemotherapy (CBCC) in patients with surgically treated advanced urothelial carcinoma (UC) remains to be fully elucidated. In the present case control study, a retrospective analysis was performed to evaluate the role of GEM monotherapy following surgical intervention for advanced UC. Between 1999 and 2013, 38 patients were identified with surgically treated advanced UC after having completed CBCC, who were additionally treated quarterly with two consecutive GEM (1,250 mg/m2) infusions as maintenance therapy. This collective was matched by propensity score matching to a control collective (n=38) that received primary CBCC alone, and the overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) rates were determined for the two collectives using Kaplan-Meier estimates and the log-rank test. Regression analysis was performed using the Cox proportional hazards model. The median follow-up time was 37 months (interquartile range: 9–148). Interestingly, patients treated with GEM following primary chemotherapy had a significantly improved outcome with respect to the 5-year OS (46.2 vs. 26.4%, P=0.0314) and 5-year CSS (61.3 vs. 33.4%, P=0.0386) rates. Notably, the 5-year PFS rate did not differ between the two groups (10.3 vs. 16.1%, P=0.134). It is proposed that additional GEM maintenance monotherapy is able to improve survival rates following primary CBCC in surgically treated patients with advanced UC, suggesting a possible treatment option for patients with, e.g., unclear disease status, or those who would require an active maintenance therapy in the future. Prospective studies should further determine the impact of GEM monotherapy with respect to PFS rates in groups comprising larger numbers of patients. PMID:27073682

  8. The Impact of Extent and Location of Mediastinal Lymph Node Involvement on Survival in Stage III Non-Small Cell Lung Cancer Patients Treated With Definitive Radiotherapy

    SciTech Connect

    Fernandes, Annemarie T.; Mitra, Nandita; Xanthopoulos, Eric; Evans, Tracey; Stevenson, James; Langer, Corey; Kucharczuk, John C.; Lin, Lilie; Rengan, Ramesh

    2012-05-01

    patients treated with definitive radiotherapy are distinct from those observed in patients who undergo surgical resection. The ultimate efficacy of radiation in locally advanced NSCLC is dependent on the intrinsic biology of the tumor.

  9. Dabrafenib for Treating Unresectable, Advanced or Metastatic BRAF V600 Mutation-Positive Melanoma: An Evidence Review Group Perspective.

    PubMed

    Fleeman, Nigel; Bagust, Adrian; Beale, Sophie; Boland, Angela; Dickson, Rumona; Dwan, Kerry; Richardson, Marty; Dundar, Yenal; Davis, Helen; Banks, Lindsay

    2015-09-01

    vemurafenib are both available to patients treated by the National Health Service (NHS) in England via a Patient Access Scheme (PAS) in which the costs of the drugs are discounted. Using these discounted costs, the incremental cost-effectiveness ratios (ICERs) generated by the company were £60,980 per quality-adjusted life-year (QALY) for dabrafenib versus dacarbazine and £11,046 per QALY gained for dabrafenib versus vemurafenib. The ERG considered the economic model structure developed by the company to derive the ICERs to be overly complex and based on unsubstantiated assumptions, most importantly in relation to the projection of OS. Applying the latest OS data from BREAK-3 to a less complex model structure increased the estimated ICER for dabrafenib compared with dacarbazine from £60,980 to £112,727 per QALY gained. Since the results from the ITC were considered by the ERG to be neither reliable nor robust, the ERG also considered a cost-effectiveness comparison to be inappropriate due to a lack of meaningful or reliable data. In spite of limitations in the data, the AC took the view that dabrafenib and vemurafenib were "likely" of similar clinical effectiveness. Since the overall costs of these two drugs were similar, the AC recommended the use of dabrafenib in patients with unresectable, advanced or metastatic BRAF V600 mutation-positive melanoma.

  10. EMP-1 promotes tumorigenesis of NSCLC through PI3K/AKT pathway.

    PubMed

    Lai, Senyan; Wang, Guihua; Cao, Xiaonian; Li, Zhaoming; Hu, Junbo; Wang, Jing

    2012-12-01

    This study examined the role of EMP-1 in tumorigenesis of non-small cell lung carcinoma (NSCLC) and the possible mechanism. Specimens were collected from 28 patients with benign lung diseases and 28 with NSCLC, and immunohistochemically detected to evaluate the correlation of EMP-1 expression to the clinical features of NSCLC. Recombinant adenovirus was constructed to over-express EMP-1 and then infect PC9 cells. Cell proliferation was measured by Ki67 staining. Western blotting was performed to examine the effect of EMP-1 on the PI3K/AKT signaling. Moreover, tumor xenografts were established by subcutaneous injection of PC9 cell suspension (about 5×10(7)/mL in 100 μL of PBS) into the right hind limbs of athymic nude mice. The results showed EMP-1 was significantly up-regulated in NSCLC patients as compared with those with benign lung diseases. Over-expression of EMP-1 promoted proliferation of PC9 cells, which coincided with the activation of the PI3K/AKT pathway. EMP-1 promoted the growth of xenografts of PC9 cells in athymic nude mice. It was concluded that EMP-1 expression may contribute to the development and progress of NSCLC by activating PI3K/AKT pathway.

  11. [Adjuvant chemotherapy for resectable non-small cell lung cancer (NSCLC)].

    PubMed

    Nakajima, Eiji; Katou, H

    2008-01-01

    A randomized clinical trial of adjuvant chemotherapy has been evaluated for non-small cell lung cancer (NSCLC) patients, because the prognosis of early NSCLC does not enough after surgery (stage I: 70-80%, stage II: 50% in overall 5-years survival). Japanese guide line for lung cancer treatment (2005 edition) recommends adjuvant chemotherapy after complete resection for pathological stage IB, II and IIIA. Previous studies have suggested that uracil-tegafur has benefit for stage IB NSCLC patients, and platinum-based adjuvant chemotherapy has benefit for stage IB, II and IIIA NSCLC patients. In 2007 ASCO Annual Meeting, Harpole D talked about molecular prognostic profiles in early resected NSCLC. The goal of this study design is to validate a molecular-based tumor model that identifies those patients at low risk for cancer recurrence who will not benefit from adjuvant chemotherapy. The remaining patients will be randomly assigned to observation (the present standard of care) or adjuvant chemotherapy to determine the efficacy of adjuvant in this population. Biomarker for response of chemotherapy will be available to know who has benefit from adjuvant chemotherapy. When each patient has appropriate adjuvant chemotherapy, the prognosis is improved by that.

  12. 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

  13. Definitive Upfront Stereotactic Ablative Radiotherapy Combined with Image-Guided, Intensity Modulated Radiotherapy (IG-IMRT) or IG-IMRT Alone for Locally Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Chi, Alexander; Wen, Sijin; Monga, Manish; Almubarak, Mohammed; He, Xiaoqing; Rojanasakul, Yon; Tse, William; Remick, Scot C.

    2016-01-01

    Background Image-guided (IG) intensity-modulated radiotherapy (IMRT) enables maximal tumor margin reduction for the sparing of organs at risk (OARs) when used to treat locally advanced non-small cell lung cancer (NSCLC) with definitive chemo-radiation. It also allows for the incorporation of stereotactic ablative radiotherapy (SABR) into the treatment regimen. Here, we describe our initial experience in combining definitive upfront SABR to the primary lesion with chemo-radiation delivered with conventionally fractionated IG-IMRT to the remaining regional disease; along with clinical outcome following chemo-radiation with conventionally fractionated IG-IMRT alone in the treatment of locally advanced NSCLC. Methods The clinical outcome of 29 patients with locally advanced NSCLC who underwent conventionally fractionated IG-IMRT, or definitive upfront SABR followed by IG-IMRT combined with chemotherapy (induction, concurrent, or both) was retrospectively reviewed. Results After a median follow up of 23.7 months, the median overall survival (OS) and progression-free survival (PFS) were 19.8 and 11.3 months, respectively. The 2 year local, regional, and distant control was 60%, 62%, and 38%, respectively. No local failure was observed in 3 patients following SABR + IG-IMRT while 6/26 patients failed locally following IG-IMRT alone. SABR + IG-IMRT was well tolerated. No ≥ grade 3 radiation-related toxicity was observed. Conclusion Definitive upfront SABR followed by IG-IMRT in selected patients with locally advanced NSCLC warrants further investigation in future clinical trials, while chemo-radiation with IG-IMRT alone was well tolerated. PMID:27611833

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

    PubMed Central

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

    2016-01-01

    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. PMID:26840022

  15. 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.

  16. 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.

  17. Foxp3 downregulation in NSCLC mediates epithelial-mesenchymal transition via NF-κB signaling.

    PubMed

    Wang, Xi; Liu, Ying; Dai, Lingling; Liu, Qi; Jia, Liuqun; Wang, Huan; An, Lin; Jing, Xiaogang; Liu, Meng; Li, Pengfei; Cheng, Zhe

    2016-10-01

    Forkhead box P3 (Foxp3) is a member of forkhead box transcription factor family and it was identified as a tumor suppressor in various solid tumors. This study evaluated the expression of Foxp3 in non-small cell lung cancer (NSCLC) and investigated its role in epithelial‑mesenchymal transition (EMT) of cancer cells. qRT-PCR and western blot analysis were used for examining the expression of Foxp3 in NSCLC tissues and the non-tumor tissues. A tissue microarray was constructed and scored for evaluating the clinical significance of Foxp3 expression in NSCLC tissues. RNAi was employed for downregulating Foxp3 expression and cell proliferation was done with MTT assay. Transwell with or without basement membrane matrix was used for cell migration and invasion assay respectively. Foxp3 was found downregulated in NSCLC tissues compared with non-tumoral tissues; downregulation of Foxp3 predicted adverse tumor stage and overall survival; silencing of FOXP3 promoted the proliferation, migration and invasion ability of NSCLC cells and influenced the expression level of EMT-associated proteins. However, forced expression of Foxp3 could reverse this effect. Moreover, Foxp3 could interact with LMO2 and affect the expression level of TAL1, which was in accordance with the findings in T-cell acute lymphoblastic leukemia. By screening the signalling pathways, we observed an obvious upregulation of phosphorylated NF-κB in A549 and H520 cells after silencing of FOXP3. Our results suggest that Foxp3 suppressed NSCLC cell metastasis, at least partially, via NF-κB signaling. PMID:27574108

  18. 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

    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

  19. 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

  20. 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

  1. Lapatinib in Treating Patients With Locally Advanced or Metastatic Biliary Tract or Liver Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2014-12-18

    Adult Primary Hepatocellular Carcinoma; Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

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

    ClinicalTrials.gov

    2016-06-20

    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

  3. [Two cases of acute large bowel obstruction caused by advanced cancer treated with stenting "bridge to surgery" procedure].

    PubMed

    Ishii, Aya; Sugiyama, Masahiko; Ohta, Mitsuhiko; Sumida, Yorinobu; Kimura, Yasue; Tsutsumi, Norifumi; Yamashita, Yo-Ichi; Saeki, Hiroshi; Uchiyama, Hideaki; Kawanaka, Hirofumi; Morita, Masaru; Sakaguchi, Yoshihisa; Ikeda, Tetsuo; Kusumoto, Tetsuya; Harada, Naohiko; Ikejiri, Koji; Maehara, Yoshihiko

    2013-12-01

    Obstructive colorectal cancer accounts for 3.1-15.8% of total colorectal cancer cases, therefore it is not a rare condition. Formerly, it has been often treated with emergent operation such as colostomy or trans-anal tube decompression. Since 2012, revision of the medical payment system, it has become possible to be treated with elective operation when using endoscopic metal stent placement that enable to decompress enlarged intestine by transanal approach. This procedure provides safe elective surgery with sufficient preoperative inspection and conventional bowel preparation. We report two cases of acute large bowel obstruction due to colon cancer treated with endoscopic stent placement as a "bridge to surgery".

  4. 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.

  5. 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.

  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. Weekly regimen of paclitaxel and carboplatin as first-line chemotherapy in elderly patients with stage IIIB-IV non small cell lung cancer (NSCLC): results of a phase II study.

    PubMed

    Rozzi, A; Nardoni, C; Corona, M; Restuccia, M R; Falbo, T; Lanzetta, G

    2010-12-01

    Single-agent chemotherapy is the preferred treatment option in chemonaive elderly patients with advanced nonsmall-cell lung cancer (NSCLC). The role of combination chemotherapy in this setting is uncertain although several studies report satisfactory efficacy and safety using weekly paclitaxel and carboplatin (AUC=6) as first-line chemotherapy in elderly patients. It is still unclear which schedule of this regimen which could offer the best therapeutic index. The aim of this study was to evaluate the activity and tolerability of concomitant weekly administration of paclitaxel and carboplatin in untreated elderly patients with advanced NSCLC. From february 2005 to April 2008 36 consecutive elderly patients with advanced NSCLC were enrolled. Median age was 74 years (range, 70-83 years) and median ECOG PS was 1 (range, 0-1). patients received carboplatin (AUC=2) and paclitaxel 80 mg/m² on days 1,8 and 15 every 28 days. All patients were evaluable for efficacy and toxicity; a median of 4 cycles was administered. Twelve patients had partial response (33%; 95% C.I. 15,8-52,3%), 10 patients (28%) showed stable disease. The median time to progression (TTP) was 5.7 months (95% C.I. 3.1-8.6 months) with a median overall survival (MOS) of 9 months (95% C.I. 4.4-13.9 months). Toxicity was mild with no cases of febrile neutropenia; 5 patients (14%) developed grade 2 neuropathy. Our study confirms the substantial activity of weekly regimen of paclitaxel and carboplatin. Due to its favorable profile of toxicity this schedule could represent an interesting therapeutic option in selected chemonaive elderly patients with advanced NSCLC.

  8. XPC inhibits NSCLC cell proliferation and migration by enhancing E-Cadherin expression

    PubMed Central

    Cui, Tiantian; Srivastava, Amit Kumar; Han, Chunhua; Yang, Linlin; Zhao, Ran; Zou, Ning; Qu, Meihua; Duan, Wenrui; Zhang, Xiaoli; Wang, Qi-En

    2015-01-01

    Xeroderma pigmentosum complementation group C (XPC) protein is an important DNA damage recognition factor in nucleotide excision repair. Deletion of XPC is associated with early stages of human lung carcinogenesis, and reduced XPC mRNA levels predict poor patient outcome for non-small cell lung cancer (NSCLC). However, the mechanisms linking loss of XPC expression and poor prognosis in lung cancer are still unclear. Here, we report evidence that XPC silencing drives proliferation and migration of NSCLC cells by down-regulating E-Cadherin. XPC knockdown enhanced proliferation and migration while decreasing E-Cadherin expression in NSCLC cells with an epithelial phenotype. Restoration of E-Cadherin in these cells suppressed XPC knockdown-induced cell growth both in vitro and in vivo. Mechanistic studies showed that the loss of XPC repressed E-Cadherin expression by activating the ERK pathway and upregulating Snail expression. Our findings indicate that XPC silencing-induced reduction of E-Cadherin expression contributes, at least in part, to the poor outcome of NSCLC patients with low XPC expression. PMID:25871391

  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. CPI-613 in Treating Patients With Advanced or Metastatic Bile Duct Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-07-26

    Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Unresectable Extrahepatic Bile Duct Cancer

  11. Bortezomib in Treating Patients With Unresectable Locally Advanced or Metastatic Adenocarcinoma of the Bile Duct or Gallbladder

    ClinicalTrials.gov

    2013-01-11

    Adenocarcinoma of the Extrahepatic Bile Duct; Adenocarcinoma of the Gallbladder; Advanced Adult Primary Liver Cancer; Gastrointestinal Cancer; Localized Unresectable Adult Primary Liver Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

  12. MicroRNA expression profiling of sputum for the detection of early and locally advanced non-small-cell lung cancer: a prospective case–control study

    PubMed Central

    Razzak, R.; Bédard, E.L.R.; Kim, J.O.; Gazala, S.; Guo, L.; Ghosh, S.; Joy, A.; Nijjar, T.; Wong, E.; Roa, W.H.

    2016-01-01

    Background Non-small-cell lung cancer (nsclc) is associated with very poor overall survival because 70% of patients present with locally advanced or metastatic disease at the time of diagnosis. Micrornas (mirnas) are a class of short, noncoding rna molecules whose presence in samples of biologic fluids such as sputum has demonstrated promise as a potential means of detecting nsclc. We investigated the stage-specific nsclc detection potential of an efficient panel of 3 mirnas (mir-21, mir-210, mir-372) using a single sputum sample. Methods A single spontaneously expectorated sputum sample was prospectively collected from 21 early nsclc (≤stage ii) patients, 22 advanced nsclc (≥stage iii) patients, and 10 control subjects. Mirna expression profiles were determined by quantitative real-time polymerase chain reaction and were analyzed by unsupervised hierarchical cluster analysis. Results Mean tumour size (±95% confidence interval) in the early and advanced nsclc patients was 3.3 cm ± 0.9 cm and 4.8 cm ± 0.7 cm respectively. Adenocarcinoma constituted 61.9% of the early and 45.5% of the advanced nsclc cases respectively. In comparing the early nsclc group with the control group, the mirna panel yielded a diagnostic sensitivity of 67% and a specificity of 90.0%. For the advanced nsclc group, the mirna panel detected nsclc with a sensitivity and specificity of 64% and 100% respectively. Conclusions A sputum mir-21, mir-210, and mir-372 expression profile might provide a sensitive and highly specific means for detecting nsclc. Sputum mirna analysis demonstrates promise as a potential complementary screening tool. PMID:27122989

  13. 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.

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

    PubMed

    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

  15. 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

  16. 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

  17. A Case of Long-term Survival of Advanced Paratesticular Rhabdomyosarcoma Treated With a Multimodal Therapy Including a Combination of Cyclophosphamide, Vincristine, Doxorubicin and Dacarbazine.

    PubMed

    Isono, Makoto; Sato, Akinori; Asano, Tomohiko

    2016-07-01

    There is no established treatment for advanced rhabdomyosarcoma (RMS) with metastases at the time of diagnosis. A 17-year-old male was referred to our hospital because of a right scrotal mass. Computed tomography showed multiple lung metastases with pleural effusion and retroperitoneal lymph node metastasis, and bone scintigraphy revealed multiple bone metastases. Right high orchiectomy was performed and the tumor was diagnosed as paratesticular embryonal RMS. He was treated with a multimodal therapy including 17 cycles of combination chemotherapy consisting of cyclophosphamide, vincristine, doxorubicin and dacarbazine (CYVADIC) and achieved a long-term survival of 4 years. PMID:27335778

  18. k-RAS mutations in non-small cell lung cancer patients treated with TKIs among smokers and non-smokers: a meta-analysis

    PubMed Central

    Lu, Hui-Yu

    2016-01-01

    Aim of the study Recent studies have suggested that k-RAS mutations are related to the response to epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitions (TKIs) in advanced non-small cell lung cancer (NSCLC) treatment. The aim of this meta-analysis was to assess the relationship between smoking history and k-RAS mutations in NSCLC treated with TKIs. Material and methods We searched MEDLINE and Web of Science up to 15 March 2014. The pooled relative risk (RR) was estimated by using fixed effect model or random effect model, according to heterogeneity between studies. We also carried out power analyses. Results We identified 12 studies with 1193 patients, including 196 patients (16.4%) with k-RAS mutations. The pooled k-RAS mutations incidence was 22.8% (174/764) in patients with smoke expose vs. 5.4% (23/429) in those with no smoke exposure. The pooled RR was 2.991 (95% CI: 1.884–4.746; Z = 4.65, p = 0.000). No publication bias was found (Begg's test: z = 1.09, p = 0.274 and Egger's test: t = 1.38, p = 0.201). In subgroup analyses, the pooled RR was 3.336 (95% CI: 1.925–5.779; Z = 4.30, p = 0.000) in the Caucasian subgroup, while in the Asian subgroup the pooled RR was 2.093 (95% CI: 0.909–4.822; Z = 1.73, p = 0.083), but the sample size was underpowered (0.465). Conclusions The current meta-analysis found that smoking was related to increased incidence of k-RAS mutations in non-small cell lung cancer treated with TKIs. This may be further evidence that smoking will lead to a worse prognosis in NSCLC patients treated with TKIs. PMID:27358590

  19. 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. PMID:26862736

  20. 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

  1. 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. PMID:27011048

  2. 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

  3. Modern radiotherapy using image guidance for unresectable non-small cell lung cancer can improve outcomes in patients treated with chemoradiation therapy

    PubMed Central

    Deek, Matthew P.; Kim, Sinae; Yue, Ning; Baby, Rekha; Ahmed, Inaya; Zou, Wei; Langenfeld, John; Aisner, Joseph

    2016-01-01

    Background To investigate the impact of advances in image-guided radiotherapy (IGRT) on the outcomes of patients with non-small cell lung cancer (NSCLC) treated with chemoradiation therapy (CRT). Methods We retrospectively reviewed 91 patients with NSCLC treated with definitive CRT using image guidance with daily orthogonal kilovoltage (kV) imaging compared to standard weekly megavoltage (MV) portal verifications. Kaplan-Meier curves for overall survival and locoregional failure were computed and stratified by image guidance techniques. Log-rank tests were used to compare strata. Cox Proportional Hazards models were used to identify risk factors for worse mortality and locoregional control. Results Fifty-four percent (n=49) of patients received weekly MV portal imaging, while 46% (n=42) underwent IGRT using daily orthogonal kV imaging. kV IGRT was associated with longer median survival (36.4 months) compared to MV imaging (14.9 months; P=0.01). kV imaging was also marginally associated with lower risk of locoregional failure. Median time to local progression in patients imaged with kV was 21.4 months compared to 10.9 months (P=0.065) for those treated with MV portal imaging. Conclusions Daily kV imaging appears to be marginally associated with better survival and disease control when compared to MV imaging. Given the small study size and the numerable factors tested, these finding require additional confirmation. PMID:27747014

  4. Inhibition of ERK1/2 down-regulates the Hippo/YAP signaling pathway in human NSCLC cells

    PubMed Central

    Xu, Zhidong; Dai, Yuyuan; Liu, Shu; Mao, Jian-Hua; Tetsu, Osamu; Li, Hui; Jablons, David M.; You, Liang

    2015-01-01

    Alterations of the EGFR/ERK and Hippo/YAP pathway have been found in non-small cell lung cancer (NSCLC). Herein, we show that ERK1 and ERK2 have an effect on the Hippo/YAP pathway in human NSCLC cells. Firstly, inhibition of ERK1/2 by siRNA or small-molecular inhibitors decreased the YAP protein level, the reporter activity of the Hippo pathway, and the mRNA levels of the Hippo downstream genes, CTGF, Gli2, and BIRC5. Secondly, degradation of YAP protein was accelerated after ERK1/2 depletion in NSCLC cell lines, in which YAP mRNA level was not decreased. Thirdly, forced over-expression of the ERK2 gene rescued the YAP protein level and Hippo reporter activity after siRNA knockdown targeting 3′UTR of the ERK2 gene in NSCLC cells. Fourthly, depletion of ERK1/2 reduced the migration and invasion of NSCLC cells. Combined depletion of ERK1/2 had a greater effect on cell migration than depletion of either one separately. Finally, the MEK1/2 inhibitor Trametinib decreased YAP protein level and transcriptional activity of the Hippo pathway in NSCLC cell lines. Our results suggest that ERK1/2 inhibition participates in reducing YAP protein level, which in turn down-regulates expression of the downstream genes of the Hippo pathway to suppress migration and invasion of NSCLC cells. PMID:25738359

  5. Optimized selection of three major EGFR-TKIs in advanced EGFR-positive non-small cell lung cancer: a network metaanalysis

    PubMed Central

    Fang, Wenfeng; Kang, Shiyang; He, Yang; Hong, Shaodong; Zhan, Jianhua; Zhao, Yuanyuan; Xue, Cong; Ma, Yuxiang; Zhou, Ting; Ma, Shuxiang; Gao, Fangfang; Qin, Tao; Hu, Zhihuang; Tian, Ying; Hou, Xue; Huang, Yan; Zhou, Ningning; Zhao, Hongyun; Zhang, Li

    2016-01-01

    Background: To answer which epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the best choice for advanced non-small cell lung cancer (NSCLC) EGFR mutants. Results: 16 phase III randomized trials involving 2962 advanced NSCLC EGFR mutants were enrolled. Multiple treatment comparisons showed different EGFR-TKIs shared equivalent curative effect in terms of all outcome measures among the overall, chemo-naïve and previously treated patients. Rank probabilities showed that erlotinib and afatinib had potentially better efficacy compared with gefitinib in both of the overall and chemo-naïve patients. Potentially survival benefit of erlotinib was also observed in previously treated patients compared with gefitinib. Additionally, EGFR-TKI showed numerically greater survival benefit in 19 Del compared with chemotherapy, while it was opposite in 21 L858R. Furthermore, afatinib, erlotinib and gefitinib had high, moderate and low risk of rash & diarrhea, respectively, while the occurrence of elevated liver transaminase was more common in gefitinib. Methods: Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events were extracted from included studies. Efficacy and toxicity of all included treatments were integrated by network meta-analyses. Conclusion: Our study indicated a high efficacy-high toxicity pattern of afatinib, a high efficacy-moderate toxicity pattern of erlotinib and a medium efficacy-moderate toxicity pattern of gefitinib. Recommended EGFR-TKI should be suggested according to patients' tolerability and therapeutic efficacy in clinical practice. Moreover, the treatment for advanced EGFR-positive NSCLC might be different between 19 Del and 21 L858R. PMID:26933807

  6. Intensity-modulated radiotherapy, not 3D conformal, is the preferred technique for treating locally advanced lung cancer

    PubMed Central

    Chang, Joe Y.

    2015-01-01

    When used to treat lung cancer, intensity-modulated radiotherapy (IMRT) can deliver higher dose to the targets and spare more critical organs in lung cancer than can 3D conformal radiotherapy (3DCRT). However, tumor-motion management and optimized radiotherapy planning based on four-dimensional computed tomography (4D CT) scanning are crucial to maximize the benefit of IMRT and to eliminate or minimize potential uncertainties. This article summarizes these strategies and reviews published findings supporting the safety and efficacy of IMRT for lung cancer. PMID:25771415

  7. Validation of an algorithm able to differentiate small-cell lung cancer (SCLC) from non-small-cell lung cancer (NSCLC) patients by means of a tumour marker panel: analysis of the errors.

    PubMed Central

    Paone, G.; De Angelis, G.; Portalone, L.; Greco, S.; Giosué, S.; Taglienti, A.; Bisetti, A.; Ameglio, F.

    1997-01-01

    By means of a mathematical score previously generated by discriminant analysis on 90 lung cancer patients, a new and larger group of 261 subjects [209 with non-small-cell lung cancer (NSCLC) and 52 with small-cell lung cancer (SCLC)] was analysed to confirm the ability of the method to distinguish between these two types of cancers. The score, which included the serum neuron-specific enolase (NSE) and CYFRA-21.1 levels, permitted correct classification of 93% of the patients. When the misclassifications were analysed in detail, the most frequent errors were associated with limited disease SCLC with low NSE levels and with advanced NSCLC with high NSE levels. This demonstrates the importance of the marker in correctly categorizing patients. PMID:9020496

  8. Pemetrexed/cisplatin as first-line chemotherapy for advanced lung cancer with brain metastases

    PubMed Central

    He, Guangzhao; Xiao, Xiaoguang; Zou, Man; Zhang, Chengliang; Xia, Shu

    2016-01-01

    Abstract Background: Brain metastases (BMs) are a common and serious complication of non-small cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT), surgery, and molecular targeted therapy are usually used to treat NSCLC with BM. Chemotherapeutic options for BM are limited by tumor resistance, ineffective agents, and the blood–brain barrier. Pemetrexed/cisplatin is the preferred chemotherapy in nonsquamous NSCLC, but the efficacy of this treatment for nonsquamous NSCLC with BM is uncertain. Methods: We present a case of nonsquamous NSCLC with asymptomatic BM presenting with irritating cough and right shoulder back pain (unknown sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase). Results: He benefited from administration of first-line chemotherapy of pemetrexed/cisplatin. Partial remission was achieved in the primary lesion of the lungs and BM lesion. He was further given 3 cycles of pemetrexed monotherapy and WBRT. Complete remission was further achieved in BM lesion. Conclusion: The findings of clinical trials and theoretical studies about the current pemetrexed/cisplatin in the treatment of nonsquamous NSCLC with BM are also summarized to provide a reference for the application of pemetrexed/cisplatin in nonsquamous NSCLC with BM. Whether or not pemetrexed/cisplatin is definitely effective in nonsquamous NSCLC with BM must be proven by subsequent phase III clinical trials. PMID:27512852

  9. [A Case of Radical Resection for Locally Advanced Pancreatic Cancer with Positive Peritoneal Cytology Treated with Chemoradiotherapy].

    PubMed

    Sato, Ryohei; Takizawa, Kazuyasu; Yuza, Kizuki; Soma, Daiki; Hirose, Yuki; Morimoto, Yuta; Miura, Kohei; Nagahashi, Masayuki; Takano, Kabuto; Sakata, Jun; Kameyama, Hitoshi; Kobayashi, Takashi; Minagawa, Masahiro; Kosugi, Shin-ichi; Wakai, Toshifumi

    2015-11-01

    A 54-year-old female patient was admitted with obstructive jaundice. The patient was diagnosed with locally advanced unresectable pancreatic cancer of the head with invasion to the super mesenteric artery and the third portion of the duodenum. A biliary- and gastric-enteric bypass surgery was performed, and peritoneal lavage cytology was positive during surgery. After 6 courses of gemcitabine and S-1 combination chemotherapy, the CA19-9 level was normalized and the primary tumor shrank to 79% of its original size. Diagnostic laparoscopy revealed that distant metastasis was not detected and the peritoneal lavage cytology was negative. After additional chemoradiation therapy, a pancreaticoduodenectomy was perfomed. Microscopic investigation revealed that about 60% of the cancer tissue had been replaced by fibrosis and no cancer cells were found at the surgical margin. The patient was alive with no evidence of recurrence 17 months after radical surgery. PMID:26805372

  10. The outcomes of Polish patients with advanced BRAF-positive melanoma treated with vemurafenib in a safety clinical trial

    PubMed Central

    Rutkowski, Piotr; Mackiewicz, Jacek; Krzemieniecki, Krzysztof; Nawrocki, Sergiusz; Wasilewska-Teśluk, Ewa; Kwinta, Łukasz; Wysocki, Piotr; Koseła-Paterczyk, Hanna; Świtaj, Tomasz

    2015-01-01

    Aim of the study The BRAF inhibitor vemurafenib has improved progression-free survival and overall survival in patients with BRAFV600-mutation-positive metastatic melanoma. Here we present the results of an open-label safety study with vemurafenib in patients with metastatic melanoma enrolled in Polish oncological centres. Material and methods Patients with untreated or previously treated Stage IIIC/IV BRAFV600 mutation-positive melanoma were treated with oral vemurafenib in an initial dose of 960 mg twice daily. Assessments for safety and efficacy were made every 28 days. For the survival analysis the Kaplan-Meier estimator was used with the log-rank tests for bivariate comparisons. Results In total, 75 Polish patients were enrolled in the safety study across four centres. At data cut-off, 28 patients died (37%), mainly (26) due to disease progression; 33 (44%) patients continued vemurafenib after disease progression. The objective response rate was 46%, including two patients with a complete response and 29 with a partial response. Median progression-free survival was 7.4 months. The one-year overall survival rate was 61.9% (median overall survival was not reached). Seventy-three (97.3%) patients reported adverse events (AEs), and grade 3–5 toxicity was reported in 49.4% (37) patients. The most common AEs were: skin lesions (including rash and photosensitivity), arthralgia, and fatigue. Conclusions The overall safety profile and response rate of vemurafenib were comparable to those reported in previous studies of this drug. Our study confirmed the value of well-established prognostic features for overall survival, such as initial LDH (lactate dehydrogenase) level and AJCC staging. PMID:26557775

  11. Expression of heme oxygenase-1 in non-small cell lung cancer (NSCLC) and its correlation with clinical data.

    PubMed

    Degese, María S; Mendizabal, Javier E; Gandini, Norberto A; Gutkind, J Silvio; Molinolo, Alfredo; Hewitt, Stephen M; Curino, Alejandro C; Coso, Omar A; Facchinetti, María M

    2012-07-01

    While changes in heme oxygenase (HO-1) in lung cancer have already been reported, conflicting results were obtained for enzyme expression in human lung cancer specimens. Therefore, the aim of this work was to study HO-1 expression in a large collection of human lung cancer samples. For this purpose, we analyzed the expression of HO-1 in an organized tissue microarray (TMA) and investigated its correlation with clinicopathological data. Ninety-six percent of tumor samples were positive for HO-1, and the expression of HO-1 was significantly higher in cancerous than in non-cancerous tissues. Importantly, HO-1 expression correlated with advanced stages and lymph node involvement. Additionally, quantitative RT-PCR in 18 pairs of human lung carcinomas and their adjacent non-malignant tissues was performed. Our results demonstrate that HO-1 protein is upregulated in epithelial malignant cells in NSCLC and its expression is associated with higher stages of the disease. Additionally, different subcellular localization is observed between tumor and adjacent non-malignant tissues.

  12. Systematic siRNA Screen Unmasks NSCLC Growth Dependence by Palmitoyltransferase DHHC5

    PubMed Central

    Tian, Hui; Lu, Jui-Yun; Shao, Chunli; Huffman, Kenneth E.; Carstens, Ryan M.; Larsen, Jill E.; Girard, Luc; Liu, Hui; Rodriguez-Canales, Jaime; Frenkel, Eugene P.; Wistuba, Ignacio I.; Minna, John D.; Hofmann, Sandra L.

    2015-01-01

    Protein S-palmitoylation is a widespread and dynamic post-translational modification that regulates protein-membrane interactions, protein-protein interactions, and protein stability. A large family of palmitoyl acyl transferases, termed the DHHC family due to the presence of a common catalytic motif, catalyzes S-palmitoylation; the role of these enzymes in cancer is largely unexplored. In this study, an RNAi-based screen targeting all 23 members of the DHHC family was conducted to examine the effects on the growth in non-small cell cancer (NSCLC). Interestingly, siRNAs directed against DHHC5 broadly inhibited the growth of multiple NSCLC lines but not normal human bronchial epithelial cell (HBEC) lines. Silencing of DHHC5 by lentivirus-mediated expression of DHHC5 shRNAs dramatically reduced in vitro cell proliferation, colony formation and cell invasion in a subset of cell lines that were examined in further detail. The phenotypes were restored by transfection of a wild-type DHHC5 plasmid but not by a plasmid expressing a catalytically inactive DHHC5. Tumor xenograft formation was severely inhibited by DHHC5 knockdown and rescued by DHHC5 expression, using both a conventional and tetracycline-inducible shRNA. These data indicate that DHHC5 has oncogenic capacity and contributes to tumor formation in NSCLC; thus representing a potential novel therapeutic target. PMID:25573953

  13. 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

  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. PMID:22053459

  15. Repeat stereotactic radiosurgery in the management of brain metastases from NSCLC: A case report and review of the literature

    PubMed Central

    MARVASO, GIULIA; BARONE, AGNESE; VACCARO, CATERINA; BRUZZANITI, VICENTE; GRESPI, SILVIA; SCOTTI, VALERIO; BIANCO, CATALDO

    2013-01-01

    The aims of radiotherapeutic treatment of brain metastases include maintaining neurocognitive function and improvement of survival. Based on these premises, we present a case report in which the role of repeat stereotactic radiosurgery (SRS) was investigated in a patient with a recurrent brain metastasis from non-small cell lung cancer in the same area as previously treated with radiosurgery. A 40-year-old male caucasian patient was diagnosed with brain metastasis from non-small cell lung cancer (NSCLC) and underwent SRS. The patient developed a recurrence of the disease and a second SRS on the same area was performed. After 8 months, tumor restaging demonstrated a lesion compatible with a recurrence and the patient underwent surgery. Histological diagnosis following surgery revealed only the occurrence of radionecrosis. Radiotherapy was well-tolerated and no grade 3/4 neurological toxicity occurred. To date, no consensus exists on the efficacy of retreatment with SRS. Despite the limited number of studies in this field, in the present case report, we outline the outcomes of this unconventional approach. PMID:24137433

  16. 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

  17. 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

  18. 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

  19. 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.

  20. 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

  1. A case of advanced intrahepatic cholangiocarcinoma accidentally, but successfully, treated with capecitabine plus oxaliplatin (CAPOX) therapy combined with bevacizumab: a case report.

    PubMed

    Uji, Masahito; Mizuno, Takashi; Ebata, Tomoki; Sugawara, Gen; Igami, Tsuyoshi; Uehara, Keisuke; Nagino, Masato

    2016-12-01

    Although surgical resection is the only way to cure biliary tract cancer (BTC), most BTCs are unresectable by the time they are diagnosed. Chemotherapy is usually used to treat unresectable BTC, but its impact on survival is small. Here, we report the case of a 70-year-old woman with a locally advanced intrahepatic cholangiocarcinoma that was initially diagnosed as an unresectable liver metastasis from colon cancer that had invaded all of the major hepatic veins. However, the tumor was noticeably reduced after treatment with CAPOX plus bevacizumab, which is an uncommon therapy for BTC. The tumor was finally resected by inferior right hepatic vein-preserving left hepatic trisectionectomy combined with a resection of the right hepatic vein after a right hepatic vein embolization. PMID:27342988

  2. Toxicity profile and clinical outcomes in locally advanced head and neck cancer patients treated with induction chemotherapy prior to concurrent chemoradiation.

    PubMed

    Ko, Eric C; Genden, Eric M; Misiukiewicz, Krzysztof; Som, Peter M; Kostakoglu, Lale; Chen, Chien-Ting; Packer, Stuart; Kao, Johnny

    2012-02-01

    The use of induction chemotherapy prior to chemoradiation for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) remains controversial. We explored whether toxicity from induction chemotherapy influenced the delivery of concurrent chemoradiation. Among 171 consecutive previously unirradiated patients with HNSCC treated with combined chemotherapy and radiation, we identified 66 patients with stage III-IVB head and neck carcinoma who were treated with induction chemotherapy prior to planned chemoradiation. The most common induction regimen was docetaxel, cisplatin and 5-FU (TPF; 80%) for 2 to 3 cycles. Mean radiation dose was 72 Gy (range, 36-75 Gy). Concurrent chemotherapy regimens included cisplatin (26%), cetuximab (5%) and 5-fluorouracil/hydroxyurea (65%)-based regimens. At a median follow-up of 27 months (range, 9-56 months), the 2-year locoregional control and distant control rates were 85 and 86%, respectively. The 2-year disease-free survival and overall survival rates were 74 and 80%, respectively. Although there were no grade 5 toxicities during induction chemotherapy, 26% of patients required hospitalization for adverse events, including 5% needing intensive care. The most common high grade adverse events were grade 4 neutropenia (21%) and neutropenic fever (17%). Six percent of patients were unable to tolerate concurrent chemotherapy. The 2-year disease-free survival was significantly higher in patients able to complete induction and concurrent chemoradiation as planned (83 vs. 27%, p<0.001). Induction chemotherapy followed by concurrent chemoradiation results in promising survival rates in our cohort of advanced head and neck carcinoma patients. Due to severe toxicities in a subset of patients, this strategy is only recommended in selected high-risk patients who are carefully followed by an experienced multidisciplinary team. PMID:22020564

  3. 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

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

    PubMed

    Jotte, Robert M; Spigel, David R

    2015-11-01

    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

  5. [A 5-year survival case of locally advanced cancer of the pancreatic body treated by distal pancreatectomy with en bloc celiac axis resection after neoadjuvant chemoradiation therapy].

    PubMed

    Iseki, Masahiro; Motoi, Fuyuhiko; Mizuma, Masamichi; Hayashi, Hiroki; Nakagawa, Kei; Okada, Takaho; Otsuka, Hideo; Ottomo, Shigeru; Sakata, Naoaki; Fukase, Koji; Yoshida, Hiroshi; Onogawa, Tohru; Naito, Takeshi; Katayose, Yu; Egawa, Shinichi; Unno, Michiaki

    2012-11-01

    A 59-year-old man was diagnosed with locally advanced cancer of the pancreatic body, involving the nerve plexus around the celiac axis, the common hepatic artery, and the splenic artery. He was treated with a combination of irradiation (2 Gy/day, total 24 Gy) and 600 mg/m2 of gemcitabine(GEM)biweekly. The tumor size and the involved plexus area were not diminished, but CA19-9 was reduced by half. Distal pancreatectomy with en bloc celiac axis resection(DP-CAR)was performed. The histological findings indicated extensive invasion into the nerve plexus, including that adjacent to the stump of the pancreas, and thus the R classification was R1. After surgery, 1,000 mg/m2 of GEM was administered biweekly. The chemotherapy has been performed for 5 years to prevent local and systemic recurrence. No recurrence has been found 5 years after surgery. Multidisciplinary treatment, combined with neoadjuvant chemoradiation therapy, curative-intent resection, and postoperative chemotherapy is important for effective treatment of locally advanced pancreatic cancer. PMID:23267939

  6. Efficacy of Anastrozole in a Consecutive Series of Advanced Breast Cancer Patients Treated with Multiple Prior Chemotherapies and Endocrine Agents: M. D. Anderson Cancer Center Experience.

    PubMed

    Knoche, A. Jolynn; Michaud, Laura Boehnke; Buzdar, Aman U.

    1999-05-01

    Anastrozole is a highly selective, nonsteroidal aromatase inhibitor approved by the U.S. Food and Drug Administration (FDA) in January 1996 for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. To date, information on anastrozole's use has been limited to breast cancer patients with minimal prior therapy. The purpose of this review was to determine, in clinical practice, the benefits of anastrozole in advanced breast cancer patients treated with multiple prior cytotoxic and endocrine therapies. This was a retrospective review of a consecutive series of 117 patients who received anastrozole after marketing in January 1996. As this was not a prospective study, rigorous response criteria could not be applied. Responses were categorized as improvement in disease (ID), stable disease (SD), or progressive disease (PD). One hundred eight patients were evaluable for response with a median age of 61 years and the number of prior therapies ranging from one to nine. Response, defined as improvement of disease or stable disease >/=8 weeks, was seen in 59% of patients. Patients with three or more prior endocrine therapies demonstrated a 61% response (ID + SD) and patients with ER-negative tumors demonstrated 50% response. Patients with prior aminoglutethamide therapy exhibited similar response rates to the overall group. One male patient received anastrozole without benefit. This data determines the activity of anastrozole even in heavily pretreated patients and suggests that patients who have tumors that are ER-negative may also benefit from anastrozole therapy. PMID:11348281

  7. Atypical skin reaction in a patient treated with gefitinib for advanced lung cancer: A case report and review of the literature

    PubMed Central

    FERRAZZI, ANNA; RUSSO, IRENE; PASELLO, GIULIA; ALAIBAC, MAURO

    2016-01-01

    Gefitinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor utilized for the treatment of advanced non-small cell lung carcinoma. The most commonly reported adverse event during gefitinib therapy is skin rash, particularly a papulopustular acne-like eruption. Cutaneous toxicities can affect treatment compliance and the quality of life of the patient. The present study reports a case of gefitinib-induced atypical skin reaction in a 73-year-old woman with advanced non-small cell lung cancer, who developed a squamous-crusted eruption on her face after 4 weeks of oral treatment with gefitinib at a dose of 250 mg/day. The patient was treated with 100 mg minocyclin (2 tablets/day, orally) and with ryfamicin topically. A complete resolution of the lesions was observed 2 weeks later. The present case report explored the pathogenesis of this skin manifestation, focusing on the underlying immunological mechanisms. A review of the literature concerning skin reactions to gefitinib was also conducted. PMID:26889239

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

    PubMed

    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.

  9. Using 18F Fluorodeoxyglucose Positron Emission Tomography (FDG PET) to Monitor Clinical Outcomes in Patients Treated with Neoadjuvant Chemo-Radiotherapy for Locally Advanced Pancreatic Cancer

    PubMed Central

    Choi, Minsig; Heilbrun, Lance K.; Venkatramanamoorthy, Raghu; Lawhorn-Crews, Jawana M.; Zalupski, Mark M.; Shields, Anthony F.

    2013-01-01

    BACKGROUND Pancreatic cancer ranks as the fourth leading cause of cancer death in the United States with five year survival ranging from 1-5%. Positron emission tomography (PET) is a metabolic imaging system that is widely used for the initial staging of cancer and detecting residual disease after treatment. There are limited data, however, on the use of this molecular imaging technique to assess early tumor response after treatment in pancreatic cancer. METHODS The objective of the study was to explore the relationship of early treatment response using the 18 F- fluorodeoxyglucose (FDG) PET with surgical outcome and overall survival in patients with locally advanced pancreatic cancer. FDG-PET measurements of maximum standardized uptake value (SUV) and kinetic parameters were compared to the clinical outcome. RESULTS Twenty patients were enrolled in the study evaluating neoadjuvant induction chemotherapy followed by concurrent chemoradiotherapy (chemo-RT) for locally advanced pancreatic cancer. All twenty patients had pre-study PET scans and a total of fifty PET scans were performed. Among patients who were PET responders (≥50% decrease in SUV after cycle 1), 100% (2/2) had complete surgical resection. Only 6% (1/16) had surgical resection in the PET non-responders (<50% decrease). Two patients did not have the second PET scan due to clinical progression or treatment toxicity. Mean survival was 23.2 months for PET responders and 11.3 months for non-responders (p=0.234). Similar differences in survival were also noted when response was measured using Patlak analysis. CONCLUSION FDG-PET can aid in monitoring the clinical outcome of patients with locally advanced pancreatic cancer treated with neoadjuvant chemo-RT. FDG-PET may be used to aid patients who could have complete surgical resection as well as prognosticate patients’ survival. PMID:19806035

  10. 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.

  11. 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.

  12. Efficacy and safety of maintenance erlotinib in Asian patients with advanced non-small-cell lung cancer: a subanalysis of the phase III, randomized SATURN study.

    PubMed

    Wu, Yi-Long; Kim, Joo-Hang; Park, Keunchil; Zaatar, Adel; Klingelschmitt, Gaëlle; Ng, Christina

    2012-08-01

    Maintenance therapy, commenced immediately after the completion of first-line chemotherapy, is a promising strategy for improving treatment outcomes in patients with non-small-cell lung cancer (NSCLC). The global phase III SequentiAl Tarceva in UnResectable NSCLC (SATURN) study evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib as maintenance treatment in NSCLC patients without progression after first-line chemotherapy. We report a retrospective subanalysis of Asian patients enrolled in SATURN. Patients with advanced NSCLC with no evidence of progression after four cycles of chemotherapy were randomized to receive erlotinib 150 mg/day or placebo, until progressive disease or limiting toxicity. The co-primary endpoints of SATURN were progression-free survival (PFS) in all patients and in those with positive EGFR immunohistochemistry (IHC) status. Secondary endpoints included overall survival (OS), disease control rate, safety, quality of life (QoL) and biomarker analyses. In total, 126 patients from East and South-East Asian centers were randomized (14% of the intent-to-treat population): 88 from Korea, 28 from China and 10 from Malaysia; one patient was excluded from this analysis due to Indian ethnicity. PFS was significantly prolonged in the erlotinib treatment arm, both overall (hazard ratio [HR]: 0.57; p=0.0067) and in patients with EGFR IHC-positive disease (HR=0.50; p=0.0057). There was a trend towards an increase in OS, which reached statistical significance in the EGFR IHC-positive subgroup (p=0.0233). The overall response rate was significantly higher with erlotinib compared with placebo (24% versus 5%; p=0.0025). Erlotinib was generally well tolerated and had no negative impact on QoL in this subpopulation. The most common treatment-related adverse events were rash, diarrhea and pruritus. Erlotinib was effective and well tolerated in Asian patients, producing benefits consistent with those

  13. High prevalence of cardiovascular and respiratory abnormalities in advanced, intensively treated (transplanted) myeloma: The case for ‘late effects’ screening and preventive strategies

    PubMed Central

    Samuelson, Clare; O'Toole, Laurence; Boland, Elaine; Greenfield, Diana; Ezaydi, Yousef; Ahmedzai, Sam H.; Snowden, John A.

    2016-01-01

    Objectives: Modern management of myeloma has significantly improved survival, with increasing numbers of patients living beyond a decade. However, little is known about the long-term cardiovascular and respiratory status of intensively treated and multiply relapsed survivors. Methods: We performed detailed cardiovascular and respiratory evaluations in patients with intensively treated, advanced but stable myeloma. All patients had received at least two lines of treatment, including at least one haematopoietic stem cell transplantation procedure, but had stable, controlled disease and were off active treatment at the time of evaluation. Results: Thirty-two patients with a median duration of 6 years (range 2–12) from original diagnosis of myeloma and three lines (range 2–6) of treatment were evaluated. Despite normal physical examination in the majority, there was a high prevalence of sub-clinical cardiac and respiratory dysfunction, reflected by abnormalities of electrocardiography (45%), echocardiography (50%), serum N-terminal pro-B-type natriuretic peptide level (NT-pro-BNP, 50%), and pulmonary function testing (45%). NT-pro-BNP level correlated negatively with quality of life (P = 0.012) and positively with serum ferritin (P = 0.027). Dyspnoea score correlated with BMI (P = 0.001). Risk factors for cardiovascular disease (obesity, hypertension, hyperlipidaemia, and hyperinsulinaemia) were common. Discussion: Even in the absence of overt clinical features, the majority of intensively treated long-term survivors of myeloma have established cardiovascular and/or respiratory dysfunction, above levels expected in the general population of a similar age. Conclusion: This study supports routine screening and lifestyle modification combined with primary and secondary preventive strategies to reduce cardiovascular and respiratory disease and to preserve quality of life in transplanted myeloma patients. PMID:27077780

  14. 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

  15. 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

  16. Continuous infusion cisplatin and 5-fluorouracil with bolus vinorelbine in the treatment of advanced nonsmall cell carcinoma of the lung.

    PubMed

    Beuzeboc, P; Livartowski, A; Dierick, A; Paraiso, D; Pouillart, P

    1995-01-01

    Thirty-three patients, with histologically proven advanced nonsmall cell lung cancer (NSCLC) were treated at Institut Curie with a three-drug combination chemotherapy. The regimen consisted of cisplatin 25 mg/m2 per day continuous infusion (CI) and 5-fluorouracil (5-FU) CI 600 mg/m2 on 5 consecutive days with 30 minutes infusion navelbine 25 mg/m2 on days 1 and 5 only. Cycles were repeated every 28 days. Response was evaluated after three cycles. One patient died of an ischemic cerebrovascular stroke after the third cycle. Thirty-two pts were evaluable. Partial response was achieved in 11/20 patients with stage III disease (55%) and in 7/12 patients with stage IV disease (58%). WHO grade 4 toxicities were leucopenia 31%, thrombocytopenia 4%, and mucositis 4%. The tolerance was acceptable. Median survival was 19 months for stage III and 9.5 months for stage IV. We conclude that the combination of 5-FU, navelbine, and cisplatin is an effective chemotherapy regimen for patients with advanced stage NSCLC.

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

    PubMed Central

    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. PMID:26905262

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

    PubMed Central

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

    2016-01-01

    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/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. PMID:27064420

  19. 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. PMID:26905262

  20. ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC.

    PubMed

    Cheng, Qijian; Zhou, Ling; Zhou, Jianping; Wan, Huanying; Li, Qingyun; Feng, Yun

    2016-09-01

    Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin-angiotensin system (RAS). Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS. We previously reported that ACE2 overexpression may inhibit cell growth and vascular endothelial growth factor (VEGF) production in vitro and in vivo. In the present study, we investigated the effect of ACE2 on tumor-associated angiogen-esis after the development of acquired platinum resistance in non-small cell lung cancer (NSCLC). Four NSCLC cell lines, A549, LLC, A549-DDP and LLC-DDP, were used in vitro, while A549 and A549-DDP cells were used in vivo. A549-DDP and LLC-DDP cells were newly established at our institution as acquired platinum-resistant sublines by culturing the former parent cells in cisplatin (CDDP)-containing conditioned medium for 6 months. These platinum-resistant cells showed significantly higher angiotensin II type 1 receptor (AT1R), ACE and VEGF production and lower ACE2 expression than their corresponding parent cells. We showed that ACE2 overexpression inhibited the production of VEGF in vitro and in vivo compared to their corresponding parent cells. We also found that ACE2 overexpression reduced the expression of AT1R and ACE. Additionally, we confirmed that ACE2 overexpres-sion inhibited cell growth and VEGF production while simultaneously suppressing ACE and AT1R expression in human lung cancer xenografts. Our findings indicate that ACE2 overexpression may potentially suppress angiogenesis in NSCLC after the development of acquired platinum resistance. PMID:27460845

  1. 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

  2. Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery

    ClinicalTrials.gov

    2013-03-29

    Recurrent Melanoma; Stage IIB Melanoma (Locally Advanced); Stage IIC Melanoma (Locally Advanced); Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma (Limited, Resectable)

  3. 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

  4. miR-125a-3p targets MTA1 to suppress NSCLC cell proliferation, migration, and invasion.

    PubMed

    Zhang, Hong; Zhu, Xiaoxia; Li, Na; Li, Dianhe; Sha, Zhou; Zheng, Xiaokang; Wang, Haofei

    2015-07-01

    Metastasis-associated gene 1 (MTA1) is associated with cell growth, metastasis, and survival in non-small-cell lung cancer (NSCLC). Several previous reports have demonstrated that microRNAs affect gene expression through interaction between their seed region and the 3'-untranslated region of the target mRNA, resulting in post-transcriptional regulation. The aim of this study was to identify miRNAs that suppress malignancy in NSCLC cells by targeting MTA1. Two human NSCLC cell lines were analyzed for the expression of MTA1 by quantitative RT-PCR and western blotting after transfection with MTA1 mimics. A luciferase reporter assay was established to test the direct connection between MTA1 and its upstream miRNAs. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 5-ethynyl-2'-deoxyuridine analysis, and colony formation assay. Cell migration and invasive capacity were evaluated by wound-healing assay and transwell assay. The miRNA/MTA1 axis was also probed by quantitative RT-PCR and western blotting in samples from eight NSCLC patients. Among the candidate miRNAs, miR-125a-3p was shown to post-transcriptionally regulate MTA1 in NSCLC cells. These data were reinforced by the luciferase reporter assay, in addition to the demonstration that MTA1 is inversely correlated with miR-125a-3p in NSCLC tissues. Furthermore, miR-125a-3p was found to inhibit NSCLC cell proliferation, migration, and invasion, through the same mechanisms of down-regulated MTA1. Our report demonstrates that miR-125a-3p inhibits the proliferation, migration, and invasion of NSCLC cells through down-regulation of MTA1, indicating the role of the miR-125a-3p/MTA1 axis in NSCLC, and may provide novel insight into the molecular mechanisms underpinning the disease and potential therapeutic targets. PMID:25998575

  5. 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. PMID:26229904

  6. Advances in treating exposed fractures☆

    PubMed Central

    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. PMID:26229904

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. HER2-siRNA delivered by EGFR-specific single chain antibody inhibits NSCLC cell proliferation and tumor growth

    PubMed Central

    Liu, Li; Li, Fakai; Zhang, Jian; Ye, Mingxiang; Zhao, Hu; Zhao, Jing; Yan, Bo; Yang, Angang; Zhang, Rui; Li, Xia; Ren, Xinling

    2016-01-01

    Overexpression of human epidermal growth factor receptor type2 (HER2) is closely associated with aggressive progression and poor prognosis in non-small cell lung cancer (NSCLC). Here, we generated an EGFR-scFv-arginine nonamer peptide fusion protein (scFv-9R) as a cargo to deliver HER2 specific siRNA into HER2-positive NSCLC cells both in vitro and in vivo. HER2-siRNAs delivered by scFv-9R effeciently silenced HER2 expression in EGFR-positive NSCLC cells, and consequently resulted in G1 arrest and cell growth inhibition. Importantly, intravenous injection of scFv-9R/HER2-siRNA complex markedly suppressed growth of EGFR-positive NSCLC xenograft in nude mice, resulting from downregulated HER2 expression, reduced cell proliferation and enhanced cell apoptosis. Collectively, our study provides a novel therapeutic strategy for the treatment of EGFR-positive, HER2-overexpressed NSCLC. PMID:26988752

  12. Genetic polymorphisms and haplotypes of TRAIL gene correlate with NSCLC susceptibility in a group of Chinese patients.

    PubMed

    Luo, Jun; Xiong, Jinmeng; Wu, Jianghua; Ye, Xujun

    2015-01-01

    The association between genetic polymorphisms and haplotypes of TNF-related apoptosis-inducing ligand (TRAIL) and the NSCLC development was investigated in 592 Chinese patients and the prevalence of G1525A, G1588A, and C1595T gene polymorphisms compared between the NSCLC patients and control group in this study. It was found that the frequencies of variant allele A and genotype GA+AA of G1525A were significantly lower and those of variant alleles A and T of G1588A and C1595T significantly higher in the NSCLC patients compared with those in control. The frequencies of variant allele T and genotype CT+TT of C1595T were significantly higher in stage III and IV than in stage I and II of the patients. Moreover, the frequencies of variant allele A and genotype GA+AA of G1525A were significantly higher in stage III and IV than in stage I and II of the patients. In addition, TRAIL gene variants G1525A/G1588A/C1595T were found to be in complete linkage disequilibrium in all patients. Compared with the healthy people, the frequency of AAT haplotype was significantly lower whereas that of GAT haplotype significantly higher in NSCLC patients. The results indicated that the genetic polymorphisms and haplotypes of TRAIL gene correlated significantly with the NSCLC susceptibility in the group of Chinese patients. PMID:26629137

  13. Induction of thymidine phosphorylase as a pharmacodynamic end-point in patients with advanced carcinoma treated with 5-fluorouracil, folinic acid and interferon alpha

    PubMed Central

    Braybrooke, J P; Propper, D J; O’Byrne, K J; Koukourakis, M I; Patterson, A V; Houlbrook, S; Love, S D; Varcoe, S; Taylor, M; Ganesan, T S; Talbot, D C; Harris, A L

    2000-01-01

    Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNα), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m–2, 9 MIU m–2and 18 MIUm–2. IFNα was administered on day 0 cycle two, day –1 and day 0 cycle three and day –2, day –1 and day 0 cycle four. A fourth cohort was treated with IFNα 9 MIU m–2three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNα. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNα led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P = 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNα. A single dose of IFNα as low as 3 MIU m–2can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNα for biomodulation of 5-FU. © 2000 Cancer Research Campaign PMID:10901374

  14. Oligometastatic non-small cell lung cancer (NSCLC): adrenal metastases. Experience in a single institution.

    PubMed

    Barone, Mirko; Di Nuzzo, Decio; Cipollone, Giuseppe; Camplese, Pierpaolo; Mucilli, Felice

    2015-12-01

    Though the actual incidence of an adrenal oligometastasis is between 1.5 and 3.5 %, secondary adrenal neoplasms occur in less than 10 % patients with non-small cell lung cancer (NSCLC). According to 7° ed. TNM staging system, the presence of an adrenal metastasis (M1b disease) configures stage IV, which is usually associated with poor prognosis. We evaluated if metastasectomy in selected patients with oligometastatic disease improves overall survival. A 15-year retrospective study concerning patients with NSCLC was performed and an oligometastatic disease was found in 1.61 % of the patients. 18 adrenalectomies were performed. Clustering the population according to different therapeutic strategies, a benefit in terms of survival was found in patients who underwent adrenalectomy. A statistical relevance was found, indeed, between adrenalectomy (p < 0.01), metachronous disease (p < 0.01), the presence of a homolateral disease (p < 0.05) and overall survival. Adrenalectomy should be offered in selected patients with oligometastatic disease.

  15. Volumetric CT-based segmentation of NSCLC using 3D-Slicer.

    PubMed

    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

  16. 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.

  17. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC)

    PubMed Central

    Hall, Richard D.; Le, Tri M.; Haggstrom, Daniel E.

    2015-01-01

    In many cancers, including non-small cell lung cancer (NSCLC), tumor angiogenesis pathways have been identified as important therapeutic targets. Angiogenesis is essential in the process of primary tumor growth, proliferation and metastasis. One of the best characterized group of protein factors for angiogenesis include the members of the vascular endothelial growth factor (VEGF) family, consisting of VEGF-(A-D), and placenta growth factor (PIGF). Targeting tumor angiogenesis has been approached through two primary methods, monoclonal antibodies that block VEGF-vascular endothelial growth factor receptor (VEGFR) binding or small molecule tyrosine kinase inhibitors (TKIs) that inhibit the downstream VEGFR mediated signaling. Many TKIs inhibit multiple pro-angiogenic and pro-proliferative pathways such as the mitogen activated protein (MAP) kinase pathway. Bevacizumab and ramucirumab, monoclonal antibodies targeting VEGF and the VEGFR, respectively, have each led to improvements in overall survival (OS) for NSCLC when added to standard first and second line chemotherapy, respectively. Small incremental gains seen with both bevacizumab and ramucirumab may be further improved upon by incorporating novel agents and treatment strategies, and many additional trials are ongoing. PMID:26629420

  18. 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

  19. 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

  20. Forced vital capacity predicts long-term survival for curative-resected NSCLC.

    PubMed

    Guo, Xi; Cao, Hongxin; Xu, Jun; Yu, Jianyu; Zheng, Chunlong; Meng, Long; Du, Jiajun

    2014-09-01

    We conducted a retrospective study in patients with non-small cell lung cancer (NSCLC) who underwent curative lung resection to seek for better lung function parameters associated with long-term survival after lung resection. From January 2006 to December 2008, 470 patients who underwent lung resection with a postoperative diagnosis of NSCLC were studied. Median survival time was 60 months. Patients with pulmonary function values <80 % of predicted were defined as lung function impairment. Patients with impaired vital capacity, maximal voluntary ventilation, forced vital capacity (FVC), forced expiratory volume in one second (FEV1) or diffusion capacity for carbon monoxide (DLCO) had significant shorter overall survival time (P = 0.024; P = 0.026; P < 0.001; P = 0.027; P = 0.007). In univariate analysis, VC, FVC, FEV1 and DLCO were found to have significant effect on overall survival. In multivariate analysis, FVC (HR, 2.029; 95 % CI 1.126-3.659; P = 0.019) was found to be an independent prognostic predictor of long-term overall survival. For cancer-specific survival, FVC (HR 2.404; 95 % CI 1.300-4.445; P = 0.005) was also found to be an independent prognostic predictor in multivariable analysis. Preoperative FVC, rather than FEV1 or DLCO, is an independent prognostic predictor for long-term survival. FVC is not only an indicator of lung function but also of great value for surgeons to predict survival after lung resection.

  1. MicroRNA-148a reduces tumorigenesis and increases TRAIL-induced apoptosis in NSCLC

    PubMed Central

    Joshi, Pooja; Jeon, Young-Jun; Laganà, Alessandro; Middleton, Justin; Secchiero, Paola; Garofalo, Michela; Croce, Carlo M.

    2015-01-01

    Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of ∼24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC. PMID:26124099

  2. [Jinlong capsule combined with chemoradiotherapy for NSCLC: a Meta-analysis].

    PubMed

    Lu, Qiang; Luo, Jing-bin; Feng, Yi-fan; She, Qin; Shi, Zhong-feng

    2015-11-01

    The purpose of this study was to evaluate the effect and safety of Jinlong capsule combined with chemotherapy or radio-therapy for non-small cell lung cancer (NSCLS) using Meta-analysis. PubMed, Embase, CNKI and Wanfang databases were all searched without language restriction, and searching time was from January 1990 to July 2015. All eligible published studies were included in this study for quality assessment and data extraction. All the data were analyzed using Revman 5.3. A total of ten studies including 736 subjects (370 in Jinlong capsule plus chemoradiotherapy and 366 in chemoradiotherapy only) were finally included in this Meta-analysis. The result of Meta analysis showed that compared with pure chemoradiotherapy group, Jinlong capsule combined with chemoradiotherapy for NSCLC could improve the patients' curative effect (OR = 1.77, 95% CI: 1.29-2.43, P < 0.05), clinical benefit rate (OR = 1.89, 95% CI: 1.22-2.91, P < 0.05), life quality improvement rate (OR = 2. 56, 95% CI: 1.61-4.05, P < 0.05), and decrease leucopenia incidence rate (OR = 0.35, 95% CI: 0. 22-0.56, P < 0.05) and gastrointestinal reaction rate (OR = 0.67, 95% CI: 0.40-1.11, P < 0.05). The pooled results showed that Jinlong capsule combined with chemoradiotherapy for NSCLC could improve the curative effect and life quality, and decrease the adverse reaction of patients. PMID:27097429

  3. [F-18] FDG-PET/CT parameters as predictors of outcome in inoperable NSCLC patients

    PubMed Central

    Nappi, Antonio; Gallicchio, Rosj; Simeon, Vittorio; Nardelli, Anna; Pelagalli, Alessandra; Zupa, Angela; Vita, Giulia; Venetucci, Angela; Di Cosola, Michele; Barbato, Francesco; Storto, Giovanni

    2015-01-01

    Background We evaluated the prognostic significance of standardized uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) in [F-18] FDG PET/CT findings in patients with inoperable non-small-cell lung cancer (NSCLC). Patients and methods. One hundred and three patients (mean age, 65.6 ± 16 years) underwent [F-18] FDG PET/CT before the chemotherapy. The SUVmax value, the MTV (cm3; 42% threshold) and the TLG (g) were registered. The patients were followed up to 18 months thereafter (range 12–55 months). Failure to respond without progression, progression and/or disease-related death constituted surrogate end-points. The optimal SUVmax, MTV and TLG cut-off to predict the patients’ outcome were estimated. PET/CT results were then related to disease outcome (progression free survival; PFS). Results The Kaplan-Meier survival analysis for SUVmax showed a significant shorter PFS in patients presenting with lower values as compared to those with higher (p < 0.05, log-rank test). MTV and TLG were not suitable for predicting PFS apart from the subset of patients with mediastinal nodal involvement. Conclusions Despite the availability of new tools for the quantitative assessment of disease activity on PET/CT, the SUVmax rather than MTV and TLG remains the only predictor for PFS in NSCLC patients. MTV holds a value only when concomitant nodal involvement occurs. PMID:26834517

  4. Improved survival of children with advanced neuroblastoma treated by intensified therapy including myeloablative chemotherapy with stem cell transplantation: a retrospective analysis from the Tohoku Neuroblastoma Study Group.

    PubMed

    Imaizumi, M; Watanabe, A; Kikuta, A; Takano, T; Ito, E; Shimizu, T; Tsuchiya, S; Iinuma, K; Konno, T; Ohi, R; Hayashi, Y

    2001-10-01

    In the hospitals of the Tohoku Neuroblastoma Study Group (TNBSG), treatment for children with advanced neuroblastoma (NB) was intensified in the mid-1990's with the introduction of myeloablative therapy (MT) with stem cell transplantation (SCT) including the use of autologous peripheral blood stem cells (PBSC) and bone marrow transplantation (BMT). In this report, we examined whether the intensified therapy improved the outcome of children with advanced NB (age> 12 months) who were diagnosed between 1991 and 1997. Patients were 36 children (23 boys and 13 girls) with an average age of 3.4 years (range; 1 to 14 years). Six of them had stage III disease, and the other 30 had stage IV. They were treated initially with induction chemotherapy, surgery, and post-operative chemoradiotherapy, after which 17 of them continued further chemotherapy and the other 19 received MT/SCT (18 with PBSCT and 1 with BMT). Progression-free survival (PFS) rate at seven years from diagnosis was 43.5% for all patients, 66.7% for stage III patients and 38.2% for stage IV patients. The difference between stage III and IV patients was not significant. Among the 30 patients with stage IV disease, PFS at seven years was significantly higher in the 19 patients who received MT/SCT (55.6%) than in the 11 patients who did not receive it (12.5%). There was no difference in clinical and biological risk factors between these two groups, except for the proportion of patients with favorable response to initial therapy (36% and 80% for patients without and with MT/SCT, respectively). Furthermore, the proportion of patients with N-myc amplification was significantly higher in patients with progressive disease (PD) after MT/SCT than in those in CR after MT/SCT. The results of this retrospective study of children with advanced NB suggest that therapy intensification involving MT/SCT might result in lengthened survival time for patients with stage IV disease, and that post-transplant PD remains a risk for

  5. Phenotyping of peripheral blood mononuclear cells of patients with advanced heavily pre-treated adenocarcinoma of the stomach and gastro-esophageal junction.

    PubMed

    Kuehnle, Marie-Cristine; Attig, Sebastian; Britten, Cedrik M; Schulze-Bergkamen, Henning; Lordick, Florian; von Wichert, Goetz; Thuss-Patience, Peter; Stein, Alexander; Schuler, Martin; Bassermann, Florian; Sahin, Ugur; Türeci, Ozlem

    2014-12-01

    Immunotherapeutic approaches are emerging as promising new treatment options for patients with solid cancers. The host immune system in cancer patients is dysfunctional due to a number of reasons. The level of immunosuppression is variable at the time of diagnosis and depends on the particular cancer entity, stage, and prior anti-cancer therapies. For many cancer entities, the immune alterations of the respective patient population have not been further characterized even though a patient's immunophenotype may be prognostic for the course of the disease or predictive for clinical/biological response to immunotherapy. In this study, we used flow cytometry to determine the phenotype of peripheral blood mononuclear cells (PBMCs) from 30 patients with heavily pre-treated, advanced adenocarcinoma of the stomach and gastro-esophageal junction. The frequencies and activation status of relevant immune effector populations were determined in PBMCs and compared to those of healthy individuals. This report provides comprehensive immune phenotyping data of a patient population with a high medical need.

  6. Dabrafenib in BRAF V600E–Mutant Advanced Non-Small Cell Lung Cancer: an Open-label, Single arm, Multicenter, Phase 2 Trial

    PubMed Central

    Planchard, David; Kim, Tae Min; Mazieres, Julien; Quoix, Elisabeth; Riely, Gregory; Barlesi, Fabrice; Souquet, Pierre-John; Smit, Egbert F.; Groen, Harry J. M.; Kelly, Ronan J.; Cho, B. C.; Socinski, Mark A.; Pandite, Lini; Nase, Christine; Ma, Bo; D’Amelio, Anthony; Mookerjee, Bijoyesh; Curtis, C. Martin; Johnson, Bruce E.

    2016-01-01

    Background Activating BRAF V600E mutations are found in approximately 1–2% of adenocarcinomas of the lung offering an opportunity to test targeted therapy for this disease. Dabrafenib is an oral selective inhibitor of the BRAF kinase. The aim of this study was to assess the clinical activity of dabrafenib in patients with advanced BRAF V600E-mutant non-small cell lung cancer (NSCLC). Methods In this phase 2, multicenter, nonrandomized, open-label study of previously treated and untreated patients with stage IV, metastatic NSCLC and BRAF V600E mutation, we evaluated the antitumor activity and safety of oral dabrafenib (150 mg twice daily). The primary endpoint was investigator-assessed overall response rate (ORR) in patients receiving ≥ 1 dose of study drug. Safety analysis was performed on the all-treated population (all previously treated and untreated patients receiving ≥ 1 dose of study drug). The study is ongoing but not enrolling participants in this cohort. This trial is registered with ClinicalTrials.gov, number NCT01336634. Findings Between August 2011 and February 2014 a total of 84 previously treated and untreated patients were enrolled. Investigator-assessed ORR for 78 pretreated patients was 33% (95% confidence interval [CI], 23·1 to 44·9). Independent review committee assessment of ORR was consistent with investigator-based assessment. Four of the six previously untreated patients had an objective response. One patient died on study due to intracranial hemorrhage that was considered by the investigator to be due to study drug. Serious adverse events were reported in 35 (42%) of 84 patients. The most frequent grade 3 or higher adverse events were cutaneous squamous cell carcinoma (10 [12%] of 84 patients), asthenia (4 [5%] of 84 patients), and basal cell carcinoma (4 [5%] of 84 patients). Interpretation This is, to our knowledge, the first prospective trial focusing on BRAF V600E-mutant NSCLC to show clinical activity of a BRAF inhibitor. The

  7. Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells

    PubMed Central

    Della Corte, Carminia Maria; Ciaramella, Vincenza; Mauro, Concetta Di; Castellone, Maria Domenica; Papaccio, Federica; Fasano, Morena; Sasso, Ferdinando Carlo; Martinelli, Erika; Troiani, Teresa; De Vita, Ferdinando; Orditura, Michele; Bianco, Roberto; Ciardiello, Fortunato; Morgillo, Floriana

    2016-01-01

    Purpose Metformin, widely used as antidiabetic drug, showed antitumoral effects expecially in combination with chemotherapy. Our group recently has demonstrated that metformin and gefitinib are synergistic in LKB1-wild-type NSCLC cells. In these models, metformin as single agent induced an activation and phosphorylation of mitogen-activated-protein-kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization. Experimental design Since single agent metformin enhances proliferating signals through the RAS/RAF/MAPK pathway, and several MEK inhibitors (MEK-I) demonstrated clinical efficacy in combination with other agents in NSCLC, we tested the effects of metformin plus MEK-I (selumetinib or pimasertib) on proliferation, invasiveness, migration abilities in vitro and in vivo in LKB1 positive NSCLC models harboring KRAS wild type and mutated gene. Results The combination of metformin with MEK-I showed a strong anti-proliferative and proapoptotic effect in Calu-3, H1299, H358 and H1975 human NSCLC cell lines, independently from the KRAS mutational status. The combination reduced the metastatic behaviour of NSCLC cells, via a downregulation of GLI1 trascritional activity, thus affecting the transition from an epithelial to a mesenchymal phenotype. Metformin and MEK-Is combinations also decreased the production and activity of MMP-2 and MMP-9 by reducing the NF-jB (p65) binding to MMP-2 and MMP-9 promoters. Conclusions Metformin potentiates the antitumor activity of MEK-Is in human LKB1-wild-type NSCLC cell lines, independently from the KRAS mutational status, through GLI1 downregulation and by reducing the NF-jB (p65)-mediated transcription of MMP-2 and MMP-9. PMID:26673006

  8. Randomized Phase II Trial of Erlotinib Alone or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers With Advanced Lung Adenocarcinoma: CALGB 30406 Trial

    PubMed Central

    Jänne, Pasi A.; Wang, Xiaofei; Socinski, Mark A.; Crawford, Jeffrey; Stinchcombe, Thomas E.; Gu, Lin; Capelletti, Marzia; Edelman, Martin J.; Villalona-Calero, Miguel A.; Kratzke, Robert; Vokes, Everett E.; Miller, Vincent A.

    2012-01-01

    Purpose Erlotinib is clinically effective in patients with non–small-cell lung cancer (NSCLC) who have adenocarcinoma, are never or limited former smokers, or have EGFR mutant tumors. We investigated the efficacy of erlotinib alone or in combination with chemotherapy in patients with these characteristics. Patients and Methods Patients with advanced NSCLC (adenocarcinoma) who were epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy naive never or light former smokers (smokers of > 100 cigarettes and ≤ 10 pack years and quit ≥ 1 year ago) were randomly assigned to continuous erlotinib or in combination with carboplatin and paclitaxel (ECP) for six cycles followed by erlotinib alone. The primary end point was progression-free survival (PFS). Tissue collection was mandatory. Results PFS was similar (5.0 v 6.6 months; P = .1988) in patients randomly assigned to erlotinib alone (arm A; n = 81) or to ECP (arm B; n = 100). EGFR mutation analysis was possible in 91% (164 of 181) of patients, and EGFR mutations were detected in 40% (51 of 128) of never smokers and in 42% (15 of 36) of light former smokers. In arm A, response rate (70% v 9%), PFS (14.1 v 2.6 months), and overall survival (OS; 31.3 v 18.1 month) favored EGFR-mutant patients. In arm B, response rate (73% v 30%), PFS (17.2 v 4.8 months), and OS (38.1 v 14.4 months) favored EGFR-mutant patients. Incidence of grades 3 to 4 hematologic (2% v 49%; P < .001) and nonhematologic (24% v 52%; P < .001) toxicity was greater in patients treated with ECP. Conclusion Erlotinib and erlotinib plus chemotherapy have similar efficacy in clinically selected populations of patients with advanced NSCLC. EGFR mutations identify patients most likely to benefit. PMID:22547605

  9. The impact of epidermal growth factor receptor mutations on patterns of disease recurrence after chemoradiotherapy for locally advanced non–small cell lung cancer: a literature review and pooled analysis

    PubMed Central

    Ochiai, Satoru; Nomoto, Yoshihito; Watanabe, Yui; Yamashita, Yasufumi; Toyomasu, Yutaka; Kawamura, Tomoko; Takada, Akinori; Noriko; Sakuma, Hajime

    2016-01-01

    The purpose of this review was to evaluate the impact of epidermal growth factor receptor (EGFR) mutation status on disease recurrence in patients treated with chemoradiotherapy (CRT) for locally advanced non–small cell lung cancer (NSCLC). A literature search was conducted and a total of three studies were analyzed. There was no significant difference in the objective response rate between the EGFR mutation group and the EGFR wild-type group (odds ratios [OR] 1.46, 95% CI, 0.79–2.70, P = 0.228), and there was no significant difference in the incidence of disease recurrence (OR 1.37, 95% CI, 0.68–2.75, P = 0.379) between the two groups. There were significant difference in the incidence of local/locoregional progression (LP) (OR 0.35, 95% CI, 0.18–0.71, P = 0.003) and distant progression (DP) (OR 2.97, 95% CI, 1.59–5.54, P < 0.001). Brain metastasis (BM) was one of the main recurrence patterns of DP, and the incidence was significantly higher in the EGFR mutant group (OR 2.75, 95% CI, 1.43–5.31, P = 0.003). There were no statistically significant heterogeneities in these pooled analyses. The patterns of recurrence after CRT for locally advanced NSCLC were different according to EGFR mutation status. LP after CRT in patients with EGFR mutation was less frequent, but the high incidence of DP, especially BM, continued to be the major problem. On the other hand, LP continued to be the major problem in EGFR wild-type patients. In multimodality treatment for inoperable locally advanced NSCLC, we may need to consider different treatment strategies according to EGFR mutation status. PMID:27534790

  10. Effects of ATP infusion on glucose turnover and gluconeogenesis in patients with advanced non-small-cell lung cancer.

    PubMed

    Agteresch, H J; Leij-Halfwerk, S; Van Den Berg, J W; Hordijk-Luijk, C H; Wilson, J H; Dagnelie, P C

    2000-06-01

    Cancer cachexia is associated with elevated lipolysis, proteolysis and gluconeogenesis. ATP infusion has been found to significantly inhibit loss of body weight, fat mass and fat-free mass in patients with advanced lung cancer. The present study was aimed at exploring the effects of ATP on whole-body glucose turnover, alanine turnover and gluconeogenesis from alanine. Twelve patients with advanced non-small-cell lung cancer (NSCLC) were studied 1 week before and during 22-24 h of continuous ATP infusion. After an overnight fast, turnover rates of glucose and alanine, and gluconeogenesis from alanine, were determined using primed constant infusions of ¿6, 6-(2)H(2)ğlucose and ¿3-(13)Călanine. Thirteen NSCLC patients and eleven healthy subjects were studied as control groups without ATP infusion. During high-dose ATP infusion (75 microg.min(-1).kg(-1)), glucose turnover was 0.62+/-0.07 mmol.h(-1).kg(-1), compared with 0. 44+/-0.13 mmol.h(-1).kg(-1) at baseline (P=0.04). For gluconeogenesis a similar, but non-significant, trend was observed ¿baseline, 0.30+/-0.16 mmol.h(-1).kg(-1); during ATP, 0.37+/-0.13 mmol.h(-1).kg(-1) (P=0.08). At lower ATP doses (37-50 microg. min(-1).kg(-1)) these effects were not detected. The relative increase in glucose turnover during ATP infusion compared with baseline showed a significant correlation with the ATP dose (r=0.58, P=0.02). No change in alanine turnover was observed at any ATP dose. The results of this study indicate an increase in glucose turnover during high-dose ATP infusion compared with baseline levels. During high-dose ATP infusion, glucose turnover was similar to that during low-dose ATP infusion and to that in control NSCLC patients. Between ATP infusions, however, glucose turnover in patients treated with high-dose ATP was significantly lower than that in the low-dose and control NSCLC patients (P=0.04 and P=0.03 respectively), and similar to that in healthy subjects. This would suggest that repeated high

  11. 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

  12. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer

    PubMed Central

    Morse, Michael A; Garst, Jennifer; Osada, Takuya; Khan, Shubi; Hobeika, Amy; Clay, Timothy M; Valente, Nancy; Shreeniwas, Revati; Sutton, Mary Ann; Delcayre, Alain; Hsu, Di-Hwei; Le Pecq, Jean-Bernard; Lyerly, H Kim

    2005-01-01

    Background There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). Methods This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. Results Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. Conclusion Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors PMID:15723705

  13. Successful pneumonectomy for invasive pulmonary aspergillosis and advanced non-small cell-lung cancer.

    PubMed

    Minesaki, Shohei; Koyama, Nobuyuki; Ishida, Hironori; Kobayashi, Kunihiko

    2013-01-01

    Aspergillus spp. is a pathogenic fungus in patients with malignancy, immunosuppression or respiratory diseases, and invasive pulmonary aspergillosis (IPA) caused by its infection is an aggressive and often lethal disorder. We report a case of non-small-cell lung cancer (NSCLC) where pneumonectomy concomitantly enabled radical cure of the underlying disease and IPA against which different antifungal drugs had been ineffective. In a patient with locally advanced NSCLC that progressed despite chemoradiation, radiation pneumonitis and subsequently cavitary disease developed following the administration of corticosteroids. Based upon the isolation of Aspergillus spp. from sputum, a diagnosis of IPA was made and since the latter was refractory to multiple antifungal drugs, pneumonectomy was undertaken which resulted in successful treatment of both NSCLC and IPA. Surgical intervention should be considered as a therapeutic option for IPA complicating NSCLC that is refractory to medical management. PMID:23505081

  14. Radiological response and survival in locally advanced non-small-cell lung cancer patients treated with three-drug induction chemotherapy followed by radical local treatment

    PubMed Central

    Bonanno, Laura; Zago, Giulia; Marulli, Giuseppe; Del Bianco, Paola; Schiavon, Marco; Pasello, Giulia; Polo, Valentina; Canova, Fabio; Tonetto, Fabrizio; Loreggian, Lucio; Rea, Federico; Conte, PierFranco; Favaretto, Adolfo

    2016-01-01

    Objectives If concurrent chemoradiotherapy cannot be performed, induction chemotherapy followed by radical-intent surgical treatment is an acceptable option for non primarily resectable non-small-cell lung cancers (NSCLCs). No markers are available to predict which patients may benefit from local treatment after induction. This exploratory study aims to assess the feasibility and the activity of multimodality treatment, including triple-agent chemotherapy followed by radical surgery and/or radiotherapy in locally advanced NSCLCs. Methods We retrospectively collected data from locally advanced NSCLCs treated with induction chemotherapy with carboplatin (area under the curve 6, d [day]1), paclitaxel (200 mg/m2, d1), and gemcitabine (1,000 mg/m2 d1, 8) for three to four courses, followed by radical surgery and/or radiotherapy. We analyzed radiological response and toxicity. Estimated progression-free survival (PFS) and overall survival (OS) were correlated to response, surgery, and clinical features. Results In all, 58 NSCLCs were included in the study: 40 staged as IIIA, 18 as IIIB (according to TNM Classification of Malignant Tumors–7th edition staging system). A total of 36 (62%) patients achieved partial response (PR), and six (10%) progressions were recorded. Grade 3–4 hematological toxicity was observed in 36 (62%) cases. After chemotherapy, 37 (64%) patients underwent surgery followed by adjuvant radiotherapy, and two patients received radical-intent radiotherapy. The median PFS and OS were 11 months and 23 months, respectively. Both PFS and OS were significantly correlated to objective response (P<0.0001) and surgery (P<0.0001 and P=0.002). Patients obtaining PR and receiving local treatment achieved a median PFS and OS of 35 and 48 months, respectively. Median PFS and OS of patients not achieving PR or not receiving local treatment were 5–7 and 11–15 months, respectively. The extension of surgery did not affect the outcome. Conclusion The

  15. Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib.

    PubMed

    Ou, Sai-Hong Ignatius; Klempner, Samuel J; Greenbowe, Joel R; Azada, Michele; Schrock, Alexa B; Ali, Siraj M; Ross, Jeffrey S; Stephens, Philip J; Miller, Vincent A

    2014-12-01

    Huntingtin-interacting protein 1 (HIP1) has recently been identified as a new fusion partner fused to anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC). To date, two variants of HIP1-ALK (H21; A20) and (H28; A20) have been identified in NSCLC. However, the response of patients with NSCLC harboring HIP1-ALK to ALK inhibitors and potential resistance mechanisms to such remain unknown. Here, we report a patient with NSCLC harboring a novel HIP1-ALK fusion variant (H30; A20). This patient and another patient with EML4-ALK variant 3a/b initially responded sequentially to crizotinib and then alectinib, a next-generation ALK inhibitor, but developed acquired resistance to alectinib with the presence of a mutation in amino acid residue 1171 (I1171N and I1171S respectively) located in the hydrophobic regulatory spine (R-spine) of the ALK kinase in both the cases as identified by a comprehensive next-generation sequencing-based assay performed on biopsies of new liver metastases that developed during alectinib treatment.

  16. 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.

  17. 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

    2011-10-01

    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.

  18. Association of CHEK2 polymorphisms with the efficacy of platinum-based chemotherapy for advanced non-small-cell lung cancer in Chinese never-smoking women

    PubMed Central

    Xu, Wen; Liu, Di; Yang, Yang; Ding, Xi; Sun, Yifeng; Zhang, Baohong

    2016-01-01

    Background Cell cycle checkpoint kinase 2 (CHEK2) plays an essential role in the repair of DNA damage. Single nucleotide polymorphisms (SNPs) in DNA repair genes are thought to influence treatment effects and survival of cancer patients. This study aimed to investigate the relationship between polymorphisms in the CHEK2 gene and efficacy of platinum-based doublet chemotherapy in never-smoking Chinese female patients with advanced non-small-cell lung cancer (NSCLC). Methods Using DNA from blood samples of 272 Chinese advanced NSCLC non-smoking female patients treated with first-line platinum-based chemotherapy, we have analyzed the relationships between four SNPs in the CHEK2 gene and clinical outcomes. Results We found that overall survival (OS) was significantly associated with CHEK2 rs4035540 (Log-Rank P=0.020), as well as the CHEK2 rs4035540 dominant model (Log-Rank P=0.026), especially in the lung adenocarcinoma group. After multivariate analysis, patients with rs4035540 A/G genotype had a significantly better OS than those with the G/G genotype (HR =0.67, 95% CI, 0.48–0.93; P=0.016). In the toxicity analysis, it was observed that patients with the CHEK2 rs4035540 A/A genotype had a higher risk of gastrointestinal toxicity than the G/G genotype group (P=0.009). However, there are no significant associations between chemotherapy treatments and genetic variations. Conclusions Our findings indicate that SNPs in CHEK2 are related to Chinese advanced NSCLC never-smoking female patients receiving platinum-based doublet chemotherapy in China. Patients with rs4035540 A/G genotype have a better OS. And patients with rs4035540 A/A genotype have a higher risk of gastrointestinal toxicity. These results point to a direction for predicting the prognosis for Chinese never-smoking NSCLC female patients. However, there are no significant associations between chemotherapy treatments and SNPs in CHEK2, which need more samples to the further study. PMID:27747004

  19. 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

  20. MicroRNA-187-5p suppresses cancer cell progression in non-small cell lung cancer (NSCLC) through down-regulation of CYP1B1.

    PubMed

    Mao, Ming; Wu, Zhouqing; Chen, Jiakuan

    2016-09-16

    Lung cancer remains a leading cause of cancer-associated mortality worldwide and non-small lung cancer (NSCLC) is responsible for over 80% of lung cancer-related deaths. Identifying novel molecular biomarker that can inhibit the progression of lung cancer will facilitate the development of new treatment strategies. Herein, we demonstrated that miR-187-5p is a tumor-suppressor miRNA in NSCLC progression. We found that expression of miR-187-5p was decreased obviously in NSCLC tissues. Down-regulation of miR-187-5p was associated with TNM stage and postoperative survival. Overexpression of miR-187-5p inhibited the growth and metastasis of NSCLC cells. The CYP1B1 was a direct target of miR-187-5p and promoted the growth and metastasis of NSCLC cells. Further study showed that CYP1B1 could reverse the inhibitory effect of miR-187-5p on growth and metastasis of NSCLC cells. Taken together, our data highlight the pivotal role of miR-187-5p in the progression of NSCLC. Thus, miR-187-5p may be a potential prognostic marker and of treatment relevance for NSCLC progression intervention. PMID:27495872

  1. 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. PMID:27138804

  2. Allyl isothiocyanate induces replication-associated DNA damage response in NSCLC cells and sensitizes to ionizing radiation.

    PubMed

    Tripathi, Kaushlendra; Hussein, Usama K; Anupalli, Roja; Barnett, Reagan; Bachaboina, Lavanya; Scalici, Jennifer; Rocconi, Rodney P; Owen, Laurie B; Piazza, Gary A; Palle, Komaraiah

    2015-03-10

    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.

  3. 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

  4. 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. PMID:27133743

  5. Total Body Metabolic Tumor Response in ALK Positive Non-Small Cell Lung Cancer Patients Treated with ALK Inhibition

    PubMed Central

    Koole, Michel J. B.; Bongaerts, Alphons H. H.; Pruim, Jan; Groen, Harry J. M.

    2016-01-01

    Background In ALK-positive advanced NSCLC, crizotinib has a high response rate and effectively increases quality of life and survival. CT measurement of the tumor may insufficiently reflect the actual tumor load changes during targeted therapy with crizotinib. We explored whether 18F-FDG PET measured metabolic changes are different from CT based changes and studied the impact of these changes on disease progression. Methods 18F-FDG PET/CT was performed prior to and after 6 weeks of crizotinib treatment. Tumor response on CT was classified with RECIST 1.1, while 18F-FDG PET response was assessed according to the 1999 EORTC recommendations and PERCIST criteria. Agreement was assessed using McNemars test. During follow-up, patients received additional PET/CT during crizotinib treatment and second generation ALK inhibition. We assessed whether PET was able to detect progression earlier then CT. Results In this exploratory study 15 patients were analyzed who were treated with crizotinib. There was a good agreement in the applicability of CT and 18F-FDG PET/CT using the EORTC recommendations. During first line crizotinib and subsequent second line ALK inhibitors, PET was able to detect progression earlier then CT in 10/22 (45%) events of progression and in the others disease progression was detected simultaneously. Conclusion In advanced ALK positive NSCLC PET was able to detect progressive disease earlier than with CT in nearly half of the assessments while both imaging tests performed similar in the others. PMID:27137772

  6. MLN0264 in Previously Treated Asian Patients With Advanced Gastrointestinal Carcinoma or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma Expressing Guanylyl Cyclase C

    ClinicalTrials.gov

    2016-06-03

    Advanced Gastrointestinal Carcinoma; Gastroesophageal Junction Adenocarcinoma; Recurrent Gastric Adenocarcinoma; Recurrent Gastroesophageal Junction Adenocarcinoma; Metastatic Gastric Adenocarcinoma; Metastatic Gastroesophageal Junction Adenocarcinoma; Recurrent Gastrointestinal Carcinoma

  7. 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

  8. 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.

  9. 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

  10. The potential role of bevacizumab in early stages and locally advanced non-small cell lung cancer

    PubMed Central

    Schettino, Clorinda; Bareschino, Maria Anna; Rossi, Antonio; Maione, Paolo; Castaldo, Vincenzo; Mazzeo, Nicole; Sacco, Paola Claudia; Ferrara, Marianna Luciana; Palazzolo, Giovanni; Ciardiello, Fortunato; Gridelli, Cesare

    2009-01-01

    Improving outcomes for early-stage non-small cell lung cancer (NSCLC) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection. Adjuvant chemotherapy prolongs survival, with an absolute improvement in 5-year overall survival of about 5% with drawbacks such as treatment toxicity. Approximately, one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection – in this setting of patients concurrent chemoradiation is the standard of therapy. However, the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing, and so new approaches are required to improve the clinical benefit in this setting of patients. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessels formation and permeability, and tumor VEGF overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival. Several agents have been developed that inhibit VEGF or its receptor signalling system. Bevacizumab is the first recombinant humanized monoclonal antibody binding VEGF to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients. These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease, and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease. PMID:21789109

  11. The potential role of bevacizumab in early stages and locally advanced non-small cell lung cancer.

    PubMed

    Schettino, Clorinda; Bareschino, Maria Anna; Rossi, Antonio; Maione, Paolo; Castaldo, Vincenzo; Mazzeo, Nicole; Sacco, Paola Claudia; Ferrara, Marianna Luciana; Palazzolo, Giovanni; Ciardiello, Fortunato; Gridelli, Cesare

    2009-07-01

    Improving outcomes for early-stage non-small cell lung cancer (NSCLC) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection. Adjuvant chemotherapy prolongs survival, with an absolute improvement in 5-year overall survival of about 5% with drawbacks such as treatment toxicity. Approximately, one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection - in this setting of patients concurrent chemoradiation is the standard of therapy. However, the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing, and so new approaches are required to improve the clinical benefit in this setting of patients. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessels formation and permeability, and tumor VEGF overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival. Several agents have been developed that inhibit VEGF or its receptor signalling system. Bevacizumab is the first recombinant humanized monoclonal antibody binding VEGF to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients. These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease, and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease.

  12. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer--a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer.

    PubMed

    Anderson, H; Hopwood, P; Stephens, R J; Thatcher, N; Cottier, B; Nicholson, M; Milroy, R; Maughan, T S; Falk, S J; Bond, M G; Burt, P A; Connolly, C K; McIllmurray, M B; Carmichael, J

    2000-08-01

    Three hundred patients with symptomatic, locally advanced or metastatic NSCLC not requiring immediate radiotherapy were enrolled into this randomized multicentre trial comparing gemcitabine + BSC vs BSC alone. Patients allocated gemcitabine received 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, for a maximum of six cycles. The main aim of this trial was to compare patient assessment of a predefined subset of commonly reported symptoms (SS14) from the EORTC QLQ-C30 and LC13 scales. The primary end-points were defined as (1) the percentage change in mean SS14 score between baseline and 2 months and (2) the proportion of patients with a marked (> or = 25%) improvement in SS14 score between baseline and 2 months sustained for > or =4 weeks. The secondary objectives were to compare treatments with respect to overall survival, and multidimensional QL parameters. The treatment groups were balanced with regard to age, gender, Karnofsky performance status (KPS) and disease stage (40% had metastatic disease). The percentage change in mean SS14 score from baseline to 2 months was a 10% decrease (i.e. improvement) for gemcitabine plus BSC and a 1% increase (i.e. deterioration) for BSC alone (P = 0.113, two-sample t-test). A sustained (> or = 4 weeks) improvement (> or =25%) on SS14 was recorded in a significantly higher proportion of gemcitabine + BSC patients (22%) than in BSC alone patients (9%) (P = 0.0014, Pearson's chi-squared test). The QLQ-C30 and L13 subscales showed greater improvement in the gemcitabine plus BSC arm (in 11 domains) than in the BSC arm (one symptom item). There was greater deterioration in the BSC alone arm (six domains/items) than in the gemcitabine + BSC arm (three QL domains). Tumour response occurred in 19% (95% CI 13-27) of gemcitabine patients. There was no difference in overall survival: median 5.7 months (95% CI 4.6-7.6) for gemcitabine + BSC patients and 5.9 months (95% CI 5.0-7.9) (log-rank, P = 0.84) for BSC patients, and 1 -year

  13. A phase II study of cisplatin, vindesine and continuously infused 5-fluorouracil in the treatment of advanced non-small-cell lung cancer. Osaka Lung Cancer Chemotherapy Study Group.

    PubMed Central

    Nakano, T.; Ikegami, H.; Nakamura, S.; Kawase, T.; Nishikawa, H.; Yokota, S.; Yoshida, M.; Tachibana, T.; Igarashi, T.; Komuta, K.; Higashino, K.

    1996-01-01

    Fifty-two previously untreated patients with advanced non-small-cell lung cancer (NSCLC) were treated on a 14 day cycle with cisplatin (60 mg m-2 i.v.) and vindesine (3 mg m-2 i.v.) on day 1, followed by a 3 day continuous infusion of 5-fluorouracil (800 mg m-2 day-1) starting on day 8. An overall response rate of 40.4% was observed in 47 evaluable patients, which included one complete response and 18 partial responses. Responses were achieved in 61.1% of stage 3 patients and 27.6% of stage 4 patients. The median progression-free interval was 19.3 weeks, and median survival time was 41.6 weeks (47.1 weeks for patients with stage 3 disease and 38.7 weeks for those with stage 4 disease). Toxicity was well tolerated. Gastrointestinal and renal toxicities did not exceed WHO grade 2. Grade 3 or 4 leucopenia and anaemia occurred in nine (19%) and four (9%) patients respectively, but only grade 2 thrombocytopenia was observed. Phlebitis at the infusion site was observed in 24 patients (53%). This treatment programme achieved a response rate similar to other active combination regimens for the treatment of advanced NSCLC, and was less toxic. PMID:8624270

  14. Comparison of dose–volume histograms between proton beam and X-ray conformal radiotherapy for locally advanced non-small-cell lung cancer

    PubMed Central

    Ohno, Toshiki; Oshiro, Yoshiko; Mizumoto, Masashi; Numajiri, Haruko; Ishikawa, Hitoshi; Okumura, Toshiyuki; Terunuma, Toshiyuki; Sakae, Takeji; Sakurai, Hideyuki

    2015-01-01

    The purpose of this study was to compare the parameters of the dose–volume histogram (DVH) between proton beam therapy (PBT) and X-ray conformal radiotherapy (XCRT) for locally advanced non-small-cell lung cancer (NSCLC), according to the tumor conditions. A total of 35 patients having NSCLC treated with PBT were enrolled in this analysis. The numbers of TNM stage and lymph node status were IIB (n = 3), IIIA (n = 15) and IIIB (n = 17), and N0 (n = 2), N1 (n = 4), N2 (n = 17) and N3 (n = 12), respectively. Plans for XCRT were simulated based on the same CT, and the same clinical target volume (CTV) was used based on the actual PBT plan. The treatment dose was 74 Gy-equivalent dose (GyE) for the primary site and 66 GyE for positive lymph nodes. The parameters were then calculated according to the normal lung dose, and the irradiation volumes of the doses (Vx) were compared. We also evaluated the feasibility of both plans according to criteria: V5 ≥ 42%, V20 ≥ 25%, mean lung dose ≥ 20 Gy. The mean normal lung dose and V5 to V50 were significantly lower in PBT than in XCRT. The differences were greater with the more advanced nodal status and with the larger CTV. Furthermore, 45.7% of the X-ray plans were classified as inadequate according to the criteria, whereas 17.1% of the proton plans were considered unsuitable. The number of inadequate X-ray plans increased in cases with advanced nodal stage. This study indicated that some patients who cannot receive photon radiotherapy may be able to be treated using PBT. PMID:25368341

  15. Dose escalation for unresectable locally advanced non-small cell lung cancer: end of the line?

    PubMed Central

    Hong, Julian C.

    2016-01-01

    Radiation Therapy Oncology Group (RTOG) 0617 was a randomized trial that investigated both the impact of radiation dose-escalation and the addition of cetuximab on the treatment of non-small cell lung cancer (NSCLC). The results of RTOG 0617 were surprising, with the dose escalation randomization being closed prematurely due to futility stopping rules, and cetuximab ultimately showing no overall survival benefit. Locally advanced unresectable NSCLC has conventionally been treated with concurrent chemoradiation. Though advances in treatment technology have improved the ability to deliver adequate treatment dose, the foundation for radiotherapy (RT) has remained the same since the 1980s. Since then, progressive studies have sought to establish the safety and efficacy of escalating radiation dose to loco-regional disease. Though RTOG 0617 did not produce the anticipated result, much interest remains in dose escalation and establishing an explanation for the findings of this study. Cetuximab was also not found to provide a survival benefit when applied to an unselected population. However, planned retrospective analysis suggests that those patients with high epidermal growth factor receptor (EGFR) expression may benefit, suggesting that cetuximab should be applied in a targeted fashion. We discuss the results of RTOG 0617 and additional findings from post-hoc analysis that suggest that dose escalation may be limited by normal tissue toxicity. We also present ongoing studies that aim to address potential causes for mortality in the dose escalation arm through adaptive or proton therapy, and are also leveraging additional concurrent systemic agents such as tyrosine kinase inhibitors (TKIs) for EGFR-activating mutations or EML4-ALK rearrangements, and poly (ADP-ribose) polymerase (PARP) inhibitors. PMID:26958507

  16. Dose escalation for unresectable locally advanced non-small cell lung cancer: end of the line?

    PubMed

    Hong, Julian C; Salama, Joseph K

    2016-02-01

    Radiation Therapy Oncology Group (RTOG) 0617 was a randomized trial that investigated both the impact of radiation dose-escalation and the addition of cetuximab on the treatment of non-small cell lung cancer (NSCLC). The results of RTOG 0617 were surprising, with the dose escalation randomization being closed prematurely due to futility stopping rules, and cetuximab ultimately showing no overall survival benefit. Locally advanced unresectable NSCLC has conventionally been treated with concurrent chemoradiation. Though advances in treatment technology have improved the ability to deliver adequate treatment dose, the foundation for radiotherapy (RT) has remained the same since the 1980s. Since then, progressive studies have sought to establish the safety and efficacy of escalating radiation dose to loco-regional disease. Though RTOG 0617 did not produce the anticipated result, much interest remains in dose escalation and establishing an explanation for the findings of this study. Cetuximab was also not found to provide a survival benefit when applied to an unselected population. However, planned retrospective analysis suggests that those patients with high epidermal growth factor receptor (EGFR) expression may benefit, suggesting that cetuximab should be applied in a targeted fashion. We discuss the results of RTOG 0617 and additional findings from post-hoc analysis that suggest that dose escalation may be limited by normal tissue toxicity. We also present ongoing studies that aim to address potential causes for mortality in the dose escalation arm through adaptive or proton therapy, and are also leveraging additional concurrent systemic agents such as tyrosine kinase inhibitors (TKIs) for EGFR-activating mutations or EML4-ALK rearrangements, and poly (ADP-ribose) polymerase (PARP) inhibitors.

  17. SEOM guidelines for the management of non-small-cell lung cancer (NSCLC).

    PubMed

    Felip, E; Garrido, P; Trigo, J M; López-Brea, M; Paz-Ares, L; Provencio, M; Isla, D

    2009-05-01

    Lung cancer is currently the most common malignancy and also the leading cause of mortality related to cancer in the world [1]. The crude incidence of lung cancer in the EU is 52.5/100,000/year, while the mortality 48.7/100,000/year. Among men the rates are 82.5 and 77.0/100,000/year, and among women 23.9 and 22.3/100,000/year, respectively. Non-small-cell lung cancer (NSCLC) accounts for 80% of all cases. In Spain, there were 16,879 deaths in men, with a mean age of 68 years, and 2634 deaths in women, with a mean age of 66 years. The incidence of lung cancer in Spain was 68.3/100,000 among men and 13.8/100,000 among women, according to the latest data published in the year 2006 by the Instituto Nacional de Estadística. About 90% of lung cancer mortality among men (and 80% among women) is attributable to smoking.

  18. Cigarette Smoking, BPDE-DNA Adducts, and Aberrant Promoter Methylations of Tumor Suppressor Genes (TSGs) in NSCLC from Chinese Population.

    PubMed

    Jin, Yongtang; Xu, Peiwei; Liu, Xinneng; Zhang, Chunye; Tan, Cong; Chen, Chunmei; Sun, Xiaoyu; Xu, Yingchun

    2016-01-01

    Non-small cell lung cancer (NSCLC) is related to the genetic and epigenetic factors. The goal of this study was to determine association of cigarette smoking and BPDE-DNA adducts with promoter methylations of several genes in NSCLC. Methylation of the promoters of p16, RARβ, DAPK, MGMT, and TIMP-3 genes of tumor tissues from 199 lung cancer patients was analyzed with methylation-specific PCR (MSP), and BPDE-DNA adduct level in lung cancer tissue was obtained by ELISA. Level of BPDE-DNA adduct increased significantly in males, aged people (over 60 years), and smokers; however, no significant difference was found while comparing the BPDE-DNA adduct levels among different tumor types, locations, and stages. Cigarette smoking was also associated with increased BPDE-DNA adducts level (OR = 2.43, p > .05) and increased methylation level in at least 1 gene (OR = 5.22, p < .01), both in dose-response manner. Similarly, cigarette smoking also significantly increase the risk of p16 or DAPK methylation (OR = 3.02, p < .05 for p16, and 3.66, p < .05 for DAPK). The highest risk of BPDE-DNA adducts was detected among individuals with cigarette smoking for more than 40 pack-years (OR = 4.21, p < .01). Furthermore, the present study did not show that BPDE-DNA adducts are significantly associated with abnormal TSGs methylations in NSCLC, including SCC and AdO, respectively. Conclusively, cigarette smoking is significantly associated with the increase of BPDE-DNA adduct level, promoter hypermethylation of p16 and DAPK genes, while BPDE-DNA adduct was not significantly related to abnormal promoter hypermethylation in TSGs, suggesting that BPDE-DNA adducts and TSGs methylations play independent roles in NSCLC.

  19. Cigarette Smoking, BPDE-DNA Adducts, and Aberrant Promoter Methylations of Tumor Suppressor Genes (TSGs) in NSCLC from Chinese Population.

    PubMed

    Jin, Yongtang; Xu, Peiwei; Liu, Xinneng; Zhang, Chunye; Tan, Cong; Chen, Chunmei; Sun, Xiaoyu; Xu, Yingchun

    2016-01-01

    Non-small cell lung cancer (NSCLC) is related to the genetic and epigenetic factors. The goal of this study was to determine association of cigarette smoking and BPDE-DNA adducts with promoter methylations of several genes in NSCLC. Methylation of the promoters of p16, RARβ, DAPK, MGMT, and TIMP-3 genes of tumor tissues from 199 lung cancer patients was analyzed with methylation-specific PCR (MSP), and BPDE-DNA adduct level in lung cancer tissue was obtained by ELISA. Level of BPDE-DNA adduct increased significantly in males, aged people (over 60 years), and smokers; however, no significant difference was found while comparing the BPDE-DNA adduct levels among different tumor types, locations, and stages. Cigarette smoking was also associated with increased BPDE-DNA adducts level (OR = 2.43, p > .05) and increased methylation level in at least 1 gene (OR = 5.22, p < .01), both in dose-response manner. Similarly, cigarette smoking also significantly increase the risk of p16 or DAPK methylation (OR = 3.02, p < .05 for p16, and 3.66, p < .05 for DAPK). The highest risk of BPDE-DNA adducts was detected among individuals with cigarette smoking for more than 40 pack-years (OR = 4.21, p < .01). Furthermore, the present study did not show that BPDE-DNA adducts are significantly associated with abnormal TSGs methylations in NSCLC, including SCC and AdO, respectively. Conclusively, cigarette smoking is significantly associated with the increase of BPDE-DNA adduct level, promoter hypermethylation of p16 and DAPK genes, while BPDE-DNA adduct was not significantly related to abnormal promoter hypermethylation in TSGs, suggesting that BPDE-DNA adducts and TSGs methylations play independent roles in NSCLC. PMID:27042875

  20. TMPRSS4 regulates levels of integrin α5 in NSCLC through miR-205 activity to promote metastasis

    PubMed Central

    Larzabal, L; de Aberasturi, A L; Redrado, M; Rueda, P; Rodriguez, M J; Bodegas, M E; Montuenga, L M; Calvo, A

    2014-01-01

    Background: TMPRSS4 is a membrane-anchored protease involved in cell migration and invasion in different cancer types including lung cancer. TMPRSS4 expression is increased in NSCLC and its inhibition through shRNA reduces lung metastasis. However, molecular mechanisms leading to the protumorigenic regulation of TMPRSS4 in lung cancer are unknown. Methods: miR-205 was identified as an overexpressed gene upon TMPRSS4 downregulation through microarray analysis. Cell migration and invasion assays and in vivo lung primary tumour and metastasis models were used for functional analysis of miR-205 overexpression in H2170 and H441 cell lines. Luciferase assays were used to identify a new miR-205 direct target in NSCLC. Results: miR-205 overexpression promoted an epithelial phenotype with increased E-cadherin and reduced fibronectin. Furthermore, miR-205 expression caused a G0/G1 cell cycle arrest and inhibition of cell growth, migration, attachment to fibronectin, primary tumour growth and metastasis formation in vivo. Integrin α5 (a proinvasive protein) was identified as a new miR-205 direct target in NSCLC. Integrin α5 downregulation in lung cancer cells resulted in complete abrogation of cell migration, a decreased capacity to adhere to fibronectin and reduced in vivo tumour growth, compared with control cells. TMPRSS4 silencing resulted in a concomitant reduction of integrin α5 levels. Conclusion: We have demonstrated for the first time a new molecular pathway that connects TMPRSS4 and integrin α5 through miR-205 to regulate cancer cell invasion and metastasis. Our results will help designing new therapeutic strategies to inhibit this novel pathway in NSCLC. PMID:24434435

  1. [Locally Advanced Breast Cancer Treated with Halsted's Operation Because of Drug-Induced Lung Injury Caused by Neoadjuvant Chemotherapy--A Case Report].

    PubMed

    Moro, Kazuki; Nagahashi, Masayuki; Tsuchida, Junko; Tatsuda, Kumiko; Toshikawa, Chie; Hasegawa, Miki; Ishikawa, Takashi; Shimada, Yoshifumi; Sakata, Jun; Kameyama, Hitoshi; Kobayashi, Takashi; Minagawa, Masahiro; Kosugi, Shin-ichi; Koyama, Yu; Wakai, Toshifumi

    2015-11-01

    A 64-year-old woman discovered a mass in her left breast and visited our hospital. A thorough examination resulted in a diagnosis of left, locally advanced breast cancer (cT4bN3, M0, cStage Ⅲc) with muscle invasion and Level Ⅲ lymph node metastases. Because of drug-induced lung disease following 4 courses of adriamycin and cyclophosphamide, the chemotherapy had to be stopped. Halsted's operation and postoperative radiotherapy (50 Gy) were performed. The patient was alive with no evidence of recurrence 9 months after surgery. Although multidisciplinary therapy is recommended in locally advanced breast cancer, chemotherapy sometimes cannot be performed due to factors such as age and physical status. Halsted's operation could be considered as a treatment of choice in patients with locally advanced breast cancer. It is important to choose the treatment strategy based on the condition of the patient. PMID:26805178

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

    PubMed Central

    Méndez, Míriam; Custodio, Ana; Provencio, Mariano

    2011-01-01

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

  3. 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

  4. 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

  5. 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

    2016-03-01

    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

  6. Id1 and Id3 co-expression correlates with clinical outcome in stage III-N2 non-small cell lung cancer patients treated with definitive chemoradiotherapy

    PubMed Central

    2013-01-01

    Background Inhibitor of DNA binding 1 (Id1) and 3 (Id3) genes have been related with the inhibition of cell differentiation, cell growth promotion and tumor metastasis. Recently, Id1 has been identified as an independent prognostic factor in patients with lung adenocarcinoma, regardless of the stage. Furthermore, Id1 may confer resistance to treatment (both, radiotherapy and chemotherapy). Methods We have studied, using monoclonal antibodies for immunohistochemistry, the Id1 and Id3 tumor epithelial expression in 17 patients with stage III-N2 non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. Results Id1 expression is observed in 82.4% of the tumors, whereas Id3 expression is present in 41.2% of the samples. Interestingly, Id1 and Id3 expression are mutually correlated (R = 0.579, p = 0.015). In a subgroup analysis of patients with the most locally advanced disease (T4N2 stage), co-expression of Id1 and Id3 showed to be related with a worse overall survival (45 vs 6 months, p = 0.002). A trend towards significance for a worse progression free survival (30 vs 1 months, p = 0.219) and a lower response rate to the treatment (RR = 50% vs 87.5%, p = 0.07) were also observed. Conclusions A correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy. PMID:23311395

  7. 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

  8. Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep

    PubMed Central

    Veiga-Lopez, Almudena; Herkimer, Carol; Abi Salloum, Bachir; Moeller, Jacob; Beckett, Evan; Sreedharan, Rohit

    2015-01-01

    Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insulin sensitizer, rosiglitazone; 5) prenatal T and postnatal flutamide; 6) prenatal T and postnatal rosiglitazone; and 7) prenatal T and postnatal metformin. Prenatal treatments spanned 30–90 days of gestation and postnatal treatments began at approximately 8 weeks of age and continued throughout. Blood samples were taken twice weekly, beginning at approximately 12 weeks of age to time puberty. Two-hour samples after the synchronization with prostaglandin F2α were taken for 120 hours to characterize LH surge dynamics at 7 and 19 months of age. Prenatal T females entered puberty earlier than controls, and all interventions prevented this advancement. Prenatal T reduced the percentage of animals having LH surge, and females that presented LH surge exhibited delayed timing and dampened amplitude of the LH surge. Prenatal androgen antagonist, but not other interventions, restored LH surges without normalizing the timing of the surge. Normalization of pubertal timing with prenatal/postnatal androgen antagonist and insulin sensitizer interventions suggests that pubertal advancement is programmed by androgenic actions of T involving insulin as a mediary. Restoration of LH surges by cotreatment with androgen antagonist supports androgenic programming at the organizational level. PMID:25919188

  9. 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

  10. 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.

  11. Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2016-07-29

    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

  12. The prognosis after contraindicated surgery of NSCLC patients with malignant pleural effusion (M1a) may be better than expected

    PubMed Central

    Liu, Yang; Xie, Dong; Zheng, Hui; He, Jiaxi; Liang, Wenhua; Jiang, Gening; Fei, Ke; Yang, Ping; He, Jianxing; Chen, Chang

    2016-01-01

    Although non-small cell lung cancer (NSCLC) with malignant pleural effusion (M1a) is generally contraindicated for surgery, several reports have demonstrated favorable prognosis. This study aimed to describe the results of surgical intervention in this disease. In this retrospective study, we evaluated NSCLC patients with ipsilateral malignant pleural effusion selected from Surveillance Epidemiology and End-Results database (SEER). Primary tumor resection was compared to no tumor resection in the overall survival (OS) and lung cancer-specific survival (LCSS). Multivariate analyses and propensity score matching were applied to compare the two groups. The study included 2,217 eligible patients. Primary tumor resection group was significantly associated with better OS and LCSS compared to no tumor resection group (the median survival time (MST), 20 vs 7 months; OS, p <0.001; LCSS, p <0.001). Multivariable analyses indicated that no primary tumor resection was associated with decreased OS (Hazard Ratio (HR), 2.136; p<0.001) and LCSS (HR, 2.053; p<0.001). In propensity score-matched pairs, better OS and LCSS were further validated in patients with ipsilateral malignant pleural effusion who underwent primary tumor resection compared to no tumor resection (MST, 20 vs 6 months; OS, p <0.001; LCSS, p <0.001). Similarly, multivariable analyses also indicated that no primary tumor resection was associated with decreased OS (HR, 2.309; p <0.001) and LCSS (HR, 2.301; p <0.001) for patients with ipsilateral malignant pleural effusion. In conclusion, the prognosis after contraindicated surgery of NSCLC patients with malignant pleural effusion (M1a) may be better than expected. Thus, subsequent studies should aim to identify patients who could benefit from surgery. PMID:27057627

  13. Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC.

    PubMed

    Nagel, Remco; Stigter-van Walsum, Marijke; Buijze, Marijke; van den Berg, Jaap; van der Meulen, Ida H; Hodzic, Jasmina; Piersma, Sander R; Pham, Thang V; Jiménez, Connie R; van Beusechem, Victor W; Brakenhoff, Ruud H

    2015-06-01

    Lung cancer is the most common cancer worldwide and on top of that has a very poor prognosis, which is reflected by a 5-year survival rate of 5% to 15%. Radiotherapy is an integral part of most treatment regimens for this type of tumor, often combined with radiosensitizing cytotoxic drugs. In this study, we identified many genes that could potentially be exploited for targeted radiosensitization using a genome-wide siRNA screen in non-small cell lung cancer (NSCLC) cells. The screen identified 433 siRNAs that potentially sensitize lung cancer cells to radiation. Validation experiments showed that knockdown of expression of Forkhead box M1 (FOXM1) or microtubule-associated serine/threonine kinase-like (MASTL) indeed causes radiosensitization in a panel of NSCLC cells. Strikingly, this effect was not observed in primary human fibroblasts, suggesting that the observed radiosensitization is specific for cancer cells. Phosphoproteomics analyses with and without irradiation showed that a number of cell-cycle-related proteins were significantly less phosphorylated after MASTL knockdown in comparison to the control, while there were no changes in the levels of phosphorylation of DNA damage response proteins. Subsequent analyses showed that MASTL knockdown cells respond differently to radiation, with a significantly shortened G2-M phase arrest and defects in cytokinesis, which are followed by a cell-cycle arrest. In summary, we have identified many potential therapeutic targets that could be used for radiosensitization of NSCLC cells, with MASTL being a very promising and druggable target to combine with radiotherapy. PMID:25808837

  14. Cucurbitacin B inhibits the stemness and metastatic abilities of NSCLC via downregulation of canonical Wnt/β-catenin signaling axis

    PubMed Central

    Shukla, Samriddhi; Sinha, Sonam; Khan, Sajid; Kumar, Sudhir; Singh, Kavita; Mitra, Kalyan; Maurya, Rakesh; Meeran, Syed Musthapa

    2016-01-01

    Lack of effective anti-metastatic drugs creates a major hurdle for metastatic lung cancer therapy. For successful lung cancer treatment, there is a strong need of newer therapeutics with metastasis-inhibitory potential. In the present study, we determined the anti-metastatic and anti-angiogenic potential of a natural plant triterpenoid, Cucurbitacin B (CuB) against non-small cell lung cancer (NSCLC) both in vitro and in vivo. CuB demonstrated a strong anti-migratory and anti-invasive ability against metastatic NSCLC at nanomolar concentrations. CuB also showed significant tumor angiogenesis-inhibitory effects as evidenced by the inhibition of migratory, invasive and tube-forming capacities of human umbilical vein endothelial cells. CuB-mediated inhibition of angiogenesis was validated by the inhibition of pre-existing vasculature in chick embryo chorio-allantoic membrane and matrigel plugs. Similarly, CuB inhibited the migratory behavior of TGF-β1-induced experimental EMT model. The CuB-mediated inhibition of metastasis and angiogenesis was attributable to the downregulation of Wnt/β-catenin signaling axis, validated by siRNA-knockdown of Wnt3 and Wnt3a. The CuB-mediated downregulation of Wnt/β-catenin signaling was also validated using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis model in vivo. Collectively, our findings suggest that CuB inhibited the metastatic abilities of NSCLC through the inhibition of Wnt/β-catenin signaling axis. PMID:26905250

  15. Busulfan, Etoposide, and Intensity-Modulated Radiation Therapy Followed By Donor Stem Cell Transplant in Treating Patients With Advanced Myeloid Cancer

    ClinicalTrials.gov

    2016-10-07

    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

  16. [A case of disseminated carcinomatosis of bone marrow with disseminated intravascular coagulation caused by advanced colon cancer treated by mFOLFOX6].

    PubMed

    Isozaki, Yutaka; Yamanishi, Masayoshi; Utsunomiya, Sakae; Yamaguchi, Shunsuke; Okita, Mika; Matsumoto, Naoyuki; Nagao, Yasuyuki; Oyamada, Hirokazu; Kokura, Satoshi; Naito, Yuji; Yoshikawa, Toshikazu

    2011-10-01

    A 45-year-old man was admitted to our hospital because of disseminated intravascular coagulation syndrome (DIC) and severe pain in his back and lumbar. Abdominal CT scan demonstrated lymph node enlargement in the whole body. FDG-PET revealed abnormal uptake of FDG in the thickening wall of the descending colon and the entire skeleton. Colonoscopy was performed continuously and revealed a poorly-differentiated adenocarcinoma of the descending colon. He was treated with the systemic chemotherapy of modified FOLFOX6 (mFOLFOX6). After one course of the treatment, DIC was resolved and severe back pain and lumbargo were improved.

  17. Angiogenesis inhibitors rechallenge in patients with advanced non-small-cell lung cancer: a pooled analysis of randomized controlled trials

    PubMed Central

    Zhao, Lingdi; Li, Wei; Zhang, Huiying; Hou, Nan; Guo, Lanwei; Gao, Quanli

    2015-01-01

    Purpose Data on the role of angiogenesis inhibitors (AIs) rechallenge in the treatment of advanced non-small-cell lung cancer (NSCLC) patients who previously received bevacizumab remain limited. We aim to investigate the efficacy of AIs in the treatment of advanced NSCLC in this setting. Methods Studies from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology meeting up to December 1, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials evaluating AIs in advanced NSCLC, with survival data on patients who previously received bevacizumab. The end points were overall survival and progression-free survival. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies. Results A total of 452 patients with advanced NSCLC who previously received bevacizumab were identified for analysis. The meta-analysis results demonstrated that AI rechallenge significantly improved progression-free survival (hazard ratio: 0.72, 95% confidence interval: 0.58–0.89, P=0.002) when compared to non-AI containing regimens. Additionally, a nonsignificant improvement in overall survival was also observed in advanced NSCLC in this setting (hazard ratio: 0.82, 95% confidence interval: 0.65–1.03, P=0.087). Similar results were also observed in subgroup analysis according to treatment regimens. Conclusion The findings of this study suggest that NSCLC patients who relapsed after a first-line bevacizumab-containing chemotherapy obtain improved clinical benefits from AI rechallenge. Prospective clinical trials investigating the role of AI rechallenge in this setting are recommended. PMID:26491352

  18. 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.

  19. 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.

  20. 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. PMID:26255127

  1. Exosomes derived from gefitinib-treated EGFR-mutant lung cancer cells alter cisplatin sensitivity via up-regulating autophagy

    PubMed Central

    Fan, Lu-Lu; Liu, Yu; Cheng, Liang; Wang, Fang; Yu, Han-Qing; Gao, Jian; Wei, Wei; Wang, Hua; Sun, Guo-Ping

    2016-01-01

    Several clinical trials indicate that concurrent administration of tyrosine kinase inhibitors (TKIs, such as gefitinib or erlotinib) with chemotherapy agents fails to improve overall survival in advanced non-small cell lung cancer (NSCLC) patients. However, the precise mechanisms underlying the antagonistic effects remain unclear. In the present study, we investigated the role of exosomes in the antagonistic effects of concurrent administration of chemotherapy and TKIs. Exosomes derived from gefitinib-treated PC9 cells (Exo-GF) decreased the antitumor effects of cisplatin, while exosomes derived from cisplatin-treated PC9 cells (Exo-DDP) did not significantly affect the antitumor effects of gefitinib. Additionally, inhibition of exosome secretion by GW4869 resulted in a modest synergistic effect when cisplatin and gefitinib were co-administered. Furthermore, Exo-GF co-incubation with cisplatin increased autophagic activity and reduced apoptosis, as demonstrated by an upregulation of LC3-II and Bcl-2 protein levels and downregulation of p62 and Bax protein levels. Thus, the antagonistic effects of gefitinib and cisplatin were mainly attributed to Exo-GF, which resulted in upregulated autophagy and increased cisplatin resistance. These results suggest that inhibition of exosome secretion may be a helpful strategy to overcome the antagonistic effects when TKIs and chemotherapeutic agents are co-administered. Before administering chemotherapy, introducing a washout period to completely eliminate TKI-related exosomes, may be a better procedure for administering chemotherapy and TKIs. PMID:27029054

  2. 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

  3. 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

    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

  4. Prospective clinical study on long-term swallowing function and voice quality in advanced head and neck cancer patients treated with concurrent chemoradiotherapy and preventive swallowing exercises.

    PubMed

    Kraaijenga, Sophie A C; van der Molen, Lisette; Jacobi, Irene; Hamming-Vrieze, Olga; Hilgers, Frans J M; van den Brekel, Michiel W M

    2015-11-01

    Concurrent chemoradiotherapy (CCRT) for advanced head and neck cancer (HNC) is associated with substantial early and late side effects, most notably regarding swallowing function, but also regarding voice quality and quality of life (QoL). Despite increased awareness/knowledge on acute dysphagia in HNC survivors, long-term (i.e., beyond 5 years) prospectively collected data on objective and subjective treatment-induced functional outcomes (and their impact on QoL) still are scarce. The objective of this study was the assessment of long-term CCRT-induced results on swallowing function and voice quality in advanced HNC patients. The study was conducted as a randomized controlled trial on preventive swallowing rehabilitation (2006-2008) in a tertiary comprehensive HNC center with twenty-two disease-free and evaluable HNC patients as participants. Multidimensional assessment of functional sequels was performed with videofluoroscopy, mouth opening measurements, Functional Oral Intake Scale, acoustic voice parameters, and (study specific, SWAL-QoL, and VHI) questionnaires. Outcome measures at 6 years post-treatment were compared with results at baseline and at 2 years post-treatment. At a mean follow-up of 6.1 years most initial tumor-, and treatment-related problems remained similarly low to those observed after 2 years follow-up, except increased xerostomia (68%) and increased (mild) pain (32%). Acoustic voice analysis showed less voicedness, increased fundamental frequency, and more vocal effort for the tumors located below the hyoid bone (n = 12), without recovery to baseline values. Patients' subjective vocal function (VHI score) was good. Functional swallowing and voice problems at 6 years post-treatment are minimal in this patient cohort, originating from preventive and continued post-treatment rehabilitation programs.

  5. 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.

  6. {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.

  7. 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

  8. 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

    2013-07-03

    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

  9. Brain perfusion and permeability in patients with advanced, refractory glioblastoma treated with lomustine and the transforming growth factor-β receptor I kinase inhibitor LY2157299 monohydrate

    PubMed Central

    SEPULVEDA-SANCHEZ, JUAN; RAMOS, ANA; HILARIO, AMAYA; DE VELASCO, GUILLERMO; CASTELLANO, DANIEL; GARCIA DE LA TORRE, MARTA; RODON, JORDI; LAHN, MICHAEL F.

    2015-01-01

    Transforming growth factor-β (TGF-β) signaling is associated with tumor progression and vascularization in malignant glioma. In the present study, magnetic resonance imaging was used to evaluate changes in the size and vascularity of glioblastomas in 12 patients who were treated with lomustine and the novel inhibitor of TGF-β signaling, LY2157299 monohydrate. A response in tumor size was observed in 2 of the 12 patients; in 1 of these 2 patients, a reduction in vascular permeability and perfusion was also detected. The effect was observed following 4 cycles of treatment (~3 months). Changes in vascularity have not previously been attributed to treatment with lomustine; therefore, the effect may be associated with LY2157299 treatment. LY2157299 does not appear to have an anti-angiogenic effect when combined with lomustine, and hence may have a different mechanism of action profile compared with anti-angiogenic drugs. PMID:26137087

  10. 18F-FDG PET/CT Reveals Disease Remission in a Patient With Ipilimumab-Refractory Advanced Melanoma Treated With Pembrolizumab.

    PubMed

    Sachpekidis, Christos; Hassel, Jessica C; Dimitrakopoulou-Strauss, Antonia

    2016-02-01

    Pembrolizumab is an anti-programmed cell death receptor 1 (anti-PD-1) antibody, recently approved for the treatment of ipilimumab-refractory metastatic melanoma. We report on a 49-year-old patient with unresectable metastatic melanoma initially treated with 4 cycles of ipilimumab. Because of demonstration of progressive disease on PET/CT, the patient was enrolled into a clinical trial of pembrolizumab. After completion of 4 cycles of pembrolizumab, the follow-up PET/CT scans performed early after and 7 months after the end of treatment exhibited complete disease remission, reflecting the potential role of the modality in treatment response evaluation of melanoma patients receiving anti-PD-1 therapy.

  11. Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer.

    PubMed

    Dang, Thu Oanh; Ogunniyi, Adebayo; Barbee, Meagan S; Drilon, Alexander

    2016-01-01

    The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.

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

    PubMed

    Zappa, Cecilia; Mousa, Shaker A

    2016-06-01

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

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

    PubMed Central

    Zappa, Cecilia

    2016-01-01

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

  14. 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.

  15. 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

  16. A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC)

    PubMed Central

    Senkus-Konefka, E; Dziadziuszko, R; Bednaruk-Młyński, E; Pliszka, A; Kubrak, J; Lewandowska, A; Małachowski, K; Wierzchowski, M; Matecka-Nowak, M; Jassem, J

    2005-01-01

    A prospective randomised study compared two palliative radiotherapy schedules for inoperable symptomatic non-small-cell lung cancer (NSCLC). After stratification, 100 patients were randomly assigned to 20 Gy/5 fractions (fr)/5 days (arm A) or 16 Gy/2 fr/day 1 and 8 (arm B). There were 90 men and 10 women aged 47–81 years (mean 66), performance status 1–4 (median 2). The major clinical characteristics and incidence and degree of initial disease-related symptoms were similar in both groups. Treatment effects were assessed using patient's chart, doctor's scoring of symptomatic change and chest X-ray. Study end points included degree and duration of symptomatic relief, treatment side effects, objective response rates and overall survival. A total of 55 patients were assigned to arm A and 45 to arm B. In all, 98 patients received assigned treatment, whereas two patients died before its termination. Treatment tolerance was good and did not differ between study arms. No significant differences between study arms were observed in the degree of relief of all analysed symptoms. Overall survival time differed significantly in favour of arm B (median 8.0 vs 5.3 months; P=0.016). Both irradiation schedules provided comparable, effective palliation of tumour-related symptoms. The improved overall survival and treatment convenience of 2-fraction schedule suggest its usefulness in the routine management of symptomatic inoperable NSCLC. PMID:15770205

  17. State of the art in surgery for early stage NSCLC-does the number of resected lymph nodes matter?

    PubMed

    Vielva, Laura Romero; Jaen, Manuel Wong; Alcácer, José A Maestre; Cardona, Mecedes Canela

    2014-04-01

    Surgery is the treatment of choice in patients with early stage NSCLC. However, the results remain poor in these patients. Lymph node involvement is the main prognostic factor in patients with NSCLC, but there is still no clear definition of the number of nodes required to consider a lymphadenectomy as complete. Although there is no defined minimum number of lymph nodes required for a complete lymphadenectomy, there are some recommendations to perform this procedure, published by different scientific societies. Current practice in thoracic surgery regarding lymphadenectomy, differs on some points from the guidelines recommendations, with data regarding patients with no mediastinal assessment between 30-45% according to some of the published data. Different studies have probed the fact that the probability of finding a positive node increases with the number of lymph nodes analyzed. Therefore, a complete lymphadenectomy provides proper staging, which helps to identify the patient's real prognosis. Several nonrandomized studies and retrospective series have shown that survival increases in the group of patients with a higher number of lymph nodes removed. There is no contraindication to performing a complete lymphadenectomy. The increase in survival in patients with a complete lymphadenectomy may be due to more accurate staging. Therefore, complete lymphadenectomy should be mandatory even in early stage patients.

  18. 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

  19. Gene Mutation Analysis in EGFR Wild Type NSCLC Responsive to Erlotinib: Are There Features to Guide Patient Selection?

    PubMed Central

    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

    2014-01-01

    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. PMID:25561229

  20. Critical appraisal of the role of gefitinib in the management of locally advanced or metastatic non-small cell lung cancer.

    PubMed

    Yuan, Ying; Li, Xiao-Fen; Chen, Jia-Qi; Dong, Cai-Xia; Weng, Shan-Shan; Huang, Jian-Jin

    2014-01-01

    Past studies have demonstrated that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors can significantly improve clinical outcomes in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and sensitive EGFR gene mutations. Gefitinib (Iressa(®)), the first oral EGFR tyrosine kinase inhibitor, has been shown to be more effective and better tolerated than chemotherapy either in first-line or second-line treatment for patients with advanced NSCLC harboring sensitive EGFR mutations. Conversely, among patients with wild-type EGFR, gefitinib is inferior to standard chemotherapy in both the first-line and second-line settings. Further, gefitinib is effective in patients with brain metastases because of its low molecular weight and excellent penetration of the blood-brain barrier. In this review, we summarize the current data from clinical trials with gefitinib and appraise its role in the management of locally advanced or metastatic NSCLC.

  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. Multiple Gingival Recession Defects Treated with Coronally Advanced Flap and Either the VISTA Technique Enhanced with GEM 21S or Periosteal Pedicle Graft: A 9-Month Clinical Study.

    PubMed

    Dandu, Shruti Raju; Murthy, K Raja

    2016-01-01

    The objective of this study was to clinically evaluate and compare the efficacy of the vestibular incision subperiosteal tunnel access (VISTA) technique using Bio-Gide (Geistlich) membrane enhanced with GEM 21S (Osteohealth) with periosteal pedicle graft (PPG) using a coronally advanced flap. Multiple gingival recession sites in 15 individuals were randomly assigned either to experimental site A (VISTA) or experimental site B (PPG) in a split-mouth design. The clinical parameters were recorded at baseline and 9 months postoperatively. Repeated measures analysis of variance with post hoc Bonferroni correction and paired t test were used to assess statistical significance (P < .05). Mean recession depth significantly decreased from 4.21 ± 1.08 mm (presurgery) to 0.61 ± 0.92 mm (9 months) with VISTA (87.37 ± 17.78% root coverage) and from 4.17 ± 1.18 mm (presurgery) to 1.16 ± 0.92 mm (9 months) with PPG (71.84 ± 19.25% root coverage). Width of keratinized tissue and clinical attachment gain were significantly higher in the VISTA group compared with the PPG group. Within the limits of the study both VISTA and PPG groups resulted in a significant amount of root coverage. The VISTA technique was less invasive and required minimal time and clinical maneuvering. It also resulted in a superior esthetic outcome. PMID:26901301

  3. Multiple Gingival Recession Defects Treated with Coronally Advanced Flap and Either the VISTA Technique Enhanced with GEM 21S or Periosteal Pedicle Graft: A 9-Month Clinical Study.

    PubMed

    Dandu, Shruti Raju; Murthy, K Raja

    2016-01-01

    The objective of this study was to clinically evaluate and compare the efficacy of the vestibular incision subperiosteal tunnel access (VISTA) technique using Bio-Gide (Geistlich) membrane enhanced with GEM 21S (Osteohealth) with periosteal pedicle graft (PPG) using a coronally advanced flap. Multiple gingival recession sites in 15 individuals were randomly assigned either to experimental site A (VISTA) or experimental site B (PPG) in a split-mouth design. The clinical parameters were recorded at baseline and 9 months postoperatively. Repeated measures analysis of variance with post hoc Bonferroni correction and paired t test were used to assess statistical significance (P < .05). Mean recession depth significantly decreased from 4.21 ± 1.08 mm (presurgery) to 0.61 ± 0.92 mm (9 months) with VISTA (87.37 ± 17.78% root coverage) and from 4.17 ± 1.18 mm (presurgery) to 1.16 ± 0.92 mm (9 months) with PPG (71.84 ± 19.25% root coverage). Width of keratinized tissue and clinical attachment gain were significantly higher in the VISTA group compared with the PPG group. Within the limits of the study both VISTA and PPG groups resulted in a significant amount of root coverage. The VISTA technique was less invasive and required minimal time and clinical maneuvering. It also resulted in a superior esthetic outcome.

  4. 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.

  5. Biomarkers and targeted systemic therapies in advanced non-small cell lung cancer.

    PubMed

    Kumar, Mukesh; Ernani, Vinicius; Owonikoko, Taofeek K

    2015-11-01

    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.

  6. 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.

  7. 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. PMID:25881553

  8. Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs

    PubMed Central

    Lin, Jessica J.; Cardarella, Stephanie; Lydon, Christine A.; Dahlberg, Suzanne E.; Jackman, David M.; Jänne, Pasi A.; Johnson, Bruce E.

    2016-01-01

    Introduction Activating mutations in the epidermal growth factor receptor (EGFR) predict for prolonged progression-free survival in patients with advanced non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy. Long-term survival outcomes, however, remain undefined. The objective of this study was to determine the 5-year survival in these patients, and identify clinical factors associated with overall survival (OS). Methods Patients with EGFR-mutant metastatic lung adenocarcinoma treated with erlotinib or gefitinib at Dana-Farber Cancer Institute between 2002 and 2009 were included. OS was analyzed. Results Among 137 patients, median PFS and OS were 12.1 months (95% CI, 10.2-13.5 months) and 30.9 months (95% CI, 28.2-35.7 months), respectively. Twenty patients (14.6%) were 5-year survivors. In multivariate analysis, exon 19 deletions (hazard ratio [HR], 0.63; 95% CI, 0.44-0.91; P = 0.01), absence of extrathoracic (HR 0.62; 95% CI, 0.41-0.93; P = 0.02) or brain metastasis (HR 0.48; 95% CI, 0.30-0.77, P = 0.002), and not a current smoker (HR 0.23; 95% CI, 0.09-0.59; P = 0.002) were associated with prolonged OS. Age, gender, stage at diagnosis, liver or bone or adrenal metastasis, specific TKI, and line of TKI therapy were not associated with OS. Conclusions Our data suggest that the prevalence of 5-year survival among EGFR-mutant metastatic lung adenocarcinoma patients treated with erlotinib or gefitinib is 14.6%. Exon 19 deletions and absence of extrathoracic or brain metastasis are associated with prolonged survival. Based on our findings, clinicians can gain an enhanced estimation of long-term outcomes in this population. PMID:26724471

  9. 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

  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. Five-Year Follow-Up of Patients With Advanced Chronic Lymphocytic Leukemia Treated With Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning

    PubMed Central

    Sorror, Mohamed L.; Storer, Barry E.; Sandmaier, Brenda M.; Maris, Michael; Shizuru, Judith; Maziarz, Richard; Agura, Edward; Chauncey, Thomas R.; Pulsipher, Michael A.; McSweeney, Peter A.; Wade, James C.; Bruno, Benedetto; Langston, Amelia; Radich, Jerald; Niederwieser, Dietger; Blume, Karl G.; Storb, Rainer; Maloney, David G.

    2008-01-01

    Purpose We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. Patients and Methods Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n = 52) or unrelated (n = 30) donors. Results Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy ≥ 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. Conclusion Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients. PMID:18794548

  12. 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.

  13. Prognostic Value of Abnormal p53 Expression in Locally Advanced Prostate Cancer Treated With Androgen Deprivation and Radiotherapy: A Study Based on RTOG 9202

    SciTech Connect

    Che Mingxin DeSilvio, Michelle; Pollack, Alan; Grignon, David J.; Venkatesan, Varagur Mohan; Hanks, Gerald E.; Sandler, Howard M.

    2007-11-15

    Purpose: The goal of this study was to verify the significance of p53 as a prognostic factor in Radiation Therapy Oncology Group 9202, which compared short-term androgen deprivation (STAD) with radiation therapy (RT) to long-term androgen deprivation + RT in men with locally advanced prostate cancer (Pca). Methods and Materials: Tumor tissue was sufficient for p53 analysis in 777 cases. p53 status was determined by immunohistochemistry. Abnormal p53 expression was defined as 20% or more tumor cells with positive nuclei. Univariate and multivariate Cox proportional hazards models were used to evaluate the relationships of p53 status to patient outcomes. Results: Abnormal p53 was detected in 168 of 777 (21.6%) cases, and was significantly associated with cause-specific mortality (adjusted hazard ratio [HR] = 1.89; 95% confidence interval (CI) 1.14 - 3.14; p = 0.014) and distant metastasis (adjusted HR = 1.72; 95% CI 1.13-2.62; p = 0.013). When patients were divided into subgroups according to assigned treatment, only the subgroup of patients who underwent STAD + RT showed significant correlation between p53 status and cause-specific mortality (adjusted HR = 2.43; 95% CI = 1.32-4.49; p = 0.0044). When patients were divided into subgroups according to p53 status, only the subgroup of patients with abnormal p53 showed significant association between assigned treatment and cause-specific mortality (adjusted HR = 3.81; 95% CI 1.40-10.37; p = 0.0087). Conclusions: Abnormal p53 is a significant prognostic factor for patients with prostate cancer who undergo short-term androgen deprivation and radiotherapy. Long-term androgen deprivation may significantly improve the cause-specific survival for those with abnormal p53.

  14. 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). PMID:25600300

  15. 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).

  16. 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.

  17. 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

  18. Erlotinib Hydrochloride and Cetuximab in Treating Patients With Advanced Gastrointestinal Cancer, Head and Neck Cancer, Non-Small Cell Lung Cancer, or Colorectal Cancer

    ClinicalTrials.gov

    2015-09-28

    Adenocarcinoma of the Colon; Adenocarcinoma of the Rectum; Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Gastrointestinal Stromal Tumor; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Colon Cancer; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Anal Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Colon Cancer; Stage IV Esophageal Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer

  19. 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

  20. Predictive and Prognostic Value of Ribonucleotide Reductase Regulatory Subunit M1 and Excision Repair Cross-Complementation Group 1 in Advanced Urothelial Carcinoma (UC) Treated with First-Line Gemcitabine Plus Platinum Combination Chemotherapy.

    PubMed

    Kim, Miso; Ku, Ja Hyeon; Kwak, Cheol; Kim, Hyeon Hoe; Lee, Eunsik; Keam, Bhumsuk; Kim, Tae Min; Heo, Dae Seog; Lee, Se-Hoon; Moon, Kyung Chul

    2015-01-01

    Preclinical and clinical studies have suggested that expression of ribonucleotide reductase regulatory subunit M1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) is associated with resistance to gemcitabine and cisplatin, respectively. We evaluated the significance of RRM1 and ERCC1 expression to predict tumor response to gemcitabine plus platinum chemotherapy (GP) and survival in advanced UC. We retrospectively collected tumor samples and reviewed clinical data of 53 patients with unresectable or metastatic UC, who were treated with first-line GP. RRM1 and ERCC1 expression were measured by immunohistochemistry. Among 53 patients, 12 (22.6%) and 26 (49.1%) patients had tumors that demonstrated a high expression for RRM1 and ERCC1, respectively. Twenty-nine (70.7%) of 41 patients with low RRM1 expression achieved a clinical response (complete + partial responses), but only 3 (25.0%) of 12 patients with high RRM1 expression achieved a clinical response after GP (P=0.007). Nineteen (70.4%) of 27 patients with low ERCC1 expression achieved a clinical response, while 13 (50.0%) of 26 patients with high ERCC1 expression achieved a clinical response (P=0.130). High RRM1 expression was associated with shorter progression free survival and overall survival (PFS P=0.006, OS P=0.006). Multivariate analysis confirmed that patients with high RRM1 expression had a significantly greater risk of progression and death than those with low RRM1 expression. ERCC1 status was not a significant predictor for PFS and OS. RRM1 expression was predictive and prognostic of clinical outcome in advanced UC treated with gemcitabine plus platinum combination chemotherapy.

  1. Relationship between quality of life and clinical outcomes in advanced non-small cell lung cancer: best supportive care (BSC) versus BSC plus chemotherapy.

    PubMed

    Thongprasert, S; Sanguanmitra, P; Juthapan, W; Clinch, J

    1999-04-01

    In a prospective randomized study, 287 patients with advanced non-small cell lung cancer (NSCLC) stage IIIb or IV with ECOG performance status (PS) 0-1 or 2 were randomly assigned to receive either best supportive care (BSC) or supportive care plus combination chemotherapy (IEP regimen: ifosfamide 3 gm/m2 IV with mesna uroprotection, epirubicin 60 mg/m2 IV on day 1 and cisplatin 60 mg/m2 IV on day 2; or MVP regimen: mitomycin-C 8 mg/m2, cisplatin 100 mg/m2 IV on day 1, vinblastine 4 mg/m2 IV on days 1 and 15). Serial assessment of Karnofsky performance status (KPS), modified Functional Living Index-Cancer (T-FLIC) and modified Quality of Life-Index (T-QLI) were used to estimate the quality of life. Interviews were done at entry, at the third month and at 2 months post complete treatment. At least two courses of chemotherapy were considered to be adequate for response evaluation. Patients were treated for a total of four to six courses or until progression of disease. Partial response rates were 40 and 41.7% in IEP and MVP arms. Median survival durations were 5.9 and 8.1 months for the IEP and MVP chemotherapy arms, and 4.1 months for BSC (log-rank test: P = 0.0003). One year survival was 13, 29.8 and 39.3% for the BSC, IEP and MVP regimens, respectively. Two years survival was 7.8, 6.4 and 13.1% for the BSC, IEP and MVP regimens, respectively. Improvement in quality of life (QOL) scores at the first, second and third interview were seen in chemotherapy arms only, not in the BSC arm. We conclude that combination chemotherapy improves the quality of life as well as prolonging the survival of patients with advanced NSCLC.

  2. Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents.

    PubMed

    Klingbeil, Olaf; Lesche, Ralf; Gelato, Kathy A; Haendler, Bernard; Lejeune, Pascale

    2016-01-01

    Non-small cell lung cancer (NSCLC) has the highest incidence of cancer-related death worldwide and a high medical need for more effective therapies. Small-molecule inhibitors of the bromodomain and extra terminal domain (BET) family such as JQ1, I-BET762 and OTX-015 are active in a wide range of different cancer types, including lung cancer. Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the effects of BET inhibition on the apoptotic pathway remain largely unknown. Here we evaluated the activity of BET bromodomain inhibitors on cell cycle distribution and on components of the apoptosis response. Using a panel of 12 KRAS-mutated NSCLC models, we found that cell lines responsive to BET inhibitors underwent apoptosis and reduced their S-phase population, concomitant with downregulation of c-Myc expression. Conversely, ectopic c-Myc overexpression rescued the anti-proliferative effect of JQ1. In the H1373 xenograft model, treatment with JQ1 significantly reduced tumor growth and downregulated the expression of c-Myc. The effects of BET inhibition on the expression of 370 genes involved in apoptosis were compared in sensitive and resistant cells and we found the expression of the two key apoptosis regulators FLIP and XIAP to be highly BET dependent. Consistent with this, combination treatment of JQ1 with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the pro-apoptotic chemotherapeutic agent cisplatin enhanced induction of apoptosis in both BET inhibitor sensitive and resistant cells. Further we showed that combination of JQ1 with cisplatin led to significantly improved anti-tumor efficacy in A549 tumor-bearing mice. Altogether, these results show that the identification of BET-dependent genes provides guidance for the choice of drug combinations in cancer treatment. They also demonstrate that BET inhibition primes NSCLC cells for induction of apoptosis and that a combination with pro

  3. Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptotic agents

    PubMed Central

    Klingbeil, Olaf; Lesche, Ralf; Gelato, Kathy A; Haendler, Bernard; Lejeune, Pascale

    2016-01-01

    Non-small cell lung cancer (NSCLC) has the highest incidence of cancer-related death worldwide and a high medical need for more effective therapies. Small-molecule inhibitors of the bromodomain and extra terminal domain (BET) family such as JQ1, I-BET762 and OTX-015 are active in a wide range of different cancer types, including lung cancer. Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the effects of BET inhibition on the apoptotic pathway remain largely unknown. Here we evaluated the activity of BET bromodomain inhibitors on cell cycle distribution and on components of the apoptosis response. Using a panel of 12 KRAS-mutated NSCLC models, we found that cell lines responsive to BET inhibitors underwent apoptosis and reduced their S-phase population, concomitant with downregulation of c-Myc expression. Conversely, ectopic c-Myc overexpression rescued the anti-proliferative effect of JQ1. In the H1373 xenograft model, treatment with JQ1 significantly reduced tumor growth and downregulated the expression of c-Myc. The effects of BET inhibition on the expression of 370 genes involved in apoptosis were compared in sensitive and resistant cells and we found the expression of the two key apoptosis regulators FLIP and XIAP to be highly BET dependent. Consistent with this, combination treatment of JQ1 with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the pro-apoptotic chemotherapeutic agent cisplatin enhanced induction of apoptosis in both BET inhibitor sensitive and resistant cells. Further we showed that combination of JQ1 with cisplatin led to significantly improved anti-tumor efficacy in A549 tumor-bearing mice. Altogether, these results show that the identification of BET-dependent genes provides guidance for the choice of drug combinations in cancer treatment. They also demonstrate that BET inhibition primes NSCLC cells for induction of apoptosis and that a combination with pro

  4. Baseline, Trend, and Normalization of Carcinoembryonic Antigen as Prognostic Factors in Epidermal Growth Factor Receptor-Mutant Nonsmall Cell Lung Cancer Patients Treated With First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

    PubMed Central

    Chen, Yu-Mu; Lai, Chien-Hao; Chang, Huang-Chih; Chao, Tung-Ying; Tseng, Chia-Cheng; Fang, Wen-Feng; Wang, Chin-Chou; Chung, Yu-Hsiu; Huang, Kuo-Tung; Chen, Hung-Cheng; Chang, Ya-Chun; Lin, Meng-Chih

    2015-01-01

    Abstract Among epidermal growth factor receptor (EGFR) mutation status unknown nonsmall cell lung cancer (NSCLC) patients, those with higher carcinoembryonic antigen (CEA) level are more likely to response to EGFR-tyrosine kinase inhibitors (TKIs) because they tend to have mutant epidermal growth factor receptor (EGFR). However, patients with higher CEA also have more tumor burden. With the above paradoxical evidence, it is prudent to understand the prognostic significance of baseline CEA in patients with EGFR-mutant NSCLC treated with first-line EGFR-TKIs. The clinical significance of the trend in CEA after treatment and the impact of CEA normalization during EGFR-TKI therapy are also unknown and potentially important. A total of 241 patients who received first-line EGFR-TKIs were included. As to baseline CEA, patients were divided into normal, low, and high baseline CEA by cut point determined by receiver operating characteristic curves. As to CEA responses, patients were divided into 3 groups accordingly to their amount of CEA change after taking TKIs. In group A, 1-month follow-up CEA level decreased more than 35% with nadir CEA normalization; in group B, 1-month follow-up CEA level decreased more than 35% without nadir CEA normalization; and in group C, 1-month follow-up CEA level decreased less than 35% or increased. Patients with higher baseline CEA levels had shorter progression-free survival (PFS) and overall survival (OS) (CEA > 32 vs 5–32 vs <5 ng/mL, PFS = 8.8 vs 11.3 vs 14.4 months, respectively, P < 0.001; OS = 17.8 vs 22.0 vs 27.9 months, respectively, P = 0.01). For trend and CEA normalization in groups A, B, and C, PFS was 14.3, 10.6, and 7.1 months, respectively (P < 0.001); OS was 29.7, 20.0, and 16.2 months, respectively (P < 0.001). Baseline, trend, and normalization of CEA levels are potential prognostic markers for patients with EGFR-mutant advanced NSCLC treated with first line EGFR-TKIs. PMID:26683939

  5. Vitamin D-Related Gene Polymorphisms, Plasma 25-Hydroxy-Vitamin D, Cigarette Smoke and Non-Small Cell Lung Cancer (NSCLC) Risk.

    PubMed

    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 rs1544410 in

  6. 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

  7. 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

  8. Maximal Oxygen Uptake--Risk Predictor of NSCLC Resection in Patients With Comorbid Emphysema: Lessons From NETT.

    PubMed

    Makey, Ian; Berger, Robert L; Cabral, Howard J; Celli, Bartolome; Folch, Erik; Whyte, Richard I

    2015-01-01

    We compared VO2 max values from ACCP Guidelines and from NETT's homogenous NULPD surrogate for predicting operative mortalities. Estimated mid and long-term non-cancer related survival in NETT's subset was also obtained. NETT and ACCP Guideline VO2 max values were similar in the "low" and "mid" risk operative mortality categories but NETT's "high" risk subset showed lower mortality (14% vs. 26%). Estimated non-cancer related survival in NETT "low", "mid" and "high" risk VO2 max categories at two and eight years were 100%, 74%, 59% and 48%, 26%, 14%, respectively. The lower predicted risk in NETT's "high- risk" subset raises the possibility of extending indications for potential curative resection in selected patients. The NETT surrogate also provides hitherto unavailable estimate on long-term non-cancer related survival after potential curative resection of NSCLC and suggests that the operation does not shorten eight-year longevity.

  9. 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.

  10. 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.

  11. An epigenetic auto-feedback loop regulates TGF-β type II receptor expression and function in NSCLC.

    PubMed

    Yang, Shanzhong; Cho, Yong-Jig; Jin, Lin; Yuan, Guandou; Datta, Arunima; Buckhaults, Phillip; Datta, Pran K

    2015-10-20

    The downregulation of transforming growth factor-β (TGF-β) type II receptor (TβRII) expression and function plays a pivotal role in the loss of the TGF-β-induced tumor suppressor function that contributes to lung cancer progression. The aberrant expression of miRNAs has been shown to be involved in the regulation of oncogenes and tumor suppressor genes. Our current study involving miRNA microarray, northern blot and QRT-PCR analysis shows an inverse correlation between miR-20a and TβRII expression in non-small cell lung cancer (NSCLC) tissues and cell lines. Stable expression of miR-20a downregulates TβRII in lung epithelial cells which results in an inhibition of TGF-β signaling and attenuation of TGF-β-induced cell growth suppression and apoptosis. Stable knock down of miR-20a increases TβRII expression and inhibits tumorigenicity of lung cancer cells in vivo. Oncogene c-Myc promotes miR-20a expression by activating its promoter leading to downregulation of TβRII expression and TGF-ß signaling. MiR-145, which is upregulated by TGF-β, inhibits miR-20a expression by targeting c-Myc and upregulates TβRII expression. These correlations among miRNAs and cellular proteins are supported by TCGA public database using NSCLC specimens. These results suggest a novel mechanism for the loss of TβRII expression and TGF-β-induced tumor suppressor functions in lung cancer through a complex auto-feedback loop TGF-β/miR-145/c-Myc/miR-20a/TβRII.

  12. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial

    PubMed Central

    Herbst, Roy S; Sun, Yan; Eberhardt, Wilfried E E; Germonpré, Paul; Saijo, Nagahiro; Zhou, Caicun; Wang, Jie; Li, Longyun; Kabbinavar, Fairooz; Ichinose, Yukito; Qin, Shukui; Zhang, Li; Biesma, Bonne; Heymach, John V; Langmuir, Peter; Kennedy, Sarah J; Tada, Hiroomi; Johnson, Bruce E

    2011-01-01

    Summary Background Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). Methods Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB–IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m2 IV every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377. Findings 1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus docetaxel alone (hazard ratio [HR] 0·79, 97·58% CI 0·70–0·90; p<0·0001); median PFS was 4·0 months in the vandetanib group versus 3·2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0·79, 0·62–1·00, p=0·024); median PFS was 4·6 months in the vandetanib group versus 4·2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel

  13. Treating Meningitis

    MedlinePlus

    ... ways to treat bacterial meningitis. 1 They compared steroids (dexamethasone) with pla- cebo. The doctors gave medication ( ... compared anti- biotics by themselves with antibiotics plus steroids. Dr. Fritz and colleagues compared the mortality (deaths) ...

  14. The role of maintenance treatment in advanced non-small-cell lung cancer: reality or early second line?

    PubMed

    Gridelli, Cesare; Rossi, Antonio; Maione, Paolo; Ambrosio, Rita; Barbato, Valentina; Bareschino, Maria Anna; Schettino, Clorinda; Palazzolo, Giovanni; Sacco, Paola Claudia

    2010-11-01

    First-line platinum-based chemotherapy has reached a plateau of effectiveness for the treatment of patients with advanced non-small-cell lung cancer (NSCLC). In patients who reported a stable disease, no more than 4 cycles of chemotherapy are recommended while a maximum of 6 cycles is recommended in patients who are responding to therapy. A potential strategy with the aim of improving outcomes for NSCLC patients is to administer more therapy. This term includes different approaches: duration of therapy, sequential therapy, consolidation therapy, and maintenance therapy. Here, we attempt to define the different approaches that fall under the rubric of maintenance strategy, and discuss the results available to date.

  15. Protein 4.1N acts as a potential tumor suppressor linking PP1 to JNK-c-Jun pathway regulation in NSCLC

    PubMed Central

    Zhou, Weihua; Liu, Feng; Zhang, Bin; Zhu, Min; Yang, Qin; Zeng, Yayue; Sun, Yang; Sun, Shuming; Wang, Yanpeng; Zhang, Yibin; Weng, Haibo; Chen, Lixiang; Ye, Mao; An, Xiuli; Liu, Jing

    2016-01-01

    Protein 4.1N is a member of protein 4.1 family and has been recognized as a potential tumor suppressor in solid tumors. Here, we aimed to investigate the role and mechanisms of 4.1N in non-small cell lung cancer (NSCLC). We confirmed that the expression level of 4.1N was inversely correlated with the metastatic properties of NSCLC cell lines and histological grade of clinical NSCLC tissues. Specific knockdown of 4.1N promoted tumor cell proliferation, migration and adhesion in vitro, and tumor growth and metastasis in mouse xenograft models. Furthermore, we identified PP1 as a novel 4.1N-interacting molecule, and the FERM domain of 4.1N mediated the interaction between 4.1N and PP1. Further, ectopic expression of 4.1N could inactivate JNK-c-Jun signaling pathway through enhancing PP1 activity and interaction between PP1 and p-JNK. Correspondingly, expression of potential downstream metastasis targets (ezrin and MMP9) and cell cycle targets (p53, p21 and p19) of JNK-c-Jun pathway were also regulated by 4.1N. Our data suggest that down-regulation of 4.1N expression is a critical step for NSCLC development and that repression of JNK-c-Jun signaling through PP1 is one of the key anti-tumor mechanisms of 4.1N. PMID:26575790

  16. Activity of topotecan given intravenously for 5 days every three weeks in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes: a phase II study.

    PubMed

    Gonzalez, Emilio Esteban; Villanueva, Noemi; Fra, Joaquin; Berros, Jose Pablo; Jimenez, Paula; Luque, María; Muñiz, Isabel; Blay, Pilar; Fernandez, Yolanda; Vieitez, José María; Muriel, Carolina; Sanmamed, Miguel; Coto, Pablo Pardo; Izquierdo, Marta; Estrada, Enrique; Lacave, Angel J

    2011-12-01

    Topotecan, a semi-synthetic camptothecin analogue with topoisomerase I interaction, has shown to be an active agent in the treatment of advanced refractory lung cancer. This paper describes the authors' experience with this drug when used as a single agent in patients (pts) with advanced non-small cell lung cancer (NSCLC) refractory to platinum- and taxane-containing chemotherapy regimens. Thirty-five patients with NSCLC refractory to previous chemotherapy and KI ≥ 60% were included in the study. Their characteristics are as follows: median age of 52 years (range 43-69) and Karnofsky PS of 70 (60-80); 27 were male and 8 were female. Twenty-one (60%) patients had adenocarcinoma; eleven (31.4%), squamous cell, and three (8.5%), undifferentiated carcinoma. There was a median of two disease sites and two prior chemotherapy regimens. Topotecan was administered at a dose of 1.25 mg/m(2) I.V. daily for 5 days, repeated every 21 days until disease progression, maximal response, or intolerable toxicity. After 73 cycles, patients received a median of 2 treatment cycles (1-9). All patients except one were considered evaluable for toxicity; eight episodes (24%) of nausea/vomiting and two episodes (6%) of grade 1-2 asthenia, respectively, were reported. Four (12%) patients developed grade 1-2 anemia and two (6%) subjects suffered grade 3 anemia. Seven (21%) patients had grade 1-2 neutropenia and one (3%) presented grade 5 neutropenia. In 33 patients evaluable for activity of the 35 subjects included in the study; one (2.8%) presented a partial response; nine (25.7%) had stable disease, and 23 (65.7%) exhibited disease progression. Median time to progression and overall survival were 54 (12-210) and 70 (12-324) days, respectively. Intravenous topotecan at that dose and administration schedule displays scant activity in terms of response rate in individuals with advanced NSCLC previously treated with platinum and taxanes. The role and usefulness of chemotherapy in this setting

  17. A phase I/II trial of irinotecan-cisplatin combined with an anti-late-diarrhoeal programme to evaluate the safety and antitumour response of this combination therapy in patients with advanced non-small-cell lung cancer.

    PubMed

    Takeda, Y; Tsuduki, E; Izumi, S; Hojo, M; Kamimura, M; Naka, G; Kobayashi, K; Kudo, K

    2005-12-12

    We conducted a phase I/II study in patients with advanced non-small-cell lung cancer (NSCLC) to increase the therapeutic index of the cisplatin-irinotecan combination by institution of an anti-late-diarrhoeal program (ADP). A total of 77 chemotherapy-naive patients with advanced NSCLC were enrolled. The cisplatin dose was fixed at 60 mg m(-2) (Day 1). Irinotecan was escalated in 5 mg m(-2) increments, starting from 60 mg m(-2) (Days 1 and 8). ADP consisted of oral sodium bicarbonate, magnesium oxide, basic water, and ursodeoxycholic acid, and was administered orally for 4 days with each dose of irinotecan. In the phase I portion, irinotecan pharmacokinetics was also examined. After the recommended dose of irinotecan with ADP was determined, a phase II study was conducted to evaluate the response. Maximum tolerated dose was reached at an irinotecan dose of 80 mg m(-2) (Grade 4 diarrhoea and neutropenia). Pharmacokinetic studies show that the maximum concentration and the area under the curve of both irinotecan and SN38 (active metabolite of irinotecan) tend to increase in the dose-dependent manner of irinotecan. The phase II portion of the study included 48 patients, who were treated with 75 mg m(-2) of irinotecan. Grade 3/4 toxicities included neutropenia in 65%, leucopenia in 33%, and late diarrhoea in 6% of the patients. During this treatment, PS did not change in 65% of patients. At the end of the chemotherapy, PS did not decline in 90% of patients. In the phase II portion, a response occurred in 63% (95% confidential interval (CI), 47-76%) of patients. Median time to progression was 19 weeks (95% CI, 15-22 weeks), and median survival was 52 weeks (95% CI, 39-64 weeks). This regimen of irinotecan and cisplatin with ADP resulted in promising efficacy with acceptable toxicity for patients with advanced NSCLC. This regimen is a candidate for the experimental arm towards future phase III studies. PMID:16288302

  18. Treatment approaches in patients with advanced non-small cell lung cancer and poor performance status.

    PubMed

    Govindan, Ramaswamy; Garfield, David H

    2004-12-01

    It is estimated that 30% to 40% of patients with advanced non-small cell lung cancer (NSCLC) have a poor performance status (PS)-defined as a score of 2 or higher on the Eastern Cooperative Oncology Group scale-because of their disease burden, comorbidities, or both. Survival is shorter in these patients than in those with a better PS, and they do not tolerate chemotherapy as well. There is now evidence that PS2 patients with advanced NSCLC can benefit from single-agent chemotherapy with drugs such as vinorelbine, gemcitabine, paclitaxel, pemetrexed, and docetaxel and that combination chemotherapy may have additional advantages. The optimal treatment for PS2 patients with NSCLC, however, has yet to be determined. The case histories in this article demonstrate that PS2 patients are a heterogeneous group and that selecting the chemotherapy for each patient must take into consideration comorbidities and disease-related symptoms, as well as the potential toxicity of treatment. Large prospective clinical trials are needed to determine whether, and in which patients, combination chemotherapy or novel agents, such as the epidermal growth factor receptor inhibitors or paclitaxel poliglumex, have advantages. Three large phase III trials-Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reactions trials (STELLAR)-are now being conducted in PS2 patients with NSCLC. It is hoped that their findings will aid in determining the best treatment options for these patients.

  19. 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

  20. Reciprocal positive regulation between Cx26 and PI3K/Akt pathway confers acquired gefitinib resistance in NSCLC cells via GJIC-independent induction of EMT

    PubMed Central

    Yang, J; Qin, G; Luo, M; Chen, J; Zhang, Q; Li, L; Pan, L; Qin, S

    2015-01-01

    Gefitinib efficiency in non-small-cell lung cancer (NSCLC) therapy is limited due to development of drug resistance. The molecular mechanisms of gefitinib resistance remain still unclear. In this study, we first found that connexin 26 (Cx26) is the predominant Cx isoform expressed in various NSCLC cell lines. Then, two gefitinib-resistant (GR) NSCLC cell lines, HCC827 GR and PC9 GR, from their parental cells were established. In these GR cells, the results showed that gefitinib resistance correlated with changes in cellular EMT phenotypes and upregulation of Cx26. Cx26 was detected to be accumulated in the cytoplasm and failed to establish functional gap-junctional intercellular communication (GJIC) either in GR cells or their parental cells. Ectopic expression of GJIC-deficient chimeric Cx26 was sufficient to induce EMT and gefitinib insensitivity in HCC827 and PC9 cells, while knockdown of Cx26 reversed EMT and gefitinib resistance in their GR cells both in vitro and in vivo. Furthermore, Cx26 overexpression could activate PI3K/Akt signaling in these cells. Cx26-mediated EMT and gefitinib resistance were significantly blocked by inhibition of PI3K/Akt pathway. Specifically, inhibition of the constitutive activation of PI3K/Akt pathway substantially suppressed Cx26 expression, and Cx26 was confirmed to functionally interplay with PI3K/Akt signaling to promote EMT and gefitinib resistance in NSCLC cells. In conclusion, the reciprocal positive regulation between Cx26 and PI3K/Akt signaling contributes to acquired gefitinib resistance in NSCLC cells by promoting EMT via a GJIC-independent manner. PMID:26203858

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

    PubMed Central

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

    2016-01-01

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

  2. 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

  3. Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced HCC patients treated with sorafenib: results from a retrospective analysis of the HCC-AVR group

    PubMed Central

    Gardini, Andrea Casadei; Scarpi, Emanuela; Marisi, Giorgia; Foschi, Francesco Giuseppe; Donati, Gabriele; Giampalma, Emanuela; Faloppi, Luca; Scartozzi, Mario; Silvestris, Nicola; Bisulli, Marcello; Corbelli, Jody; Gardini, Andrea; Barba, Giuliano La; Veneroni, Luigi; Tamberi, Stefano; Cascinu, Stefano; Frassineti, Giovanni Luca

    2016-01-01

    Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (−0.30, p=0.0008) in the responder group (−0.58, p=0.003) than in those with progressive disease (−0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatment. PMID:26893366

  4. 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.

  5. 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 of diagnosis. Results Preoperative treatment achieved clinical response in 76.6% of patients and complete pathologic response in 5%. The clinical, pathological and immunohistochemical parameters were not able to predict response to therapy and, only HER2 protein overexpression was associated with a decrease in disease free and overall survival (P = 0.0007 and P = 0.003) as shown by multivariate analysis. Conclusion Immunohistochemical phenotypes were not able to predict response to neoadjuvant chemotherapy. Clinical response is inversely correlated with a risk of death in patients submitted to neoadjuvant chemotherapy and HER2 overexpression is the major prognostic factor in stage II and III breast cancer patients treated with a neoadjuvant docetaxel and epirubicin combination. PMID:17324279

  6. Treating Sludges

    ERIC Educational Resources Information Center

    Josephson, Julian

    1978-01-01

    Discussed are some of the ways to handle municipal and industrial wastewater treatment sludge presented at the 1978 American Chemical Society meeting. Suggestions include removing toxic materials, recovering metals, and disposing treated sewage sludge onto farm land. Arguments for and against land use are also given. (MA)

  7. Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer?

    PubMed Central

    Wang, Shuai; Yang, Zhe; Wang, Zhou

    2015-01-01

    Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) might be new therapeutic strategies for advanced non-small cell lung cancer (NSCLC). Here a total of 12,520 patients from 23 randomized controlled trials (RCTs) were enrolled to evaluate the efficacy and safety of VEGFR-TKIs quantitatively in advanced NSCLC. Compared with non-VEGFR-TKIs, VEGFR-TKIs regimen significantly improved progression-free survival (PFS) [hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.805-0.874, P < 0.001], objective response rates (ORR) [relative risk (RR): 1.374, 95% CI: 1.193-1.583, P < 0.001] and disease control rates (DCR) (RR: 1.113, 95% CI: 1.027-1.206, P = 0.009), but not overall survival (OS) (HR: 0.960, 95% CI: 0.921-1.002, P = 0.060) for NSCLC patients. The RR of all-grade neutropenia, thrombocytopenia, hypertension, hemorrhage, fatigue, anorexia, stomatitis, diarrhea, rash, hand-foot skin reaction (HFSR) were increased in patients received VEGFR-TKIs. As for high-grade (≥ 3) adverse events (AEs), VEGFR-TKIs were associated with higher RR of neutropenia, thrombocytopenia, hypertension, fatigue, stomatitis, diarrhea, rash and HFSR. This study demonstrates VEGFR-TKIs improve PFS, ORR and DCR, but not OS in advanced NSCLC patients. VEGFR-TKIs induce more frequent and serious AEs compared with control therapies. PMID:26156021

  8. Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) – From Preclinical Studies to a Clinical Phase II Trial

    PubMed Central

    Specht, Hanno M.; Ahrens, Norbert; Blankenstein, Christiane; Duell, Thomas; Fietkau, Rainer; Gaipl, Udo S.; Günther, Christine; Gunther, Sophie; Habl, Gregor; Hautmann, Hubert; Hautmann, Matthias; Huber, Rudolf Maria; Molls, Michael; Offner, Robert; Rödel, Claus; Rödel, Franz; Schütz, Martin; Combs, Stephanie E.; Multhoff, Gabriele

    2015-01-01

    Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both

  9. Phase 2 Study of Concurrent Cetuximab Plus Definitive Thoracic Radiation Therapy Followed by Consolidation Docetaxel Plus Cetuximab in Poor Prognosis or Elderly Patients With Locally Advanced Non-Small Cell Lung Cancer

    SciTech Connect

    Dilling, Thomas J.; Extermann, Martine; Kim, Jongphil; Thompson, Lora M.; Yue, Binglin; Stevens, Craig W.; Antonia, Scott; Gray, Jhanelle; Williams, Charles; Haura, Eric; Pinder-Schenck, Mary; Tanvetyanon, Tawee; Kim, Sungjune; Chiappori, Alberto

    2014-11-15

    Background: Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab. Methods and Materials: Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-“dry” IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). Results: From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board–approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications. Conclusions: Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause.

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

    PubMed Central

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

    2013-01-01

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

  11. A patient previously treated with ALK inhibitors for central nervous system lesions from ALK rearranged lung cancer: a case report

    PubMed Central

    Kashima, Jumpei; Okuma, Yusuke; Hishima, Tsunekazu

    2016-01-01

    Background Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) are now preferentially treated with tyrosine kinase inhibitors (TKIs). However, patients treated with ALK inhibitors end up with acquired resistance. Case presentation We present a patient with recurrent ALK-rearranged NSCLC that developed multiple brain metastases and meningitis carcinomatosa after sequential treatment with several lines of cytotoxic chemotherapy, crizotinib, and alectinib. After the patient underwent retreatment with crizotinib as salvage therapy because of poor performance status, the intracranial metastatic foci and meningeal thickening were shrank within 1 week. Conclusion Our experience with this case suggests that alectinib may restore sensitivity to crizotinib or amplified pathway such as MET which bestowed alectinib resistance was inhibited with crizotinib. PMID:27785052

  12. Second- and Further-Line Therapy with Erlotinib in Patients with Advanced Non-Small-Cell Lung Cancer in Daily Clinical Practice

    PubMed Central

    Krainhöfer, Josephine; Steinert, Matthias; Reissig, Angelika

    2014-01-01

    Introduction. The aim of this retrospective study was to examine effect of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) in second-line and further therapy in daily clinical practice. Methods. Patients with histologically or cytologically proven NSCLC (n = 84) treated with erlotinib in second-line (n = 34), third-line (n = 36), and more-line therapy (n = 14) were examined for progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of therapy, and adverse effects. Results. Median PFS of all lines was 83 days (CI 70.0–96.0), OS was 7 months (CI 4.7–9.3), DCR was 66.2% (CI 55–77%), and 1-year survival rate was 33% (CI 22–43%), with no significant difference between therapy lines. Median duration of treatment was 76 days (IQR 39–139.5). Patients with epidermal growth factor receptor mutation (EGFR-M) reached the highest PFS (204 days), as did patients with good performance status (ECOG 0-1: 94 versus ECOG 2-3: 65 days, P = 0.035). Patients with EGFR-M also revealed a DCR of 100%. The most frequent side effects were rash (69%) and diarrhoea (41%), without any significant difference between therapy lines. In 24 patients, the treatment dose was reduced and in 18, the therapy was paused. Conclusion. Erlotinib works in all therapy lines without any significant differences in efficacy and side effects. PMID:25028671

  13. Comparative metabolomics profiling of isogenic KRAS wild type and mutant NSCLC cells in vitro and in vivo

    PubMed Central

    Brunelli, Laura; Caiola, Elisa; Marabese, Mirko; Broggini, Massimo; Pastorelli, Roberta

    2016-01-01

    Oncogenes induce metabolic reprogramming on cancer cells. Recently, G12C KRAS mutation in isogenic NSCLC cell line has been shown to be a key player in promoting metabolic rewiring mainly through the regulation of glutamine metabolism to fuel growth and proliferation. Even though cell lines possessing many of the genetic backgrounds of the primary cancer they derive from could be a valuable pre-clinical model, they do not have the additional complexity present in the whole tumor that impact metabolism. This preliminary study is aimed to explore how cancer cell metabolism in culture might recapitulate the metabolic alterations present in vivo. Our result highlighted that the gross metabolic changes observed in G12C KRAS mutant cells growing in culture were also maintained in the derived xenograft model, suggesting that a simple in vitro cell model can give important insights into the metabolic alterations induced by cancer. This is of relevance for guiding effective targeting of those metabolic traits that underlie tumor progression and anticancer treatment responses. PMID:27329432

  14. FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC

    PubMed Central

    Merolla, Francesco; Poser, Ina; Visconti, Roberta; Ilardi, Gennaro; Paladino, Simona; Inuzuka, Hiroyuki; Guggino, Gianluca; Monaco, Roberto; Colecchia, David; Monaco, Guglielmo; Cerrato, Aniello; Chiariello, Mario; Denning, Krista; Claudio, Pier Paolo; Staibano, Stefania; Celetti, Angela

    2015-01-01

    CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet. We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response. Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy. PMID:25885523

  15. FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC.

    PubMed

    Morra, Francesco; Luise, Chiara; Merolla, Francesco; Poser, Ina; Visconti, Roberta; Ilardi, Gennaro; Paladino, Simona; Inuzuka, Hiroyuki; Guggino, Gianluca; Monaco, Roberto; Colecchia, David; Monaco, Guglielmo; Cerrato, Aniello; Chiariello, Mario; Denning, Krista; Claudio, Pier Paolo; Staibano, Stefania; Celetti, Angela

    2015-05-20

    CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response.Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy.

  16. Adenovirus-mediated wild-type p53 gene transfer in combination with bronchial arterial infusion for treatment of advanced non-small-cell lung cancer, one year follow-up

    PubMed Central

    Guan, Yong-song; Liu, Yuan; Zou, Qing; He, Qing; La, Zi; Yang, Lin; Hu, Ying

    2009-01-01

    Objective: In the present study, we have examined the safety and efficacy of recombinant adenovirus encoding human p53 tumor suppressor gene (rAd-p53) injection in patients with advanced non-small-cell lung cancer (NSCLC) in the combination with the therapy of bronchial arterial infusion (BAI). Methods: A total of 58 patients with advanced NSCLC were enrolled in a non-randomized, two-armed clinical trial. Of which, 19 received a combination treatment of BAI and rAd-p53 (the combo group), while the remaining 39 were treated with only BAI (the control group). Patients were followed up for 12 months, with safety and local response evaluated by the National Cancer Institute’s Common Toxicity Criteria and response evaluation criteria in solid tumor (RECIST), respectively. Time to progression (TTP) and survival rates were also analyzed by Kaplan-Meier method. Results: In the combo group, 19 patients received a total of 49 injections of rAd-p53 and 46 times of BAI, respectively, while 39 patients in the control group received a total of 113 times of BAI. The combination treatment was found to have less adverse events such as anorexia, nausea and emesis, pain, and leucopenia (P<0.05) but more arthralgia, fever, influenza-like symptom, and myalgia (P<0.05), compared with the control group. The overall response rates (complete response (CR)+partial response (PR)) were 47.3% and 38.4% for the combo group and the control group, respectively (P>0.05). Patients in the combo group had a longer TTP than those in the control group (a median 7.75 vs 5.5 months, P=0.018). However, the combination treatment did not lead to better survival, with survival rates at 3, 6, and 12 months in the combo group being 94.74%, 89.47%, and 52.63%, respectively, compared with 92.31%, 69.23%, and 38.83% in the control group (P=0.224). Conclusion: Our results show that the combination of rAd-p53 and BAI was well tolerated in patients with NSCLC and may have improved the quality of life and delayed

  17. Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study

    SciTech Connect

    Vainshtein, Jeffrey M.; Schipper, Matthew; Zalupski, Mark M.; Lawrence, Theodore S.; Abrams, Ross; Francis, Isaac R.; Khan, Gazala; Leslie, William; Ben-Josef, Edgar

    2013-05-01

    Purpose: Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. Methods and Materials: Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factors on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. Results: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). Conclusions: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression

  18. Efficacy of targeted agents in the treatment of elderly patients with advanced non-small-cell lung cancer: a systematic review and meta-analysis

    PubMed Central

    Chen, Jianqing; Chen, Jianbo; Wu, Xiaoan; Shi, Tao; Kang, Meiling

    2016-01-01

    Purpose The efficacy of targeted agents (TAs) in the treatment of elderly patients with advanced non-small-cell lung cancer (NSCLC) remains controversial. We aimed to assess the efficacy of TAs in the treatment of advanced NSCLC in this setting. Materials and methods Relevant trials were identified by searching electronic databases and conference meetings. Prospective randomized controlled trials assessing chemotherapies with or without TAs in elderly patients with advanced NSCLC were included. Outcomes of interest included overall survival (OS) and progression-free survival (PFS) in elderly patients with advanced NSCLC. Results A total of 4,093 elderly patients from 17 randomized controlled trials were included for analysis. The addition of TAs to chemotherapy significantly improved PFS (hazard ratio [HR] 0.85, 95% confidence interval [CI]: 0.75–0.96, P=0.01) when compared to chemotherapy alone. There was also a tendency to improve OS in the combination groups (HR 0.92, 95% CI: 0.85–1.01, P=0.064). Subgroup analysis based on treatment line indicated that TAs plus chemotherapy as first-line chemotherapy in elderly patients with advanced NSCLC significantly improved PFS (HR 0.80, 95% CI: 0.68–0.95, P=0.01) and OS (HR 0.91, 95% CI: 0.83–0.99, P=0.037), while the use of TA-containing regimens as second-line therapy in these patients did not significantly improve PFS (HR 0.91, 95% CI: 0.75–1.10, P=0.33) and OS (HR 1.04, 95% CI: 0.81–1.33, P=0.77) in comparison with chemotherapy alone. No publication bias was detected by Begg’s and Egger’s tests for OS. Conclusion The findings of this study suggest that the addition of TAs to first-line chemotherapy in elderly patients with advanced NSCLC offers an improved PFS and OS. Further trials are recommended to clearly investigate the efficacy of adding specific TAs to first-line chemotherapy for advanced NSCLC in this setting. PMID:27536143

  19. Resveratrol overcomes gefitinib resistance by increasing the intracellular gefitinib concentration and triggering apoptosis, autophagy and senescence in PC9/G NSCLC cells

    PubMed Central

    Zhu, Yinsong; He, Wenjuan; Gao, Xiujuan; Li, Bin; Mei, Chenghan; Xu, Rong; Chen, Hui

    2015-01-01

    Gefitinib (Gef) provides clinical benefits to non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. However, acquired resistance (AR) is a major obstacle to effective Gef therapy. This study demonstrated that resveratrol (Res) could synergize with Gef to inhibit the proliferation of Gef-resistant NSCLC cells. The underlying mechanisms of synergism were investigated, and the results showed that cotreatment with Gef and Res could inhibit EGFR phosphorylation by increasing intracellular Gef accumulation through the impairment of Gef elimination from PC9/G cells. Consistently, CYP1A1 and ABCG2 expression were inhibited. Meanwhile, the cotreatment significantly induced cell apoptosis, autophagy, cell cycle arrest and senescence accompanied by increased expression of cleaved caspase-3, LC3B-II, p53 and p21. Further studies revealed that autophagy inhibition enhanced apoptosis and abrogated senescence while apoptosis inhibition had no notable effect on cell autophagy and senescence during cotreatment with Gef and Res. These results indicated that in addition to apoptosis, senescence promoted by autophagy contributes to the antiproliferation effect of combined Gef and Res on PC9/G cells. In conclusion, combined treatment with Gef and Res may represent a rational strategy to overcome AR in NSCLC cells. PMID:26635117

  20. LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small cell lung cancer (NSCLC) cells

    PubMed Central

    Whang, Young Mi; Park, Serk In; Trenary, Irina A.; Egnatchik, Robert A.; Fessel, Joshua P.; Kaufman, Jacob M.; Carbone, David P.; Young, Jamey D.

    2015-01-01

    The tumor suppressor serine/threonine kinase 11 (STK11 or LKB1) is mutated in 20–30% of non-small cell lung cancer (NSCLC) patient tumors. Loss of LKB1-AMPK signaling confers sensitivity to metabolic inhibition or stress-induced mitochondrial insults. We tested the hypothesis that loss of LKB1 sensitizes NSCLC cells to energetic stress induced by treatment with erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib in vitro and in vivo that was associated with alterations in energy metabolism and mitochondrial dysfunction. Loss of LKB1 expression altered the cellular response to erlotinib treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species (ROS). Furthermore, erlotinib selectively blocked mTOR signaling, inhibited cell growth, and activated apoptosis in LKB1-deficient cells. Erlotinib treatment also induced AMPK activation despite loss of LKB1 expression, which was partially reduced by the application of a CaMKKβ inhibitor (STO-609) or calcium chelator (BAPTA-AM). These findings may have significant implications for the design of novel NSCLC treatments that target dysregulated metabolic and signaling pathways in LKB1-deficient tumors. PMID:26119936

  1. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations

    PubMed Central

    Wang, Jun; Wang, Baocheng; Chu, Huili; Yao, Yunfeng

    2016-01-01

    Identifying activating EGFR mutations is a useful predictive strategy that helps select a population of advanced non-small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors (TKIs). Patients with sensitizing EGFR mutations (predominantly an in-frame deletion in exon 19 and an L858R substitution) are highly responsive to first-generation EGFR TKIs, such as gefitinib and erlotinib, and show improved progression-free survival without serious side effects. However, all patients with activating EGFR mutations who are initially responsive to EGFR TKIs eventually develop acquired resistance after a median progression-free survival of 10–16 months, followed by disease progression. Moreover, ~20%–30% of NSCLC patients have no objective tumor regression on initial EGFR TKI treatment, although they harbor an activating EGFR mutation. These patients represent an NSCLC subgroup that is defined as having intrinsic or primary resistance to EGFR TKIs. Different mechanisms of acquired EGFR TKI resistance have been identified, and several novel compounds have been developed to reverse acquired resistance, but little is known about EGFR TKI intrinsic resistance. In this review, we summarize the latest findings involving mechanisms of intrinsic resistance to EGFR TKIs in advanced NSCLC with activating EGFR mutations and present possible therapeutic strategies to overcome this resistance. PMID:27382309

  2. Risk of venous and arterial thromboembolic events associated with anti-VEGF agents in advanced non-small-cell lung cancer: a meta-analysis and systematic review

    PubMed Central

    Zhang, Dianbao; Zhang, Xianfen; Zhao, Chunling

    2016-01-01

    Aims To assess the incidence and risk of arterial and venous thromboembolic events (ATEs and VTEs) associated with antivascular endothelial growth factor (VEGF) agents, including VEGF receptor-tyrosine kinase inhibitors and VEGF monoclonal antibodies, in advanced non-small-cell lung cancer (NSCLC) patients. Methods We performed a broad search of PubMed for relevant trials. Prospective randomized trials evaluating therapy with or without anti-VEGF agents in patients with advanced NSCLC were included for analysis. Data on VTEs and ATEs were extracted. The overall incidence, Peto odds ratio (Peto OR), and 95% confidence intervals (CIs) were pooled according to the heterogeneity of included trials. Results A total of 13,436 patients from 23 trials were included for analysis. Our results showed that anti-VEGF agents significantly increased the risk of developing high-grade ATEs (Peto OR: 1.44, 95% CI: 1.00–2.07, P=0.048), but not for all-grade ATEs (Peto OR: 0.94, 95% CI: 0.56–1.59, P=0.82) compared with controls. Additionally, no increased risk of all-grade and high-grade VTEs (Peto OR: 0.94, 95% CI: 0.67–1.31, P=0.71 and Peto OR: 0.95, 95% CI: 0.73–1.22, P=0.67, respectively) was observed in advanced NSCLC patients receiving anti-VEGF agents. Conclusion The use of anti-VEGF agents in advanced NSCLC patients significantly increased the risk of high-grade ATEs, but not for VTEs. Clinicians should be aware of the risk of severe ATEs with administration of these drugs in advanced NSCLC patients. PMID:27382307

  3. 8-Oxoguanine incision activity is impaired in lung tissues of NSCLC patients with the polymorphism of OGG1 and XRCC1 genes.

    PubMed

    Janik, Justyna; Swoboda, Maja; Janowska, Beata; Cieśla, Jarosław M; Gackowski, Daniel; Kowalewski, Janusz; Olinski, Ryszard; Tudek, Barbara; Speina, Elżbieta

    2011-05-10

    Decreased repair of oxidative DNA damage is a risk factor for developing certain human malignancies. We have previously found that the capacity of 8-oxo-7,8-dihydroguanine repair was lower in leukocytes of NSCLC patients than in controls. To explain these observations, we searched for mutations and polymorphisms in the OGG1 gene among 88 NSCLC patients and 79 controls. One patient exhibited a heterozygous mutation in exon 1, which resulted in Arg46Gln substitution. Normal lung and tumor tissue carrying this mutation showed markedly lower 8-oxoG incision activity than the mean for all patients. The predominant polymorphism of OGG1 was Ser326Cys. A significant difference was observed in the frequencies of the OGG1 variants between populations of NSCLC patients and controls. The frequency of the Cys326 allele and the number of Cys326Cys homozygotes was higher among patients than controls. In individuals with either Ser326Cys or Cys326Cys genotype 8-oxoG incision rate was lower than in those with both Ser326 alleles, either in lung or leukocytes. Moreover, 8-oxodG level was higher in lung tissue and leukocytes of patients carrying two Cys326 alleles and in leukocytes of patients with the Ser326Cys genotype. We also screened for polymorphisms of the XRCC1 gene. Only heterozygotes of the XRCC1 variants Arg194Trp, Arg280His and Arg399Gln were found among patients and controls, with the frequency of Arg280His being significantly higher among patients. NSCLC patients with Arg280His or Arg399Gln polymorphism revealed lower 8-oxoG incision activity in their lung tissues, but not in leukocytes. We can conclude that the OGG1 Ser326Cys polymorphisms may have an impact on the efficiency of 8-oxoG incision in humans and the XRCC1 His280 and Gln399 may influence the OGG1 activity in tissues exposed to chronic oxidative/inflammatory stress. Higher frequency of the OGG1 Cys326 allele among NSCLC patients may partially explain the impairment of the 8-oxoG repair observed in their

  4. Investigations of (99m)Tc-labeled glucarate as a SPECT radiotracer for non-small cell lung cancer (NSCLC) and potential tumor uptake mechanism.

    PubMed

    Meng, Lanfang; Xiu, Yan; Li, Yanli; Xu, Xiaobo; Li, Shanqun; Li, Xiao; Pak, Koon Y; Shi, Hongcheng; Cheng, Dengfeng

    2015-07-01

    This study attempted to evaluate the feasibility of (99m)Tc-labeled glucarate ((99m)Tc-GLA) imaging in non-small cell lung cancer (NSCLC) and the potential tumor uptake mechanism. Cell lysates from two NSCLC cell lines, H292 and H1975, were immunoblotted with anti-glucose transporter 5 (GLUT5) antibody for Western blotting. Thereafter, the two cell lines were used to examine cellular uptake of (99m)Tc-GLA with or without fructose. SPECT/CT imaging studies were performed on small animals bearing H292 and H1975 tumors. Biodistribution studies were also conducted to achieve accurate tissue uptake of this tracer in two tumor models. Hematoxylin & eosin (H&E) staining and GLUT5, Ki67 and cytokeratin-7 (CK-7) immunohistochemistry (IHC) analysis were further investigated on tumor tissues. In Western blotting, H292 cells showed higher levels of GLUT5 compared to the H1975 cells. Meanwhile, the in vitro cell assays indicated GLUT5-dependent uptake of (99m)Tc-GLA in H292 and H1975 cells. The fructose competition assays showed a significant decrease in (99m)Tc-GLA uptake by H292 and H1975 cells when fructose was added. The (99m)Tc-GLA accumulation was as much as two-fold higher in H292 implanted tumors than in H1975 implanted tumors. (99m)Tc-GLA exhibited rapid clearance pharmacokinetics and reasonable uptake in human NSCLC H292 (1.69±0.37 ID%/g) and H1975 (0.89±0.06 ID%/g) implanted tumors at 30min post injection. Finally, the expression of GLUT5, Ki67 and CK-7 on tumor tissues also exhibited positive correlation with the in vitro cell test results and in vivo SPECT/CT imaging results in xenograft tumors. Both in vitro and ex vivo studies demonstrated that the uptake of (99m)Tc-GLA in NSCLC is highly related to GLUT5 expression. Imaging and further IHC results support that (99m)Tc-GLA could be a promising SPECT imaging agent for NSCLC diagnosis and prognosis evaluation. PMID:25890861

  5. First-line systemic treatment of advanced stage non-small-cell lung cancer in Asia: consensus statement from the Asian Oncology Summit 2009.

    PubMed

    Soo, Ross A; Anderson, Benjamin O; Cho, Byoung Chul; Yang, Chih-Hsin; Liao, Meilin; Lim, Wan-Teck; Goldstraw, Peter; Mok, Tony S

    2009-11-01

    Non-small-cell lung cancer (NSCLC) is an increasing global challenge, especially in low-income countries. Most guidelines for the management of advanced-stage NSCLC have limited effect in countries with resource constraints. Following a systematic literature search, we present an overview of the management of advanced-stage NSCLC in the first-line setting, discuss resources required for systemic therapy, and provide treatment recommendations stratified to four resources levels. Treatment guidelines appropriate for different resource levels offer a realistic approach to management of advanced-stage NSCLC, by recognising the limitations of a particular health-care system. Although there are many barriers to cancer control in low-resource countries, these can be overcome by using measures that are culturally appropriate, economically feasible, and evidence-based. Initiatives include strategic planning, tobacco control, training of health-care workers, access to therapeutic agents, acquisition of information, public education, and alliances with established institutions and international organisations. PMID:19880064

  6. Genetic variants of CHRNA5-A3 and CHRNB3-A6 predict survival of patients with advanced non-small cell lung cancer

    PubMed Central

    Wang, Yang; Peng, Xiaonu; Zhu, Lijun; Hu, Likuan; Song, Yipeng

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) play a key role in carcinogenesis and progression of lung cancer; and polymorphisms in CHRNA5-A3 and CHRNB3-A6, two gene clusters encoding nAChR subunits, have been associated with lung cancer risk. In this study, we investigated whether variants in the two gene clusters were associated with prognosis of advanced non-small cell lung cancer (NSCLC). A total of 165 stage IIIB–IV NSCLC patients were enrolled in this study. Three polymorphisms (rs667282 and rs3743073 in CHRNA5-A3 and rs13280604 in CHRNB3-A6) were genotyped using the TaqMan method. Overall survival (OS) was estimated using the log-rank test and the Cox models. Our results showed that patients with CHRNA5-A3 rs667282 TT or TC genotypes had a significantly shorter OS than those carrying the CC genotype (Log-rank, P = 0.043). Furthermore, multivariate Cox regression analysis showed that rs667282 TT/TC genotypes are significantly associated with increased risk of overall deaths (adjusted hazard ratio, 1.7; 95% CI, 1.1–2.7). However, the similar results were not observed for other two polymorphisms. Furthermore, no evident association was found between these variants and clinicopathologic features of advanced NSCLC. Our present study suggested that rs667282 in CHRNA5-A3 may modify the prognosis of patients with advanced NSCLC. PMID:27050379

  7. Exercise and nutrition interventions in advanced lung cancer: a systematic review

    PubMed Central

    Payne, C.; Larkin, P.J.; McIlfatrick, S.; Dunwoody, L.; Gracey, J.H.

    2013-01-01

    In this systematic review, we sought to evaluate the effect of physical activity or nutrition interventions (or both) in adults with advanced non-small-cell lung cancer (nsclc). Methods A systematic search for relevant clinical trials was conducted in 6 electronic databases, by hand searching, and by contacting key investigators. No limits were placed on study language. Information about recruitment rates, protocol adherence, patient-reported and clinical outcome measures, and study conclusions was extracted. Methodologic quality and risk of bias in each study was assessed using validated tools. Main Results Six papers detailing five studies involving 203 participants met the inclusion criteria. Two of the studies were single-cohort physical activity studies (54 participants), and three were controlled nutrition studies (149 participants). All were conducted in an outpatient setting. None of the included studies combined physical activity with nutrition interventions. Conclusions Our systematic review suggests that exercise and nutrition interventions are not harmful and may have beneficial effects on unintentional weight loss, physical strength, and functional performance in patients with advanced nsclc. However, the observed improvements must be interpreted with caution, because findings were not consistent across the included studies. Moreover, the included studies were small and at significant risk of bias. More research is required to ascertain the optimal physical activity and nutrition interventions in advanced inoperable nsclc. Specifically, the potential benefits of combining physical activity with nutrition counselling have yet to be adequately explored in this population. PMID:23904771

  8. Efficacy of Addition of Antiangiogenic Agents to Taxanes-Containing Chemotherapy in Advan