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Sample records for advanced stage nsclc

  1. 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. PMID:27296106

  2. High serum level of C-reactive protein is associated with worse outcome of patients with advanced-stage NSCLC treated with erlotinib.

    PubMed

    Fiala, Ondrej; Pesek, Milos; Finek, Jindrich; Topolcan, Ondrej; Racek, Jaroslav; Minarik, Marek; Benesova, Lucie; Bortlicek, Zbynek; Poprach, Alexandr; Buchler, Tomas

    2015-12-01

    Erlotinib is a low molecular weight tyrosine kinase inhibitor (TKI) directed at epidermal growth factor receptor (EGFR), widely used in the treatment of locally advanced or metastatic-stage non-small cell lung cancer (NSCLC). Although introduction of EGFR-TKIs have significantly extended survival of advanced-stage NSCLC patients, their efficacy in the entire patient population is relatively low. Aside from activating EGFR mutations, no reliable biochemical or molecular predictors of response to erlotinib have been established. The aim of our retrospective study was to evaluate the association of baseline serum levels of C-reactive protein (CRP) with outcomes in patients with advanced-stage NSCLC treated with erlotinib. We retrospectively analyzed clinical data of 595 patients with advanced-stage NSCLC (IIIB or IV) treated with erlotinib. Serum CRP was measured using an immunoturbidimetric method. High baseline levels of CRP (≥10 mg/l) were measured in 387 (65 %) patients, and normal levels (<10 mg/l) were measured in 208 (35 %) patients. The median progression-free survival (PFS) and overall survival (OS) for patients with high CRP was 1.8 and 7.7 compared to 2.8 and 14.4 months for patients with low CRP (p < 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that CRP was significantly associated with PFS and also with OS (hazard ratio (HR) = 1.57, p < 0.001, and HR = 1.63, p < 0.001, respectively). In conclusion, the results of the conducted retrospective study suggest that high baseline level of CRP was independently associated with worse outcome of patients with advanced-stage NSCLC treated with erlotinib. CRP is a commonly used biomarker which is simple and easy to detect, and thus, it is feasible for the use in the routine clinical practice. PMID:26088452

  3. 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

  4. Quantification of Cell-Free mSHOX2 Plasma DNA for Therapy Monitoring in Advanced Stage Non-Small Cell (NSCLC) and Small-Cell Lung Cancer (SCLC) Patients

    PubMed Central

    Schmidt, Bernd; Beyer, Julia; Dietrich, Dimo; Bork, Ines; Liebenberg, Volker; Fleischhacker, Michael

    2015-01-01

    Purpose Most patients suffering from advanced lung cancer die within a few months. To exploit new therapy regimens we need better methods for the assessment of a therapy response. Material and Methods In a pilot study we prospectively enrolled 36 patients with advanced NSCLC and SCLC (34 stage IV, 2 stage IIIB) of whom 34 received standard platinum-based chemo/radiotherapy and two were treated with a tyrosine kinase inhibitor. We measured the levels of extracellular methylated SHOX2 DNA (mSHOX2) in plasma before and during therapy until re-staging. The mSHOX2 analysis was blinded with respect to the clinical data making it an observational study. Results According to the re-staging of 31 first-line patients, 19 patients were classified as non-responders while 12 patients were in the responder group. We observed a tight correlation between radiological data and the change of plasma mSHOX2 level as the equivalent for a therapy response. A ROC analysis showed a high discriminatory power for both patient groups already one week after therapy start (AUC 0.844). Additionally, a Kaplan-Meier and Cox Proportional Hazards analyses revealed a strong relationship between survival and plasma mSHOX2 value p≤0.001 (hazard ratio 11.08) providing some evidence for mSHOX2 also being a predictive marker. Conclusion The longitudinal measurement of extracellular plasma mSHOX2 DNA yields information about the response to cytotoxic treatment and allows an early assessment of treatment response for lung cancer patients. If confirmed in a larger study this would be a valuable tool for selecting and guiding a cytotoxic treatment. PMID:25675432

  5. Tracheo-parenchymal fistula following concurrent chemo-radiation for stage III NSCLC.

    PubMed

    Alzghoul, Bashar; Meena, Nikhil

    2016-01-01

    Non-Small Cell Cancer (NSCLC) are frequently diagnosed at a later stage [1]. Treatment involves chemotherapy and radiation, either sequentially or concurrently [2]. Concurrent therapy is more efficacious but also associated with more complications [4-6]. We present a rare care of trachea-pulmonary fistula formation after concurrent chemo and radiation in a patient with Squamous Cell Cancer (SCC). PMID:27144112

  6. Diagnostic value of Cyfra21-1, SCC and CEA for differentiation of early-stage NSCLC from benign lung disease.

    PubMed

    Chen, Feng; Wang, Xiu-Ying; Han, Xiao-Hong; Wang, Hai; Qi, Jun

    2015-01-01

    Non-small cell lung cancer (NSCLC), which account for the most of lung carcinoma, is sometimes difficult to differentiate from benign lung diseases presented with nodular shadow in imaging scan. There is a need to find another non-invasive way to diagnosis early-stage NSCLC. To examine the potential diagnostic value of SCC, CFYRA 21-1 and CEA for the differentiation of early-stage NCSCL from benign lung diseases, we analyzed serum levels of tumor markers in 278 patients, including 248 patients with NSCLC and 30 patients with benign lung diseases. These benign lung diseases were presented with evidence of a high likelihood of having lung cancer. After surgical operation, diagnosis of lung cancer and benign lung disease were confirmed by histological examination. Preoperative tumor marker levels were quantified. Mann-Whitney U test was used to compare median levels of SCC, CFYRA 21-1 and CEA between the benign group and lung cancer group. Analysis of variance results were used for differences between different clinical stages of NSCLC. ROC was used to evaluate the diagnostic value of tumor markers. The median levels of Cyfra21-1, SCC and CEA were much higher in NSCLC than those in benign lung diseases. And we found that the mean levels of tumor marker were higher in advanced stage of NSCLC. The combination of tumor markers resulted in a higher sensitivity (91.3%) and a lower specificity (86.7%). In conclusion, the combination of positive SCC, positive CEA and positive Cyfra21-1 appear to be helpful in distinguishing early-stage NSCLC from benign lung disease which presented with suspicious pulmonary masses. PMID:26379938

  7. Diagnostic value of Cyfra21-1, SCC and CEA for differentiation of early-stage NSCLC from benign lung disease

    PubMed Central

    Chen, Feng; Wang, Xiu-Ying; Han, Xiao-Hong; Wang, Hai; Qi, Jun

    2015-01-01

    Non-small cell lung cancer (NSCLC), which account for the most of lung carcinoma, is sometimes difficult to differentiate from benign lung diseases presented with nodular shadow in imaging scan. There is a need to find another non-invasive way to diagnosis early-stage NSCLC. To examine the potential diagnostic value of SCC, CFYRA 21-1 and CEA for the differentiation of early-stage NCSCL from benign lung diseases, we analyzed serum levels of tumor markers in 278 patients, including 248 patients with NSCLC and 30 patients with benign lung diseases. These benign lung diseases were presented with evidence of a high likelihood of having lung cancer. After surgical operation, diagnosis of lung cancer and benign lung disease were confirmed by histological examination. Preoperative tumor marker levels were quantified. Mann-Whitney U test was used to compare median levels of SCC, CFYRA 21-1 and CEA between the benign group and lung cancer group. Analysis of variance results were used for differences between different clinical stages of NSCLC. ROC was used to evaluate the diagnostic value of tumor markers. The median levels of Cyfra21-1, SCC and CEA were much higher in NSCLC than those in benign lung diseases. And we found that the mean levels of tumor marker were higher in advanced stage of NSCLC. The combination of tumor markers resulted in a higher sensitivity (91.3%) and a lower specificity (86.7%). In conclusion, the combination of positive SCC, positive CEA and positive Cyfra21-1 appear to be helpful in distinguishing early-stage NSCLC from benign lung disease which presented with suspicious pulmonary masses. PMID:26379938

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

    PubMed Central

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

    2012-01-01

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

  9. 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

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

    PubMed Central

    Kavanagh, Brian D.; Karam, Sana D.

    2015-01-01

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

  11. 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

  12. Stereotactic body radiotherapy in operable patients with stage I NSCLC: where is the evidence?

    PubMed

    Guckenberger, Matthias

    2015-05-01

    This review summarizes the evidence of stereotactic body radiotherapy (SBRT) as an alternative to surgery (lobectomy and sublobar resection) for stage I NSCLC. Three randomized trials comparing SBRT and surgery were initiated but all three were stopped early due to poor accrual. As the next level of evidence, results from matched-pair analyses performed in single-institutional (n = 4), multi-institutional (n = 3) and population-based (n = 3) settings are available. There was close agreement between all studies that SBRT is at least equivalent to sublobar resection making it the preferred treatment for a high-risk population. SBRT was equivalent to lobectomy in the endpoints of loco-regional control and cancer-specific survival. Disease-free survival and overall survival were inferior after SBRT compared with lobectomy in one and two studies, respectively, and not significantly different in all other studies. Consequently, for patients without relevant comorbidities, who are accepting the risk of a surgical procedure, lobectomy remains the standard of care. PMID:25761997

  13. Prediction models for platinum-based chemotherapy response and toxicity in advanced NSCLC patients.

    PubMed

    Yin, Ji-Ye; Li, Xi; Li, Xiang-Ping; Xiao, Ling; Zheng, Wei; Chen, Juan; Mao, Chen-Xue; Fang, Chao; Cui, Jia-Jia; Guo, Cheng-Xian; Zhang, Wei; Gao, Yang; Zhang, Chun-Fang; Chen, Zi-Hua; Zhou, Hui; Zhou, Hong-Hao; Liu, Zhao-Qian

    2016-07-10

    In this study, we aimed to establish a platinum-based chemotherapy response and toxicity prediction model in advanced non-small cell lung cancer (NSCLC) patients. 416 single nucleotide polymorphisms (SNPs) in 185 genes were genotyped, and their association with drug response and toxicity were estimated using logistic regression. Nine data mining techniques were employed to establish the prediction model; the sensitivity, specificity, overall accuracy and receiver operating characteristic (ROC) curve were used to assess the models' performance. Finally, selected models were validated in an independent cohort. The models established by naïve Bayesian algorithm had the best performance. The response prediction model achieved a sensitivity of 0.90 and a specificity of 0.47 with the ROC area under curve (AUC) of 0.80. The overall toxicity prediction model achieved a sensitivity of 0.86 and a specificity of 0.46 with the ROC AUC of 0.73. The hematological toxicity prediction model achieved a sensitivity of 0.89 and a specificity of 0.39 with the ROC AUC of 0.76. The gastrointestinal toxicity prediction model achieved a sensitivity of 0.93 and a specificity of 0.35 with the ROC AUC of 0.80. In conclusion, we provided platinum-based chemotherapy response and toxicity prediction models for advanced NSCLC patients. PMID:27126360

  14. 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

  15. 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

  16. 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

  17. CT-guided permanent brachytherapy for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC).

    PubMed

    Martínez-Monge, Rafael; Pagola, María; Vivas, Isabel; López-Picazo, José María

    2008-08-01

    Seven patients with early stage T1N0M0 NSCLC who had medical contraindications for surgical resection were treated with CT-guided percutaneous implantation of (103)Pd or (125)I seeds. After the procedure, two patients developed pneumothorax and hemo/pneumothorax that was managed with aspirative drainage. One patient developed a focal pneumonitis 3 months after the procedure. After a median follow-up of 13 months (4.6-41.0+ months), no patient has developed local or regional failure. PMID:18243409

  18. 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

  19. 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

  20. 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

  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. EGFR testing and clinical management of advanced NSCLC: a Galician Lung Cancer Group study (GGCP 048-10)

    PubMed Central

    Vázquez, Sergio; Casal, Joaquín; Afonso Afonso, Francisco Javier; Fírvida, José Luis; Santomé, Lucía; Barón, Francisco; Lázaro, Martín; Pena, Carolina; Amenedo, Margarita; Abdulkader, Ihab; González-Arenas, Carmen; Fachal, Laura; Vega, Ana

    2016-01-01

    Purpose This study aimed to assess the incidence of mutations in the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients in the Galician region of Spain and the clinical management and outcome of patients carrying EGFR mutations. Patients and methods All newly diagnosed advanced or metastatic NSCLC patients were screened for EGFR mutations in matched tumor samples (tissue or cytology specimens) and serum samples. Results Of 198 patients screened for EGFR mutations in tumor samples, 184 had evaluable data and, of these, 25 (13.6%) had EGFR mutations (84% sensitizing mutations). EGFR mutation was found in serum in 14 (8.1%) patients (of 174 evaluable). Compared to matched tumor tissue, serum EGFR mutation testing specificity and sensitivity were 99% and 52%, respectively. All but two patients received gefitinib. Median progression-free survival and overall survival were 10 (95% confidence interval: 4.8–15.3) months and 17.8 (95% confidence interval: 13.9–21.6) months, respectively, in patients carrying sensitizing mutations. Conclusion The incidence of EGFR mutations in Galicia is consistent with previous data in Spain. Our results also support the feasibility of EGFR testing to guide treatment decision making using tumor tissue or cytology samples, or serum samples if tumor specimens are unavailable. These findings also confirm that first-line gefitinib is an active treatment option in Caucasians with EGFR mutation-positive NSCLC. PMID:26893581

  3. 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

  4. F-18-FDG-PET Confined Radiotherapy of Locally Advanced NSCLC With Concomitant Chemotherapy: Results of the PET-PLAN Pilot Trial

    SciTech Connect

    Fleckenstein, Jochen; Hellwig, Dirk; Kremp, Stephanie; Grgic, Aleksandar; Groeschel, Andreas; Kirsch, Carl-Martin; Nestle, Ursula; Ruebe, Christian

    2011-11-15

    Purpose: The integration of fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the process of radiotherapy (RT) planning of locally advanced non-small-cell lung cancer (NSCLC) may improve diagnostic accuracy and minimize interobserver variability compared with target volume definition solely based on computed tomography. Furthermore, irradiating only FDG-PET-positive findings and omitting elective nodal regions may allow dose escalation by treating smaller volumes. The aim of this prospective pilot trial was to evaluate the therapeutic safety of FDG-PET-based RT treatment planning with an autocontour-derived delineation of the primary tumor. Methods and Materials: Eligible patients had Stages II-III inoperable NSCLC, and simultaneous, platinum-based radiochemotherapy was indicated. FDG-PET and computed tomography acquisitions in RT treatment planning position were coregistered. The clinical target volume (CTV) included the FDG-PET-defined primary tumor, which was autodelineated with a source-to-background algorithm, plus FDG-PET-positive lymph node stations. Limited by dose restrictions for normal tissues, prescribed total doses were in the range of 66.6 to 73.8 Gy. The primary endpoint was the rate of out-of-field isolated nodal recurrences (INR). Results: As per intent to treat, 32 patients received radiochemotherapy. In 15 of these patients, dose escalation above 66.6 Gy was achieved. No Grade 4 toxicities occurred. After a median follow-up time of 27.2 months, the estimated median survival time was 19.3 months. During the observation period, one INR was observed in 23 evaluable patients. Conclusions: FDG-PET-confined target volume definition in radiochemotherapy of NSCLC, based on a contrast-oriented source-to-background algorithm, was associated with a low risk of INR. It might provide improved tumor control because of dose escalation.

  5. Pilot study of radiofrequency hyperthermia in combination with gefitinib in gefitinib‐effective patients with advanced NSCLC

    PubMed Central

    Qin, Yijia; Sun, Yu; Liu, Yongmei; Luo, Yiqiao

    2016-01-01

    Background Non‐small‐cell lung cancer (NSCLC) is the leading cause of death from cancer in China. Gefitinib is effective for patients with positive epidermal growth factor receptor gene mutation; however, acquired drug resistance counteracts the duration response. Hyperthermia is widely clinically applied in the treatment of solid tumors. This pilot study was designed to evaluate the feasibility of the combination of gefitinib and hyperthermia. Methods Patients newly diagnosed with advanced NSCLC were screened. Eleven patients who responded to first‐line gefitinib treatment were enrolled in the study. Along with 250 mg gefitinib daily, local radiofrequency hyperthermia was administered twice a week until tumor progression was observed. The serum, heat shock protein (HSP)70, was also frequently detected during the course. Results The most common toxicity included skin rash (81.8%) and abnormal liver function (45.5%) when treated with gefitinib, and fatty scleroma (36.4%) was observed when combined with hyperthermia. Grade 3 side effects (skin rash) occurred in only one patient. Median progression‐free survival was 22 months (95% confidence interval [CI]: 12.95–31.05 months) and median overall survival was 26 months (95% CI: 22.81–29.19 months). Serum HSP70 concentration increased and maintained a significantly high level compared with the baseline before hyperthermia administration. Conclusions The novel therapy of gefitinib combined with radiofrequency hyperthermia is safe and effective for advanced NSCLC patients. Whether an improvement in therapeutic efficacy is associated with the elevation of serum HSP70 concentration requires further study.

  6. Specific Safety Profile of Bevacizumab in Asian Patients With Advanced NSCLC

    PubMed Central

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

    2015-01-01

    Abstract 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.

  7. CEA serum level as early predictive marker of outcome during EGFR-TKI therapy in advanced NSCLC patients.

    PubMed

    Facchinetti, Francesco; Aldigeri, Raffaella; Aloe, Rosalia; Bortesi, Beatrice; Ardizzoni, Andrea; Tiseo, Marcello

    2015-08-01

    Considering the role of carcinoembryonic antigen (CEA) serum levels as potential useful predictive marker during chemotherapy treatment, we studied its applicability in advanced non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). Our retrospective cohort consists of 79 patients (33 EGFR mutated and 46 EGFR wild type or unknown) affected by advanced NSCLC, for whom CEA serum values at the beginning of TKI therapy and after the first month of treatment were available, regardless of treatment line. Baseline CEA value, percentage of CEA reduction after 1 month, and percentage of patients with ≥20 % CEA decrease after 1 month (CEA response) were correlated with disease control rate (DCR), progression-free (PFS), and overall (OS) survival, according to EGFR mutational status. Median baseline CEA levels were significantly higher in EGFR mutated (40.9 ng/ml; interquartile range (IQR) 8.9-197.6) than in wild-type cases (6.2 ng/ml; IQR 2.8-12.8; p = 0.003). Both percentage reduction in CEA levels (-10.7 vs. +13.4 %) and percentage of cases with CEA response (42 vs. 20 %) were significantly higher in mutated vs. wild-type/unknown patients (p = 0.007 and p = 0.027, respectively). In wild-type/unknown patients, CEA response was significantly correlated with DCR (p = 0.001) and resulted as a significant predictor of PFS both in univariate (p = 0.002) and in multivariate analyses (hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.11-0.66; p = 0.004); only a trend was found for OS prediction (p = 0.082). In EGFR-mutated group, CEA reduction did not show any correlation either with PFS or OS. CEA response after 1 month of EGFR-TKI therapy could be a useful marker, worthy to further studies, as early predictor of treatment outcome in EGFR wild-type/unknown unselected NSCLC cases for which no molecular predictor is yet available. PMID:25731731

  8. Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

    PubMed Central

    Sutiman, Natalia; Zhang, Zhenxian; Tan, Eng Huat; Ang, Mei Kim; Tan, Shao-Weng Daniel; Toh, Chee Keong; Ng, Quan Sing; Chowbay, Balram; Lim, Wan-Teck

    2016-01-01

    Purpose This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC). Methods This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily. Results The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group. Conclusions Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups. Trial Registration ClinicalTrials.gov NCT00702182 PMID:27135612

  9. Advanced two-stage incinerator

    SciTech Connect

    Rehmat, A.; Khinkis, M.

    1991-01-01

    The Institute of Gas Technology (IGT) is developing an advanced incinerator that combines the fluidized-bed agglomeration/incineration and cyclonic combustion/incineration technologies that have been developed separately at IGT over many years. This combination results in a unique and extremely flexible incinerator for solid, sludge, liquid, and gaseous wastes. This system can operate over a wide range of conditions in the first stage, from low temperature (desorption) to high temperature (agglomeration), including gasification of high-Btu wastes. In the combined system, solid, liquid, and gaseous organic wastes would be easily and efficiently destroyed (>99.99% destruction and removal efficiency (DRE)), whereas solid inorganic contaminants would be contained within a glassy matrix, rendering them benign and suitable for disposal in an ordinary landfill. This technology is different from other existing technologies because of its agglomeration and encapsulation capability and its flexibility with respect to the types wastes it can handle. Both the fluidized-bed as well as the cyclonic incineration technologies have been fully developed and tested separately at pilot scales. 12 refs., 4 figs., 4 tabs.

  10. 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.

  11. Systematic Endobronchial Ultrasound-guided Mediastinal Staging Versus Positron Emission Tomography for Comprehensive Mediastinal Staging in NSCLC Before Radical Radiotherapy of Non-small Cell Lung Cancer: A Pilot Study.

    PubMed

    Steinfort, Daniel P; Siva, Shankar; Leong, Tracy L; Rose, Morgan; Herath, Dishan; Antippa, Phillip; Ball, David L; Irving, Louis B

    2016-02-01

    Despite known limitations of positron emission tomography (PET) for mediastinal staging of non-small cell lung cancer (NSCLC), radiation treatment fields are generally based on PET-identified disease extent. However, no studies have examined the accuracy of FDG-PET/CT on a per-node basis in patients being considered for curative-intent radiotherapy in NSCLC.In a prospective trial, patients with NSCLC being considered for definitive thoracic radiotherapy (± systemic chemotherapy) underwent minimally invasive systematic mediastinal evaluation with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) following noninvasive staging with integrated PET-CT.Thirty patients underwent EBUS-TBNA, with TBNA performed from a mean 2.5 lymph node (LN) stations per patient (median 3, range 1-5). Discordant findings between PET-CT and EBUS-TBNA were observed in 10 patients (33%, 95% CI 19%-51%). PET-occult LN metastases were demonstrated by EBUS in 4 patients, whereas a lesser extent of mediastinal involvement, compared with FDG-PET, was demonstrated by EBUS in 6 patients, including 2 patients downstaged from cN3 to pN2. LNs upstaged by EBUS were significantly smaller than nodes downstaged by EBUS, 7.5 mm (range 7-9) versus 12 mm (range 6-21), P = 0.005.A significant proportion of patients considered for definitive radiotherapy (+/-chemotherapy) undergoing systematic mediastinal evaluation with EBUS-TBNA in this study have an extent of mediastinal NSCLC involvement discordant with that indicated by PET-CT. Systematic EBUS-TBNA may aid in defining the extent of mediastinal involvement in NSCLC patients undergoing radiotherapy. Systematic EBUS-TBNA has the potential to contribute significantly to radiotherapy planning and delivery, by either identifying occult nodal metastases, or demonstrating FDG-avid LNs to be disease-free. PMID:26937894

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

    PubMed

    Gadgeel, Shirish M

    2016-01-01

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

  13. The Efficacy of Bevacizumab Compared with Other Targeted Drugs for Patients with Advanced NSCLC: A Meta-Analysis from 30 Randomized Controlled Clinical Trials

    PubMed Central

    Zhu, Min; Liu, Tianshu; Zhao, Naiqing

    2013-01-01

    Background The extent of the benefit of bevacizumab combined with chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) is still unclear. We performed this meta-analysis to compare the efficacy of bevacizumab with other commonly used targeted drugs for different patients with advanced NSCLC. Methods We searched PubMed, Cochrane Library, EMBASE and abstracts from the proceedings of the American Society of Clinical Oncology (ASCO), and identified 30 randomized controlled clinical trials published within 1999 to 2011 for meta-analysis. Results The outcomes of treatment efficacy included response rate, PFS and OS. Comparing bevacizumab (15 mg/kg) with chemotherapy to standard chemotherapy alone, for chemotherapy-naïve patients, the pooled OR of response rate was 2.741(95%CI: 2.046, 3.672), the pooled HR for disease progression was 0.645 (95%CI: 0.561, 0.743), and the pooled HR for death was 0.790 (95%CI: 0.674, 0.926), respectively. In addition, the adjusted HR for previously-treated patients was 0.680 (95%CI: 0.492, 0.942) comparing bevacizumab combined with chemotherapy to standard chemotherapy alone. Conclusions Bevacizumab accompanied by chemotherapy was found to significantly improve patients' response rate, progression free survival (PFS), and overall survival (OS) among chemotherapy-naïve patients compared to other targeted drugs in the treatment of non-small cell lung carcinoma (NSCLC). PMID:23614008

  14. 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. PMID:27517300

  15. Protocol for the isotoxic intensity modulated radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC): a feasibility study

    PubMed Central

    Haslett, Kate; Franks, Kevin; Harden, Susan; Hatton, Matthew; McDonald, Fiona; Ashcroft, Linda; Falk, Sally; Groom, Nicki; Harris, Catherine; McCloskey, Paula; Whitehurst, Philip; Bayman, Neil

    2016-01-01

    Introduction The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of ‘isotoxic’ radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable. Methods and analysis Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years. Ethics and dissemination The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West—Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally. Trial registration number NCT01836692; Pre-results. PMID:27084277

  16. 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

  17. Use of CD-ROM-based tool for analyzing contouring variations in involved-field radiotherapy for Stage III NSCLC

    SciTech Connect

    Soernsen De Koste, John R. van . E-mail: j.vansornsendekoste@vumc.nl; Senan, Suresh; Underberg, Rene W.M.; Oei, Swie Swat; Elshove, Dionne; Slotman, Ben J.; Lagerwaard, Frank J.

    2005-10-01

    Background: Interclinician variability in defining target volumes is a problem in conformal radiotherapy. A CD-ROM-based contouring tool was used to conduct a dummy run in an international trial of involved-field chemoradiotherapy for Stage III non-small-cell lung cancer. Methods and Materials: The CT scan of an eligible patient was installed on an 'auto-run' CD-ROM incorporating a contouring program based on ImageJ for Windows, which runs on any personal computer equipped with a CD-ROM drive. This tool was initially piloted at four academic centers and was subsequently mailed, together with all relevant clinical, radiologic, and positron emission tomography findings, to all participating centers in the international trial. Clinicians were instructed to contour separate gross tumor volumes (GTVs) for the tumor and two enlarged nodes and a clinical target volume for the hilus. A reference 'consensus' target volume for each target was jointly generated by three other clinicians. Results: The data received from the four academic centers and 16 study participants were suitable for analysis. Data from one center was unsuitable for detailed analysis because the target volumes were contoured at 1.2-cm intervals. GTVs were available for a total of 21 tumors and 19 nodes, and 15 hilar clinical target volumes were available. The mean GTV of the primary tumor was 13.6 cm{sup 3} (SD, 5.2; median, 12.3; range, 8.3-26.9). The variation in the center of the mass relative to the mean center of the mass in the left-right, ventrodorsal, and craniocaudal axes was 1.5, 0.4, and 1.0 mm, respectively. The largest volume variation was observed for the right hilar clinical target volume (mean, 33.7 cm{sup 3}; SD, 31.2; median, 20.3; range, 4.8-109.9). Smaller variations were observed for the subcarinal node (mean, GTV, 1.9 cm{sup 3}; SD, 1.2; median, 1.7; range, 0.5-5.3), except caudally where the node was difficult to distinguish from the pericardium. The 'consensus' volumes for all

  18. 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

  19. A Phase II Study of Modulated-Capecitabine and Docetaxel in Chemonaive Patients with Advanced Non-Small Cell Lung Cancer (NSCLC)

    PubMed Central

    Bertino, Erin M.; Bekaii-Saab, Tanios; Fernandez, Soledad; Diasio, Robert B.; Karim, Nagla A.; Otterson, Gregory A.; Villalona-Calero, Miguel A.

    2012-01-01

    Introduction This phase II single-arm trial of docetaxel and capecitabine in previously untreated non-small cell lung cancer (NSCLC) patients was designed to evaluate response rate of this regimen based on promising efficacy data from phase II testing in pre-treated NSCLC patients. The trial also evaluated the correlation between peripheral blood dihydropyrimidine dehydrogenase (DPD) expression and efficacy/toxicity. Methods Patients with advanced NSCLC (metastatic, including malignant pleural effusion) without prior chemotherapy were enrolled. Baseline DPD screening was performed; patients with baseline DPD level < 0.07 nmol/min/mg protein were considered ineligible for the study. Treatment included a 28-day cycle of docetaxel 36 mg/m2 days 1, 8, 15 and capecitabine 1250 mg/m2/day in divided doses on days 5–18. Overall response rate (RR) was the primary endpoint with a target RR of 50%. Correlative studies included evaluation of DPD activity levels in peripheral blood and correlation with clinical responses. Results Twenty-eight patients received 86 cycles of treatment (median 3 cycles) and were evaluable for response. The RR was 18% (5 patients); RR did not meet the pre-specified efficacy endpoint and the trial was stopped. 14 patients had stable disease (SD - 50%) and 4 pts had SD > 12 weeks. Median time to progression was 3.3 months (95% CI 1.5 – 4.6 months). Median overall survival was 10.5 months (95% CI: 3.2 – 15 months). Main toxicities included fatigue, stomatitis and leukopenia. DPD levels ranged from 0.06 to 0.26 nmol/min/mg. The majority of responders (4/5) had DPD levels ≤ 0.1 nmol/min/mg. Most of the responders (4/5) experienced grade 3 toxicities including leukopenia, dehydration, fatigue, and diarrhea. None of the patients (0/4) with higher DPD levels (>0.2 nmol/min/mg) had a response. Conclusion The response rate for the regimen did not demonstrate sufficient activity and further study of this regimen in this setting is not indicated

  20. Treatment of advanced-stage Hodgkin lymphoma.

    PubMed

    Vassilakopoulos, Theodoros P; Johnson, Peter W M

    2016-07-01

    There is now good evidence that the escalated BEACOPP regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) is more effective in controlling advanced-stage Hodgkin lymphoma (HL) than the widely used ABVD regimen (adriamycin, bleomycin, vinblastine, dacarbazine), but the extra efficacy comes at the expense of both short- and long-term toxicity, and there is debate as to whether overall survival is affected. Baseline prognostic factors have proven of limited utility for determining which patients require more intensive therapy and recent studies have sought to use interim fluoro-deoxyglucose positron emission tomography (FDG-PET) evaluation as a means to guide the modulation of treatment, both upwards and downwards in intensity. These suggest that if treatment starts with ABVD then patients remaining PET-positive after 2 months can be salvaged with escalated BEACOPP in around 65% of cases, but those becoming PET-negative may still experience recurrences in 15%-20%, an event that is more common in those with more advanced disease at presentation. There are early data to suggest that starting with escalated BEACOPP may reduce the rate of recurrence after a negative interim PET to less than 10%. This may be an attractive approach for those with very high-risk features at presentation, but risks overtreating many patients if applied nonselectively. New regimens incorporating antibody-drug conjugates may shift the balance of efficacy and toxicity once again, and further studies are underway to evaluate this. PMID:27496308

  1. Advanced two-stage compressor program design of inlet stage

    NASA Technical Reports Server (NTRS)

    Bryce, C. A.; Paine, C. J.; Mccutcheon, A. R. S.; Tu, R. K.; Perrone, G. L.

    1973-01-01

    The aerodynamic design of an inlet stage for a two-stage, 10/1 pressure ratio, 2 lb/sec flow rate compressor is discussed. Initially a performance comparison was conducted for an axial, mixed flow and centrifugal second stage. A modified mixed flow configuration with tandem rotors and tandem stators was selected for the inlet stage. The term conical flow compressor was coined to describe a particular type of mixed flow compressor configuration which utilizes axial flow type blading and an increase in radius to increase the work input potential. Design details of the conical flow compressor are described.

  2. Circulating tumor DNA identified by targeted sequencing in advanced-stage non-small cell lung cancer patients.

    PubMed

    Xu, Song; Lou, Feng; Wu, Yi; Sun, Da-Qiang; Zhang, Jing-Bo; Chen, Wei; Ye, Hua; Liu, Jing-Hao; Wei, Sen; Zhao, Ming-Yu; Wu, Wen-Jun; Su, Xue-Xia; Shi, Rong; Jones, Lindsey; Huang, Xue F; Chen, Si-Yi; Chen, Jun

    2016-01-28

    Non-small cell lung cancers (NSCLC) have unique mutation patterns, and some of these mutations may be used to predict prognosis or guide patient treatment. Mutation profiling before and during treatment often requires repeated tumor biopsies, which is not always possible. Recently, cell-free, circulating tumor DNA (ctDNA) isolated from blood plasma has been shown to contain genetic mutations representative of those found in the primary tumor tissue DNA (tDNA), and these samples can readily be obtained using non-invasive techniques. However, there are still no standardized methods to identify mutations in ctDNA. In the current study, we used a targeted sequencing approach with a semi-conductor based next-generation sequencing (NGS) platform to identify gene mutations in matched tDNA and ctDNA samples from 42 advanced-stage NSCLC patients from China. We identified driver mutations in matched tDNA and ctDNA in EGFR, KRAS, PIK3CA, and TP53, with an overall concordance of 76%. In conclusion, targeted sequencing of plasma ctDNA may be a feasible option for clinical monitoring of NSCLC in the near future. PMID:26582655

  3. Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC).

    PubMed

    Cohen, Martin H; Cortazar, Patricia; Justice, Robert; Pazdur, Richard

    2010-01-01

    On July 2, 2009, the U.S. Food and Drug Administration approved pemetrexed injection (Alimta® Injection; Eli Lilly and Company, Indianapolis, IN) for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based doublet induction chemotherapy. A double-blind study of pemetrexed plus best supportive care versus placebo plus best supportive care was conducted. Pemetrexed, 500 mg/m(2) i.v., was administered every 21 days until disease progression. Folic acid, vitamin B(12), and a corticosteroid were given to all study patients. There were 663 randomized patients (pemetrexed, 441; placebo, 222). Treatments were well balanced with respect to baseline disease characteristics and stratification factors. The median overall survival (OS) time for intent-to-treat (ITT) patients was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65-0.95; p = .012). Median OS times were 15.5 months versus 10.3 months for patients with nonsquamous histologies receiving pemetrexed and placebo, respectively (HR, 0.70; 95% CI, 0.56-0.88). The median OS time in patients with squamous histology receiving pemetrexed was 9.9 months, versus 10.8 months for those receiving placebo (HR, 1.07; 95% CI, 0.77-1.50). A significantly longer progression-free survival interval for both the ITT and nonsquamous patient populations receiving pemetrexed maintenance therapy was also observed. The most common (>5%) adverse reactions in patients receiving pemetrexed were hematologic toxicity, an increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy, and skin rash. PMID:21148615

  4. Association of CD44 Gene Polymorphism with Survival of NSCLC and Risk of Bone Metastasis

    PubMed Central

    Liu, Yaosheng; Qing, Haifeng; Su, Xiuyun; Wang, Cheng; Li, Zhuo; Liu, Shubin

    2015-01-01

    Background Previous studies have reported CD44 expression influenced the development and progression of tumors. The aim of this study was to investigate whether single-nucleotide polymorphisms (SNPs) of the CD44 gene are associated with survival of non-small cell lung cancer (NSCLC) and occurrence rate of bone metastasis. Material/Methods A total of 234 patients with NSCLC between 2003 and 2010 were enrolled in this study and 468 healthy persons were used as controls. Two polymorphisms, rs13347 and rs187115, in the CD44 gene were genotyped using DNA from blood lymphocytes. For statistical analysis we used the chi-square test, Fisher’s exact test, Kaplan-Meier method, and log-rank test. Results CD44 gene rs13347 polymorphism was not associated with NSCLC risk. For rs187115, the association with NSCLC risk was observed (P<0.001). Allele G carriers had significantly higher occurrence rates of bone metastasis (OR=0.4, 95%CI: 0.20–0.64, P<0.001) and more advanced tumor stage (OR=2.6, 95%CI: 1.50–4.45, P=0.001) compared to carriers of allele A. The survival rates for patients with AA genotype were significantly higher than for patients with the AG+GG genotypes (P<0.001). In multivariate analysis of survival in NSCLC patients, significant predictors were CD44 gene (AG+GG) (RR=0.48, 95%CI: 0.34–0.68, P<0.001), tumor stage (RR=0.45, 95%CI: 0. 0.31–0.65, P<0.001), and bone metastasis (RR=1.52, 95%CI: 1.05–2.21, P=0.027). Conclusions CD44 gene rs187115 polymorphism is a potential predictive marker of survival in NSCLC patients, and is significantly correlated with bone metastasis and tumor stage. PMID:26356590

  5. Trial Comparing the Use of FLT PET to Standard CT to Assess Treatment Response of Neoadjuvant Docetaxel and Cisplatin in Stage IB-IIIA Resectable NSCLC

    ClinicalTrials.gov

    2015-04-30

    Recurrent Non-Small Cell Lung Carcinoma; Stage IB Non-Small Cell Lung Carcinoma; Stage IIA Non-Small Cell Lung Carcinoma; Stage IIB Non-Small Cell Lung Carcinoma; Stage IIIA Non-Small Cell Lung Cancer; Stage IV Non-Small Cell Lung Cancer

  6. 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

  7. Statins augment efficacy of EGFR-TKIs in patients with advanced-stage non-small cell lung cancer harbouring KRAS mutation.

    PubMed

    Fiala, Ondrej; Pesek, Milos; Finek, Jindrich; Minarik, Marek; Benesova, Lucie; Bortlicek, Zbynek; Topolcan, Ondrej

    2015-08-01

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represent novel effective agents approved for the treatment of patients with advanced-stage NSCLC. KRAS mutations have been reported as a negative prognostic and predictive factor in patients with NSCLC treated with EGFR-TKIs. Several studies have recently shown that statins can block tumour cell growth, invasion and metastatic potential. We analysed clinical data of 67 patients with locally advanced (IIIB) or metastatic stage (IV) NSCLC harbouring Kirsten rat sarcoma viral oncogene (KRAS) mutation treated with erlotinib or gefitinib. Twelve patients were treated with combination of EGFR-TKI and statin and 55 patients were treated with EGFR-TKI alone. Comparison of patients' survival (progression-free survival (PFS) and overall survival (OS)) according to the treatment used was performed using the Gehan-Wilcoxon test. The median of PFS and OS for patients treated with EGFR-TKI alone was 1.0 and 5.4 months compared to 2.0 and 14.0 months for patients treated with combination of EGFR-TKI and statin (p = 0.025, p = 0.130). In conclusion, the study results suggest significant improvement of PFS for patients treated with combination of statin and EGFR-TKI, and the difference in OS was not significant. PMID:25702091

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

    PubMed

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

    2016-06-01

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

  9. Image Guided Hypofractionated 3-Dimensional Radiation Therapy in Patients With Inoperable Advanced Stage Non-Small Cell Lung Cancer

    SciTech Connect

    Osti, Mattia Falchetto; Agolli, Linda; Valeriani, Maurizio; Falco, Teresa; Bracci, Stefano; De Sanctis, Vitaliana; Enrici, Riccardo Maurizi

    2013-03-01

    Purpose: Hypofractionated radiation therapy (HypoRT) can potentially improve local control with a higher biological effect and shorter overall treatment time. Response, local control, toxicity rates, and survival rates were evaluated in patients affected by inoperable advanced stage non-small cell lung cancer (NSCLC) who received HypoRT. Methods and Materials: Thirty patients with advanced NSCLC were enrolled; 27% had stage IIIA, 50% had stage IIIB, and 23% had stage IV disease. All patients underwent HypoRT with a prescribed total dose of 60 Gy in 20 fractions of 3 Gy each. Radiation treatment was delivered using an image guided radiation therapy technique to verify correct position. Toxicities were graded according to Radiation Therapy Oncology Group morbidity score. Survival rates were estimated using the Kaplan-Meier method. Results: The median follow-up was 13 months (range, 4-56 months). All patients completed radiation therapy and received the total dose of 60 Gy to the primary tumor and positive lymph nodes. The overall response rate after radiation therapy was 83% (3 patients with complete response and 22 patients with partial response). The 2-year overall survival and progression-free survival rates were 38.1% and 36%, respectively. Locoregional recurrence/persistence occurred in 11 (37%) patients. Distant metastasis occurred in 17 (57%) patients. Acute toxicities occurred consisting of grade 1 to 2 hematological toxicity in 5 patients (17%) and grade 3 in 1 patient; grade 1 to 2 esophagitis in 12 patients (40%) and grade 3 in 1 patient; and grade 1 to 2 pneumonitis in 6 patients (20%) and grade 3 in 2 patients (7%). Thirty-three percent of patients developed grade 1 to 2 late toxicities. Only 3 patients developed grade 3 late adverse effects: esophagitis in 1 patient and pneumonitis in 2 patients. Conclusions: Hypofractionated curative radiation therapy is a feasible and well-tolerated treatment for patients with locally advanced NSCLC. Randomized

  10. Liquid Biopsies in the Screening of Oncogenic Mutations in NSCLC and its Application in Targeted Therapy.

    PubMed

    Tang, Jason H; Chia, David

    2015-01-01

    Non-small cell lung cancer (NSCLC) still dominates cancer-related deaths in America. Despite this, new discoveries and advancements in technology are helping with the detection and treatment of NSCLC. The discovery of circulating tumor DNA in blood and other biofluids is essential for the creation of a DNA biomarker. Limitations in technology and sequencing have stunted assay development, but with recent advancements in the next-generation sequencing, droplet digital PCR, and EFIRM, the detection of mutations in biofluids has become possible with reasonable sensitivity and specificity. These methods have been applied to the detection of mutations in NSCLC by measuring the levels of circulating tumor DNA. ALK fusion genes along with mutations in EGFR and KRAS have been shown to correlate to tumor size and metastasis. These methods allow for noninvasive, affordable, and efficient diagnoses of oncogenic mutations that overcome the issues of traditional biopsies. These issues include tumor heterogeneity and early detection of cancers with asymptomatic early stages. Early detection and treatment remain the best way to ensure survival. This review aims to describe these new technologies along with their application in mutation detection in NSCLC in order to proactively utilize targeted anticancer therapy. PMID:27279235

  11. Plasma EGFR T790M ctDNA status is associated with clinical outcome in advanced NSCLC patients with acquired EGFR-TKI resistance.

    PubMed

    Zheng, D; Ye, X; Zhang, M Z; Sun, Y; Wang, J Y; Ni, J; Zhang, H P; Zhang, L; Luo, J; Zhang, J; Tang, L; Su, B; Chen, G; Zhu, G; Gu, Y; Xu, J F

    2016-01-01

    EGFR T790M mutation occurs in half of non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI (TKI) resistance, based on tumor re-biopsies using an invasive clinical procedure. Here, we dynamically monitored T790M mutation in circulating tumor DNA (ctDNA) using serial plasma samples from NSCLC patients receiving TKI through Droplet Digital PCR (ddPCR) method and the associations between overall survival (OS) starting from initial TKI treatment and the T790M ctDNA status detected in plasma were analyzed. Among 318 patients, 117 who acquired TKI resistance were eligible for the analysis. T790M ctDNA was detected in the plasma of 55/117 (47%) patients. Almost half of the T790M ctDNA positive patients were identified at a median time of 2.2 months prior to clinically progressive disease (PD). Furthermore, within the patients receiving TKI treatment at 2(nd) line or later, the T790M ctDNA positive group had significantly shorter OS than the negative group (median OS: 26.9 months versus NA, P = 0.0489). Our study demonstrates the feasibility of monitoring EGFR mutation dynamics in serial plasma samples from NSCLC patients receiving TKI therapy. T790M ctDNA can be detected in plasma before and after PD as a poor prognostic factor. PMID:26867973

  12. Upregulation of the long noncoding RNA PCAT-1 correlates with advanced clinical stage and poor prognosis in esophageal squamous carcinoma.

    PubMed

    Shi, Wei-hong; Wu, Qing-quan; Li, Su-qing; Yang, Tong-xin; Liu, Zi-hao; Tong, Yu-suo; Tuo, Lei; Wang, Shan; Cao, Xiu-Feng

    2015-04-01

    Recent studies reveal that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. Prostate cancer-associated ncRNA transcript 1 (PCAT-1) is one of the lncRNAs involved in cell apoptosis and proliferation of prostate cancer. This study aimed to assess the potential role of PCAT-1 specifically in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PCAT-1 in matched cancerous tissues and adjacent noncancerous tissues from 130 patients with ESCC, 34 patients with non-small cell lung cancer (NSCLC), and 30 patients with gastric carcinoma (GC). The correlation of PCAT-1 with clinicopathological features and prognosis were also analyzed. The expression of PCAT-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (70.8%, p < 0.01), and the high level of PCAT-1 expression was significantly correlated with invasion of the tumor (p = 0.024), advanced clinical stage (p = 0.003), lymph node metastasis (p = 0.032), and poor prognosis. However, PCAT-1 mRNA expression had no significant difference between paired primary cancerous tissues and the adjacent noncancerous tissues in 34 cases of NSCLC (p = 0.293) and 30 cases of GC (p = 0.125). High expression of PCAT-1 was specifically correlated with invasion of cancer tissues, metastasis of lymph node, and advanced tumor stage of ESCC. High expression of PCAT-1 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Adjuvant therapy targeting PCAT-1 molecule might be effective in treatment of ESCC. PMID:25731728

  13. Advances take stage - Office of Cancer Clinical Proteomics Research

    Cancer.gov

    Regulatory advances in proteomics will be taking center stage at a Symposia scheduled to occur at the 2011 American Association for Clinical Chemistry (AACC) Annual Meeting. The symposium entitled "Enabling Translational Proteomics with NCI's Clinical Proteomic Technologies for Cancer" is scheduled for July 25, 2011 at AACC's annual Meeting.

  14. 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

  15. 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

  16. Peripheral Blood miR-328 Expression as a Potential Biomarker for the Early Diagnosis of NSCLC

    PubMed Central

    Ulivi, Paola; Foschi, Giovanni; Mengozzi, Marta; Scarpi, Emanuela; Silvestrini, Rosella; Amadori, Dino; Zoli, Wainer

    2013-01-01

    Lung cancer is often diagnosed at an advanced stage, with subsequently poor prognosis. There are no biomarkers available to facilitate early diagnosis or to discriminate between benign and malignant nodules. MicroRNAs (miRNAs) are stable molecules that can be found and measured in peripheral blood, thus representing potential diagnostic biomarkers. We evaluated 100 individuals comprising 86 patients with predominantly early-stage non-small cell lung cancer (NSCLC) and 24 healthy donors. RNA was extracted from peripheral blood samples and the expression of a panel of miRNAs was analyzed by Real-Time PCR method. Expression levels of miR-328, miR-18a, miR-339 and miR-140 were significantly higher in NSCLC patients than in healthy donors (p < 0.05). In particular, miR-328 showed good diagnostic accuracy in discriminating between patients with early NSCLC and healthy donors (AUC ROC 0.82, 95% CI 0.72–0.92), with 70% sensitivity and 83% specificity at the best relative expression cut-off of 300. Moreover, miR-339 was a good discriminant between healthy donors and late-stage NSCLC patients (AUC ROC 0.79, 95% CI 0.68–0.91). In conclusion, miR-328 represents a potential diagnostic biomarker of NSCLC, especially for the identification of early-stage tumors. Its role in discriminating between benign and malignant nodules detected by spiral CT warrants further investigation. PMID:23681013

  17. Advanced technologies for rocket single-stage-to-orbit vehicles

    NASA Technical Reports Server (NTRS)

    Wilhite, Alan W.; Bush, Lance B.; Cruz, Christopher I.; Lepsch, Roger A.; Morris, W. Douglas; Stanley, Douglas O.; Wurster, Kathryn E.

    1991-01-01

    A single-stage-to-orbit vertical takeoff/horizontal landing rocket vehicle was studied to determine the benefits of advanced technology. Advanced technologies that were included in the study were variable mixture ratio oxygen/hydrogen rocket engines and materials, structures, and subsystem technologies currently being developed in the National Aero-Space Plane Program. The application of advanced technology results in an 85 percent reduction in vehicle dry weight. With advanced materials, an external thermal protection system, like the Space Shuttle tiles, was not required. Compared to an all-airbreathing horizontal takeoff/horizontal landing vehicle using the same advanced technologies and mission requirements, the rocket vehicle is lighter in dry weight and has fewer subsystems. To increase reliability and safety, operational features were included in the rocket vehicle-robust subsystems, 5 percent additional margin, no slush hydrogen, fail-operational with an engine out, and a crew escape module. The resulting vehicle grew in dry weight and was still lower in dry weight than the airbreathing vehicle.

  18. Advanced Low-Noise Research Fan Stage Design

    NASA Technical Reports Server (NTRS)

    Neubert, Robert; Bock, Larry; Malmborg, Eric; Owen-Peer, William

    1997-01-01

    This report describes the design of the Advanced Low-Noise Research Fan stage. The fan is a variable pitch design, which is designed at the cruise pitch condition. Relative to the cruise setting, the blade is closed at takeoff and opened for reverse thrust operation. The fan stage is a split flow design with fan exit guide vanes (FEGVs) and core stators. The fan stage design is combined with a nacelle and engine core duct to form a powered fan/nacelle subscale model. This model is intended for use in combined aerodynamic, acoustic, and structural testing in a wind tunnel. The fan has an outer diameter of 22 in. and a hub-to-tip of 0.426 in., which allows the use of existing NASA fan and cowl force balance and rig drive systems. The design parameters were selected to permit valid acoustic and aerodynamic comparisons with the Pratt & Whitney (P&W) 17- and 22-in. rigs previously tested under NASA contract. The fan stage design is described in detail. The results of the design axisymmetric and Navier-Stokes aerodynamic analysis are presented at the critical design conditions. The structural analysis of the fan rotor and attachment is included. The blade and attachment are predicted to have adequate low-cycle fatigue life and an acceptable operating range without resonant stress or flutter. The stage was acoustically designed with airfoil counts in the FEGV and core stator to minimize noise. A fan/FEGV tone analysis developed separately under NASA contract was used to determine the optimum airfoil counts. The fan stage was matched to the existing nacelle, designed under the previous P&W low-noise contract, to form a fan/nacelle model for wind tunnel testing. It is an axisymmetric nacelle for convenience in testing and analysis. Previous testing confirmed that the nacelle performed as required at various aircraft operating conditions.

  19. Role of Gemcitabine and Pemetrexed as Maintenance Therapy in Advanced NSCLC: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Feng, Xuqin; Wen, Shimin; Fu, Xi; Guo, Cuihua; He, Wenwu

    2016-01-01

    Background Gemcitabine and pemetrexed have been used as maintenance therapy. However, few systematic reviews and meta-analyses have assessed their effects in the newest studies. This systematic review and meta-analysis were conducted to assess the role of gemcitabine and pemetrexed in the maintenance treatment of non-small-cell lung carcinoma (NSCLC). Methods We performed a literature search using PubMed, EMBASE and Cochrane library databases from their inceptions to September 16, 2015. We also searched the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) databases from 2008 to 2015. Two authors independently extracted the data. The Cochrane Collaboration’s risk of bias graph was used to assess the risk of bias. The GRADE system was used to assess the grading of evidence, and a meta-analysis was conducted using Stata 11.0 software. Results Eleven randomized controlled trial (RCT) studies were collected. Ten studies were included in the meta-analysis and divided into the following 4 groups: gemcitabine vs. best supportive care (BSC)/observation, pemetrexed vs. BSC/placebo, pemetrexed + bevacizumab vs. bevacizumab and pemetrexed vs. bevacizumab. Gemcitabine exhibited significantly improved progression-free survival (PFS) compared with BSC (hazard ratio (HR) = 0.62, p = 0.000). Pemetrexed exhibited significantly improved PFS (HR = 0.54, p = 0.000) and OS (HR = 0.75, p = 0.000) compared with BSC. Pemetrexed + bevacizumab almost exhibited significantly improved PFS (HR = 0.71, p = 0.051) compared with bevacizumab. Pemetrexed exhibited no improvement in PFS or overall survival (OS) compared with bevacizumab. Regarding the grade, the GRADE system indicated that the gemcitabine group was "MODERATE", the pemetrexed group was "HIGH", and both the pemetrexed + bevacizumab vs. bevacizumab groups and pemetrexed vs. B groups were "LOW". Conclusions Gemcitabine or pemetrexed compared

  20. Consolidation chwemotherapy after concurrent chemoradiotherapy vs. chemoradiotherapy alone for locally advanced unresectable stage III non-small-cell lung cancer: A meta-analysis

    PubMed Central

    Chang, Xiu-Jun; Wang, Zi-Tong; Yang, Lei

    2016-01-01

    Concurrent chemoradiotherapy (CCRT) has been considered to be the standard of care for locally advanced unresectable stage III non-small-cell lung cancer (LA-NSCLC). Whether consolidation chemotherapy (CCT) following CCRT is able to further improve the clinical outcome remains unclear. We therefore undertook a meta-analysis to compare the two regimens for LA-NSCLC. A literature search was performed through PubMed, Embase, Cochrane Library and Chinese Biology Medicine, from their inception to November, 2015. Irrelevant studies were excluded using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. Our primary endpoint was overall survival (OS), which was defined as the time from randomisation until death from any cause; the secondary endpoint was progression-free survival (PFS). All analyses were by intention-to-treat. Five phase III randomized controlled trials with 958 patients were included in the present meta-analysis. The results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Compared with CCRT, CCT after CCRT was not associated with statistically significant differences in OS (OR=1.24; 95% CI: 0.89–1.72; P=0.21) or PFS (OR=1.16; 95% CI: 0.74–1.83; P=0.53), but increased the risk of toxicity, including infection (P=0.02), pneumonitis (P=0.003) and treatment-related death (P=0.04). There were no significant differences in terms of benefit according to particular patient characteristics, such as age, gender, performance status, tumor histology or clinical stage. Thus, the present study failed to support the use of CCT after CCRT over CCRT alone, as there was no significant OS and PFS benefit for LA-NSCLC patients, but the use of CCT after CCRT resulted in increased toxicity. PMID:27446563

  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. Can advanced-stage ovarian cancer be cured?

    PubMed

    Narod, Steven

    2016-04-01

    Approximately 20% of women with advanced-stage ovarian cancer survive beyond 12 years after treatment and are effectively cured. Initial therapy for ovarian cancer comprises surgery and chemotherapy, and is given with the goal of eradicating as many cancer cells as possible. Indeed, the three phases of therapy are as follows: debulking surgery to remove as much of the cancer as possible, preferably to a state of no visible residual disease; chemotherapy to eradicate any microscopic disease that remains present after surgery; and second-line or maintenance therapy, which is given to delay disease progression among patients with tumour recurrence. If no cancer cells remain after initial therapy is completed, a cure is expected. By contrast, if residual cancer cells are present after initial treatment, then disease recurrence is likely. Thus, the probability of cure is contingent on the combination of surgery and chemotherapy effectively eliminating all cancer cells. In this Perspectives article, I present the case that the probability of achieving a cancer-free state is maximized through a combination of maximal debulking surgery and intraperitoneal chemotherapy. I discuss the evidence indicating that by taking this approach, cures could be achieved in up to 50% of women with advanced-stage ovarian cancer. PMID:26787282

  3. Cyberknife treatment for advanced or terminal stage hepatocellular carcinoma

    PubMed Central

    Kato, Hiroyuki; Yoshida, Hideo; Taniguch, Hiroyoshi; Nomura, Ryutaro; Sato, Kengo; Suzuki, Ichiro; Nakata, Ryo

    2015-01-01

    AIM: To investigate the safety and efficacy of the Cyberknife treatment for patients with advanced or terminal stage hepatocellular carcinoma (HCC). METHODS: Patients with HCC with extrahepatic metastasis or vascular or bile duct invasion were enrolled between May 2011 and June 2015. The Cyberknife was used to treat each lesion. Treatment response scores were based on Response Evaluation Criteria in Solid Tumors v1.1. The trends of tumor markers, including alpha fetoprotein (AFP) and proteins induced by vitamin K absence II (PIVKA II) were assessed. Prognostic factors for tumor response and tumor markers were evaluated with Fisher’s exact test and a logistic regression model. Survival was evaluated with the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards model. RESULTS: Sixty-five patients with 95 lesions were enrolled. Based on the Barcelona Clinic Liver Cancer classification, all patients were either in the advanced or terminal stage of the disease. The target lesions were as follows: 52 were bone metastasis; 9, lung metastasis; 7, brain metastasis; 9, portal vein invasion; 4, hepatic vein invasion; 4, bile duct invasion; and 10 other lesion types. The response rate and disease control rate were 34% and 53%, respectively. None of the clinical factors correlated significantly with tumor response. Fiducial marker implantation was associated with better control of both AFP (HR = 0.152; 95%CI: 0.026-0.887; P = 0.036) and PIVKA II (HR = 0.035; 95%CI: 0.003-0.342; P = 0.004). The median survival time was 9 mo (95%CI: 5-15 mo). Terminal stage disease (HR = 9.809; 95%CI: 2.589-37.17, P < 0.001) and an AFP of more than 400 ng/mL (HR = 2.548; 95%CI: 1.070-6.068, P = 0.035) were associated with worse survival. A radiation dose higher than 30 Gy (HR = 0.274; 95%CI: 0.093-0.7541, P = 0.012) was associated with better survival. In the 52 cases of bone metastasis, 36 patients (69%) achieved pain relief. One patient had cerebral

  4. Treatment results in advanced stage Hodgkin's lymphoma: A retrospective study

    PubMed Central

    Jain, H; Sengar, M; Nair, R; Menon, H; Laskar, S; Shet, T; Gujral, S; Sridhar, E

    2015-01-01

    Background: Hodgkin's lymphoma displays distinct epidemiological attributes in Asian population thus making it relevant to study whether there are any differences in treatment outcomes too when treated with current standard of care. Aim: To evaluate the treatment outcomes of de-novo advanced stage HL in adults. Materials and Methods: This retrospective study included de-novo advanced stage HL patients (≥15 years) registered at our center from January 2004 to December 2007. Treatment outcomes were measured in terms of response rates, overall survival (OS) and progression-free survival (PFS). Overall and PFS were calculated with Kaplan-Meier methodology and Cox-proportional hazards model was used for multivariate analysis to identify prognostic factors. Results: There were 125 patients (males 77%) who received minimum one cycle of chemotherapy with median age of 32 years (Range 15-65 years). Stage IV disease was seen in (46 patients) 37%; 75% (94 patients) patients had B symptoms. International prognostic score (IPS) ≤4 was seen in 95/112 (85%) patients. ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy was given to 94%. Radiation to residual/bulky sites was given to 36% (45 patients). Response data was available for 112 patients; complete response in 76%; partial response in 10 % and progressive disease in 3 patients. Nineteen deaths (progressive disease-7, toxicity-8, unrelated cause-4) were observed. At median follow-up of 28 months, estimated 5-year OS and PFS were 60% and 58%, respectively. On multivariate analysis, IPS and response to treatment were significant factors for both OS and PFS. Conclusions: The treatment outcomes in this study are comparable with the published literature with limited follow-up data. PMID:25766339

  5. Challenges and Opportunities for Cancer Vaccines in the Current NSCLC Clinical Scenario

    PubMed Central

    Rodriguez, Pedro C; Sanchez, Belinda

    2013-01-01

    This review is aimed to focus on NSCLC as an emerging and promising model for active immunotherapy and the challenges for its inclusion in the current clinical scenario. Cancer vaccines for NSCLC have been focused as a therapeutic option based on the identification of a tumor hallmark and the active immunization with the related molecules that triggers cellular and/or humoral responses that consequently destroy or delay the rate of malignant progression. This therapeutic intervention in an established disease state has been aimed to impact into prolonging patient´s survival with ethically accepted quality of life. Understanding of relationship between structure and function in cancer vaccines is essential to interpret their opportunities to impact into prolonging survival and increasing quality of life in cancer patients. It is widely accepted that the failure of the cancer vaccines in the NSCLC scenario is related with its introduction in the advanced disease stages and poor performance status of the patients due to the combination of the tumor induced immunosuppression with the immune senescence. Despite first, second and emerging third line of onco-specific treatments the life expectancy for NSCLC patients diagnosed at advanced stages is surrounding the 12 months of median survival and in facts the today real circumstances are extremely demanding for the success inclusion of cancer vaccines as therapeutic choice in the clinical scenario. The kinetics of the active immunizations encompasses a sequential cascade of clinical endpoints: starting by the activation of the immune system, followed by the antitumor response and finalizing with the consequential impact on patients’ overall survival. Today this cascade of clinical endpoints is the backbone for active immunization assessment and moreover the concept of cancer vaccines, applied in the NSCLC setting, is just evolving as a complex therapeutic strategy, in which the opportunities for cancer vaccines start

  6. 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

  7. Advanced Therapies For End-Stage Heart Failure

    PubMed Central

    Katz, Jason N; Waters, Sarah B; Hollis, Ian B; Chang, Patricia P

    2015-01-01

    Management of the advanced heart failure patient can be complex. Therapies include cardiac transplantation and mechanical circulatory support, as well inotropic agents for the short-term. Despite a growing armamentarium of resources, the clinician must carefully weigh the risks and benefits of each therapy to develop an optimal treatment strategy. While cardiac transplantation remains the only true “cure” for end-stage disease, this resource is limited and the demand continues to far outpace the supply. For patients who are transplant-ineligible or likely to succumb to their illness prior to transplant, ventricular assist device therapy has now become a viable option for improving morbidity and mortality. Particularly for the non-operative pa-tient, intravenous inotropes can be utilized for symptom control. Regardless of the treatments considered, care of the heart failure patient requires thoughtful dialogue, multidisciplinary collaboration, and individualized care. While survival is important, most patients covet quality of life above all outcomes. An often overlooked component is the patient’s control over the dying process. It is vital that clinicians make goals-of-care discussions a priority when seeing patients with advanced heart failure. The use of palliative care consultation is well-validated and facilitates these difficult conversations to ensure that all patient needs are ultimately met. PMID:24251460

  8. Surgical techniques for advanced stage pelvic organ prolapse.

    PubMed

    Brown, Douglas N; Strauchon, Christopher; Gonzalez, Hector; Gruber, Daniel

    2016-02-01

    Pelvic organ prolapse is an extremely common condition, with approximately 12% of women requiring surgical correction over their lifetime. This manuscript reviews the most recent literature regarding the comparative efficacy of various surgical repair techniques in the treatment of advanced stage pelvic organ prolapse. Uterosacral ligament suspension has similar anatomic and subjective outcomes when compared to sacrospinous ligament fixation at 12 months and is considered to be equally effective. The use of transvaginal mesh has been shown to be superior to native tissue vaginal repairs with respect to anatomic outcomes but at the cost of a higher complication rate. Minimally invasive sacrocolpopexy appears to be equivalent to abdominal sacrocolpopexy (ASC). Robot-assisted sacrocolpopexy (RSC) and laparoscopic sacrocolpopexy (LSC) appear as effective as abdominal sacrocolpopexy, however, prospective studies of comparing long-term outcomes of ASC, LSC, and RSC in relation to health care costs is paramount in the near future. Surgical correction of advanced pelvic organ prolapse can be accomplished via a variety of proven techniques. Selection of the correct surgical approach is a complex decision process and involves a multitude of factors. When deciding on the most suitable surgical intervention, the chosen route must be individualized for each patient taking into account the specific risks and benefits of each procedure. PMID:26448444

  9. Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC

    PubMed Central

    Gupta, Ravi; Fischer, Kari R.; Choi, Hyejin; El Rayes, Tina; Ryu, Seongho; Nasar, Abu; Spinelli, Cathy F.; Andrews, Weston; Elemento, Olivier; Nolan, Daniel; Stiles, Brendon; Rafii, Shahin; Narula, Navneet; Davuluri, Ramana; Altorki, Nasser K.; Mittal, Vivek

    2015-01-01

    Lung cancer is the leading cause of cancer related mortality worldwide, with non-small cell lung cancer (NSCLC) as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor “activated/reprogrammed” stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM)-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils) identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN), chemokine (C-C motif) ligand 7 (CCL7) and thrombospondin 1 (TSP1) were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value. PMID:26046767

  10. Evolving molecularly targeted therapies for advanced-stage thyroid cancers.

    PubMed

    Bible, Keith C; Ryder, Mabel

    2016-07-01

    Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered - and might further refine - patient care, and identify open questions for future research. PMID:26925962

  11. ERCC1 protein as a guide for individualized therapy of late-stage advanced non-small cell lung cancer

    PubMed Central

    GAO, ZHIQIANG; HAN, BAOHUI; SHEN, JIE; GU, AIQIN; QI, DAJIANG; HUANG, JINSU; SHI, CHUNLEI; XIONG, LIWEN; ZHAO, YIZHUO; JIANG, LIYAN; WANG, HUIMIN; CHEN, YURONG

    2011-01-01

    Excision repair cross-complementation group 1 (ERCC1) protein has been associated with cisplatin resistance. The objective of this study was to investigate the correlation between ERCC1 protein levels and the therapeutic effect of individualized therapy in advanced non-small cell lung cancer (NSCLC). A total of 190 advanced NSCLC patients were included in this study. Patients were randomized into either the individualized therapy group or the standard therapy group at a ratio of 2:1. Patients in the standard therapy group were treated with either gemcitabine plus cisplatin or vinorelbine plus cisplatin. The expression of ERCC1 protein in lung cancer tissues of patients from the individualized therapy group was detected with immunohistochemistry. Patients with low ERCC1 levels received either gemcitabine plus cisplatin or vinorelbine plus cisplatin, and patients with high levels received gemcitabine plus vinorelbine. The main outcome assessments were response rate (RR), overall survival (OS) and time to progression (TTP). Follow-up data were recorded until September 30, 2010. RR, 1-year survival rate and TTP were not statistically significant. The median survival time was 10.10 months in the standard therapy group (95% CI 8.48–11.92) and 13.59 months in the individualized therapy group (95% CI 11.86–14.74). The difference in median survival time was significantly different between these groups (P=0.036). The median survival time was longer in the individualized group compared to the standard therapy group. ERCC1 protein expression in advanced NSCLC patients, however, was not significantly correlated with RR, OS and TTP in the individualized therapy group. Therefore, this study suggests that ERCC1 protein levels should be assessed in combination with additional biomarkers to determine an optimal index for individualized therapy in advanced NSCLC patients. PMID:22977580

  12. Associations of deregulation of mir-365 and its target mRNA TTF-1 and survival in patients with NSCLC

    PubMed Central

    Sun, Ruifang; Liu, Zhigang; Ma, Gang; Lv, Weidong; Zhao, Xinliang; Lei, Guangyan; Xu, Changfu

    2015-01-01

    microRNA (mir)-365 exerts tumor suppressor function by targeting thyroid transcription factor-1 (TTF-1) in lung cancer cells. The purpose of the present study was to assess mir-365 and its target mRNA TTF-1 in lung cancer and their correlations with patients’ survival. Quantitative real-time PCR was used to examine the expression levels of mir-365 and TTF-1 in tumor tissue and its adjacent noncancerous tissue of 126 patients with non-small cell lung cancer (NSCLC). Our results showed that mir-365 was significantly decreased in tumor tissue than that in normal tissue (P=0.006), however, TTF-1 was significantly increased in tumor tissue than in normal tissue (P<0.001). Besides, significant correlations between decreased mir-365 and advanced tumor-node-metastasis (TNM) stage (P=0.001) and regional lymph node involvement (P=0.037) was observed. The similar result was also found between increased TTF-1 and TNM stage (P=0.003). Furthermore, mir-365 downregulation or TTF-1 upregulation were associated with poor outcome of patients than mir-365 upregulation or TTF-1 downregulation (for mir-365: P<0.001; for TTF-1: P=0.002). Of note, combination of decreased mir-365 and increased TTF-1 had worst overall survival (P<0.001). In conclusion, aberrant expression of mir-365/TTF-1 may be involved in the tumor development in patients with NSCLC. Moreover, mir-365 and TTF-1 could jointly predict the prognosis of patients and their combination may serve as a biomarker to predict risk of poor survival in NSCLC patients. Mir-365/TTF-1 might serve as a potential therapeutic target for clinical treatment of NSCLC. PMID:26045746

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

    PubMed Central

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

    2011-01-01

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

  14. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC

    PubMed Central

    Besse, Benjamin; Charrier, Mélinda; Lapierre, Valérie; Dansin, Eric; Lantz, Olivier; Planchard, David; Le Chevalier, Thierry; Livartoski, Alain; Barlesi, Fabrice; Laplanche, Agnès; Ploix, Stéphanie; Vimond, Nadège; Peguillet, Isabelle; Théry, Clotilde; Lacroix, Ludovic; Zoernig, Inka; Dhodapkar, Kavita; Dhodapkar, Madhav; Viaud, Sophie; Soria, Jean-Charles; Reiners, Katrin S.; Pogge von Strandmann, Elke; Vély, Frédéric; Rusakiewicz, Sylvie; Eggermont, Alexander; Pitt, Jonathan M.; Zitvogel, Laurence; Chaput, Nathalie

    2016-01-01

    ABSTRACT Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN-γ-free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN-γ-Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN-γ-Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN-γ-Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN-γ-Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC. PMID:27141373

  15. Advanced two-stage incineration: Research and development

    SciTech Connect

    Rehmat, A.; Khinkis, M.

    1991-01-01

    IGT is currently developing a two-stage fluidized-bed/cyclonic agglomerating incineration system that is based on combining the fluidized-bed agglomeration/incineration and cyclonic combustion technologies, both of which have been developed individually at IGT over many years. This combination has resulted in a unique and extremely flexible incinerator for solid, liquid, and gaseous wastes. The system can operate over a wide range of conditions in the first stage, from low temperature (desorption) to high temperature (agglomeration), including gasification of high-Btu wastes. In the combined system, solid, liquid, and gaseous organic wastes are expected to be easily and efficiently destroyed (>99.99% destruction and removal efficiency (DRE)) while solid inorganic contaminants are expected to be contained within a glassy matrix, rendering them benign and suitable for disposal in an ordinary landfill. The development of the two-stage incinerator is a culmination of extensive research and development efforts on each stage of the incinerator. A variety of data obtained for both stages includes agglomeration of ash, incineration and reclamation of used blast grit and foundry sand, partial combustion of carbonaceous fuels, in-situ desulfurization, combustion of low-Btu gases, incineration of industrial wastewater, and incineration of carbon tetrachloride.

  16. [Modalities of use of ceritinib (Zykadia™), a 2nd generation ALK inhibitor, in advanced stage non-small cell lung cancer].

    PubMed

    Giroux Leprieur, Etienne; Fallet, Vincent; Wislez, Marie

    2015-12-01

    Around 4% of advanced non-small cell lung cancers (NSCLC) harbor a ALK rearrangement, with high sensitivity to ALK inhibitor as crizotinib. However, the vast majority of these tumors end with a tumor progression after several months of treatment with crizotinib. Ceritinib is a 2nd generation ALK inhibitor, which showed high efficiency in NSCLC with ALK rearrangement. Results from phase I trial showed a response rate at 58% in these tumors, with a similar rate for previously crizotinib-treated patients or crizotinib-naïve patients. Moreover, cerebral responses were observed with ceritinib. Preliminary date from a phase 2 trial confirmed these results. These promising results allowed a European marketing authorization (autorisation de mise sur le marché [AMM]) since May 2015 for the treatment of advanced NSCLC with ALK rearrangement and resistance or intolerance to crizotinib. PMID:26597476

  17. Staging laparoscopy improves treatment decision-making for advanced gastric cancer

    PubMed Central

    Hu, Yan-Feng; Deng, Zhen-Wei; Liu, Hao; Mou, Ting-Yu; Chen, Tao; Lu, Xin; Wang, Da; Yu, Jiang; Li, Guo-Xin

    2016-01-01

    AIM: To evaluate the clinical value of staging laparoscopy in treatment decision-making for advanced gastric cancer (GC). METHODS: Clinical data of 582 patients with advanced GC were retrospectively analyzed. All patients underwent staging laparoscopy. The strength of agreement between computed tomography (CT) stage, endoscopic ultrasound (EUS) stage, laparoscopic stage, and final stage were determined by weighted Kappa statistic (Kw). The number of patients with treatment decision-changes was counted. A χ2 test was used to analyze the correlation between peritoneal metastasis or positive cytology and clinical characteristics. RESULTS: Among the 582 patients, the distributions of pathological T classifications were T2/3 (153, 26.3%), T4a (262, 45.0%), and T4b (167, 28.7%). Treatment plans for 211 (36.3%) patients were changed after staging laparoscopy was performed. Two (10.5%) of 19 patients in M1 regained the opportunity for potential radical resection by staging laparoscopy. Unnecessary laparotomy was avoided in 71 (12.2%) patients. The strength of agreement between preoperative T stage and final T stage was in almost perfect agreement (Kw = 0.838; 95% confidence interval (CI): 0.803-0.872; P < 0.05) for staging laparoscopy; compared with CT and EUS, which was in fair agreement. The strength of agreement between preoperative M stage and final M stage was in almost perfect agreement (Kw = 0.990; 95% CI: 0.977-1.000; P < 0.05) for staging laparoscopy; compared with CT, which was in slight agreement. Multivariate analysis revealed that tumor size (≥ 40 mm), depth of tumor invasion (T4b), and Borrmann type (III or IV) were significantly correlated with either peritoneal metastasis or positive cytology. The best performance in diagnosing P-positive was obtained when two or three risk factors existed. CONCLUSION: Staging laparoscopy can improve treatment decision-making for advanced GC and decrease unnecessary exploratory laparotomy. PMID:26855545

  18. Exprimental Results of the First Two Stages of an Advanced Transonic Core Compressor Under Isolated and Multi-Stage Conditions.

    NASA Technical Reports Server (NTRS)

    Prahst, Patricia S.; Kulkarni, Sameer; Sohn, Ki H.

    2015-01-01

    NASA's Environmentally Responsible Aviation (ERA) Program calls for investigation of the technology barriers associated with improved fuel efficiency for large gas turbine engines. Under ERA, the highly loaded core compressor technology program attempts to realize the fuel burn reduction goal by increasing overall pressure ratio of the compressor to increase thermal efficiency of the engine. Study engines with overall pressure ratio of 60 to 70 are now being investigated. This means that the high pressure compressor would have to almost double in pressure ratio while keeping a high level of efficiency. NASA and GE teamed to address this challenge by testing the first two stages of an advanced GE compressor designed to meet the requirements of a very high pressure ratio core compressor. Previous test experience of a compressor which included these front two stages indicated a performance deficit relative to design intent. Therefore, the current rig was designed to run in 1-stage and 2-stage configurations in two separate tests to assess whether the bow shock of the second rotor interacting with the upstream stage contributed to the unpredicted performance deficit, or if the culprit was due to interaction of rotor 1 and stator 1. Thus, the goal was to fully understand the stage 1 performance under isolated and multi-stage conditions, and additionally to provide a detailed aerodynamic data set for CFD validation. Full use was made of steady and unsteady measurement methods to understand fluid dynamics loss source mechanisms due to rotor shock interaction and endwall losses. This paper will present the description of the compressor test article and its measured performance and operability, for both the single stage and two stage configurations. We focus the paper on measurements at 97% corrected speed with design intent vane setting angles.

  19. The Critical Technologies and Applications on Advanced Upper Stage Vehicles

    NASA Astrophysics Data System (ADS)

    Qi, Feng; Wang, Guo-hui

    2016-07-01

    Upper Stage Vehicle(USV) is a kind of independent one-stop-into-space launching vehicles. In this article, different new-conception USVs are mentioned and out of them, on basis of the possibility in future application, laser propelling USV and nuclear-thermal propelling USV are selected and discussed in technical details, especially in critical technologies and recent relative technical improvements about new propelling methods within these two kinds. Furthermore, laser propelled USV and nuclear-thermal propelled USV both seem to have important roles to play in future space exploring projects. And several possible applications of the two kinds of USVs emphasized above are carried out at the end of this piece of article.

  20. 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

  1. Experimental Results of the First Two Stages of an Advanced Transonic Core Compressor Under Isolated and Multi-Stage Conditions

    NASA Technical Reports Server (NTRS)

    Prahst, Patricia S.; Kulkarni, Sameer; Sohn, Ki H.

    2015-01-01

    NASA's Environmentally Responsible Aviation (ERA) Program calls for investigation of the technology barriers associated with improved fuel efficiency of large gas turbine engines. Under ERA the task for a High Pressure Ratio Core Technology program calls for a higher overall pressure ratio of 60 to 70. This mean that the HPC would have to almost double in pressure ratio and keep its high level of efficiency. The challenge is how to match the corrected mass flow rate of the front two supersonic high reaction and high corrected tip speed stages with a total pressure ratio of 3.5. NASA and GE teamed to address this challenge by using the initial geometry of an advanced GE compressor design to meet the requirements of the first 2 stages of the very high pressure ratio core compressor. The rig was configured to run as a 2 stage machine, with Strut and IGV, Rotor 1 and Stator 1 run as independent tests which were then followed by adding the second stage. The goal is to fully understand the stage performances under isolated and multi-stage conditions and fully understand any differences and provide a detailed aerodynamic data set for CFD validation. Full use was made of steady and unsteady measurement methods to isolate fluid dynamics loss source mechanisms due to interaction and endwalls. The paper will present the description of the compressor test article, its predicted performance and operability, and the experimental results for both the single stage and two stage configurations. We focus the detailed measurements on 97 and 100 of design speed at 3 vane setting angles.

  2. Advanced MRI and staging of multiple sclerosis lesions.

    PubMed

    Absinta, Martina; Sati, Pascal; Reich, Daniel S

    2016-06-01

    Over the past few decades, MRI-based visualization of demyelinated CNS lesions has become pivotal to the diagnosis and monitoring of multiple sclerosis (MS). In this Review, we outline current efforts to correlate imaging findings with the pathology of lesion development in MS, and the pitfalls that are being encountered in this research. Multimodal imaging at high and ultra-high magnetic field strengths is yielding biologically relevant insights into the pathophysiology of blood-brain barrier dynamics and both active and chronic inflammation, as well as mechanisms of lesion healing and remyelination. Here, we parallel the results in humans with advances in imaging of a primate model of MS - experimental autoimmune encephalomyelitis (EAE) in the common marmoset - in which demyelinated lesions resemble their human counterparts far more closely than do EAE lesions in the rodent. This approach holds promise for the identification of innovative biological markers, and for next-generation clinical trials that will focus more on tissue protection and repair. PMID:27125632

  3. 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

  4. Three emerging new drugs for NSCLC: pemetrexed, bortezomib, and cetuximab.

    PubMed

    Dubey, Sarita; Schiller, Joan H

    2005-04-01

    Despite advances made in cytotoxic chemotherapy, the prognosis for patients with non-small cell lung cancer (NSCLC) continues to be poor. New, more effective drugs must be identified and developed to improve the outcome of these patients. Three drugs with promising activity in NSCLC are pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com), bortezomib (Velcade; Millennium Pharmaceuticals, Inc., Cambridge, MA, http://www.mlnm.com), and cetuximab (Erbitux; ImClone Systems, Inc., New York, NY, http://www.imclone.com). Pemetrexed inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase, enzymes necessary for purine and pyrimidine synthesis, thus causing cell-cycle arrest in the S phase. Bortezomib, a proteasome inhibitor, interferes with the cytosolic protein degradation machinery, namely the ubiquitin-proteasome complex, causing breakdown of cell-cycle regulators and cell-cycle arrest. Cetuximab is a chimeric mouse-human antibody that inhibits ligand-dependent activation of the epidermal growth factor receptor, resulting in receptor internalization and inhibition of downstream pathways that, in turn, causes cell growth and progression. All three drugs are approved for different tumor types, and studies defining their role in NSCLC are under way. PMID:15821248

  5. Bronchial involvement in advanced stage lymphangioleiomyomatosis: histopathologic and molecular analyses.

    PubMed

    Hayashi, Takuo; Kumasaka, Toshio; Mitani, Keiko; Okada, Yoshinori; Kondo, Takashi; Date, Hiroshi; Chen, Fengshi; Oto, Takahiro; Miyoshi, Shinichiro; Shiraishi, Takeshi; Iwasaki, Akinori; Hara, Kieko; Saito, Tsuyoshi; Ando, Katsutoshi; Kobayashi, Etsuko; Gunji-Niitsu, Yoko; Kunogi, Makiko; Takahashi, Kazuhisa; Yao, Takashi; Seyama, Kuniaki

    2016-04-01

    Lymphangioleiomyomatosis (LAM), a rare progressive disease that almost exclusively affects women, is characterized by pulmonary cysts and neoplastic proliferation of smooth muscle-like cells (LAM cells). Airflow obstruction is a physiologic consequence that is commonly observed in LAM and has been attributed to narrowing of peripheral airways. However, histopathologic examinations of the entire airway have been precluded by the limited availability of such specimens. Here, we used explanted lung tissues from 30 LAM patients for a thorough histologic analysis with a special emphasis on the bronchi. We found bronchial involvement by LAM cells and lymphatics in all patients examined. Furthermore, a moderate to severe degree of chronic inflammation (73%), goblet cell hyperplasia (97%), squamous cell metaplasia (83%) of the epithelium, and thickening of basal lamina (93%) were identified in the bronchi. Because LAM cells are transformed by the functional loss of the TSC genes leading to a hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, we confirmed the expression of phospho-p70S6K, phospho-S6, phospho-4E-BP1, and vascular endothelial growth factor (VEGF)-D in LAM cells from all of the patients examined. In contrast, no protein expression of hypoxia-inducible factor 1α, a downstream molecule indicative of mTORC1 activation and leading to VEGF production, was detected in any patient. Our study indicates that late-stage LAM patients commonly have bronchi involved by the proliferation of both LAM cells and lymphatics and that chronic inflammation complicated their disease. Furthermore, the up-regulation of hypoxia-inducible factor 1α, a common event in mTORC1-driven tumor cells, does not occur in LAM cells and plays no role in VEGF-D expression in LAM cells. PMID:26997436

  6. Multiple Marker Detection in Peripheral Blood for NSCLC Diagnosis

    PubMed Central

    Ulivi, Paola; Mercatali, Laura; Casoni, Gian-Luca; Scarpi, Emanuela; Bucchi, Lauro; Silvestrini, Rosella; Sanna, Stefano; Monteverde, Marco; Amadori, Dino; Poletti, Venerino; Zoli, Wainer

    2013-01-01

    Background Non-invasive early detection of lung cancer could reduce the number of patients diagnosed with advanced disease, which is associated with a poor prognosis. We analyzed the diagnostic accuracy of a panel of peripheral blood markers in detecting non small cell lung cancer (NSCLC). Methods 100 healthy donors and 100 patients with NSCLC were enrolled onto this study. Free circulating DNA, circulating mRNA expression of peptidylarginine deiminase type 4 (PAD4/PADI4), pro-platelet basic protein (PPBP) and haptoglobin were evaluated using a Real-Time PCR-based method. Results Free circulating DNA, PADI4, PPBP and haptoglobin levels were significantly higher in NSCLC patients than in healthy donors (p<0.0001, p<0.0001, p = 0.0002 and p = 0.0001, respectively). The fitted logistic regression model demonstrated a significant direct association between marker expression and lung cancer risk. The odds ratios of individual markers were 6.93 (95% CI 4.15–11.58; p<0.0001) for free DNA, 6.99 (95% CI 3.75–13.03; p<0.0001) for PADI4, 2.85 (95% CI 1.71–4.75; p<0.0001) for PPBP and 1.16 (95% CI 1.01–1.33; p = 0.031) for haptoglobin. Free DNA in combination with PPBP and PADI4 gave an area under the ROC curve of 0.93, 95% CI = 0.90–0.97, with sensitivity and specificity over 90%. Conclusions Free circulating DNA analysis combined with PPBP and PADI4 expression determination appears to accurately discriminate between healthy donors and NSCLC patients. This non-invasive multimarker approach warrants further research to assess its potential role in the diagnostic or screening workup of subjects with suspected lung cancer. PMID:23468981

  7. Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application

    PubMed Central

    Sacco, Paola Claudia; Sgambato, Assunta; Casaluce, Francesca; Rossi, Antonio; Gridelli, Cesare

    2015-01-01

    The discovery that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by druggable protein kinases has led to a revolutionary change in nonsmall cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the targets of several tyrosine kinase inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. First-generation agents offer, in target populations, a substantial improvement of outcomes compared with standard chemotherapy in the treatment of advanced NSCLC. Unfortunately, drug resistance develops after initial benefit through a variety of mechanisms. Novel generation EGFR and ALK inhibitors are currently in advanced clinical development and are producing encouraging results in patients with acquired resistance to previous generation agents. The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations or ALK rearrangements is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC. PMID:26327924

  8. Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application.

    PubMed

    Maione, Paolo; Sacco, Paola Claudia; Sgambato, Assunta; Casaluce, Francesca; Rossi, Antonio; Gridelli, Cesare

    2015-09-01

    The discovery that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by druggable protein kinases has led to a revolutionary change in nonsmall cell lung cancer (NSCLC) treatment. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the targets of several tyrosine kinase inhibitors (TKIs), some of them approved for treatment and others currently in clinical development. First-generation agents offer, in target populations, a substantial improvement of outcomes compared with standard chemotherapy in the treatment of advanced NSCLC. Unfortunately, drug resistance develops after initial benefit through a variety of mechanisms. Novel generation EGFR and ALK inhibitors are currently in advanced clinical development and are producing encouraging results in patients with acquired resistance to previous generation agents. The search for new drugs or strategies to overcome the TKI resistance in patients with EGFR mutations or ALK rearrangements is to be considered a priority for the improvement of outcomes in the treatment of advanced NSCLC. PMID:26327924

  9. Transcriptomic analysis of stage 1 versus advanced adult granulosa cell tumors

    PubMed Central

    Leung, Dilys; Gould, Jodee A.; Jobling, Tom; Fuller, Peter J.

    2016-01-01

    Ovarian granulosa cell tumors (GCT) are hormonally-active neoplasms characterized, in the adult-subtype, by a mutation in the FOXL2 gene (C134W). They exhibit an indolent course with an unexplained propensity for late recurrence; ∼80% of patients with aggressive, advanced stage tumors die from their disease; aside from surgery, therapeutic options are limited. To identify the molecular basis of advanced stage disease we have used whole transcriptome analysis of FOXL2 C134W mutation positive adult (a)GCT to identify genes that are differentially expressed between early (stage 1) and advanced (stage 3) aGCT. Transcriptome profiles for early (n = 6) and stage 3 (n = 6) aGCT, and for the aGCT-derived KGN, cell line identified 24 genes whose expression significantly differs between the early and stage 3 aGCT. Of these, 16 were more abundantly expressed in the stage 3 aGCT and 8 were higher in the stage 1 tumors. These changes were further examined for the genes which showed the greatest fold change: the cytokine CXCL14, microfibrillar-associated protein 5, insulin-like 3 and desmin. Gene Set Enrichment Analysis identified overexpression of genes on chromosome 7p15 which includes the homeobox A gene locus. The analysis therefore identifies a small number of genes with clearly discriminate patterns of expression arguing that the clinicopathological-derived distinction of the tumor stage is robust, whilst confirming the relative homogeneity of expression for many genes across the cohort and hence of aGCT. The expression profiles do however identify several overexpressed genes in both stage 1 and/or stage 3 aGCT which warrant further study as possible therapeutic targets. PMID:26893359

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

    PubMed

    Pillai, Rathi N; Ramalingam, Suresh S

    2014-03-01

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

  11. The clinicopathological significance and potential drug target of E-cadherin in NSCLC.

    PubMed

    Zhong, Kaize; Chen, Weiwen; Xiao, Ning; Zhao, Jian

    2015-08-01

    Human epithelial cadherin (E-cadherin), a member of transmembrane glycoprotein family, encoded by the E-cadherin gene, plays a key role in cell-cell adhesion, adherent junction in normal epithelial tissues, contributing to tissue differentiation and homeostasis. Although previous studies indicated that inactivation of the E-cadherin is mainly induced by hypermethylation of E-cadherin gene, evidence concerning E-cadherin hypermethylation in the carcinogenesis and development of non-small cell lung carcinoma (NSCLC) remains controversial. In this study, we conducted a meta-analysis to quantitatively evaluate the effects of E-cadherin hypermethylation on the incidence and clinicopathological characteristics of NSCLC. A comprehensive search of PubMed and Embase databases was performed up to October 2014. Analyses of pooled data were performed. Odds ratios (ORs) were calculated and summarized. Our meta-analysis combining 18 published articles demonstrated that the hypermethylation frequencies in NSCLC were significantly higher than those in normal control tissues, OR = 3.55, 95 % confidence interval (CI) = 1.98-6.36, p < 0.0001. Further analysis showed that E-cadherin hypermethylation was not strongly associated with the sex or smoking status in NSCLC patients. In addition, E-cadherin hypermethylation was also not strongly associated with pathological types, differentiated status, clinical stages, or metastatic status in NSCLC patients. The results from the current study indicate that the hypermethylation frequency of E-cadherin in NSCLC is strongly associated with NSCLC incidence and it may be an early event in carcinogenesis of NSCLC. We also discussed the potential value of E-cadherin as a drug target that may bring new direction and hope for cancer treatment through gene-targeted therapy. PMID:25758052

  12. [Advances in Surgical Treatment of Early Stage Non-small Cell Lung Cancer].

    PubMed

    Hu, Jian; Bao, Feichao

    2016-06-20

    Lung cancer is the leading cause of cancer-related deaths worldwide, computed tomography screening has made the disease spectrum of lung cancer shift from the previously predominating central local advanced squamous cell carcinoma to early stage lung adenocarcinoma represented by solitary pulmonary nodule, ground-glass opacity (GGO) and sub-centimeter nodule. This paper reviewed the recent proceeding in the surgical management of early stage lung cancer. PMID:27335305

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

    PubMed Central

    Bayraktar, Soley; Rocha-Lima, Caio M

    2013-01-01

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

  14. Prognostic significance of circulating laminin gamma2 for early-stage non-small-cell lung cancer

    PubMed Central

    Teng, Yu; Wang, Zitong; Ma, Li; Zhang, Lina; Guo, Yinan; Gu, Meng; Wang, Ziyu; Wang, Yue; Yue, Wentao

    2016-01-01

    Background Laminin gamma2 (Ln-γ2) chain, a distinctive subunit of heterotrimeric laminin-332, is frequently upregulated in carcinomas and is of great importance in cell migration and invasion. Despite this, the status of circulating Ln-γ2 in lung cancer patients is still uncertain. Patients and methods In this retrospective study, serum samples from 538 all-stage (stages I–IV) patients with non-small-cell lung cancer (NSCLC) and 94 age-matched healthy volunteers were investigated by enzyme-linked immunosorbent assay. Data were statistically analyzed in combination with clinicopathological information. Results Circulating Ln-γ2 was markedly increased in NSCLC, even in stage I cases (P<0.01), reflecting the progression of lung cancer. Survival analysis on 370 eligible patients indicated that serum Ln-γ2-negative patients survived much longer compared with Ln-γ2-positive individuals (P=0.028), and it was especially the case for stage I (P<0.001), stage T1 (P=0.001), and stage N0 patients (P=0.038), all of whom represented early-stage cases. For the advanced patients, however, overall survivals were not significantly different among stages II–IV (P=0.830), stages T2–T4 (P=0.575), stages N1–N3 (P=0.669), and stage M1 (P=0.849). Cox analysis subsequently defined serum Ln-γ2 as an independent prognostic indicator of NSCLC, particularly for early-stage patients. Furthermore, we demonstrated the association of serum Ln-γ2 with smoking behavior, but its association with tumor progression and early prognostic significance were not altered in the nonsmoking cohort. Conclusion Our study demonstrated that elevation of circulating Ln-γ2 was an early-emerging event in NSCLC and was significantly associated with poor prognosis in NSCLC, especially for early-stage cases. PMID:27462170

  15. Systematic genomic identification of colorectal cancer genes delineating advanced from early clinical stage and metastasis

    PubMed Central

    2013-01-01

    Background Colorectal cancer is the third leading cause of cancer deaths in the United States. The initial assessment of colorectal cancer involves clinical staging that takes into account the extent of primary tumor invasion, determining the number of lymph nodes with metastatic cancer and the identification of metastatic sites in other organs. Advanced clinical stage indicates metastatic cancer, either in regional lymph nodes or in distant organs. While the genomic and genetic basis of colorectal cancer has been elucidated to some degree, less is known about the identity of specific cancer genes that are associated with advanced clinical stage and metastasis. Methods We compiled multiple genomic data types (mutations, copy number alterations, gene expression and methylation status) as well as clinical meta-data from The Cancer Genome Atlas (TCGA). We used an elastic-net regularized regression method on the combined genomic data to identify genetic aberrations and their associated cancer genes that are indicators of clinical stage. We ranked candidate genes by their regression coefficient and level of support from multiple assay modalities. Results A fit of the elastic-net regularized regression to 197 samples and integrated analysis of four genomic platforms identified the set of top gene predictors of advanced clinical stage, including: WRN, SYK, DDX5 and ADRA2C. These genetic features were identified robustly in bootstrap resampling analysis. Conclusions We conducted an analysis integrating multiple genomic features including mutations, copy number alterations, gene expression and methylation. This integrated approach in which one considers all of these genomic features performs better than any individual genomic assay. We identified multiple genes that robustly delineate advanced clinical stage, suggesting their possible role in colorectal cancer metastatic progression. PMID:24308539

  16. Advanced Development Program for a 625 lbf thrust engine for Ares First Stage Roll Control System

    NASA Technical Reports Server (NTRS)

    Dawson, Matt; Chenevert, Blake; Brewster, Gerry; Frei, Tom; Bullard, Brad; Fuller, Ray

    2009-01-01

    NASA's new Ares Launch Vehicle will require twelve thrusters to provide roll control of the vehicle during the first stage firing. All twelve roll control thrusters will be located at the inter-stage segment that separates the solid rocket booster first stage from the second stage. NASA selected a mono propellant hydrazine solution and as a result awarded Aerojet-General a contract in 2007 for an advanced development program for an MR-80- series 625 Ibf vacuum thrust monopropellant hydrazine thruster. This thruster has heritage dating back to the 1976 Viking Landers and most recently for the 2011 Mars Science Laboratory. Prior to the Ares application, the MR-80-series thrusters had been equipped with throttle valves and not typically operated in pulse mode. The primary objective of the advanced development program was to increase the technology readiness level and retire major technical risks for the future flight qualification test program. Aerojet built on their heritage MR-80 rocket engine designs to achieve the design and performance requirements. Significant improvements to cost and lead-time were achieved by applying Design for Manufacturing and Assembly (DFMA) principles. AerojetGeneral has completed Preliminary and Critical Design Reviews, followed by two successful rocket engine development test programs. The test programs included qualification random vibration and firing lite that significantly exceed the flight qualification requirements. This paper discusses the advanced development program and the demonstrated capability of the MR-80C engine. Y;

  17. Downregulation of the long non-coding RNA TUSC7 promotes NSCLC cell proliferation and correlates with poor prognosis

    PubMed Central

    Wang, Zhongwei; Jin, Yingying; Ren, Hongtao; Ma, Xiulong; Wang, Baofeng; Wang, Yali

    2016-01-01

    Background: Emerging evidence indicated that dysregulated long non-coding RNAs (lncRNAs) was implicated in the tumorigenesis and progression. LncRNA TUSC7 was involved in various malignancies. However, the role of TUSC7 in human non-small-cell lung cancer (NSCLC) remains unclear. Methods: Expression of TUSC7 was analyzed in 112 cases of NSCLC tissues and six lung cancer cell lines by quantitative real-time PCR (qRT-PCR). Then the correlation of TUSC7 expression with clinicopathological features and prognosis was aslo studied. Furthermore, overexpression of TUSC7 was performed and its role in tumor progression was explored. Results: The expression level of TUSC7 was lower in NSCLC tissues and lung cancer cells compared with their normal counterparts. Lower expression of TUSC7 in NSCLC tissues was associated with larger tumor size and higher TNM stage. Patients with lower TUSC7 expression had worse overall survival compared with the high expression cases. Univariate and multivariate analyses suggested that low expression of TUSC7 was an independent poor prognostic indicator for NSCLC patients. Moreover, upregulation of TUSC7 expression could inhibit proliferation of lung cancer cell in vitro. Conclusions: Our results suggested that TUSC7 was a potential biomarker for NSCLC prognosis, and the dysregulation of TUSC7 may play an important role in the NSCLC progression. PMID:27158360

  18. Reusable launch vehicles, enabling technology for the development of advanced upper stages and payloads

    SciTech Connect

    Metzger, John D.

    1998-01-15

    In the near future there will be classes of upper stages and payloads that will require initial operation at a high-earth orbit to reduce the probability of an inadvertent reentry that could result in a detrimental impact on humans and the biosphere. A nuclear propulsion system, such as was being developed under the Space Nuclear Thermal Propulsion (SNTP) Program, is an example of such a potential payload. This paper uses the results of a reusable launch vehicle (RLV) study to demonstrate the potential importance of a Reusable Launch Vehicle (RLV) to test and implement an advanced upper stage (AUS) or payload in a safe orbit and in a cost effective and reliable manner. The RLV is a horizontal takeoff and horizontal landing (HTHL), two-stage-to-orbit (TSTO) vehicle. The results of the study shows that an HTHL is cost effective because it implements airplane-like operation, infrastructure, and flight operations. The first stage of the TSTO is powered by Rocket-Based-Combined-Cycle (RBCC) engines, the second stage is powered by a LOX/LH rocket engine. The TSTO is used since it most effectively utilizes the capability of the RBCC engine. The analysis uses the NASA code POST (Program to Optimize Simulated Trajectories) to determine trajectories and weight in high-earth orbit for AUS/advanced payloads. Cost and reliability of an RLV versus current generation expandable launch vehicles are presented.

  19. The Influence of Social Norms on Advancement Through Bystander Stages for Preventing Interpersonal Violence.

    PubMed

    Deitch-Stackhouse, Jacqueline; Kenneavy, Kristin; Thayer, Richard; Berkowitz, Alan; Mascari, Janine

    2015-10-01

    This research evaluates the impact of social norms on the advancement through the bystander stages toward prosocial (active) intervention in interpersonal violence (IPV): emotional abuse, physical violence, controlling behavior, sexual violence, and stalking. The influence of social norms on bystander behavior across stages and types of violence varies. Accurate social norms perceptions are associated with routine intervention, although social norms misperceptions are not always a strong deterrent to intervention. Interpretation of a violent situation as problematic predicts increased willingness to intervene. Implications for the development of social norms antiviolence campaigns and strategies for reducing barriers to prosocial intervention are discussed. PMID:26175519

  20. 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

  1. Stages of Change for the Component Behaviors of Advance Care Planning

    PubMed Central

    Fried, Terri R.; Redding, Colleen; Robbins, Mark; Paiva, Andrea; O’Leary, John R.; Iannone, Lynne

    2010-01-01

    Objectives 1) To develop stages of change measures for advance care planning (ACP), conceptualized as a group of interrelated but separate behaviors. 2) To use these measures to characterize older persons’ engagement in and factors associated with readiness to participate in ACP. Design Observational cohort study. Setting Community. Participants Persons age ≥ 65 recruited from physician offices and a senior center. Measurements Stages of change for six ACP behaviors: completion of a living will and health care proxy, communication with loved ones regarding use of life-sustaining treatments and quantity versus quality of life (QOL), and communication with physicians about these same issues. Results Readiness to participate in ACP varied widely across behaviors. Whereas between approximately 50–60% of participants were in the action or maintenance stage for communicating with loved ones and completing a living will, 40% were in the precontemplation stage for communicating with loved ones about quantity versus QOL, and 70–75% were in the precontemplation stage for communicating with physicians. Participants were frequently in different stages for the different behaviors. Relatively few sociodemographic, health, or psychosocial factors were associated with stages of change for completing a living will, but a broader range of factors was associated with stages of change for communication with loved ones about quantity versus QOL. Conclusion Older persons show a range of readiness to engage in different aspects of ACP. Individualized assessment and interventions targeted to stage of behavior change for each component of ACP may be an effective strategy to increase participation in ACP. PMID:21143441

  2. Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation

    PubMed Central

    Groenendijk, Floris H; Mellema, Wouter W; van der Burg, Eline; Schut, Eva; Hauptmann, Michael; Horlings, Hugo M; Willems, Stefan M; van den Heuvel, Michel M; Jonkers, Jos; Smit, Egbert F; Bernards, René

    2015-01-01

    The multikinase inhibitor sorafenib is under clinical investigation for the treatment of many solid tumors, but in most cases, the molecular target responsible for the clinical effect is unknown. Furthermore, enhancing the effectiveness of sorafenib using combination strategies is a major clinical challenge. Here, we identify sorafenib as an activator of AMP-activated protein kinase (AMPK), in a manner that involves either upstream LKB1 or CAMKK2. We further show in a phase II clinical trial in KRAS mutant advanced non-small cell lung cancer (NSCLC) with single agent sorafenib an improved disease control rate in patients using the antidiabetic drug metformin. Consistent with this, sorafenib and metformin act synergistically in inhibiting cellular proliferation in NSCLC in vitro and in vivo. A synergistic effect of both drugs is also seen on phosphorylation of the AMPKα activation site. Our results provide a rationale for the synergistic antiproliferative effects, given that AMPK inhibits downstream mTOR signaling. These data suggest that the combination of sorafenib with AMPK activators could have beneficial effects on tumor regression by AMPK pathway activation. The combination of metformin or other AMPK activators and sorafenib could be tested in prospective clinical trials. PMID:25080865

  3. 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

  4. The experience of living with advanced-stage cancer: a thematic synthesis of the literature.

    PubMed

    García-Rueda, N; Carvajal Valcárcel, A; Saracíbar-Razquin, M; Arantzamendi Solabarrieta, M

    2016-07-01

    The aim of the study was to understand the experience of people living with advanced-stage cancer through literature. The search included The Cochrane Library, PubMed, PsycInfo, CINAHL and Cuiden. Thirteen studies were included. A qualitative meta-synthesis was conducted. One thread emerged from the thematic synthesis: the desire to live as normally as possible, despite being aware of the proximity of death. Three themes also emerged: "a process that is unique" with its four sub-themes; "support network" and "health context," each of them having two sub-themes. This study concludes that living with advanced-stage cancer is a unique and complex process which has both positive and negative aspects. The review provides a comprehensive view of the experience, which considers the importance of the support network and the health context in which the person lives. In this study, "normalcy" is the adjustment to the new reality and living as closely as possible to the way one lived before the disease, while developing a new relationship with being finite and death. A better understanding of the experience of living with advanced-stage cancer will help health professionals to identify the needs of the patients in order to plan individual, high-quality care. PMID:27297131

  5. Physical Activity in Patients With Advanced-Stage Cancer: A Systematic Review of the Literature

    PubMed Central

    Albrecht, Tara A.; Taylor, Ann Gill

    2014-01-01

    The importance of physical activity for chronic disease prevention and management has become generally well accepted. The number of research interventions and publications examining the benefits of physical activity for patients with cancer has been rising steadily. However, much of that research has focused on the impact of physical activity either prior to or early in the cancer diagnosis, treatment, and survivorship process. Research focusing on the effects of physical activity, specifically for patients with advanced-stage cancer and poorer prognostic outcomes, has been addressed only recently. The purpose of this article is to examine the state of the science for physical activity in the advanced-stage disease subset of the cancer population. Exercise in a variety of intensities and forms, including yoga, walking, biking, and swimming, has many health benefits for people, including those diagnosed with cancer. Research has shown that, for people with cancer (including advanced-stage cancer), exercise can decrease anxiety, stress, and depression while improving levels of pain, fatigue, shortness of breath, constipation, and insomnia. People diagnosed with cancer should discuss with their oncologist safe, easy ways they can incorporate exercise into their daily lives. PMID:22641322

  6. Current approaches to the treatment of advanced-stage Hodgkin's disease.

    PubMed Central

    Rusthoven, J J

    1986-01-01

    Combination chemotherapy (CT) has been the mainstay of treatment of advanced-stage Hodgkin's disease since the late 1960s. Although treatment with MOPP (nitrogen mustard, vincristine sulfate [Oncovin], procarbazine and prednisone) has resulted in long-term disease-free survival rates exceeding 50%, newer approaches have been studied to improve on this success rate and to reduce the toxic effects associated with MOPP. Prognostic factors have now been defined that identify patients who may require more aggressive treatment; they include age greater than 40 years, presence of B symptoms and more advanced (especially extranodal) disease. A small number of patients with pathological stage III disease may still be successfully treated with extensive radiotherapy (RT) alone. Among patients with advanced-stage disease, significantly better therapeutic results are being obtained with newer treatment approaches than with MOPP, particularly in patients with factors that predict a poor outcome. These newer approaches include combination CT plus RT, alternating cycles of two non-cross-resistant CT regimens and hybrid regimens, which combine agents from two different CT regimens in one cycle. The prognosis of patients who suffer relapse after combination CT remains poor, even with newer drug regimens. The newer treatment approaches may well lead to better cure rates and fewer short-term and long-term toxic effects. PMID:2427176

  7. Physical activity in patients with advanced-stage cancer: a systematic review of the literature.

    PubMed

    Albrecht, Tara A; Taylor, Ann Gill

    2012-06-01

    The importance of physical activity for chronic disease prevention and management has become generally well accepted. The number of research interventions and publications examining the benefits of physical activity for patients with cancer has been rising steadily. However, much of that research has focused on the impact of physical activity either prior to or early in the cancer diagnosis, treatment, and survivorship process. Research focusing on the effects of physical activity, specifically for patients with advanced-stage cancer and poorer prognostic outcomes, has been addressed only recently. The purpose of this article is to examine the state of the science for physical activity in the advanced-stage disease subset of the cancer population. Exercise in a variety of intensities and forms, including yoga, walking, biking, and swimming, has many health benefits for people, including those diagnosed with cancer. Research has shown that, for people with cancer (including advanced-stage cancer), exercise can decrease anxiety, stress, and depression while improving levels of pain, fatigue, shortness of breath, constipation, and insomnia. People diagnosed with cancer should discuss with their oncologist safe, easy ways they can incorporate exercise into their daily lives. PMID:22641322

  8. Treatment of Children with Advanced-Stage Lymphoblastic Lymphoma with Pegaspargase

    PubMed Central

    Yu-tong, Zhang; Li-hua, FENG; Xiao-dan, Zhong; Li-zhe, Wang; Jian, Chang

    2014-01-01

    Objective: To evaluate the feasibility of Pegaspargase instead of L-asparaginase to treat children with advanced-stage lymphoblastic lymphoma (LBL) on the Berlin-Frankfurt-Munster (BFM)-95 protocol. Methods: Fifty-four newly diagnosed patients with stage III or IV LBL and without any treatment were enrolled in this study. Pegaspargase took place of L-asparaginase in BFM-95. The complications and treatment responses of patients treated on the BFM-95 protocol and modified BFM-95 protocol were then evaluated respectively. Findings : For LBL patients treated with BFM-95 protocol or modified BFM-95 protocol, the complete response, event-free survival, overall survival were similar. Stage 4 myelosuppression was the most common complication in both groups. Besides that, among 31 patients receiving modified BFM-95 protocol, coagulation defects were the most common complication. In contrast, anaphylactic reaction was the most common complication in the other 23 patients receiving BFM-95 protocol. Conclusion: Modified BFM-95 protocol is available to children with advanced-stage LBL with an equal outcome and enhances its compliance and decreases the incidence of anaphylactic reaction, compared to BFM-95 protocol. Coagulation defects are the major complication and tolerable in modified one. PMID:25793049

  9. Differential oxidative status and immune characterization of the early and advanced stages of human breast cancer.

    PubMed

    Panis, C; Victorino, V J; Herrera, A C S A; Freitas, L F; De Rossi, T; Campos, F C; Simão, A N Colado; Barbosa, D S; Pinge-Filho, P; Cecchini, R; Cecchini, A L

    2012-06-01

    Breast cancer is the malignant neoplasia with the highest incidence in women worldwide. Chronic oxidative stress and inflammation have been indicated as major mediators during carcinogenesis and cancer progression. Human studies have not considered the complexity of tumor biology during the stages of cancer advance, limiting their clinical application. The purpose of this study was to characterize systemic oxidative stress and immune response parameters in early (ED; TNM I and II) and advanced disease (AD; TNM III and IV) of patients diagnosed with infiltrative ductal carcinoma breast cancer. Oxidative stress parameters were evaluated by plasmatic lipoperoxidation, carbonyl content, thiobarbituric reactive substances (TBARS), nitric oxide levels (NO), total radical antioxidant parameter (TRAP), superoxide dismutase, and catalase activities and GSH levels. Immune evaluation was determined by TNF-α, IL-1β, IL-12, and IL-10 levels and leukocytes oxidative burst evaluation by chemiluminescence. Tissue damage analysis included heart (total CK and CKMB), liver (AST, ALT, GGT), and renal (creatinine, urea, and uric acid) plasmatic markers. C-reactive protein (CRP) and iron metabolism were also evaluated. Analysis of the results verified different oxidative stress statuses occur at distinct cancer stages. ED was characterized by reduction in catalase, 8-isoprostanes, and GSH levels, with enhanced lipid peroxidation and TBARS levels. AD exhibited more pronounced oxidative status, with reduction in catalase activity and TRAP, intense lipid peroxidation and high levels of NO, TBARs, and carbonyl content. ED patients presented a Th2 immune pattern, while AD exhibited Th1 status. CRP levels and ferritin were increased in both stages of disease. Leukocytes burst impairment was observed in both the groups. Plasma iron levels were significantly elevated in AD. The data obtained indicated that oxidative stress enhancement and immune response impairment may be necessary to ensure

  10. Ares First Stage "Systemology" - Combining Advanced Systems Engineering and Planning Tools to Assure Mission Success

    NASA Technical Reports Server (NTRS)

    Seiler, James; Brasfield, Fred; Cannon, Scott

    2008-01-01

    Ares is an integral part of NASA s Constellation architecture that will provide crew and cargo access to the International Space Station as well as low earth orbit support for lunar missions. Ares replaces the Space Shuttle in the post 2010 time frame. Ares I is an in-line, two-stage rocket topped by the Orion Crew Exploration Vehicle, its service module, and a launch abort system. The Ares I first stage is a single, five-segment reusable solid rocket booster derived from the Space Shuttle Program's reusable solid rocket motor. The Ares second or upper stage is propelled by a J-2X main engine fueled with liquid oxygen and liquid hydrogen. This paper describes the advanced systems engineering and planning tools being utilized for the design, test, and qualification of the Ares I first stage element. Included are descriptions of the current first stage design, the milestone schedule requirements, and the marriage of systems engineering, detailed planning efforts, and roadmapping employed to achieve these goals.

  11. Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases.

    PubMed

    Dudnik, Elizabeth; Yust-Katz, Shlomit; Nechushtan, Hovav; Goldstein, Daniel A; Zer, Alona; Flex, Dov; Siegal, Tali; Peled, Nir

    2016-08-01

    Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking. We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade≥3 adverse events were observed. Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation. PMID:27393516

  12. Two-stage, low noise advanced technology fan. 5: Acoustic final report

    NASA Technical Reports Server (NTRS)

    Sofrin, T. G.; Riloff, N., Jr.

    1975-01-01

    The NASA Q2S(quiet two-stage) fan is a 0.836m (32.9 in.) diameter model of the STF 433 engine fan, selected in a 1972 study for an Advanced Technology Transport (ATT) airplane. Noise-control features include: low tip speed, moderate stage pressure rise, large blade-vane spacings, no inlet guide vanes, and optimum blade and vane numbers. Tests were run on the baseline Q2S fan with standard inlet and discharge ducts. Further tests were made of a translating centerbody sonic inlet device and treated discharge ducts. Results were scaled to JT8D and JT3D engine fan size for comparison with current two-stage fans, and were also scaled to STF 433 fan size to compare calculated ATT flyover noise with FAR 36 limits. Baseline Q2S results scaled to JT8D and JT3D engine fan sizes showed substantial noise reductions. Calculated unsuppressed baseline ATT flyovers averaged about 2.5 EPNdB below FAR 36 limits. Using measured sonic inlet results, scaled baseline Q2S fan results, and calculated attenuations for a 1975 technology duct liner, projected flyover noise calculations for the ATT averaged about FAR 36 limits minus 10 EPNdB. Advances in suppression technology required to meet the 1985 goal of FAR 36 limits minus 20 EPNdB are discussed.

  13. Health-related quality of life in end-stage COPD and lung cancer patients.

    PubMed

    Habraken, Jolanda M; ter Riet, Gerben; Gore, Justin M; Greenstone, Michael A; Weersink, Els J M; Bindels, Patrick J E; Willems, Dick L

    2009-06-01

    Historically, palliative care has been developed for cancer patients and is not yet generally available for patients suffering from chronic life-limiting illnesses, such as chronic obstructive pulmonary disease (COPD). To examine whether COPD patients experience similar or worse disease burden in comparison with non-small cell lung cancer (NSCLC) patients, we compared the health-related quality of life (HRQOL) scores of severe COPD patients with those of advanced NSCLC patients. We also formally updated previous evidence in this area provided by a landmark study published by Gore et al. in 2000. In updating this previous evidence, we addressed the methodological limitations of this study and a number of confounding variables. Eighty-two GOLD IV COPD patients and 19 Stage IIIb or IV NSCLC patients completed generic and disease-specific HRQOL questionnaires. We used an individual patient data meta-analysis to integrate the new and existing evidence (total n=201). Finally, to enhance between-group comparability, we performed a sensitivity analysis using a subgroup of patients with a similar degree of "terminality," namely those who had died within one year after study entry. Considerable differences in HRQOL were found for physical functioning, social functioning, mental health, general health perceptions, dyspnea, activities of daily living, and depression. All differences favored the NSCLC patients. The sensitivity analysis, using only terminal NSCLC and COPD patients, confirmed these findings. In conclusion, end-stage COPD patients experience poor HRQOL comparable to or worse than that of advanced NSCLC patients. We discuss these findings in the light of the notion that these COPD patients may have a similar need for palliative care. PMID:19394792

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

    PubMed Central

    2016-01-01

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

  15. A Two Stage Solution Procedure for Production Planning System with Advance Demand Information

    NASA Astrophysics Data System (ADS)

    Ueno, Nobuyuki; Kadomoto, Kiyotaka; Hasuike, Takashi; Okuhara, Koji

    We model for ‘Naiji System’ which is a unique corporation technique between a manufacturer and suppliers in Japan. We propose a two stage solution procedure for a production planning problem with advance demand information, which is called ‘Naiji’. Under demand uncertainty, this model is formulated as a nonlinear stochastic programming problem which minimizes the sum of production cost and inventory holding cost subject to a probabilistic constraint and some linear production constraints. By the convexity and the special structure of correlation matrix in the problem where inventory for different periods is not independent, we propose a solution procedure with two stages which are named Mass Customization Production Planning & Management System (MCPS) and Variable Mesh Neighborhood Search (VMNS) based on meta-heuristics. It is shown that the proposed solution procedure is available to get a near optimal solution efficiently and practical for making a good master production schedule in the suppliers.

  16. Advanced Strategies for End-Stage Heart Failure: Combining Regenerative Approaches with LVAD, a New Horizon?

    PubMed Central

    Tseng, Cheyenne C. S.; Ramjankhan, Faiz Z.; de Jonge, Nicolaas; Chamuleau, Steven A. J.

    2015-01-01

    Despite the improved treatment of cardiovascular diseases, the population with end-stage heart failure (HF) is progressively growing. The scarcity of the gold standard therapy, heart transplantation, demands novel therapeutic approaches. For patients awaiting transplantation, ventricular-assist devices have been of great benefit on survival. To allow explantation of the assist device and obviate heart transplantation, sufficient and durable myocardial recovery is necessary. However, explant rates so far are low. Combining mechanical circulatory support with regenerative therapies such as cell (-based) therapy and biomaterials might give rise to improved long-term results. Although synergistic effects are suggested with mechanical support and stem cell therapy, evidence in both preclinical and clinical setting is lacking. This review focuses on advanced and innovative strategies for the treatment of end-stage HF and furthermore appraises clinical experience with combined strategies. PMID:25905105

  17. 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

  18. 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

  19. A panel of promoter methylation markers for invasive and noninvasive early detection of NSCLC using a quantum dots-based FRET approach.

    PubMed

    Ma, Yunfei; Bai, Yanan; Mao, Hailei; Hong, Qunying; Yang, Dawei; Zhang, Honglian; Liu, Fangming; Wu, Zhenhua; Jin, Qinghui; Zhou, Hongbo; Cao, Jian; Zhao, Jianlong; Zhong, Xinhua; Mao, Hongju

    2016-11-15

    Non-small-cell lung cancer (NSCLC) leads to a significant proportion of cancer-related deaths, and early detection of NSCLC can significantly increase cancer survival rates. A promising approach has been studied to exploit DNA methylation, which is closely correlated to early cancer diagnosis. Herein, in order to realize the early detection of NSCLC, we utilized the developed quantum dots-based (QDs-based) fluorescence resonance energy transfer (FRET) nanosensor technique to analyze the promoter methylation in early stage NSCLC tissue samples and noninvasive bronchial brushing specimens. Using this method, the methylation levels can be quantitatively determined by measuring the signal amplification during FRET. A panel of three tumor suppressor genes (PCDHGB6, HOXA9 and RASSF1A) was assessed in 50 paired early stage NSCLC and their adjacent nontumorous tissue (NT) samples, and 50 early stage NSCLC bronchial brushing and normal specimens. The combined detection was able to identify not only tissue samples but noninvasive bronchial brushing specimens from control cases with a high degree of sensitivity of 92% (AUC=0.977, P<0.001) and 80% (AUC=0.907, P<0.001) respectively, indicating the versatility of promoter expression in invasive and noninvasive NSCLC samples. Therefore this approach can be used to sensitively analyze the methylation levels of cancer-related genes, which might be a potential tool for noninvasive early clinical diagnosis of cancers. PMID:27240011

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

    PubMed

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

    2016-08-01

    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

  1. Long-Term Results of Concurrent Chemoradiotherapy for Advanced N2-3 Stage Nasopharyngeal Carcinoma

    PubMed Central

    Wang, Xue; Chen, Meng; Wu, Jing; Xu, Jian-Hua; Qian, Pu-Dong; Guo, Wen-Jie; Jiang, Xue-Song; Zhu, Huan-Feng; Gu, Jia-Jia; Wu, Jian-Feng; Zhang, Ye-wei; He, Xia

    2015-01-01

    Background N-stage is related to distant metastasis in nasopharyngeal carcinoma (NPC) patients. The purpose of this study was to evaluate the efficacy and toxicity of different nedaplatin-based chemotherapy regimens in advanced N2-3 stage NPC patients treated with intensity modulated radiation therapy (IMRT). Patients and Methods Between April 2005 and December 2009, a total of 128 patients with N2-3 advanced NPC were retrospectively analyzed. Patients were treated with IMRT concurrent with 2 cycles of chemotherapy consisting of either nedaplatin plus paclitaxel (NP group, n = 67) or nedaplatin plus fluorouracil and paclitaxel (NFP group, n = 61). Two to four cycles of adjuvant chemotherapy were then administered every 21 days following concurrent chemoradiotherapy. Results With a median follow-up of 60 months, the 5-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) for all patients were 81.4%, 71.5%, 87.8% and 82.0%, respectively. No significant difference in PFS (66.6% vs. 76.7%, P = 0.212) and LRRFS rates (89.0% vs. 86.3%, P = 0.664) was observed between the NP and NFP groups. The 5-year OS (75.4% vs. 88.5%, P = 0.046) and DMFS (75.1% vs. 89.0%, P = 0.042) rate were superior in the NFP group compared with the NP group. The NFP group had a higher incidence of grade 3–4 acute toxicities including bone marrow suppression (leukopenia: χ2 = 3.935, P = 0.047; anemia: χ2 = 9.760, P = 0.002; thrombocytopenia: χ2 = 8.821, P = 0.003), and both liver and renal dysfunction (χ2 = 5.206, P = 0.023) compared with the NP group. Late toxicities were moderate and no difference was observed between the two groups. Conclusion IMRT concurrent with nedaplatin-based chemotherapy is an advocated regimen for patients with advanced N2-3 stage NPC. Patients with advanced N2-3 stage may be better candidates for the NFP regimen although this regimen was associated with a high acute

  2. Recent advances in renal transplantation: antibody-mediated rejection takes center stage

    PubMed Central

    Chen, Chien Chia; Sicard, Antoine; Rabeyrin, Maud; Morelon, Emmanuel; Dubois, Valérie

    2015-01-01

    Overlooked for decades, antibodies have taken center stage in renal transplantation and are now widely recognized as the first cause of allograft failure. Diagnosis of antibody-mediated rejection has considerably improved with identification of antibody-mediated lesions in graft biopsies and advances made in the detection of circulating donor-specific antibodies. Unfortunately, this progress has not yet translated into better outcomes for patients. Indeed, in the absence of a drug able to suppress antibody generation by plasma cells, available therapies can only slow down graft destruction. This review provides an overview of the current knowledge of antibody-mediated rejection and discusses future interesting research directions. PMID:26097724

  3. Prospective Evaluation of First-Line Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Carrying an Activating EGFR Mutation: A Multicenter Academic Phase II Study in Caucasian Patients (FIELT)

    PubMed Central

    De Grève, Jacques; Van Meerbeeck, Jan; Vansteenkiste, Johan F.; Decoster, Lore; Meert, Anne-Pascale; Vuylsteke, Peter; Focan, Christian; Canon, Jean-Luc; Humblet, Yves; Berchem, Guy; Colinet, Benoit; Galdermans, Danny; Bosquée, Lionel; Vermeij, Joanna; Dewaele, Alex; Geers, Caroline; Schallier, Denis; Teugels, Erik

    2016-01-01

    Introduction Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor. Methods Multicenter academic prospective phase II study with erlotinib in patients with an activating EGFR tyrosine kinase (TK) domain somatic mutation (any exon encoding the kinase domain) in the tumor and no prior treatment for their advanced disease. Results Phenotypic preselecting of 229 patients led to a high EGFR mutation detection rate of 24% of which 46 patients were included in the phase II study. With a progression free survival (PFS) of 81% at three months the study met its primary endpoint for presumed superiority over chemotherapy. With an overall median PFS of 11 months and a median overall survival (OS) of 23 months, the results compare favorably with results obtained in randomized studies using TKI in first line in EGFR mutation positive adenocarcinoma of the lung. Conclusion The present study reinforces the use of EGFR tyrosine kinase inhibition (TKI) as a first line treatment of choice for advanced adenocarcinoma of the lung carrying an activating EGFR mutation. The mutation rate in preselected Caucasian patients is higher than previously reported. Issues relevant for clinical practice are discussed. Trial Registration ClinicalTrials.gov NCT00339586 PMID:27032107

  4. P08: Somatostatin analogs plus prednisone in aggressive histotype and advanced stage of thymic epithelial tumors

    PubMed Central

    Ottaviano, Margaret; Damiano, Vincenzo; Nappi, Lucia; Rescigno, Pasquale; Marino, Mirella; Del Vecchio, Silvana; Tucci, Irene; von Arx, Claudia; Palumbo, Giuliano; Palmieri, Giovannella

    2015-01-01

    Background Thymic epithelial tumors (TETs) are rare neoplasms characterized by histological variability and different expression at the molecular level. Several biological agents have been evaluated in TETs in small phase II trials. Efficacy of octreotide/lanreotide with or without prednisone in TETs OctreoScan positive has been widely demonstrated in thymoma, but no clearly in thymic carcinoma. Methods Twelve patients (five men, seven women; median age 47 years; range, 27–70 years) with advanced stage disease according to the Masaoka-Koga staging system (seven with IVa stage; five with IVb stage), and aggressive histotype according to WHO classification, revised by central review (two B2/B3; five B3; one B3/thymic carcinoma; four thymic carcinoma) were enrolled in this monocentric referral study. All the patients showed a progressive disease according to RECIST 1.1 criteria to previous conventional chemotherapeutic regimens platinum or not platinum-based. All the patients performed OctreoScan. The schedule includes administration of long-acting analog octreotide (30 mg/every 28 days intramuscularly) plus prednisone 0.2 mg/kg/day until progression of disease was documented. Overall response rate and toxicity were evaluated. Results The median time to progression was 6 months (range, 3–24 months), the overall response rate was 74.9%, particularly three patients (25%) obtained stable disease; four patients (33.3%) partial response; two patients (16.6%) complete response; three patients (25%) progression disease. One patient with Good Syndrome interrupted treatment after 6 months for infection disease. One patient has been lost to follow-up after 24 months of treatment. One patient died after progression disease for PRCA. Treatment was generally well tolerated with acceptable toxicity: no symptomatic cholelithiasis (one patient), grade 1 diarrhea (two patients) hyperglycemia (one patient). One patient with thymic carcinoma and IVB stage had PS improvement from 2

  5. 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

  6. Selecting the best strategy of treatment in newly diagnosed advanced-stage ovarian cancer patients

    PubMed Central

    Minig, Lucas; Zorrero, Cristina; Iserte, Pablo Padilla; Poveda, Andres

    2015-01-01

    Although it is assumed that the combination of chemotherapy and radical surgery should be indicated in all newly diagnosed advanced-stage ovarian cancer patients, one of the main raised questions is how to select the best strategy of initial treatment in this group of patients, neoadjuvant chemotherapy followed by interval debulking surgery or primary debulking surgery followed by adjuvant chemotherapy. The selection criteria to offer one strategy over the other as well as a stepwise patient selection for initial treatment are described. Selecting the best strategy of treatment in newly diagnosed advanced stage ovarian cancer patients is a multifactorial and multidisciplinary decision. Several factors should be taken into consideration: (1) the disease factor, related to the extension and localization of the disease as well as tumor biology; (2) the patient factor, associated with patient age, poor performance status, and co-morbidities; and (3) institutional infrastructure factor, related to the lack of prolonged operative time, an appropriate surgical armamentarium, as well as well-equipped intensive care units with well-trained personnel. PMID:26713279

  7. 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

  8. Are Early Relapses in Advanced-Stage Ovarian Cancer Doomed to a Poor Prognosis?

    PubMed Central

    Vidal, Fabien; Guerby, Paul; Luyckx, Mathieu; Haddad, Pascale; Stoeckle, Eberhard; Morice, Philippe; Leblanc, Eric; Lecuru, Fabrice; Daraï, Emile; Classe, Jean Marc; Pomel, Christophe; Filleron, Thomas; Ferron, Gwenael; Querleu, Denis; Rafii, Arash

    2016-01-01

    Objective Early recurrence (ER) after completion of therapeutic regimen in advanced-stage ovarian cancer is a challenging clinical situation. Patients are perceived as invariably having a poor prognosis. We investigated the possibility of defining different prognostic subgroups and the parameters implicated in prognosis of ER patients. Study Design We analyzed a multi-centric database of 527 FIGO stage IIIC and IV ovarian cancer patients. We defined patients relapsing within 12 months as ER and investigated using Cox logistic regression the prognostic factors in ER group. We subsequently divided ER patients into good and poor prognosis groups according to a lower or higher overall survival (OS) at 12 months after relapse and determined parameters associated to poor prognosis. Results The median follow up was 49 months. One hundred and thirty eight patients recurred within 12 months. OS and Disease Free Survival (DFS) were 24.6 and 8.6 months, respectively, in this group of patients. Among the ER patients, 73 had a poor prognosis with an OS after relapse below 12 months (mean OS = 5.2 months) and 65 survived after one year (mean OS = 26.9 months). Residual disease (RD) after debulking surgery and mucinous histological subtype negatively impacted prognosis (HR = 1.758, p = 0.017 and HR = 8.641, p = 0.001 respectively). The relative risk of death within 12 months following relapse in ER patients was 1.61 according to RD status. However, RD did not affect DFS (HR = 0.889, p = 0.5). Conclusion ER in advanced-stage ovarian cancer does not inevitably portend a short-term poor prognosis. RD status after initial cytoreduction strongly modulates OS, that gives additional support to the concept of maximum surgical effort even in patients who will experience early recurrence. The heterogeneity in outcomes within the ER group suggests a role for tumor biology in addition to classical clinical parameters. PMID:26820579

  9. Two-stage, low noise advanced technology fan. Volume 2: Aerodynamic data

    NASA Technical Reports Server (NTRS)

    Harley, K. G.; Odegard, P. A.

    1975-01-01

    Aerodynamic data from static tests of a two-stage advanced technology fan designed to minimize noise are presented. Fan design conditions include delivery of 209.1kg/sec/sq m (42.85 lbm/sec/sq ft) specific corrected flow at an overall pressure ratio of 1.9 and an adiabatic efficiency of 85.3 percent. The 0.836m (2.74ft) diameter first stage rotor has a hub/tip ratio of 0.4 and 365.8m/sec (1200ft/sec) design tip speed. In addition to the moderate tip speed and pressure rise per stage, other noise control design features involve widely spaced blade rows and proper selection of blade-vane ratios. Aerodynamic data are presented for tests with unifrom and with hub and tip radially distorted inlet flow. Aerodynamic data are also presented for tests of this fan with acoustic treatments, including acoustically treated casing walls, a flowpath exit acoustic ring, and a translating centerbody sonic inlet device. A complete tabulation of the overall performance data, the blade element data, and the power spectral density information relating to turbulence levels generated by the sonic inlet obtained during these tests is included. For vol. 1, see N74-33789.

  10. Advanced stages of PD: interventional therapies and related patient-centered care.

    PubMed

    Krüger, Rejko; Hilker, Rüdiger; Winkler, Christian; Lorrain, Michael; Hahne, Matthias; Redecker, Christoph; Lingor, Paul; Jost, Wolfgang H

    2016-01-01

    During the last decades, symptomatic treatment of motor symptoms of Parkinson's disease (PD) improved continuously and is reflected by long-range independency of the patient during the disease course. However, advanced stages of PD still represent an important challenge to patients, caregivers and treating physicians. In patients with advanced PD, interventional therapy strategies are increasingly applied. These device-related treatment strategies using pump-based continuous dopaminergic stimulation (CDS) or deep brain stimulation (DBS) opened new treatment options especially if motor complications predominate. Well-designed clinical studies on these interventional therapeutic approaches provided class 1 evidence for the efficacy of DBS and CDS in advanced PD and opened new perspectives for their use in earlier disease stages also. Therefore, careful selection of patients amenable to the (semi)invasive therapy options becomes more and more important and requires an interdisciplinary setting that accounts for (i) optimal patient information and awareness, (ii) selection of best individual treatment modality, (iii) training of relatives and caregivers, (iv) management of complications, and (v) follow-up care. Here, we address these topics by summarizing current state-of-the-art in patient selection, providing specificities of treatment options and troubleshooting, and defining steps towards an optimized patient-centered care. Interventional therapies pioneer in the area of individualized treatment approaches for PD, and may be complemented in the future by biomarker-based improved stratification and by closed-loop systems for adaptive therapeutic strategies. In the present review, we summarize the proceedings of an Expert Workshop on Parkinson's disease held on November 22, 2014 in Frankfurt, Germany. PMID:26138439

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

    PubMed Central

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

    2015-01-01

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

  12. Advanced stage ovarian juvenile granuloza cell tumor causing acute abdomen: a case report.

    PubMed

    Bedir, Recep; Mürtezaoğlu, Afşin Rahman; Calapoğlu, Ahmet Salih; Şehitoğlu, İbrahim; Yurdakul, Cüneyt

    2014-09-01

    Ovary juvenile granulosa cell tumors (JGCT) are rare sex cord-stromal tumors that are most commonly encountered in prepubertal girls. These tumors can be of the adult type (95%) and juvenile type (5%). The main causes of complaint are abdominal distention and abdominal pain. Definitive diagnosis is confirmed by histopathologal and immunohistochemical examinations. A 10-year old girl presented with massive abdominal distention, acute abdomen findings and ascites. Abdominopelvic magnetic resonance imaging showed masses with multiple cysts and solid components in the left ovary. Tumor markers were normal, but serum estradiol level was elevated. The patient underwent mass resection with left salpingo-oophorectomy and total omentectomy. Final histopathological diagnosis was JGCT. We herein reporte an extremely rare case of advanced stage JGCT causing massive ascites and acute abdomen. PMID:25204485

  13. Advanced glycation end-products and skin autofluorescence in end-stage renal disease: a review.

    PubMed

    Arsov, Stefan; Graaff, Reindert; van Oeveren, Wim; Stegmayr, Bernd; Sikole, Aleksandar; Rakhorst, Gerhard; Smit, Andries J

    2014-01-01

    Chronic kidney disease (CKD), especially in its end stage, is marked by extremely high cardiovascular rates of morbidity and mortality; hemodialysis patients have a five-fold shorter life expectancy than healthy subjects of the same age. In CKD the metabolic products that accumulate in the body are so-called uremic toxins. These include advanced glycation end-products (AGE). AGE levels are markedly increased in CKD patients not only because of impaired excretion but also because of increased production. AGE formation has initially been described as a non-enzymatic reaction between proteins and glucose in the so-called Maillard reaction, but they are also more rapidly formed during oxidative stress and subsequent formation of reactive carbonyl compounds like (methyl)glyoxal. AGE accumulate in tissue where they cross-link with proteins, e.g., collagen, inducing tissue stiffening of blood vessels and skin. They may also interact with receptor of AGE (RAGE) and other receptors, which lead to activation of intracellular transduction mechanisms resulting in cytokine release and further tissue damage in CKD. The accumulation of AGE in the skin can be measured non-invasively using autofluorescence. The skin autofluorescence is a strong marker of cardiovascular mortality in CKD. The focus of this review is on the role of tissue and plasma AGE, and of skin autofluorescence as a proxy of tissue AGE accumulation, in the increase in cardiovascular disease in end stage renal disease (ESRD). This review will also present the possibility of reducing the AGE accumulation in ESRD patients using the following five methods: 1) use of low AGE peritoneal dialysis solutions; 2) use of advanced hemodialysis techniques; 3) use of AGE reducing drugs; 4) optimizing the nutrition of hemodialysis patients; and 5) renal transplantation. PMID:23612551

  14. MRI Helps Depict Clinically Undetectable Risk Factors in Advanced Stage Retinoblastomas

    PubMed Central

    Hadjistilianou, Theodora; Cerase, Alfonso; Toti, Paolo; Leonini, Sara; Bracco, Sandra; de Francesco, Sonia; Galimberti, Daniela; Balducci, Donatella; Piu, Pietro; Monti, Lucia; Bellini, Matteo; Caini, Mauro; Rossi, Alessandro

    2015-01-01

    SUMMARY This study compared high-resolution MRI with histology in advanced stage retinoblastomas in which ophthalmoscopy and ultrasonography did not give an exhaustive depiction of the tumour and/or its extension. MRI of orbits and head in 28 retinoblastoma patients (28 eyes) treated with primary enucleation were evaluated. Iris neoangiogenesis, infiltrations of optic nerve, choroid, anterior segment and sclera suspected at MR and histology were compared. Abnormal anterior segment enhancement (AASE) was also correlated with histologically proven infiltrations. Brain images were also evaluated. Significant values were obtained for: prelaminar optic nerve (ON) sensitivity (0.88), positive predictive value (PPV) (0.75) and negative predictive value (NPV) (0.71); post-laminar ON sensitivity (0.50), specificity (0.83), PPV (0.50) and NPV (0.83); overall choroid sensitivity (0.82), and massive choroid NPV (0.69); scleral specificity (1), and NPV (1). AASE correlated with iris neoangiogenesis in 14 out of 19 eyes, and showed significant values for: overall ON PPV (0.65), prelaminar ON sensitivity (0.65), and PPV (0.61), post-laminar ON NPV (0.64); overall choroid sensitivity (0.77), PPV (0.59) and NPV (0.73); scleral NPV (0.83); anterior segment sensitivity (1), and NPV (1). Odds ratios (OR) and accuracy were significant in scleral and prelaminar optic nerve infiltration. Brain examination was unremarkable in all cases. High-resolution MRI may add important findings to clinical evaluation of advanced stage retinoblastomas. PMID:25924174

  15. Up-regulation of stromal versican expression in advanced stage serous ovarian cancer

    PubMed Central

    Ghosh, Sue; Albitar, Lina; LeBaron, Richard; Welch, William R.; Samimi, Goli; Birrer, Michael J.; Berkowitz, Ross S.; Mok, Samuel C.

    2010-01-01

    Objective The purpose of this study is to examine the role of versican (VCAN) in advanced stage serous ovarian cancer by investigating its expression, its function, and its correlation with clinical outcomes. Methods Microarray analysis was performed on RNA isolated from tumor and stromal components of advanced stage serous ovarian cancer and normal ovarian epithelial tissue to identify genes up-regulated in ovarian tumor stroma. Validation studies using immunohistochemistry and quantitative real-time PCR (Q-RT-PCR) was performed on one of the up-regulated genes, VCAN. Immunolocalization of VCAN (n=111) and CD31 (n= 56) were done on serous ovarian tumors. CD31 staining was performed to examine microvessel density (MVD). Q-RT-PCR was performed on 65 samples to evaluate the differential expression of VCAN isoforms. Cell proliferation and invasion assays were performed to examine how V1-treated ovarian cancer cell lines and an endothelial cell line would differ from controls. Univariate survival analyses were done with VCAN expression. Correlation analysis was done with CD31, platinum resistance, and clinical data. Results Validation studies using Q-RT-PCR and immunohistochemistry showed significantly higher VCAN V1 isoform expression in ovarian cancer stroma compared with normal ovarian stroma and ovarian cancer cells. Correlation studies showed stromal VCAN expression was associated with poorer overall and progression free survival, platinum resistance, and increased MVD. VCAN-treated ovarian cancer and endothelial cells showed increased invasion potential. Conclusions VCAN overexpression is associated with increased MVD and invasion potential, which may lead to poorer overall and progression free survival and platinum resistance. PMID:20619446

  16. Single stage, low noise advanced technology fan. Volume 3: Acoustic design

    NASA Technical Reports Server (NTRS)

    Kazin, S. B.; Mishler, R. B.

    1976-01-01

    The acoustic design for a half-scale fan vehicle, which would have application on an advanced transport aircraft, is described. The single stage advanced technology fan was designed to a pressure ratio of 1.8 at a tip speed of 503 m/sec (1,650 ft/sec). The two basic approaches taken in the acoustic design were: (1) minimization of noise at the source, and (2) suppression of the generated noise in the inlet and bypass exhaust duct. Suppression of the generated noise is accomplished in the inlet through use of the hybrid concept (wall acoustic treatment plus airflow acceleration suppression) and in the exhaust duct with extensive acoustic treatment including a splitter. The goal of the design was attainment of twenty effective perceived noise decibels (20 EPNdB) below current Federal Air Regulation noise standards for a full-scale fan at the takeoff, cutback, and approach conditions. Predicted unsuppressed and suppressed fore and aft maximum perceived noise levels indicate that the cutback condition is the most critical with respect to the goal, which is probably unattainable for that condition. This is also true for aft radiated noise in the approach condition.

  17. Single stage, low noise, advanced technology fan. Volume 1: Aerodynamic design

    NASA Technical Reports Server (NTRS)

    Sullivan, T. J.; Younghans, J. L.; Little, D. R.

    1976-01-01

    The aerodynamic design for a half-scale fan vehicle, which would have application on an advanced transport aircraft, is described. The single stage advanced technology fan was designed to a pressure ratio of 1.8 at a tip speed of 503 m/sec 11,650 ft/sec). The fan and booster components are designed in a scale model flow size convenient for testing with existing facility and vehicle hardware. The design corrected flow per unit annulus area at the fan face is 215 kg/sec sq m (44.0 lb m/sec sq ft) with a hub-tip ratio of 0.38 at the leading edge of the fan rotor. This results in an inlet corrected airflow of 117.9 kg/sec (259.9 lb m/sec) for the selected rotor tip diameter if 90.37 cm (35.58 in.). The variable geometry inlet is designed utilizing a combination of high throat Mach number and acoustic treatment in the inlet diffuser for noise suppression (hybrid inlet). A variable fan exhaust nozzle was assumed in conjunction with the variable inlet throat area to limit the required area change of the inlet throat at approach and hence limit the overall diffusion and inlet length. The fan exit duct design was primarily influenced by acoustic requirements, including length of suppressor wall treatment; length, thickness and position on a duct splitter for additional suppressor treatment; and duct surface Mach numbers.

  18. Transformer 2β (Tra2β/SFRS10) positively regulates the progression of NSCLC via promoting cell proliferation.

    PubMed

    Ji, Lili; Ni, Tingting; Shen, Yanbo; Xue, Qun; Liu, Yifei; Chen, Buyou; Cui, Xuefan; Lv, Liting; Yu, Xiafei; Cui, Yuan; Lu, Xiaoning; Chen, Jie; Mao, Guoxin; Wang, Yuchan

    2014-10-01

    Transformer 2β (Tra2β), a member of the serine/arginine-rich-like protein family, is an important RNA-binding protein involved in alternative splice. Deregulation of Tra2β has been observed in several cancers. However, the detailed role of Tra2β in non-small cell lung cancer (NSCLC) has not been elucidated. In this study, the contribution of Tra2β to NSCLC development was investigated. On histological level, the expression of Tra2β was determined by Western and immunohistochemistry assays. It demonstrated that Tra2β was expressed higher in NSCLC tumor tissues compared with adjacent non-tumor tissues. In addition to confirm the association of Tra2β expression with histological differentiation and clinical stage (p < 0.05), we also confirmed significant positive correlation between the expression level of Tra2β and that of Ki67 (p < 0.05, r = 0.446) by Spearman rank correlation test. Moreover, high expression of Tra2β predicted poor prognosis by Kaplan-Meier survival analysis. And Tra2β among with other clinicopathologic variables was an independent prognostic indicator for patients' overall survival by multivariate analysis. On cellular level, Tra2β expression was demonstrated to promote proliferation of NSCLC cells through a series of assays, including serum starvation and release assay, Western blot assay and flow cytometry analysis. Moreover, knockdown of Tra2β was confirmed to inhibit proliferation and to induce apoptosis of NSCLC cells through flow cytometry analysis, western analysis, cell counting kit-8 assay and Tunnel assay. Our results indicated that Tra2β was involved in the tumorigenesis of NSCLC and might be a potential therapeutic target of NSCLC. PMID:24952301

  19. Pair-wise comparison analysis of differential expression of mRNAs in early and advanced stage primary colorectal adenocarcinomas

    PubMed Central

    Lau, Tze Pheng; Roslani, April Camilla; Lian, Lay Hoong; Chai, Hwa Chia; Lee, Ping Chin; Hilmi, Ida; Goh, Khean Lee; Chua, Kek Heng

    2014-01-01

    Objectives To characterise the mRNA expression patterns of early and advanced stage colorectal adenocarcinomas of Malaysian patients. Design Comparative expression analysis. Setting and participants We performed a combination of annealing control primer (ACP)-based PCR and reverse transcription-quantitative real-time PCR for the identification of differentially expressed genes (DEGs) associated with early and advanced stage primary colorectal tumours. We recruited four paired samples from patients with colorectal cancer (CRC) of Dukes’ A and B for the preliminary differential expression study, and a total of 27 paired samples, ranging from CRC stages I to IV, for subsequent confirmatory test. The tumouric samples were obtained from the patients with CRC undergoing curative surgical resection without preoperative chemoradiotherapy. The recruited patients with CRC were newly diagnosed with CRC, and were not associated with any hereditary syndromes, previously diagnosed cancer or positive family history of CRC. The paired non-cancerous tissue specimens were excised from macroscopically normal colonic mucosa distally located from the colorectal tumours. Primary and secondary outcome measures The differential mRNA expression patterns of early and advanced stage colorectal adenocarcinomas compared with macroscopically normal colonic mucosa were characterised by ACP-based PCR and reverse transcription-quantitative real-time PCR. Results The RPL35, RPS23 and TIMP1 genes were found to be overexpressed in both early and advanced stage colorectal adenocarcinomas (p<0.05). However, the ARPC2 gene was significantly underexpressed in early colorectal adenocarcinomas, while the advanced stage primary colorectal tumours exhibited an additional overexpression of the C6orf173 gene (p<0.05). Conclusions We characterised two distinctive gene expression patterns to aid in the stratification of primary colorectal neoplasms among Malaysian patients with CRC. Further work can be done to

  20. Does aggressive surgical resection improve survival in advanced stage 3 and 4 neuroblastoma? A systematic review and meta-analysis.

    PubMed

    Mullassery, Dhanya; Farrelly, Paul; Losty, Paul D

    2014-11-01

    The role of surgery in the management of advanced staged neuroblastoma (NBL) is controversial. A systematic review and meta-analysis is reported to address robust evidence for curative "gross total tumor resection" (GTR) in Stage 3 and Stage 4 neuroblastoma. Studies were identified using Medline, Embase, and Cochrane databases using pre-specified search terms. Primary outcomes were 5-year overall (OS) and disease-free survival (DFS) after GTR and subtotal resection (STR) in Stage 3 or 4 NBL. Data were analyzed using Review Manager. The Mantel-Haenszel method and a random effects model was utilized to calculate odds ratios (95% CI). Fifteen studies (five Stage 3 and 13 Stage 4) met full inclusion criteria. The pooled odds ratio for 5 year OS in Stage 3 following GTR compared to STR was 2.4 (95% CI 1.19-4.85). In Stage 4 disease, the pooled odds ratio for 5 year overall survival (OS) following GTR compared to STR was 1.65 (95% CI 0.96-1.91); a pooled odds ratio for 5 year DFS following GTR compared to STR was 1.55 (95% CI 1.12-2.14). A clear survival benefit is shown for GTR over STR in Stage 3 NBL only. Though some advantage can be demonstrated for GTR as defined by DFS in Stage 4 NBL GTR did not significantly improve OS in Stage 4 disease. PMID:25247398

  1. 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

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

    PubMed Central

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

    2015-01-01

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

  3. 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

    2015-01-01

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

  4. Endoscopic ultrasonography/fine-needle aspiration and endobronchial ultrasonography/fine-needle aspiration for lung cancer staging.

    PubMed

    Lankarani, Ali; Wallace, Michael B

    2012-04-01

    This article reviews different techniques available for diagnosis and staging of patients with non-small cell lung cancer (NSCLC). The advantages and disadvantages of each staging method are highlighted. The role of the gastroenterologist in NSCLC staging is explored. A new algorithm is proposed for the staging of NSCLC that incorporates endoscopic and endobronchial ultrasonography for mediastinal staging in patients with intrathoracic disease. PMID:22632944

  5. Predictive potential role of GSTs gene polymorphisms in the treatment outcome of advanced non-small cell lung cancer patients.

    PubMed

    Liu, Kaixiong; Lin, Qichang; Ding, Haibo; Jin, Yongxu; Chen, Gongping

    2015-01-01

    This study aimed to investigate the possible association between GSTP1, GSTM1, and GSTT1 polymorphisms and treatment outcome of advanced NSCLC. Between October 2009 and October 2011, a total of 308 patients of NSCLC on stage IIIA, IIIB or IV, treated with cisplatin-based chemotherapy were included. Polymerase chain reaction-restriction fragment length polymorphism was used to genotype the GSTP1 and GSTM1, and GSTT1 polymorphisms. We found that the IIe/Val and Val/Val genotypes of GSTP1 showed more CR+PR to chemotherapy in advanced NSCLC when compared with IIe/IIe genotype, and the Ors (95% CI) were 0.37 (0.18-0.71) and 0.15 (0.07-0.38). The IIe/Val and Val/Val genotypes of GSTP1 were associated with longer overall survival of advanced NSCLC when compared with the IIe/IIe genotype (For IIe/Val vs IIe/IIe, 37.63 ± 2.01 months vs 30.25 ± 2.06 months; for Val/Val vs IIe/IIe, 39.84 ± 3.36 months vs 30.25 ± 2.06 months). In the Cox proportional hazards model, the IIe/Val and Val/Val genotypes significantly decreased risk of death from all causes in patients with advanced NSCLC, and the HRs (95% CIs) were 0.51 (0.28-0.94) and 0.35 (0.16-0.78), respectively. We found that the GSTP1 polymorphisms might affect the clinical outcome of patients with advanced NSCLC, and our results could help us to facilitate therapeutic decision for individualized therapy. PMID:26885019

  6. Cognitive benefits of memantine in Alzheimer's 5XFAD model mice decline during advanced disease stages.

    PubMed

    Devi, Latha; Ohno, Masuo

    2016-05-01

    Memantine, a noncompetitive NMDA receptor antagonist with neuroprotective properties, has been used for the treatment of Alzheimer's disease (AD). Administration of memantine to various transgenic AD mice has been reported to improve cognitive deficits, very often completely back to normal wild-type control levels. However, such great benefits of memantine in preclinical studies do not translate into clinical results of this drug, showing only marginal and transient efficacy in moderate to severe AD. To further address in vivo efficacy, we compared the effects of memantine at different disease stages in 5XFAD mice, one of the rapid-onset and most aggressive amyloid models. Specifically, we administered memantine once daily for 30days to 5XFAD mice, which showed moderate (6-7months of age) and robust (12-15months) β-amyloid (Aβ) accumulation. Treatments with memantine (10mg/kg, i.p.) reversed memory impairments in the younger 5XFAD mice, as tested by the contextual fear conditioning and spontaneous alternation Y-maze paradigms. Memantine had no effects on soluble Aβ oligomer or total Aβ42 levels in 5XFAD mouse brains. In contrast, subchronic treatments with memantine showed no behavioral benefits in the older 5XFAD group, which exhibited more profound memory deficits concomitant with highly increased concentrations of Aβ as compared with those of the younger 5XFAD group. Since subchronic memantine at the higher dose (30mg/kg) impaired memory performances in wild-type controls, we further tested acute administration of 50mg/kg memantine, which was reported to enhance hippocampal adult neurogenesis and memory function. However, this treatment also failed to rescue memory deficits in 12-15-month-old 5XFAD mice. Collectively, our results demonstrate that cognitive benefits of memantine independent of Aβ reductions were no longer observed in the 5XFAD Alzheimer mouse model during advanced stages, which may be reflective of the limited efficacy of memantine in

  7. Perioperative Outcomes of Robotic Assisted Laparoscopic Surgery Versus Conventional Laparoscopy Surgery for Advanced-Stage Endometriosis

    PubMed Central

    Sirota, Ido

    2014-01-01

    Background and Objectives: To determine perioperative outcome differences in patients undergoing robotic-assisted laparoscopic surgery (RALS) versus conventional laparoscopic surgery (CLS) for advanced-stage endometriosis. Methods: This retrospective cohort study at a minimally invasive gynecologic surgery center at 2 academically affiliated, urban, nonprofit hospitals included all patients treated by either robotic-assisted or conventional laparoscopic surgery for stage III or IV endometriosis (American Society for Reproductive Medicine criteria) between July 2009 and October 2012 by 1 surgeon experienced in both techniques. The main outcome measures were extent of surgery, estimated blood loss, operating room time, intraoperative and postoperative complications, and length of stay, with medians for continuous measures and distributions for categorical measures, stratified by body mass index values. Robotically assisted laparoscopy and conventional laparoscopy were then compared by use of the Wilcoxon rank sum, χ2, or Fisher exact test, as appropriate. Results: Among 86 conventional laparoscopic and 32 robotically assisted cases, the latter had a higher body mass index (27.36 kg/m2 [range, 23.90–34.09 kg/m2] versus 24.53 kg/m2 [range, 22.27–26.96 kg/m2]; P < .0079) and operating room time (250.50 minutes [range, 176–328.50 minutes] versus 173.50 minutes [range, 123–237 minutes]; P < .0005) than did conventional laparoscopy patients. After body mass index stratification, obese patients varied in operating room time (282.5 minutes [range, 224–342 minutes] for robotic-assisted laparoscopy versus 174 minutes [range, 130–270 minutes] for conventional laparoscopy; P < .05). No other significant differences were noted between the robotic-assisted and conventional laparoscopy groups. Conclusion: Despite a higher operating room time, robotic-assisted laparoscopy appears to be a safe minimally invasive approach for patients, with all other perioperative

  8. Influence of various operating conditions on advanced PFBC with staged combustion

    SciTech Connect

    Moersch, O.; Nagel, H.; Spliethoff, H.; Hein, K.R.G.

    1999-07-01

    The development of PFBC towards advanced or second generation PFBC focuses on an increase of temperature at the gas turbine inlet to bring forth a substantial improvement of the turbine itself and the overall system performance. Most of such advanced systems described in literature include a carbonizer for partial conversion of coal producing a low calorific pressurized syngas and a PFBC burning the remaining char. After hot gas clean-up the syngas and the O{sub 2}-rich fuel gas from the PFBC are led to the combustion chamber of the gas turbine. In the proposed staged combustion concept (PFBC-SC), which also aims at raising the temperatures at the gas turbine inlet, coal is burned substoichiometrically in a pressurized fluidized bed producing a low calorific gas. After hot gas clean-up the gas undergoes post-combustion with pressurized air and enters the gas turbine at approximately 1,450 K. The advantages of PFBC-SC over APFBC as described above are the lower investment costs and the simpler process, because no separate gasifier including hot gas cleaning device is needed. At the IVD's 50 kWth PFBC test facility, experimental investigations were done into substoichiometrical combustion with regard to composition of the produced gas, carbon-conversion and afterburner temperature. The results of the experiments which were carried out at various temperatures (1,073--1,200 K), pressures (1--13 bar), air ratios (0.5--0.9) and with different coals were compared with chemical equilibrium calculations. In contrast to the operating pressure the heating value of the syngas ({ge}CO, H{sub 2}, CH{sub 4}) could be increased significantly with increasing temperatures. Due to the better gasification behavior of subbituminous coal compared with bituminous coal almost equilibrium conditions were achieved. At high pressures and temperatures (13 bar/1,173 K) the carbon conversion rate 97.5% at all air ratios.

  9. Glutathione S-transferase pi polymorphism contributes to the treatment outcomes of advanced non-small cell lung cancer patients in a Chinese population.

    PubMed

    Chen, J B; Wang, F; Wu, J J; Cai, M

    2016-01-01

    We analyzed the association between polymorphisms in three glutathione S-transferase genes (GSTP1, GSTM1, and GSTT1) and the treatment outcome for advanced non-small cell lung cancer (NSCLC). We recruited 284 NSCLC patients at advanced stage from Department of Radiotherapy in Peace Hospital Attached to Changzhi Medical College between May 2009 and May 2011, who had received cisplatin-based chemotherapy. The GSTP1, GSTM1, and GSTT1 genotyping for was determined using DNA pyrosequencing on an ABI Prism 3100 DNA analyzer. In the Cox proportional hazards model, the IIe/Val and Val/Val genotypes of GSTP1 were associated with lower risk of disease progression compared with the IIe/IIe genotype, and the HRs (95%CIs) were 0.37 (0.18-0.74) and 0.15 (0.06-0.35), respectively. The IIe/Val and Val/Val genotypes significantly decreased risk of death from all causes in patients with NSCLC, and the HRs (95%CIs) were 0.52 (0.29-0.92) and 0.37 (0.17- 0.79), respectively No significant association was observed between GSTM1 and GSTT1 polymorphisms and progression-free survival and overall survival in the NSCLC patients. In summary, we suggest that GSTP1 polymorphisms might influence the treatment outcome of advanced NSCLC patients, and our results could help improve individualized therapy. PMID:27525853

  10. HLA-G Expression and Role in Advanced-Stage Classical Hodgkin Lymphoma

    PubMed Central

    Caocci, G.; Greco, M.; Fanni, D.; Senes, G.; Littera, R.; Lai, S.; Risso, P.; Carcassi, C.; Faa, G.; La Nasa, G.

    2016-01-01

    Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2. PMID:27349312

  11. Short-term morbidity in transdiaphragmatic cardiophrenic lymph node resection for advanced stage gynecologic cancer.

    PubMed

    LaFargue, C J; Sawyer, B T; Bristow, R E

    2016-08-01

    Ovarian cancer is commonly diagnosed at an advanced stage, with disease involving the upper abdomen. The finding of enlarged cardiophrenic lymph nodes (CPLNs) on pre-operative imaging often indicates the presence of malignant spread to the mediastinum. Surgical resection of CPLN through a transdiaphragmatic approach can help to achieve cytoreduction to no gross residual. A retrospective chart review was conducted on all patients who underwent transdiaphragmatic cardiophrenic lymph node resection from 8/1/11 through 2/1/15. All relevant pre-, intra-, and post-operative characteristics and findings were recorded. A brief description of the surgical technique is included for reference. Eleven patients were identified who had undergone transdiaphragmatic resection of cardiophrenic lymph nodes. Malignancy was identified in 18/21 (86%) of total lymph nodes submitted. The median number of post-operative days was 7. The overall post-operative morbidity associated with CPLN resection was low, with the most common finding being a small pleural effusion present on chest x-ray between POD# 3-5 (55%). Transdiaphragmatic CPLN resection is a feasible procedure with relatively minor short-term post-operative morbidities that can be used to achieve cytoreduction to no gross residual disease. PMID:27354998

  12. Advanced Imaging and Receipt of Guideline Concordant Care in Women with Early Stage Breast Cancer.

    PubMed

    Loggers, Elizabeth Trice; Buist, Diana S M; Gold, Laura S; Zeliadt, Steven; Hunter Merrill, Rachel; Etzioni, Ruth; Ramsey, Scott D; Sullivan, Sean D; Kessler, Larry

    2016-01-01

    Objective. It is unknown whether advanced imaging (AI) is associated with higher quality breast cancer (BC) care. Materials and Methods. Claims and Surveillance Epidemiology and End Results data were linked for women diagnosed with incident stage I-III BC between 2002 and 2008 in western Washington State. We examined receipt of preoperative breast magnetic resonance imaging (MRI) or AI (defined as computed tomography [CT]/positron emission tomography [PET]/PET/CT) versus mammogram and/or ultrasound (M-US) alone and receipt of guideline concordant care (GCC) using multivariable logistic regression. Results. Of 5247 women, 67% received M-US, 23% MRI, 8% CT, and 3% PET/PET-CT. In 2002, 5% received MRI and 5% AI compared to 45% and 12%, respectively, in 2008. 79% received GCC, but GCC declined over time and was associated with younger age, urban residence, less comorbidity, shorter time from diagnosis to surgery, and earlier year of diagnosis. Breast MRI was associated with GCC for lumpectomy plus radiation therapy (RT) (OR 1.55, 95% CI 1.08-2.26, and p = 0.02) and AI was associated with GCC for adjuvant chemotherapy for estrogen-receptor positive (ER+) BC (OR 1.74, 95% CI 1.17-2.59, and p = 0.01). Conclusion. GCC was associated with prior receipt of breast MRI and AI for lumpectomy plus RT and adjuvant chemotherapy for ER+ BC, respectively. PMID:27525122

  13. Advanced Imaging and Receipt of Guideline Concordant Care in Women with Early Stage Breast Cancer

    PubMed Central

    Buist, Diana S. M.; Gold, Laura S.; Zeliadt, Steven; Hunter Merrill, Rachel; Etzioni, Ruth; Ramsey, Scott D.; Sullivan, Sean D.; Kessler, Larry

    2016-01-01

    Objective. It is unknown whether advanced imaging (AI) is associated with higher quality breast cancer (BC) care. Materials and Methods. Claims and Surveillance Epidemiology and End Results data were linked for women diagnosed with incident stage I-III BC between 2002 and 2008 in western Washington State. We examined receipt of preoperative breast magnetic resonance imaging (MRI) or AI (defined as computed tomography [CT]/positron emission tomography [PET]/PET/CT) versus mammogram and/or ultrasound (M-US) alone and receipt of guideline concordant care (GCC) using multivariable logistic regression. Results. Of 5247 women, 67% received M-US, 23% MRI, 8% CT, and 3% PET/PET-CT. In 2002, 5% received MRI and 5% AI compared to 45% and 12%, respectively, in 2008. 79% received GCC, but GCC declined over time and was associated with younger age, urban residence, less comorbidity, shorter time from diagnosis to surgery, and earlier year of diagnosis. Breast MRI was associated with GCC for lumpectomy plus radiation therapy (RT) (OR 1.55, 95% CI 1.08–2.26, and p = 0.02) and AI was associated with GCC for adjuvant chemotherapy for estrogen-receptor positive (ER+) BC (OR 1.74, 95% CI 1.17–2.59, and p = 0.01). Conclusion. GCC was associated with prior receipt of breast MRI and AI for lumpectomy plus RT and adjuvant chemotherapy for ER+ BC, respectively. PMID:27525122

  14. Effects of icotinib on early-stage non-small-cell lung cancer as neoadjuvant treatment with different epidermal growth factor receptor phenotypes

    PubMed Central

    Wang, Tao; Liu, Yang; Zhou, Bin; Wang, Zhi; Liang, Naichao; Zhang, Yundong; Dong, Zhouhuan; Li, Jie

    2016-01-01

    Purpose Epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR–TKIs) have demonstrated efficacy in treating advanced non-small-cell lung cancer (NSCLC). Preliminary findings suggested that EGFR–TKIs might also be beneficial in neoadjuvant therapy in treating NSCLC. Therefore, this study aimed to evaluate the efficacy and safety of neoadjuvant therapy with icotinib in patients with early-stage NSCLC. Patients and methods We retrospectively reviewed the medical history of patients who were initially diagnosed with stage IA–IIIA NSCLC and were under icotinib administration before surgery between December 2011 and December 2014. Tumor assessment was conducted between the second and fourth week from initial icotinib treatment. The association between personal characteristics, smoking status, disease stage, EGFR mutation status, and clinical outcomes were investigated using multivariate logistic regression analysis. Results A total of 67 patients with NSCLC were reviewed, and approximately half (38/67) of them were identified as having EGFR-mutant tumors. The overall response rate of all patients was 26.7% at 2–4 weeks’ assessment. Multivariate analysis showed that female sex (38.5% versus 10.7% in males, P=0.028) and EGFR mutation status (42.1% versus 6.9% in EGFR wild type, P=0.011) were independent predictive factors. The analysis also showed that the most common adverse effects were rash (43.3%) and dry skin (34.4%), which were tolerable. Conclusion Icotinib induced clinical response with minimal toxicity as neoadjuvant treatment in early NSCLC, especially in patients with common EGFR mutations. Further studies are warranted to confirm our findings. PMID:27042123

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

    PubMed Central

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

    2015-01-01

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

  16. Increased IL-17-producing cells correlate with poor survival and lymphangiogenesis in NSCLC patients.

    PubMed

    Chen, Xi; Wan, Jin; Liu, Jiankun; Xie, Wei; Diao, Xinwei; Xu, Jianping; Zhu, Bo; Chen, Zhengtang

    2010-09-01

    The presence of IL-17-positive cells is observed in a variety of inflammatory associated cancers and IL-17 has been found to be involved in angiogenesis. The aim of this study is to determine the prognostic significance of IL-17 in NSCLC patients and to examine the correlation between IL-17 expression and lymphatic vessel density in NSCLC tissues. The expression of IL-17 was measured by immunohistochemistry in 52 paraffin-embedded tissues with non-small cell lung cancer. The chi(2) test was used to analyze the correlation between IL-17 expression and clinical parameters and lymphatic vessel density (LVD). The Kaplan-Meier method, univariate and multivariate regression analysis was used to analyze the correlation between IL-17 expression and overall survival and disease-free survival. High expression of IL-17 was observed in 25 of 52 lung cancer patients and was associated with smoking status, TNM stage, LVD, overall survival and disease-free survival. Univariate and multivariate analysis showed that IL-17 was an independent prognostic factor for overall survival and disease-free survival. Our results indicate that IL-17 may play a role in the metastasis of lung cancer by promoting lymphangiogenesis. IL-17 expression is an independent prognostic factor in both overall and disease-free survival in NSCLC. PMID:20022135

  17. Evaluation of mean platelet volume, neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in advanced stage endometriosis with endometrioma

    PubMed Central

    Yavuzcan, Ali; Çağlar, Mete; Üstün, Yusuf; Dilbaz, Serdar; Özdemir, İsmail; Yıldız, Elif; Özkara, Atilla; Kumru, Selahattin

    2013-01-01

    Objective We compared the preoperative values of mean platelet volume (MPV) and peripheral systemic inflammatory response (SIR) markers (neutrophil/lymphocyte ratio and platelet/lymphocyte ratio) between patients with advanced-stage (stage 3/4) endometriosis having endometrioma (OMA) and patients with a non-neoplastic adnexal mass other than endometrioma (non-OMA). Material and Methods Patients who underwent operations with the pre-diagnosis of infertility or adnexal mass and who underwent laparoscopic tubal ligation were included. Results Haemoglobin levels, leucocyte count, platelet count, neutrophil count and lymphocyte count were not significantly different between patients with advanced stage endometriosis having OMA, patients with non-OMA and patients in the control group (p=0.970, p=0.902, p=0.373, p=0.501 and p=0.463, respectively). Patients with stage 3/4 endometriosis having OMA, patients with non-OMA and control patients were also not significantly different in terms of MPV (p=0.836), neutrophil/lymphocyte ratio (NLR) (p=0.555) and platelet/lymphocyte ratio (PLR) (p=0.358). Preoperative cancer antigen 125 (Ca-125) levels were significantly higher in patients with OMA (p=0.006). Mean size of the OMAs was significantly lower than non-OMAs (p=0.000). Conclusion It is very important to determine advanced stage endometriosis and OMAs during preoperative evaluation in order to inform patients and plan an appropriate surgical approach. We demonstrate that MPV, NLR and PLR values are not useful for this purpose in patients with advanced stage endometriosis that are proven to develop severe inflammation at either the cellular or molecular level. PMID:24592108

  18. Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications.

    PubMed

    Boiocchi, Leonardo; Gianelli, Umberto; Iurlo, Alessandra; Fend, Falko; Bonzheim, Irina; Cattaneo, Daniele; Knowles, Daniel M; Orazi, Attilio

    2015-11-01

    Polycythemia vera in 20-30% of cases progresses towards post-polycythemic myelofibrosis, an advanced phase characterized by decreased red blood cells counts and increasing splenomegaly with extramedullary hematopoiesis. There is evidence that the presence of neutrophilic leukocytosis at polycythemia vera disease outset is associated with an increased risk of recurrent thrombosis. However, its clinical significance when developing later in the course of the disease is not well defined. Over a period of 8 years we identified from the files of two reference centers 10 patients (7M/3F, median age: 68 years) who developed persistent absolute leukocytosis ≥ 13 × 10⁹/l (median: 25.1 × 10⁹/l; range: 16.1-89.7 × 10⁹/l) at or around the time of diagnosis of post-polycythemic myelofibrosis (median interval from diagnosis:0 months; range: -6/31) and persisted for a median period of 13 months. Peripheral blood smears showed numerous neutrophils without dysplastic features and, in four, ≥ 10% immature myeloid precursors. In five cases, corresponding marrow specimens obtained at or immediately after the onset of leukocytosis showed a markedly increased myeloid:erythroid ratio due to granulocytic proliferation. No change in JAK2 and BCR-ABL1 status or cytogenetic evolution was associated with the development of leukocytosis. The mutational status of CSF3R, SETBP1, and SRSF2, genes associated with other chronic myeloid neoplasms where neutrophilic leukocytosis occurs, was investigated but all cases showed wild-type only alleles. Four patients died after developing leukocytosis and one experienced worsening disease. Compared with a control group of post-polycythemic myelofibrosis patients (n=23) who never developed persistent leukocytosis, patients with leukocytosis showed higher white blood cells counts and a shorter overall survival. This is the first study describing the development of significant neutrophilic leukocytosis during advanced stages of polycythemia vera

  19. Solid rocket technology advancement for Space Tug and IUS applications. [Interim Upper Stage

    NASA Technical Reports Server (NTRS)

    Ascher, W.; Bailey, R. L.; Behm, J. W.; Gin, W.

    1975-01-01

    Two-burn restartable solid propellant rocket motors for the kick stage (auxiliary stage) of the Shuttle Tug, or Interim Upper Stage, are described, with details on features and test results of the ignition and quench (thrust termination) systems and procedures, fabrication of propellant and insulation, explosion hazards of propellants, and comparative data on present and future motor design. These rocket motor systems are designed for upper stage augmentation of launch vehicles and possible service in Shuttle-launched outer planet spacecraft.

  20. Expression of Ribonucleotide Reductase Subunit-2 and Thymidylate Synthase Correlates with Poor Prognosis in Patients with Resected Stages I–III Non-Small Cell Lung Cancer

    PubMed Central

    Grossi, Francesco; Dal Bello, Maria Giovanna; Salvi, Sandra; Puzone, Roberto; Pfeffer, Ulrich; Fontana, Vincenzo; Alama, Angela; Rijavec, Erika; Barletta, Giulia; Genova, Carlo; Sini, Claudio; Ratto, Giovanni Battista; Taviani, Mario; Truini, Mauro; Merlo, Domenico Franco

    2015-01-01

    Biomarkers can help to identify patients with early-stages or locally advanced non-small cell lung cancer (NSCLC) who have high risk of relapse and poor prognosis. To correlate the expression of seven biomarkers involved in DNA synthesis and repair and in cell division with clinical outcome, we consecutively collected 82 tumour tissues from radically resected NSCLC patients. The following biomarkers were investigated using IHC and qRT-PCR: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2), subunit p53R2, thymidylate synthase (TS), and class III beta-tubulin (TUBB3). Gene expression levels were also validated in an available NSCLC microarray dataset. Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS). Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours. For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels. The NSCLC microarray dataset showed RRM2 and TS as biomarkers significantly associated with OS. This study suggests that high expression levels of RRM2 and TS might be negative prognostic factors for resected NSCLC patients. PMID:26663950

  1. HLA-G expression and role in advanced-stage classical Hodgkin lymphoma.

    PubMed

    Caocci, G; Greco, M; Fanni, D; Senes, G; Littera, R; Lai, S; Risso, P; Carcassi, C; Faa, G; La Nasa, G

    2016-01-01

    Non-classical human leucocyte antigen (HLA)-G class I molecules have an important role in tumor immune escape mechanisms. We investigated HLA-G expression in lymphonode biopsies taken from 8 controls and 20 patients with advanced-stage classical Hodgkin lymphoma (cHL), in relationship to clinical outcomes and the HLA-G 14-basepair (14-bp) deletion-insertion (del-ins) polymorphism. Lymphnode tissue sections were stained using a specific murine monoclonal HLA-G antibody. HLA-G protein expression was higher in cHL patients than controls. In the group of PET-2 positive (positron emission tomography carried out after 2 cycles of standard chemotherapy) patients with a 2-year progression-free survival rate (PFS) of 40%, we observed high HLA-G protein expression within the tumor microenvironment with low expression on Hodgkin and Reed-Sternberg (HRS) cells. Conversely, PET-2 negative patients with a PFS of 86% had higher HLA-G protein expression levels on HRS cells compared to the microenvironment. Lower expression on HRS cells was significantly associated with the HLA-G 14-bp ins/ins genotype. These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2.These preliminary data suggest that the immunohistochemical pattern of HLA-G protein expression may represent a useful tool for a tailored therapy in patients with cHL, based on the modulation of HLA-G expression in relation to achievement of negative PET-2. PMID:27349312

  2. Low-Noise Potential of Advanced Fan Stage Stator Vane Designs Verified in NASA Lewis Wind Tunnel Test

    NASA Technical Reports Server (NTRS)

    Hughes, Christopher E.

    1999-01-01

    With the advent of new, more stringent noise regulations in the next century, aircraft engine manufacturers are investigating new technologies to make the current generation of aircraft engines as well as the next generation of advanced engines quieter without sacrificing operating performance. A current NASA initiative called the Advanced Subsonic Technology (AST) Program has set as a goal a 6-EPNdB (effective perceived noise) reduction in aircraft engine noise relative to 1992 technology levels by the year 2000. As part of this noise program, and in cooperation with the Allison Engine Company, an advanced, low-noise, high-bypass-ratio fan stage design and several advanced technology stator vane designs were recently tested in NASA Lewis Research Center's 9- by 15-Foot Low-Speed Wind Tunnel (an anechoic facility). The project was called the NASA/Allison Low Noise Fan.

  3. The Role of Stereotactic Ablative Radiotherapy for Early-Stage and Oligometastatic Non-small Cell Lung Cancer: Evidence for Changing Paradigms

    PubMed Central

    Dahele, Max

    2011-01-01

    A compelling body of non-randomized evidence has established stereotactic ablative lung radiotherapy (SABR) as a standard of care for medically inoperable patients with peripheral early-stage non-small cell lung cancer (NSCLC). This convenient outpatient therapy, which is typically delivered in 3-8 fractions, is also well tolerated by elderly and frail patients, makes efficient use of resources and is feasible using standard commercial equipment. The introduction of lung SABR into large populations has led to an increased utilization of radiotherapy, a reduction in the proportion of untreated patients and an increase in overall survival. In selected patients, the same ablative technology can now achieve durable local control of NSCLC metastases in a variety of common locations including the adrenal glands, bone, brain, and liver. At the same time as this, advances in prognostic molecular markers and targeted systemic therapies mean that there is now a subgroup of patients with stage IV NSCLC and a median survival of around 2 years. This creates opportunities for new trials that incorporate SABR and patient-specific systemic strategies. This selective mini-review focuses on the emerging role of SABR in patients with early-stage and oligometastatic NSCLC. PMID:21811422

  4. Advanced Launch Vehicle Upper Stages Using Liquid Propulsion and Metallized Propellants

    NASA Technical Reports Server (NTRS)

    Palaszewski, Bryan A.

    1990-01-01

    Metallized propellants are liquid propellants with a metal additive suspended in a gelled fuel or oxidizer. Typically, aluminum (Al) particles are the metal additive. These propellants provide increase in the density and/or the specific impulse of the propulsion system. Using metallized propellant for volume-and mass-constrained upper stages can deliver modest increases in performance for low earth orbit to geosynchronous earth orbit (LEO-GEO) and other earth orbital transfer missions. Metallized propellants, however, can enable very fast planetary missions with a single-stage upper stage system. Trade studies comparing metallized propellant stage performance with non-metallized upper stages and the Inertial Upper Stage (IUS) are presented. These upper stages are both one- and two-stage vehicles that provide the added energy to send payloads to altitudes and onto trajectories that are unattainable with only the launch vehicle. The stage designs are controlled by the volume and the mass constraints of the Space Transportation System (STS) and Space Transportation System-Cargo (STS-C) launch vehicles. The influences of the density and specific impulse increases enabled by metallized propellants are examined for a variety of different stage and propellant combinations.

  5. Integrative Discovery of Epigenetically Derepressed Cancer Testis Antigens in NSCLC

    PubMed Central

    Glazer, Chad A.; Smith, Ian M.; Ochs, Michael F.; Begum, Shahnaz; Westra, William; Chang, Steven S.; Sun, Wenyue; Bhan, Sheetal; Khan, Zubair; Ahrendt, Steven; Califano, Joseph A.

    2009-01-01

    Background Cancer/testis antigens (CTAs) were first discovered as immunogenic targets normally expressed in germline cells, but differentially expressed in a variety of human cancers. In this study, we used an integrative epigenetic screening approach to identify coordinately expressed genes in human non-small cell lung cancer (NSCLC) whose transcription is driven by promoter demethylation. Methodology/Principal Findings Our screening approach found 290 significant genes from the over 47,000 transcripts incorporated in the Affymetrix Human Genome U133 Plus 2.0 expression array. Of the top 55 candidates, 10 showed both differential overexpression and promoter region hypomethylation in NSCLC. Surprisingly, 6 of the 10 genes discovered by this approach were CTAs. Using a separate cohort of primary tumor and normal tissue, we validated NSCLC promoter hypomethylation and increased expression by quantitative RT-PCR for all 10 genes. We noted significant, coordinated coexpression of multiple target genes, as well as coordinated promoter demethylation, in a large set of individual tumors that was associated with the SCC subtype of NSCLC. In addition, we identified 2 novel target genes that exhibited growth-promoting effects in multiple cell lines. Conclusions/Significance Coordinated promoter demethylation in NSCLC is associated with aberrant expression of CTAs and potential, novel candidate protooncogenes that can be identified using integrative discovery techniques. These findings have significant implications for discovery of novel CTAs and CT antigen directed immunotherapy. PMID:19997593

  6. Method and apparatus for advanced staged combustion utilizing forced internal recirculation

    DOEpatents

    Rabovitser, Iosif K.; Knight, Richard A.; Cygan, David F.; Nester, Serguei; Abbasi, Hamid A.

    2003-12-16

    A method and apparatus for combustion of a fuel in which a first-stage fuel and a first-stage oxidant are introduced into a combustion chamber and ignited, forming a primary combustion zone. At least about 5% of the total heat output produced by combustion of the first-stage fuel and the first-stage oxidant is removed from the primary combustion zone, forming cooled first-stage combustion products. A portion of the cooled first-stage combustion products from a downstream region of the primary combustion zone is recirculated to an upstream region of primary combustion zone. A second-stage fuel is introduced into the combustion chamber downstream of the primary combustion zone and ignited, forming a secondary combustion zone. At least about 5% of the heat from the secondary combustion zone is removed. In accordance with one embodiment, a third-stage oxidant is introduced into the combustion chamber downstream of the secondary combustion zone, forming a tertiary combustion zone.

  7. Gene Expression Profile for Predicting Survival in Advanced-Stage Serous Ovarian Cancer Across Two Independent Datasets

    PubMed Central

    Yoshihara, Kosuke; Tajima, Atsushi; Yahata, Tetsuro; Kodama, Shoji; Fujiwara, Hiroyuki; Suzuki, Mitsuaki; Onishi, Yoshitaka; Hatae, Masayuki; Sueyoshi, Kazunobu; Fujiwara, Hisaya; Kudo, Yoshiki; Kotera, Kohei; Masuzaki, Hideaki; Tashiro, Hironori; Katabuchi, Hidetaka; Inoue, Ituro; Tanaka, Kenichi

    2010-01-01

    Background Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS)-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer. Methodology/Principal Findings Advanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p<0.01) and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR), 3.72; 95% confidence interval (CI), 2.66–5.43; p<0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20–1.98; p = 0.0008). Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008). Conclusions/Significance The prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer. PMID:20300634

  8. 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

  9. Updating advances on recombinant human endostatin combined with radiotherapy for non-small cell lung cancer with brain metastasis

    PubMed Central

    Qiao, Yun

    2012-01-01

    Brain metastases (BM) heavily affects the prognosis of advanced non-small cell lung cancer (NSCLC). Although whole-brain radiotherapy remains the mainstream therapy for BM caused by NSCLC, the effectiveness is unsatisfactory. Endostar, a recombinant human endostatin (RHES), has shown certain therapeutic effect on advanced NSCLC. This article reviews the feasibility of Endostar combined with radiotherapy in the treatment of BM caused by NSCLC. PMID:25806159

  10. Changes in inflorescence protein during advanced stages of floret development in Buchloe dactyloides (Poaceae).

    PubMed

    Zhou, Y-J; Xue, J-G; Wang, X-G; Zhang, X-Q

    2012-01-01

    Buffalograss, Buchloe dactyloides, is a dioecious species native to the Great Plains of North America. The florets at the early stages of development possess both gynoecium and androecium organ primordia but later become unisexual. Very little is known about the proteomic changes that occur when the florets change from hermaphroditism to unisexuality. We compared the protein composition of florets at the hermaphroditic stage with that at the unisexual stage. The development stage of the floret was determined by stereomicroscopic observation. Two-dimensional gel electrophoresis was used to separate the proteins extracted from female and male inflorescences. Stage- specific protein maps, with an average of about 400 spots per map, were analyzed with the protein analysis software. Eighteen spots were found to be differentially expressed between the hermaphrodite and unisexual stages. Of these, 12 were present at both stages but with a different expression value. Four specific spots appeared at the hermaphrodite stage and disappeared at the unisexual stage. Two specific protein spots were associated with female and male floret differentiation. One appears to be associated with contabescence in the female floret and the final protein appears to lead to the abortion of gynoecium in the male floret. The MALDI TOF/TOF technique was used for peptide mass fingerprinting of the differentially expressed proteins and the MASCOT software was used to search the protein database. However, only two protein spots were identified from the database. These were aldolase1 and Os05g0574400 (similar to malate dehydrogenase). This type of proteomic study can help to identify novel protein products and determine the mechanisms involved in the floral sex differentiation process in buffalo grass. PMID:22930428

  11. Combine therapy of gefitinib and fulvestrant enhances antitumor effects on NSCLC cell lines with acquired resistance to gefitinib.

    PubMed

    Xu, Ruitong; Shen, Hua; Guo, Renhua; Sun, Jing; Gao, Wen; Shu, Yongqian

    2012-07-01

    Gefitinib, an EGFR receptor tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC), but the emergence of mutations resistant to these inhibitors, such as T790M, has become a clinical problem. According to statistics, female patients, the presence of adenocarcinoma or non-smokers experienced a higher response rate. This may be involved in interaction between the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR). To test whether inhibition of the ER signaling pathway affects the antitumor effect of gefitinib, gefitinib and an ER antagonist, fulvestrant, were administered to NSCLC cell lines with acquired resistance to gefitinib. Compared with treatment of either fulvestrant or gefitinib alone, drug combination obviously decreased proliferation of H1976, H1650 and PC-9 cells coming from adenocarcinoma. Rapid activations of EGFR pathway by E2β were observed in H1975 cells with T790M mutation. Additionally, EGFR and ERs expression were down-regulated respectively in response to estrogen and EGF but up-regulated in response to fulvestrant and gefitinib in vitro. These results suggest that there is a functional cross-signaling between the EGFR/ER pathways in NSCLC with acquired resistance to gefitinib, possibly providing rationale for combining gefitinib with anti-estrogen therapy for advanced NSCLC treatment. PMID:22560634

  12. Expression of paired basic amino acid-cleaving enzyme 4 (PACE4) correlated with prognosis in non-small cell lung cancer (NSCLC) patients

    PubMed Central

    Lin, Yun-En; Wu, Qi-Nian; Lin, Xiao-Dong; Li, Guang-Qiu

    2015-01-01

    Background Paired basic amino acid-cleaving enzyme 4 (PACE4) was shown to enhance tumor cells proliferation and invasive. This study provides the first investigation of PACE4 expression in non-small cell lung cancer (NSCLC) and the correlation with clinicopathologic features, prognostic indicators of 172 cases. Methods Quantitative real-time PCR (RT-PCR) and immunofluorescence (IF) were applied to detect PACE4 expression in NSCLC and 16HBE cell lines, then 172 consecutive NSCLC and 15 normal lung tissues were studied through immunohistochemistry (IHC). The association between PACE4 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of PACE4 expression on survival. Results PACE4 expression in NSCLC were significantly higher than normal lung cell and tissues (P<0.05). PACE4 had cytoplasmic expression and was observed in 111 of the 172 (64.5%) NSCLC patients. Clinicopathologically, PACE4 expression was significantly associated with lymph node metastasis (N stage) (P=0.007), and clinical stage (P=0.024). Multivariable analysis confirmed that PACE4 expression increased the hazard of death after adjusting for other clinicopathological factors [hazards ratio (HR): 1.584; 95% confidence interval (CI): 1.167-2.151; P<0.001]. Overall survival (OS) was significantly prolonged in PACE4 negative group when compared with PACE4 positive group (5-year survival rates, 23.1% vs. 54.5%, log-rank test, χ2=17.717, P<0.001), as was disease-free survival (DFS) (5-year survival rates, 23.4% vs. 55.4%, log-rank test, χ2=20.486, P<0.001). Conclusions Our results suggest that positive expression of PACE4 is an independent factor for NSCLC patients and it might serve as a potential prognostic biomarker for patients with NSCLC. PMID:26101640

  13. 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

  14. Promoter methylation of APC and RAR-β genes as prognostic markers in non-small cell lung cancer (NSCLC).

    PubMed

    Feng, Hongxiang; Zhang, Zhenrong; Qing, Xin; Wang, Xiaowei; Liang, Chaoyang; Liu, Deruo

    2016-02-01

    Aberrant promoter hypermethylations of tumor suppressor genes are promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine methylation status at APC and RAR-β promoters in primary NSCLC, and whether they have any relationship with survival. APC and RAR-β promoter methylation status were determined in 41 NSCLC patients using methylation specific PCR. APC promoter methylation was detectable in 9 (22.0%) tumor samples and 6 (14.6%) corresponding non-tumor samples (P=0.391). RAR-β promoter methylation was detectable in 13 (31.7%) tumor samples and 4 (9.8%) corresponding non-tumor samples (P=0.049) in the NSCLC patients. APC promoter methylation was found to be associated with T stage (P=0.046) and nodal status (P=0.019) in non-tumor samples, and with smoking (P=0.004) in tumor samples. RAR-β promoter methylation was found associated with age (P=0.031) in non-tumor samples and with primary tumor site in tumor samples. Patients with APC promoter methylation in tumor samples showed significantly longer survival than patients without it (Log-rank P=0.014). In a multivariate analysis of prognostic factors, APC methylation in tumor samples was an independent prognostic factor (P=0.012), as were N1 positive lymph node number (P=0.025) and N2 positive lymph node number (P=0.06). Our study shows that RAR-β methylation detected in lung tissue may be used as a predictive marker for NSCLC diagnosis and that APC methylation in tumor sample may be a useful marker for superior survival in NSCLC patients. PMID:26681652

  15. Modeling of an advanced concept of a double stage Hall effect thruster

    SciTech Connect

    Garrigues, L.; Boniface, C.; Hagelaar, G. J. M.; Boeuf, J. P.

    2008-11-15

    We present a study of the principle and operation of a two-stage Hall effect thruster, the SPT-MAG, using a two-dimensional quasineutral hybrid model coupled with a Monte Carlo simulation of electron transport. The purpose of the two-stage design is the separation of ion production and acceleration in two separate chambers, the ionization stage and the acceleration stage, with separate control of acceleration voltage and total ionization. The originality of the SPT-MAG lies in the magnetic field configuration in the ionization chamber. Electrons are confined by this magnetic field while ions are supposed to be trapped in the electric potential well supposedly resulting from the magnetic configuration, and guided toward the acceleration stage. The acceleration stage is similar to the channel of a conventional Hall effect thruster. The purpose of this paper is to clarify the physics of the SPT-MAG and to understand the formation of the positive ion trap in the ionization chamber. Using a hybrid model and a Monte Carlo simulation we show that under typical operating conditions most of the ionization in the chamber is due to high energy electrons accelerated in the channel and entering the chamber rather than to electrons accelerated by the voltage applied in the ionization chamber. We also raise the question of the possible role of an additional emissive cathode inside the ionization chamber. The model predicts that an electric potential well guiding the ions to the channel entrance forms in the chamber only if the intermediate electrode inside the chamber is an emissive cathode (which is not the case in recent configurations used for this thruster)

  16. Transoral Laser Microsurgery (TLM) ± Adjuvant Therapy for Advanced Stage Oropharyngeal Cancer: Outcomes and Prognostic Factors

    PubMed Central

    Rich, Jason T.; Milov, Simon; Lewis, James S.; Thorstad, Wade L.; Adkins, Douglas R.; Haughey, Bruce H.

    2013-01-01

    Objectives/Hypothesis Document survival, prognostic variables, and functional outcomes of patients with AJCC stage III or IV oropharyngeal cancer, treated with transoral laser microsurgery (TLM) ± adjuvant therapy. Study Design Analysis of prospectively assembled data pertaining to the above-described patient cohort. Methods Patients treated with TLM for AJCC stage III or IV oropharyngeal cancer at Washington University School of Medicine from 1996 to 2006 were followed for a minimum of 2 years. Recurrence, survival, functional, and human papilloma virus data were analyzed. Results Eighty-four patients met inclusion criteria. Mean follow-up was 52.6 months. Overall AJCC stages were: III 15% and IV 85%. T stages were T1–2, 74%; T3–4, 26%. Eighty-three patients underwent neck dissection, 50 received adjuvant radiotherapy, and 28 received adjuvant chemoradiotherapy. Overall survival at 2 and 5 years was 94% and 88%, respectively. Disease-specific survival at 2 and 5 years was 96% and 92%, respectively. Six patients recurred (7%): locally (one), regionally (four), and distant (five). T stage, positive margins, and p16 status significantly impacted survival. The addition of adjuvant chemo-therapy in high-risk patients did not significantly impact survival. Five patients (6%) had major surgical complications, but without mortality. Eighty-one percent of patients had acceptable swallowing function at last follow-up. Immediately postoperatively, 17% required G-tubes, which dropped to 3.4% of living patients at 3 years. Conclusions In this population, our findings validate TLM ± adjuvant therapy as a highly effective strategy for survival, locoregional control, and swallowing recovery in AJCC stage III and IV oropharyngeal cancer. Our finding also show that p16 positivity improves survival. PMID:19572271

  17. Efficacy Comparison Between Total Laryngectomy and Nonsurgical Organ-Preservation Modalities in Treatment of Advanced Stage Laryngeal Cancer

    PubMed Central

    Fu, Xiaoyuan; Zhou, Qi; Zhang, Xianquan

    2016-01-01

    Abstract It remains unclear whether the efficacy of nonsurgical organ-preservation modalities (NOP) in the treatment of advanced-stage laryngeal cancer was noninferiority compared with that of total laryngectomy (TL). The objective of this study was to compare the curative effects between TL and NOP in the treatment of advanced-stage laryngeal cancer through a meta-analysis. Clinical studies were retrieved from the electronic databases of PubMed, Embase, Wanfang, and Chinese National Knowledge infrastructure. A meta-analysis was performed to investigate the differences in the curative efficacy of advanced-stage laryngeal cancer between TL and the nonsurgical method. Two reviewers screened all titles and abstracts, and independently assessed all articles. All identified studies were retrospective. Sixteen retrospective studies involving 8308 patients (4478 in the TL group and 3701 in the nonsurgical group) were included in this meta-analysis. The analysis results displayed the advantage of TL for 2-year and 5-year overall survival (OS)(OR 2.79, 95% CI 1.85–4.23 and OR 1.52, 95% CI 1.09–2.14) as well as in 5-year disease-specific survival (DSS)(OR 1.79, 95% CI 1.61–1.98), but no significant difference in 2-year DSS was detected between the 2 groups (OR = 2.09,95% CI0.69–6.40). Additionally, there were no significant differences between TL and NOP for 5-year local control (LC) either (OR = 1.75, 95% CI 0.87–3.53). When we carried out subgroup analyses, the advantage of TL was especially obvious in T4 subgroups, but not in T3 subgroups. This is the first study to compare the curative effects on advanced-stage laryngeal cancer using meta-analytic methodology. Although there was a trend in favor of TL for OS and DSS, there is no clear difference in oncologic outcome between TL and NOP. Therefore, other factors such as tumor T-stage and size, lymph node metastasis, and physical condition are also important indicators for treatment choice. PMID:27057837

  18. Prognosis and Clinicopathologic Features of Patients With Advanced Stage Isocitrate Dehydrogenase (IDH) Mutant and IDH Wild-Type Intrahepatic Cholangiocarcinoma

    PubMed Central

    Goyal, Lipika; Govindan, Aparna; Sheth, Rahul A.; Nardi, Valentina; Blaszkowsky, Lawrence S.; Faris, Jason E.; Clark, Jeffrey W.; Ryan, David P.; Kwak, Eunice L.; Allen, Jill N.; Murphy, Janet E.; Saha, Supriya K.; Hong, Theodore S.; Wo, Jennifer Y.; Ferrone, Cristina R.; Tanabe, Kenneth K.; Chong, Dawn Q.; Deshpande, Vikram; Borger, Darrell R.; Iafrate, A. John; Bardeesy, Nabeel; Zheng, Hui

    2015-01-01

    Background. Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with advanced-stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC. Methods. Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild-type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging. Results. Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19-9 (CA19-9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status. Conclusion. The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19-9 level at presentation. Implications for Practice: Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early-stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with

  19. Radiofrequency Ablation in the Management of Advanced Stage Thymomas: A Case Report on a Novel Multidisciplinary Therapeutic Approach

    PubMed Central

    Pala, Carlo; Versace, Renato

    2014-01-01

    We describe in this report a case of successful radiofrequency ablation of an unresectable stage III-type B3 thymoma, and we discuss the role of this novel approach in the management of patients with advanced stage thymoma. The patient, a 59-year-old Caucasian male underwent neoadjuvant chemotherapy with only a slight reduction of the mass. Subsequently, an explorative sternotomy and debulking were performed; before closing the thorax, radiofrequency ablation of the residual tumor was carried out and a partial necrosis of the mass was achieved. A further percutaneous radiofrequency ablation was performed subsequently, obtaining complete necrosis of the lesion. Successively, the patient underwent adjuvant radiotherapy. As a result of this multidisciplinary treatment, complete and stable response was obtained. It is hard to say which of the single treatments had the major impact on cure; nevertheless, the results obtained suggest that radiofrequency ablation must be taken into account for the treatment of advanced stage thymomas, and its effectiveness must be further assessed in future studies. PMID:25574416

  20. Advanced-stage nodular lymphocyte predominant Hodgkin lymphoma compared with classical Hodgkin lymphoma: a matched pair outcome analysis.

    PubMed

    Xing, Katharine H; Connors, Joseph M; Lai, Anky; Al-Mansour, Mubarak; Sehn, Laurie H; Villa, Diego; Klasa, Richard; Shenkier, Tamara; Gascoyne, Randy D; Skinnider, Brian; Savage, Kerry J

    2014-06-01

    Due to disease rarity, there is limited information regarding the optimal therapy and outcome for patients with advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Forty-two patients with NLPHL by the Revised European-American Lymphoma/World Health Organization classification with advanced-stage disease were identified and paired 1:2 with a matched control with classical Hodgkin lymphoma (CHL) matched by age, gender, stage, decade of diagnosis, and treatment received. The median follow-up was 11.3 years (range, 1.9 to 35.5 years) for NLPHL patients and 10.7 years (range, 1.6 to 26.3 years) for CHL patients. The majority received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)-like chemotherapy. Although the 10-year overall survival (OS) (P = .579) and HL freedom from treatment failure (HL-FFTF) were similar between NLPHL and CHL patients (75% vs 73%; P = .610), the time to progression (TTP), which also includes the development of secondary aggressive lymphoma, was inferior in NLPHL (10-year, 63% vs 73%; P = .040). Splenic involvement was associated with an inferior 10-year TTP in patients treated with ABVD (48% vs 71%; P = .049) and an increased cumulative incidence of secondary aggressive lymphoma (P = .014) providing a rationale for further evaluation of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with rituximab in NLPHL. PMID:24713929

  1. A heartrending burden of gynaecological cancers in advance stage at nuclear institute of medicine and radiotherapy Jamshoro Sindh

    PubMed Central

    Bibi, Seema; Ashfaque, Sanober; Laghari, Naeem Ahmed

    2016-01-01

    Objectives: In Pakistan gynaecological cancers are among the leading causes of women’s morbidity and mortality posing huge financial burden on families, communities and state. Due to lack of national cancer registry exact facts and figures are unknown therefore this study was planned to find out prevalence, age, site and stage of presentation of gynaecological cancers at Nuclear Institute of Medicine and Radiotherapy (NIMRA), Jamshoro. Methods: A retrospective, cross sectional study was conducted from 1st January 2011 to 31st December 2011 at NIMRA Jamshoro. All cases of genital tract cancers were evaluated, required data was entered on predesigned performa and results were analyzed manually. Results: Out of 2401 total registered cancer cases, 231 (9.6%) patients were suffering from gynaecological cancer making it third most common cancer. Ovary was commonest site followed by cervix and uterus. More than 60% cases presented in advanced stage, mostly during 4th and 5th decade of life. Conclusion: Gynecological cancer was among top three cancers at one of the busiest public sector cancer institute in Sindh province and significant number presented in advance stage making treatment difficult and expensive. There is urgent need for development and implementation of an effective health policy regarding cancer prevention and treatment. PMID:27022358

  2. [Treatment of pain in advanced-stage intra-abdominal neoplasms].

    PubMed

    Polati, E; Finco, G; Rigo, V; Gottin, L; Pinaroli, A M; Iacono, C; Mangiante, G; Serio, G; Ischia, S

    1993-01-01

    Different types of pain are present in far advanced intra-abdominal cancer, sometimes in the same site too. An accurate semeiological analysis of pain is important because different types of pain often differently respond to the available therapeutical tools. In this paper the results and the complications of the most important methods of pain management in far advanced intra-abdominal cancer are examined. Analysis of the data reveals that the association of more methods, pharmacological and non, should be a rule rather than the exception. PMID:7923502

  3. Improved Outcomes Associated with Higher Surgery Rates for Older Patients with Early-Stage Non-Small Cell Lung Cancer

    PubMed Central

    Gray, Stacy W.; Landrum, Mary Beth; Lamont, Elizabeth B.; McNeil, Barbara J.; Jaklitsch, Michael T.; Keating, Nancy L.

    2011-01-01

    Background Although surgery offers the greatest chance of cure for patients with early stage non-small cell lung cancer (NSCLC), older and sicker patients often fail to undergo resection. The benefits of surgery in older patients and patients with multiple co-morbidities are uncertain. Methods We identified a national cohort of 17,638 Medicare beneficiaries, aged ≥66 years living in Surveillance, Epidemiology, and End Results (SEER) areas who were diagnosed with stage I or II NSCLC during 2001–2005. We compared areas with high and low rates of curative surgery for early-stage lung cancer to estimate the effectiveness of surgery in older and sicker patients. We used logistic regression models to assess mortality by quintile of area-level surgery rates, adjusting for potential confounders. Findings Fewer than 63% of patients underwent surgery in low-surgery areas while >79% underwent surgery in high-surgery areas. High-surgery areas operated on more patients with advanced age and COPD than low-surgery areas. Adjusted all-cause one year mortality was 18.0% in high-surgery areas vs. 22.8% in low-surgery areas (adjusted odds ratio (OR)=0.89 (95% confidence interval [CI] 0.86–0.93) for each 10% increase in surgery rates). One year lung-cancer-specific mortality was similarly lower in high-versus low-surgery areas (12.0% versus 16.9%), adjusted OR=0.86 (95% CI 0.82–0.91) for each 10% increase in surgery rates. Interpretations Higher rates of surgery for stage I/II NSCLC are associated with improved survival, even when older patients and sicker patients undergo resection. More work is needed to identify and reduce barriers to surgery for early-stage NSCLC. PMID:21800285

  4. PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study.

    PubMed

    Barrington, Sally F; Kirkwood, Amy A; Franceschetto, Antonella; Fulham, Michael J; Roberts, Thomas H; Almquist, Helén; Brun, Eva; Hjorthaug, Karin; Viney, Zaid N; Pike, Lucy C; Federico, Massimo; Luminari, Stefano; Radford, John; Trotman, Judith; Fosså, Alexander; Berkahn, Leanne; Molin, Daniel; D'Amore, Francesco; Sinclair, Donald A; Smith, Paul; O'Doherty, Michael J; Stevens, Lindsey; Johnson, Peter W

    2016-03-24

    International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a κ (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice. PMID:26747247

  5. MicroRNA-related single-nucleotide polymorphism of XPO5 is strongly correlated with the prognosis and chemotherapy response in advanced non-small-cell lung cancer patients.

    PubMed

    Geng, Ji-Qun; Wang, Xiao-Chen; Li, Long-Fei; Zhao, Jun; Wu, Song; Yu, Gui-Ping; Zhu, Kou-Jun

    2016-02-01

    This study was performed to investigate if the microRNA-related single-nucleotide polymorphisms (miR-SNPs) of XPO5 gene predicted the prognosis and pathological features of advanced non-small-cell lung cancer patients receiving chemotherapy. A total of 131 advanced non-small-cell lung cancer (NSCLC) patients were recruited. MicroRNA (miRNA) binding site prediction software was adopted for the prediction and screening of SNPs in XPO5 and miRNA binding regions. Polymerase chain reaction (PCR) amplification was further performed. Time-dependent survival-free curves were constructed using the Kaplan-Meier technique. Univariate and the multivariate survival analyses were conducted for confirmation of prognostic factor for advanced NSCLC patients receiving chemotherapy. There were no significant differences of SNP distribution frequencies between groups, without statistical significance (P > 0.05). Included clinical pathological features and chemotherapy regimens showed no apparent statistical significance in influencing the curative effect of chemotherapy in advanced NSCLC patients (all P > 0.05). While the objective response rate (ORR) in patients who carried AA and AC genotype was 35.48 and 51.22 %, respectively, with statistically significant difference (P < 0.05). Univariate survival analysis indicated that patients who carried AA genotype showed a significantly lower 5-year survival rate to those who carried AC genotype (P < 0.05). And, considering pathological features, statistical significance was found in patients with different pathological types, lymph node metastasis, differentiation degree, T staging, and pathological staging (all P < 0.05). Multivariate analysis results indicated that the SNP sites of rs11077 might be an independent prognostic factor of advanced NSCLC patients receiving chemotherapy (risk ratio [RR] = 0.346; 95 % confidence interval [95 % CI] = 0.174-0.685, P = 0.002). Other clinical features were all

  6. The conjoint use of music therapy and reflexology with hospitalized advanced stage cancer patients and their families.

    PubMed

    Magill, Lucanne; Berenson, Susan

    2008-09-01

    Advanced stage cancer patients experience debilitating physical symptoms as well as profound emotional and spiritual struggles. Advanced disease is accompanied by multiple changes and losses for the patient and the family. Palliative care focuses on the relief of overall suffering of patients and families, including symptom control, psychosocial support, and the meeting of spiritual needs. Music therapy and reflexology are complementary therapies that can soothe and provide comfort. When used conjointly, they provide a multifaceted experience that can aid in the reduction of anxiety, pain, and isolation; facilitate communication between patients, family members, and staff; and provide the potential for a more peaceful dying experience for all involved. This article addresses the benefits of the combined use of music therapy and reflexology. Two case studies are presented to illustrate the application and benefits of this dual approach for patients and their families regarding adjustment to the end of life in the presence of anxiety and cognitive impairment. PMID:18662423

  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. Two stage low noise advanced technology fan. 1: Aerodynamic, structural, and acoustic design

    NASA Technical Reports Server (NTRS)

    Messenger, H. E.; Ruschak, J. T.; Sofrin, T. G.

    1974-01-01

    A two-stage fan was designed to reduce noise 20 db below current requirements. The first-stage rotor has a design tip speed of 365.8 m/sec and a hub/tip ratio of 0.4. The fan was designed to deliver a pressure ratio of 1.9 with an adiabatic efficiency of 85.3 percent at a specific inlet corrected flow of 209.2kg/sec/sq m. Noise reduction devices include acoustically treated casing walls, a flowpath exit acoustic splitter, a translating centerbody sonic inlet device, widely spaced blade rows, and the proper ratio of blades and vanes. Multiple-circular-arc rotor airfoils, resettable stators, split outer casings, and capability to go to close blade-row spacing are also included.

  9. What is the correct staging and treatment strategy for locally advanced prostate cancer extending to the bladder?

    PubMed

    Yüksel, Özgür Haki; Verit, Ayhan; Ürkmez, Ahmet

    2015-06-01

    In locally advanced prostate cancer with bladder invasion, frequently encountered problems such as bleeding, urinary retention, hydronephrosis, and pain create distress for the patients. Therefore patients' quality of life is disrupted and duration of hospitalization is prolonged. Relevant literature about accurate staging and treatment of locally advanced prostate cancer with bladder invasion was investigated. Locally advanced prostate cancer can present as a large-volume aggressive tumor extending beyond boundaries of prostate gland, and involving neighboring structures which can be involved as recurrence(s) following initial local therapy. Survival times of these patients can range between 5 and 8 years. Their common characteristics are adverse and severe local symptoms unfavorably affecting quality of life Control of local symptoms and their effective palliation are independent clinical targets influencing survival outcomes of these patients. The treatment outcomes of locally advanced prostate cancer into the bladder are currently debatable. Although in the current TNM classification, it is defined in T4a, we think that this may be categorized as a subgroup of T3 and thus encourage surgeons for the indication of radical surgeries (radical prostatectomy, radical cystoprostatectomy) in selected patient populations after discussing issues concerning consequences of the treatment alternatives, and expectations with the patients. Cystoprostatectomy followed by immediate androgen deprivation therapy may be a feasible option for selected patients with previously untreated prostate cancer involving the bladder neck because of excellent local control and long term survival. PMID:26150029

  10. Technology requirements for advanced earth-orbital transportation systems: Summary report. [single stage to orbit vehicles

    NASA Technical Reports Server (NTRS)

    Haefeli, R. C.; Littler, E. G.; Hurley, J. B.; Winter, M. G.

    1977-01-01

    Areas of advanced technology that are either critical or offer significant benefits to the development of future Earth-orbit transportation systems were identified. Technology assessment was based on the application of these technologies to fully reusable, single-state-to-orbit (SSTO) vehicle concepts with horizontal landing capability. Study guidelines included mission requirements similar to space shuttle, an operational capability beginning in 1995, and main propulsion to be advanced hydrogen-fueled rocket engines. The technical and economic feasibility of this class of SSTO concepts were evaluated as well as the comparative features of three operational take-off modes, which were vertical boost, horizontal sled launch, and horizontal take-off with subsequent inflight fueling. Projections of both normal and accelerated technology growth were made. Figures of merit were derived to provide relative rankings of technology areas. The influence of selected accelerated areas on vehicle design and program costs was analyzed by developing near-optimum point designs.

  11. Expression of poly(C)-binding protein 1 (PCBP1) in NSCLC as a negative regulator of EMT and its clinical value

    PubMed Central

    Liu, Yifei; Gai, Ling; Liu, Jian; Cui, Yuan; Zhang, Yan; Feng, Jia

    2015-01-01

    Poly (C)-binding Protein 1 (PCBP1) is a 35 kDa protein involved in a number of biological processes. Recently, the research found that PCBP1 might be involved in epithelial-mesenchymal transition (EMT). However, the role of PCBP1 in non-small-cell lung cancer (NSCLC) metastasis needs further elucidation. The purpose of this study was to determine whether PCBP1 could serve as a biomarker for stratification and prediction of prognosis in NSCLC as a regulator of EMT formation. In this study, PCBP1 expression was evaluated by Western blot in 8 fresh lung cancer tissues and immunohistochemistry (IHC) on 145 paraffin-embedded slices. PCBP1 was highly expressed in non-metastatic NSCLC specimens and significantly correlated with lymph node status (P < 0.001), clinical stage (P = 0.001), vimentin expression (P = 0.033) and E-cadherin expression (P = 0.042). Our study showed that the low expression of PCBP1 was correlated with decreased expression of E-cadherin and elevated expression of vimentin, which were the markers of EMT. Besides, high expression of PCBP1 was correlated with better prognosis. These findings suggested that PCBP1 might play an important role in preventing the process of EMT in NSCLC, thus be a promising therapeutic target to inhibit NSCLC metastasis. PMID:26261610

  12. 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

  13. Long-term outcome of patients with advanced-stage cutaneous T cell lymphoma treated with gemcitabine.

    PubMed

    Pellegrini, Cinzia; Stefoni, Vittorio; Casadei, Beatrice; Maglie, Roberto; Argnani, Lisa; Zinzani, Pier Luigi

    2014-11-01

    The choice of treatment for cutaneous T cell lymphoma (CTCL) is often determined by institutional experience, particularly as there is a paucity of data from phase III trials and a lack of consensus concerning treatment of the advanced stages. Among the several second-line and experimental drugs, gemcitabine could be considered one of the most suitable options for pretreated CTCL. Since it is difficult to find in literature the long-term outcome regarding the efficacy of a single-agent drug in pretreated patients and, in particular, in rare diseases such as CTCL, a retrospective observational study was conducted with the aim of evaluating the long-term outcome of CTCL patients treated with gemcitabine. Twenty-five patients with at least one therapy (range 1-8) performed prior to gemcitabine were found. After gemcitabine treatment, the overall response was 48 % with a 20 % of complete responses. At 15 years, the estimated overall survival is 47 %, progression-free survival 8.8 %, and disease-free survival 40 % (median reached at 2.9 years). All patients received at least three cycles and no grade 3-4 hematological adverse events occurred. At the latest follow-up, two patients are still in continuous complete response. This long-term update on the role of gemcitabine as a single agent in pretreated advanced-stage CTCL confirms this monotherapy as effective and safe. PMID:24908331

  14. Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: Implications in lung cancer pathogenesis and prognosis

    PubMed Central

    Tang, Ximing; Kadara, Humam; Behrens, Carmen; Liu, Diane D.; Xiao, Yun; Rice, David; Gazdar, Adi F.; Fujimoto, Junya; Moran, Cesar; Varella-Garcia, Marileila; Lee, J. Jack; Hong, Waun Ki; Wistuba, Ignacio I.

    2011-01-01

    PURPOSE Emerging evidence suggests that aberrant expression of oncogenes contributes to development of lung malignancy. The thyroid transcription factor 1 (TITF-1) gene functions as a lineage survival gene abnormally expressed in a significant fraction of NSCLCs, in particular lung adenocarcinomas. EXPERIMENTAL DESIGN To better characterize TITF-1 abnormality: patterns in NSCLC, we studied TITF-1’s gene copy number using fluorescent in situ hybridization (FISH) and quantitative PCR, as well as its protein expression by immunohistochemistry analysis in a tissue microarray comprised of surgically resected NSCLC (N=321) including 204 adenocarcinomas and 117 squamous cell carcinomas (SCCs). TITF-1 copy number and protein expression were correlated with patients’ clinicopathologic characteristics, and in a subset of adenocarcinomas with EGFR and KRAS mutation status. RESULTS We found that increased TITF-1 protein expression was prevalent in lung adenocarcinomas only and was significantly associated with female gender (p<0.001), never smokers (p=0.004), presence of EGFR mutations (p=0.05) and better overall survival (all stages, p=0.0478. stages I and II, p=0.002). TITF-1 copy number gain (CBG) was detected by FISH analysis in both adenocarcinomas (18.9%; high CNG, 8.3%) and SCCs (20.1%; high CNG, 3.0%), and correlated significantly with the protein product (p=0.004) and presence of KRAS mutations (p=0.008) in lung adenocarcinomas. Moreover, multivariate analysis revealed that TITF-1 copy number gain was an independent predictor of poor survival of NSCLC (p=0.039). CONCLUSIONS Our integrative study demonstrates that the protein versus genomic expression patterns of TITF-1 have opposing roles in lung cancer prognosis and may occur preferentially in different subsets of NSCLC patients with distinct oncogene mutations. PMID:21257719

  15. Advances of multidetector computed tomography in the characterization and staging of renal cell carcinoma

    PubMed Central

    Tsili, Athina C; Argyropoulou, Maria I

    2015-01-01

    Renal cell carcinoma (RCC) accounts for approximately 90%-95% of kidney tumors. With the widespread use of cross-sectional imaging modalities, more than half of RCCs are detected incidentally, often diagnosed at an early stage. This may allow the planning of more conservative treatment strategies. Computed tomography (CT) is considered the examination of choice for the detection and staging of RCC. Multidetector CT (MDCT) with the improvement of spatial resolution and the ability to obtain multiphase imaging, multiplanar and three-dimensional reconstructions in any desired plane brought about further improvement in the evaluation of RCC. Differentiation of RCC from benign renal tumors based on MDCT features is improved. Tumor enhancement characteristics on MDCT have been found closely to correlate with the histologic subtype of RCC, the nuclear grade and the cytogenetic characteristics of clear cell RCC. Important information, including tumor size, localization, and organ involvement, presence and extent of venous thrombus, possible invasion of adjacent organs or lymph nodes, and presence of distant metastases are provided by MDCT examination. The preoperative evaluation of patients with RCC was improved by depicting the presence or absence of renal pseudocapsule and by assessing the possible neoplastic infiltration of the perirenal fat tissue and/or renal sinus fat compartment. PMID:26120380

  16. 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

  17. Advanced Stage Mucinous Adenocarcinoma of the Ovary is both Rare and Highly Lethal: A Gynecologic Oncology Group Study

    PubMed Central

    Zaino, Richard J.; Brady, Mark F.; Lele, Subodh M.; Michael, Helen; Greer, Benjamin; Bookman, Michael A.

    2010-01-01

    Background Primary mucinous adenocarcinomas of the ovary are uncommon and their biologic behavior uncertain. Retrospective studies suggest that many mucinous carcinomas diagnosed as primary to the ovary were actually metastatic from another site. A prospective randomized trial provided an opportunity to estimate the frequency of mucinous tumors, diagnostic reproducibility, and clinical outcomes. Methods A phase III trial enrolled 4000 women with stage III or IV ovarian carcinoma, treated by surgical staging and debulking, with randomization to one of five chemotherapeutic arms. Slides and pathology reports classified as primary mucinous carcinoma were reviewed independently by three pathologists. Cases were re-classified as primary or metastatic to the ovary according to two methods. Overall survival (OS) of reclassified groups was compared with each other and with that of patients with serous carcinomas. Results Forty-four cases were classified as mucinous adenocarcinoma at review. Using either method, only about one third were interpreted by the three reviewers as primary mucinous carcinomas. Reproducibility of interpretations among the reviewers was high with unanimity of opinion in 30 of the 44 (68%) cases. The median survival (MS) did not differ significantly between the groups interpreted as primary or metastatic, but the OS was significantly less than that for women with serous carcinoma (14 vs 42 months, p<0.001). Conclusion Advanced stage mucinous carcinoma of the ovary is very rare and is associated with poor OS. Many mucinous adenocarcinomas that are diagnosed as primary ovarian neoplasms appear to be metastatic to the ovary. PMID:20862744

  18. Design and development of an advanced two-stage centrifugal compressor

    NASA Astrophysics Data System (ADS)

    Palmer, D. L.; Waterman, W. F.

    1995-04-01

    This paper describes the aeromechanical design and development of a 3.3 kg/s (7.3 lb/sec), 14:1 pressure ratio two-stage centrifugal compressor, which is used in the T800-LHT-800 helicopter engine. The design employs highly nonradial, splitter bladed impellers with swept leading edges and compact vaned diffusers to achieve high performance in a small and robust configuration. The development effort quantified the effects of impeller diffusion and passive inducer shroud bleed on surge margin as well as the effects of impeller loading on tip clearance sensitivity and the impact of sand erosion and shroud roughness on performance. The developed compressor exceeded its performance objectives with a minimum of 23 percent surge margin without variable geometry. The compressor provides a high-performance, rugged, low-cost configuration ideally suited for helicopter applications.

  19. Design and development of an advanced two-stage centrifugal compressor

    SciTech Connect

    Palmer, D.L.; Waterman, W.F.

    1995-04-01

    Small turboshaft engines require high-pressure-ratio, high-efficiency compressors to provide low engine fuel consumption. This paper describes the aeromechanical design and development of a 3.3 kg/s (7.3 lb/sec), 14:1 pressure ratio two-stage centrifugal compressor, which is used in the T800-LHT-800 helicopter engine. The design employs highly nonradial, splitter bladed impellers with swept leading edges and compact vaned diffusers to achieve high performance in a small and robust configuration. The development effort quantified the effects of impeller diffusion and passive inducer shroud bleed on surge margin as well as the effects of impeller loading on tip clearance sensitivity and the impact of sand erosion and shroud roughness on performance. The developed compressor exceeded its performance objectives with a minimum of 23% surge margin without variable geometry. The compressor provides a high-performance, rugged, low-cost configuration ideally suited for helicopter applications.

  20. Staged Penetrating Sclerokeratoplasty and Penetrating Keratoplasty for Management of Advanced Acquired Anterior Staphyloma

    PubMed Central

    de la Torre-Gonzalez, Enrique; de León Ascencio, Carolina Ponce

    2011-01-01

    Herein we describe a staged surgical technique consisting of penetrating sclerokeratoplasty (PSKP) followed by penetrating keratoplasty (PKP) and present its clinical course and complications over two years of follow-up. A 23-year-old man presented with cosmetically unacceptable protrusion of the globe corresponding to the cornea and sclera. PSKP was performed transplanting a full-thickness beveled 13 mm corneoscleral tectonic graft. Hypotony developed subsequently and was successfully managed medically, however corneal graft failure occurred. After 15 months, a 7.5 mm PKP was performed for optical reasons, which subsequently remained clear with a healthy epithelium. In this particular case, cosmetic, tectonic, therapeutic, and optical requirements were met. PSKP is a surgical procedure which entails a high rate of complications but may be the only alternative when the main goal of intervention is restoration of the globe in complicated cases such as our patient. PMID:22454726

  1. EGFR-TKI resistance in NSCLC patients: mechanisms and strategies

    PubMed Central

    Lin, Yuxin; Wang, Xian; Jin, Hongchuan

    2014-01-01

    The epidermal growth factor receptor (EGFR) is a kind of receptor tyrosine kinase (RTK) that plays a critical role in the initiation and development of malignant tumors via modulating downstream signaling pathways. In non-small cell lung cancer (NSCLC), the activating mutations located in the tyrosine kinase domains of EGFR have been demonstrated in multiple researches as the “Achilles’ heel” of this deadly disease since they could be well-targeted by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, it’s still too early to celebrate since the first-generation EGFR-TKIs such as gefitinib and erlotinib have only achieved limited clinical benefits and acquired resistance to this kind of drugs occurred inevitably in almost all the NSCLC patients. In order to make the most of EGFR-TKIs and develop more effective regimens for the NSCLC patients, researchers majoring in different aspects start a battle against EGFR-TKI resistance. Challenging as it is, we still progress stably and step firmly toward the final victory. This review will summarize the major mechanisms of acquired resistance to EGFR-TKIs, and then discuss the development of rationally designed molecular target drugs in accordance with each mechanism, in the hope of shedding light on the great achievements we have obtained and tough obstacles we have to overcome in the battle against this deadly disease. PMID:25232485

  2. 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

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

    PubMed Central

    2011-01-01

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

  4. Lung Cancer Staging and Prognosis.

    PubMed

    Woodard, Gavitt A; Jones, Kirk D; Jablons, David M

    2016-01-01

    The seventh edition of the non-small cell lung cancer (NSCLC) TNM staging system was developed by the International Association for the Staging of Lung Cancer (IASLC) Lung Cancer Staging Project by a coordinated international effort to develop data-derived TNM classifications with significant survival differences. Based on these TNM groupings, current 5-year survival estimates in NSLCC range from 73 % in stage IA disease to 13 % in stage IV disease. TNM stage remains the most important prognostic factor in predicting recurrence rates and survival times, followed by tumor histologic grade, and patient sex, age, and performance status. Molecular prognostication in lung cancer is an exploding area of research where interest has moved beyond TNM stage and into individualized genetic tumor analysis with immunohistochemistry, microarray, and mutation profiles. However, despite intense research efforts and countless publications, no molecular prognostic marker has been adopted into clinical use since most fail in subsequent cross-validation with few exceptions. The recent interest in immunotherapy for NSCLC has identified new biomarkers with early evidence that suggests that PD-L1 is a predictive marker of a good response to new immunotherapy drugs but a poor prognostic indicator of overall survival. Future prognostication of outcomes in NSCLC will likely be based on a combination of TNM stage and molecular tumor profiling and yield more precise, individualized survival estimates and treatment algorithms. PMID:27535389

  5. Primary Tumor Site as a Predictor of Treatment Outcome for Definitive Radiotherapy of Advanced-Stage Oral Cavity Cancers

    SciTech Connect

    Lin, Chien-Yu; Wang, Hung-Ming; Kang, Chung-Jan; Lee, Li-Yu; Huang, Shiang-Fu; Fan, Kang-Hsing; Chen, Eric Yen-Chao

    2010-11-15

    Purpose: To evaluate the outcome of definitive radiotherapy (RT) for oral cavity cancers and to assess prognostic factors. Methods and Materials: Definitive RT was performed on 115 patients with oral cavity cancers at Stages III, IVA, and IVB, with a distribution of 6%, 47%, and 47%, respectively. The median dose of RT was 72Gy (range, 62-76Gy). Cisplatin-based chemotherapy was administered to 95% of the patients. Eleven patients underwent salvage surgery after RT failure. Results: Eight-eight (76.5%) patients responded partially and 23 (20%) completely; of the patients who responded, 18% and 57%, respectively, experienced a durable effect of treatment. The 3-year overall survival, disease-specific survival, and progression-free survival were 22%, 27%, and 25%, respectively. The 3-year PFS rates based on the primary tumor sites were as follows: Group I (buccal, mouth floor, and gum) 51%, Group II (retromolar and hard palate) 18%, and Group III (tongue and lip) 6% (p < 0.0001). The 3-year progression-free survival was 41% for N0 patients and 19% for patients with N+ disease (p = 0.012). The T stage and RT technique did not affect survival. The patients who underwent salvage surgery demonstrated better 3-year overall survival and disease-specific survival (53% vs. 19%, p = 0.015 and 53% vs. 24%, p = 0.029, respectively). Subsite group, N+, and salvage surgery were the only significant prognostic factors for survival after multivariate analysis. Conclusion: The primary tumor site and neck stage are prognostic predictors in advanced-stage oral cancer patients who received radical RT. The primary tumor extension and RT technique did not influence survival.

  6. Penetration of Recommended Procedures for Lung Cancer Staging and Management in the United States Over 10 Years: A Quality Research in Radiation Oncology Survey

    SciTech Connect

    Komaki, Ritsuko; Khalid, Najma; Langer, Corey J.; Kong, Feng-Ming; Owen, Jean B.; Crozier, Cheryl L.; Wilson, J. Frank; Wei, Xiong; Movsas, Benjamin

    2013-03-15

    Purpose: To document the penetration of clinical trial results, practice guidelines, and appropriateness criteria into national practice, we compared the use of components of staging and treatment for lung cancer among patients treated in 2006-2007 with those used in patients treated in 1998-1999. Methods and Materials: Patient, staging work-up, and treatment characteristics were extracted from the process survey database of the Quality Research in Radiation Oncology (QRRO), consisting of records of 340 patients with locally advanced non-small cell lung cancer (LA-NSCLC) at 44 institutions and of 144 patients with limited-stage small cell lung cancer (LS-SCLC) at 39 institutions. Data were compared for patients treated in 2006-2007 versus those for patients treated in 1998-1999. Results: Use of all recommended procedures for staging and treatment was more common in 2006-2007. Specifically, disease was staged with brain imaging (magnetic resonance imaging or computed tomography) and whole-body imaging (positron emission tomography or bone scanning) in 66% of patients with LA-NSCLC in 2006-2007 (vs 42% in 1998-1999, P=.0001) and in 84% of patients with LS-SCLC in 2006-2007 (vs 58.3% in 1998-1999, P=.0011). Concurrent chemoradiation was used for 77% of LA-NSCLC patients (vs 45% in 1998-1999, P<.0001) and for 90% of LS-SCLC patients (vs 62.5% in 1998-1999, P<.0001). Use of the recommended radiation dose (59-74 Gy for NSCLC and 60-70 Gy as once-daily therapy for SCLC) did not change appreciably, being 88% for NSCLC in both periods and 51% (2006-2007) versus 43% (1998-1999) for SCLC. Twice-daily radiation for SCLC was used for 21% of patients in 2006-2007 versus 8% in 1998-1999. Finally, 49% of patients with LS-SCLC received prophylactic cranial irradiation (PCI) in 2006-2007 (vs 21% in 1998-1999). Conclusions: Although adherence to all quality indicators improved over time, brain imaging and recommended radiation doses for stage III NSCLC were used in <90% of cases. Use

  7. Rocket-Induced Magnetohydrodynamic Ejector: A Single-Stage-to-Orbit Advanced Propulsion Concept

    NASA Technical Reports Server (NTRS)

    Cole, John; Campbell, Jonathan; Robertson, Anthony

    1995-01-01

    During the atmospheric boost phase of a rocket trajectory, magnetohydrodynamic (MHD) principles can be utilized to augment the thrust by several hundred percent without the input of additional energy. The concept is an MHD implementation of a thermodynamic ejector. Some ejector history is described and some test data showing the impressive thrust augmentation capabilities of thermodynamic ejectors are provided. A momentum and energy balance is used to derive the equations to predict the MHD ejector performance. Results of these equations are compared with the test data and then applied to a specific performance example. The rocket-induced MHD ejector (RIME) engine is described and a status of the technology and availability of the engine components is provided. A top level vehicle sizing analysis is performed by scaling existing MHD designs to the required flight vehicle levels. The vehicle can achieve orbit using conservative technology. Modest improvements are suggested using recently developed technologies, such as superconducting magnets, which can improve predicted performance well beyond those expected for current single-stage-to-orbit (SSTO) designs.

  8. Latest research and clinical treatment of advanced-stage epithelial ovarian cancer

    PubMed Central

    Coleman, Robert L.; Monk, Bradley J.; Sood, Anil K.; Herzog, Thomas J.

    2013-01-01

    The natural history of ovarian cancer continues to be characterized by late-stage presentation, metastatic bulky disease burden and stagnant mortality statistics despite prolific drug development. Robust clinical investigation, particularly with modifications to primary treatment surgical goals and adjuvant therapy are increasing median progression-free and overall survival, although the cure rates have only modestly been affected. Maintenance therapy holds promise, but studies have yet to identify an agent and/or strategy that can affect survival. Recurrent disease is largely an incurable state; however, current intervention with selected surgery, combination and targeted therapy and investigational protocols are impacting progression-free survival. Ovarian cancer is a diverse and genomically complex disease, which commands global attention. Rational investigation must balance the high rate of discovery with lagging clinical investigation and limited patient resources. Nevertheless, armamentarium growth offers unprecedented opportunities for patients suffering with this disease. This Review presents and reviews the contemporary management of the disease spectrum termed epithelial ‘ovarian’ cancer and introduces the direction and early results of clinical investigation. PMID:23381004

  9. Trousseau’s syndrome in a patient with advanced stage gastric cancer

    PubMed Central

    Chien, Tai-Long; Rau, Kung-Ming; Chung, Wen-Jung; Tai, Wei-Chen; Wang, Shih-Ho; Chiu, Yi-Chun; Wu, Keng-Liang; Chou, Yeh-Pin; Wu, Chia-Che; Chen, Yen-Hao; Chuah, Seng-Kee

    2015-01-01

    Patients with cancer are at high risk for thrombotic events, which are known collectively as Trousseau’s syndrome. Herein, we report a 66-year-old male patient who was diagnosed with terminal stage gastric cancer and liver metastasis and who had an initial clinical presentation of upper gastrointestinal bleeding. Acute ischemia of the left lower leg that resulted in gangrenous changes occurred during admission. Subsequent angiography of the left lower limb was then performed. This procedure revealed arterial thrombosis of the left common iliac artery with extension to the external iliac artery, the left common iliac artery, the posterior tibial artery, and the peroneal artery, which were occluded by thrombi. Aspiration of the thrombi demonstrated that these were not tumor thrombi. The interesting aspect of our case was that the disease it presented as arterial thrombotic events, which may correlate with gastric adenocarcinoma. In summary, we suggested that the unexplained thrombotic events might be one of the initial presentations of occult malignancy and that thromboprophylaxis should always be considered. PMID:26379411

  10. Advanced transportation system studies technical area 3: Alternate propulsion system concepts. SSME upper stage use

    NASA Technical Reports Server (NTRS)

    Strangeland, Eric; Levak, Daniel

    1993-01-01

    The main objective was to determine viable methods for starting the Space Shuttle Main Engine (SSME) in an altitude environment and restarting it in an orbit environment with minimum changes in utilization of the engine system or hardware. The study concluded that the use of the SSME in an upper stage is feasible with minimal changes to the engine systems. The altitude start case requires only a change in the valve sequencing during start and reorificing of the ASI lines. Inlet pressures can be moderately low at 40 psia for the LOX and 32 psia for the H2. The orbital restart case adds the need to recirculate propellant and thermal control paint (to keep the turbomachinery inlets cold to minimize the tank pressures needed), and the need to heat two small components (to maintain acceptable mixture ratios during the early part of the start). These actions allow start anytime after approximately 120 minutes. Earlier starts (approximately one hour) are also possible but would require additional component heating for mixture ratio control during the early portion of the start sequence.

  11. Regulation of striatal astrocytic receptor for advanced glycation end-products variants in an early stage of experimental Parkinson's disease.

    PubMed

    Viana, Sofia D; Valero, Jorge; Rodrigues-Santos, Paulo; Couceiro, Patrícia; Silva, Andréa M; Carvalho, Félix; Ali, Syed F; Fontes-Ribeiro, Carlos A; Pereira, Frederico C

    2016-08-01

    Convincing evidence indicates that advanced glycation end-products and danger-associated protein S100B play a role in Parkinson's disease (PD). These agents operate through the receptor for advanced glycation end-products (RAGE), which displays distinct isoforms playing protective/deleterious effects. However, the nature of RAGE variants has been overlooked in PD studies. Hence, we attempted to characterize RAGE regulation in early stages of PD striatal pathology. A neurotoxin-based rodent model of PD was used in this study, through administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice. Animals were killed 6 h post-MPTP to assess S100B/RAGE contents (RT-qPCR, ELISA) and RAGE isoform density (WB) and cellular distribution (immunohistochemistry). Dopaminergic and gliotic status were also mapped (HPLC-ED, WB, immunohistochemistry). At this preliminary stage of MPTP-induced PD in mice, RAGE inhibitory isoforms were increased whereas full-length RAGE was not affected. This putative cytoprotective RAGE phenotype paired an inflammatory and pro-oxidant setting fueling DAergic denervation. Increased RAGE inhibitory variants occur in astrocytes showing higher S100B density but no overt signs of hypertrophy or NF-κB activation, a canonical effector of RAGE. These findings expand our understanding of the toxic effect of MPTP on striatum and offer first in vivo evidence of RAGE being a responder in early stages of astrogliosis dynamics, supporting a protective rather tissue-destructive phenotype of RAGE in the initial phase of PD degeneration. These data lay the groundwork for future studies on the relevance of astrocytic RAGE in DAergic neuroprotection strategies. We report increased antagonistic RAGE variants paralleling S100B up-regulation in early stages of MPTP-induced astrogliosis dynamics . We propose that selective RAGE regulation reflects a self-protective mechanism to maintain low levels of RAGE ligands , preventing long

  12. Limited Genomic Heterogeneity of Circulating Melanoma Cells in Advanced Stage Patients

    PubMed Central

    Ruiz, Carmen; Li, Julia; Luttgen, Madelyn S.; Kolatkar, Anand; Kendall, Jude T.; Flores, Edna; Topp, Zheng; Samlowski, Wolfram E.; McClay, Ed; Bethel, Kelly; Ferrone, Soldano; Hicks, James; Kuhn, Peter

    2015-01-01

    Purpose Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design Blood samples from 40 metastatic melanoma patients and 10 normal blood donors (NBD) were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAb) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification (WGA) and copy number variation (CNV) analysis. Results Based on CSPG4 expression and nuclear size, 1 to 250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5 to 371.5 CMCs/ml). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this population may contribute to develop effective therapeutic strategies. PMID:25574741

  13. Limited genomic heterogeneity of circulating melanoma cells in advanced stage patients

    NASA Astrophysics Data System (ADS)

    Ruiz, Carmen; Li, Julia; Luttgen, Madelyn S.; Kolatkar, Anand; Kendall, Jude T.; Flores, Edna; Topp, Zheng; Samlowski, Wolfram E.; McClay, Edward; Bethel, Kelly; Ferrone, Soldano; Hicks, James; Kuhn, Peter

    2015-02-01

    Purpose. Circulating melanoma cells (CMCs) constitute a potentially important representation of time-resolved tumor biology in patients. To date, genomic characterization of CMCs has been limited due to the lack of a robust methodology capable of identifying them in a format suitable for downstream characterization. Here, we have developed a methodology to detect intact CMCs that enables phenotypic, morphometric and genomic analysis at the single cell level. Experimental design. Blood samples from 40 metastatic melanoma patients and 10 normal blood donors were prospectively collected. A panel of 7 chondroitin sulfate proteoglycan 4 (CSPG4)-specific monoclonal antibodies (mAbs) was used to immunocytochemically label CMCs. Detection was performed by automated digital fluorescence microscopy and multi-parametric computational analysis. Individual CMCs were captured by micromanipulation for whole genome amplification and copy number variation (CNV) analysis. Results. Based on CSPG4 expression and nuclear size, 1-250 CMCs were detected in 22 (55%) of 40 metastatic melanoma patients (0.5-371.5 CMCs ml-1). Morphometric analysis revealed that CMCs have a broad spectrum of morphologies and sizes but exhibit a relatively homogeneous nuclear size that was on average 1.5-fold larger than that of surrounding PBMCs. CNV analysis of single CMCs identified deletions of CDKN2A and PTEN, and amplification(s) of TERT, BRAF, KRAS and MDM2. Furthermore, novel chromosomal amplifications in chr12, 17 and 19 were also found. Conclusions. Our findings show that CSPG4 expressing CMCs can be found in the majority of advanced melanoma patients. High content analysis of this cell population may contribute to the design of effective personalized therapies in patients with melanoma.

  14. From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage.

    PubMed

    Mastellos, Dimitrios C; Reis, Edimara S; Yancopoulou, Despina; Hajishengallis, George; Ricklin, Daniel; Lambris, John D

    2016-10-01

    Complement dysregulation is increasingly recognized as an important pathogenic driver in a number of clinical disorders. Complement-triggered pathways intertwine with key inflammatory and tissue destructive processes that can either increase the risk of disease or exacerbate pathology in acute or chronic conditions. The launch of the first complement-targeted drugs in the clinic has undeniably stirred the field of complement therapeutic design, providing new insights into complement's contribution to disease pathogenesis and also helping to leverage a more personalized, comprehensive approach to patient management. In this regard, a rapidly expanding toolbox of complement therapeutics is being developed to address unmet clinical needs in several immune-mediated and inflammatory diseases. Elegant approaches employing both surface-directed and fluid-phase inhibitors have exploited diverse components of the complement cascade as putative points of therapeutic intervention. Targeting C3, the central hub of the system, has proven to be a promising strategy for developing biologics as well as small-molecule inhibitors with clinical potential. Complement modulation at the level of C3 has recently shown promise in preclinical primate models, opening up new avenues for therapeutic intervention in both acute and chronic indications fueled by uncontrolled C3 turnover. This review highlights recent developments in the field of complement therapeutics, focusing on C3-directed inhibitors and alternative pathway (AP) regulator-based approaches. Translational perspectives and considerations are discussed, particularly with regard to the structure-guided drug optimization and clinical advancement of a new generation of C3-targeted peptidic inhibitors. PMID:27353192

  15. Initial Staging of Locally Advanced Rectal Cancer and Regional Lymph Nodes

    PubMed Central

    Cerny, Milena; Dunet, Vincent; Prior, John Olivier; Hahnloser, Dieter; Wagner, Anna Dorothea; Meuli, Reto Antoine; Schmidt, Sabine

    2016-01-01

    Purpose The aim of the study was to compare diffusion-weighted MRI (DW-MRI) parameters with 18F-FDG PET/CT in primary locally advanced rectal cancer (LARC). Methods From October 2012 to September 2014, 24 patients with histologically confirmed and untreated LARC (T3–T4) prospectively underwent a pelvic 1.5-T DW-MRI (b = 0 s/mm2, b = 600 s/mm2) and a whole-body 18F-FDG PET/CT, before neoadjuvant therapy. The 2 examinations were performed on the same day. Two readers measured 18F-FDG SUVmax and SUVmean of the rectal tumor and of the pathological regional lymph nodes on PET/CT and compared these with minimum and mean values of the ADC (ADCmin and ADCmean) on maps generated from DW-MRI. The diagnostic performance of ADC values in identifying pathological lymph nodes was also assessed. Results Regarding tumors (n = 24), we found a significant negative correlation between SUVmean and corresponding ADCmean values (ρ = −0.61, P = 0.0017) and between ADCmin and SUVmax (ρ = −0.66, P = 0.0005). Regarding the lymph nodes (n = 63), there was a significant negative correlation between ADCmean and SUVmean values (ρ = −0.38, P = 0.0021), but not between ADCmin and SUVmax values (ρ = −0.11, P = 0.41). Neither ADCmean nor ADCmin values helped distinguish pathological from benign lymph nodes (AUC of 0.24 [confidence interval, 0.10–0.38] and 0.41 [confidence interval, 0.22–0.60], respectively). Conclusions The correlations between ADCmean and SUVmean suggest an association between tumor cellularity and metabolic activity in untreated LARC and in regional lymph nodes. However, compared with 18F-FDG PET/CT, ADC values are not reliable for identifying pathological lymph nodes. PMID:26828149

  16. 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.

  17. Understanding the Racial and Ethnic Differences in Cost and Mortality Among Advanced Stage Prostate Cancer Patients (STROBE).

    PubMed

    Chhatre, Sumedha; Bruce Malkowicz, Stanley; Sanford Schwartz, J; Jayadevappa, Ravishankar

    2015-08-01

    The aims of the study were to understand the racial/ethnic differences in cost of care and mortality in Medicare elderly with advanced stage prostate cancer.This retrospective, observational study used SEER-Medicare data. Cohort consisted of 10,509 men aged 66 or older and diagnosed with advanced-stage prostate cancer between 2001and 2004. The cohort was followed retrospectively up to 2009. Racial/ethnic variation in cost was analyzed using 2 part-models and quantile regression. Step-wise GLM log-link and Cox regression was used to study the association between race/ethnicity and cost and mortality. Propensity score approach was used to minimize selection bias.Pattern of cost and mortality varies between racial/ethnic groups. Compared with other racial/ethnic groups, non-Hispanic white patients had higher unadjusted costs in treatment and follow-up phases. Quintile regression results indicated that in treatment phase, Hispanics had higher costs in the 95th quantile and non-Hispanic blacks had lower cost in the 95th quantile, compared with non-Hispanic white men. In terminal phase non-Hispanic blacks and Hispanics had higher cost. After controlling for treatment, all-cause and prostate cancer-specific mortality was not significant for non-Hispanic black men, compared with non-Hispanic white men. However, for Asians, mortality remained significantly lower compared with non-Hispanic white men.In conclusion, relationship between race/ethnicity, cost of care, and mortality is intricate. For non-Hispanic black men, disparity in mortality can be attributed to treatment differences. To reduce racial/ethnic disparities in prostate cancer care and outcomes, tailored policies to address underuse, overuse, and misuse of treatment and health services are necessary. PMID:26266389

  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. PMID:27042875

  19. A Population-Based Comparative Effectiveness Study of Radiation Therapy Techniques in Stage III Non-Small Cell Lung Cancer

    SciTech Connect

    Harris, Jeremy P.; Murphy, James D.; Hanlon, Alexandra L.; Le, Quynh-Thu; Loo, Billy W.; Diehn, Maximilian

    2014-03-15

    Purpose: Concerns have been raised about the potential for worse treatment outcomes because of dosimetric inaccuracies related to tumor motion and increased toxicity caused by the spread of low-dose radiation to normal tissues in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy (IMRT). We therefore performed a population-based comparative effectiveness analysis of IMRT, conventional 3-dimensional conformal radiation therapy (3D-CRT), and 2-dimensional radiation therapy (2D-RT) in stage III NSCLC. Methods and Materials: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify a cohort of patients diagnosed with stage III NSCLC from 2002 to 2009 treated with IMRT, 3D-CRT, or 2D-RT. Using Cox regression and propensity score matching, we compared survival and toxicities of these treatments. Results: The proportion of patients treated with IMRT increased from 2% in 2002 to 25% in 2009, and the use of 2D-RT decreased from 32% to 3%. In univariate analysis, IMRT was associated with improved overall survival (OS) (hazard ratio [HR] 0.90, P=.02) and cancer-specific survival (CSS) (HR 0.89, P=.02). After controlling for confounders, IMRT was associated with similar OS (HR 0.94, P=.23) and CSS (HR 0.94, P=.28) compared with 3D-CRT. Both techniques had superior OS compared with 2D-RT. IMRT was associated with similar toxicity risks on multivariate analysis compared with 3D-CRT. Propensity score matched model results were similar to those from adjusted models. Conclusions: In this population-based analysis, IMRT for stage III NSCLC was associated with similar OS and CSS and maintained similar toxicity risks compared with 3D-CRT.

  20. Sulfur removal in advanced two stage pressurized fluidized bed combustion. Technical report, March 1--May 31, 1995

    SciTech Connect

    Abbasian, J.

    1995-12-31

    The objective of this study is to obtain data on the rates and the extent of sulfation reactions involving partially sulfided calcium-based sorbents, and oxygen as well as sulfur dioxide, at operating conditions closely simulating those prevailing in the second stage (combustor) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors. In these systems the CO{sub 2} partial pressure generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, calcium sulfate is produced through the reactions between SO{sub 2} and calcium carbonate as well as the reaction between calcium sulfide and oxygen. To achieve this objective, the rates of reaction involving SO{sub 2} and oxygen, calcium sulfide and calcium carbonate will be determined by conducting tests in a pressurized thermogravimetric analyzer unit. The sulfate tests conducted during this quarter, focused on the determination of the rate of sulfation reaction involving partially sulfided half-calcined dolomite and oxygen. The test parameters included CO{sub 2} and O{sub 2} concentrations, reaction temperature and pressure, as well as the sorbent particle size. The results obtained during this quarter suggest that the rate of sulfation reaction involving partially sulfided half-calcined dolomite and oxygen is very fast at temperatures above 850 C which rapidly increases with increasing temperature, achieving more than 85% conversion in less than a few minutes. The reaction appears to continue to completion, however, above 85% conversion, the rate of reaction appears to be low, requiring long residence time to reach complete conversion.

  1. Sulfur removal in advanced two stage pressurized fluidized bed combustion. Technical report, December 1, 1994--February 28, 1995

    SciTech Connect

    Abbasian, J.

    1996-03-01

    The objective of this study is to obtain data on the rates and the extent of sulfation reactions involving partially sulfided calcium-based sorbents, and oxygen as well as sulfur dioxide, at operating conditions closely simulating those prevailing in the second stage (combustor) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors (PFBC). In these systems the CO{sub 2} partial pressure generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, calcium sulfate is produced through the reactions between SO{sub 2} and calcium carbonate as well as the reaction between calcium sulfide and oxygen. To achieve this objective, the rates of reaction involving SO{sub 2} and oxygen (gaseous reactant); and calcium sulfide and calcium carbonate (solid reactants), will be determined by conducting tests in a pressurized thermogravimetric analyzer (HPTGA) unit. The effects of sorbent type, sorbent particle size, reactor temperature and pressure; and O{sub 2} as well as SO{sub 2} partial pressures on the sulfation reactions rate will be determined. During this quarter, samples of the selected limestone and dolomite, sulfided in the fluidized-bed reactor during last quarter, were analyzed. The extent of sulfidation in these samples was in the range of 20 to 50%, which represent carbonizer discharge material at different operating conditions. The high pressure thermogravimetric analyzer (BPTGA) unit has been modified and a new pressure control system was installed to eliminate pressure fluctuation during the sulfation tests.

  2. Sulfur removal in advanced two stage pressurized fluidized bed combustion. Technical report, September 1--November 30, 1994

    SciTech Connect

    Abbasian, J.; Hill, A.; Wangerow, J.R.

    1994-12-31

    The objective of this study is to obtain data on the rates and the extent of sulfation reactions involving partially sulfided calcium-based sorbents, and oxygen as well as sulfur dioxide, at operating conditions closely simulating those prevailing in the second stage (combustor) of Advanced Two-Stage Pressurized Fluidized-Bed Combustors (PFBC). In these systems the CO{sub 2} partial pressure generally exceeds the equilibrium value for calcium carbonate decomposition. Therefore, calcium sulfate is produced through the reactions between SO{sub 2} and calcium carbonate as well as the reaction between calcium sulfide and oxygen. To achieve this objective, the rates of reaction involving SO{sub 2} and oxygen (gaseous reactant); and calcium sulfide and calcium carbonate (solid reactants), will be determined by conducting tests in a pressurized thermogravimetric analyzer (HPTGA) unit. The effects of sorbent type, sorbent particle size, reactor temperature and pressure; and O{sub 2} as well as SO{sub 2} partial pressures on the sulfation reactions rate will be determined. During this quarter, samples of the selected limestone and dolomite were sulfided in the fluidized-bed reactor. These tests were conducted in both calcining and non-calcining operating conditions to produce partially-sulfided sorbents containing calcium oxide and calcium carbonate, respectively. These samples which represent the carbonizer discharge material, will be used as the feed material in the sulfation tests to be conducted in the HPTGA unit during the next quarter.

  3. Endoscopic ultrasound for the characterization and staging of rectal cancer. Current state of the method. Technological advances and perspectives.

    PubMed

    Gersak, Mariana M; Badea, Radu; Graur, Florin; Hajja, Nadim Al; Furcea, Luminita; Dudea, Sorin M

    2015-06-01

    Endoscopic ultrasound is the most accurate type of examination for the assessment of rectal tumors. Over the years, the method has advanced from gray-scale examination to intravenous contrast media administration and to different types of elastography. The multimodal approach of tumors (transrectal, transvaginal) is adapted to each case. 3D ultrasound is useful for spatial representation and precise measurement of tumor formations, using CT/MR image reconstruction; color elastography is useful for tumor characterization and staging; endoscopic ultrasound using intravenous contrast agents can help study the amount of contrast agent targeted at the level of the tumor formations and contrast wash-in/wash-out time, based on the curves displayed on the device. The transvaginal approach often allows better visualization of the tumor than the transrectal approach. Performing the procedure with the rectal ampulla distended with contrast agent may be seen as an optimization of the examination methodology. All these aspects are additional methods for gray-scale endoscopic ultrasound, capable of increasing diagnostic accuracy. This paper aims at reviewing the progress of transrectal and transvaginal ultrasound, generically called endoscopic ultrasound, for rectal tumor diagnosis and staging, with emphasis on the current state of the method and its development trends. PMID:26052575

  4. Results of Two-Stage Light-Gas Gun Development Efforts and Hypervelocity Impact Tests of Advanced Thermal Protection Materials

    NASA Technical Reports Server (NTRS)

    Cornelison, C. J.; Watts, Eric T.

    1998-01-01

    Gun development efforts to increase the launching capabilities of the NASA Ames 0.5-inch two-stage light-gas gun have been investigated. A gun performance simulation code was used to guide initial parametric variations and hardware modifications, in order to increase the projectile impact velocity capability to 8 km/s, while maintaining acceptable levels of gun barrel erosion and gun component stresses. Concurrent with this facility development effort, a hypervelocity impact testing series in support of the X-33/RLV program was performed in collaboration with Rockwell International. Specifically, advanced thermal protection system materials were impacted with aluminum spheres to simulate impacts with on-orbit space debris. Materials tested included AETB-8, AETB-12, AETB-20, and SIRCA-25 tiles, tailorable advanced blanket insulation (TABI), and high temperature AFRSI (HTA). The ballistic limit for several Thermal Protection System (TPS) configurations was investigated to determine particle sizes which cause threshold TPS/structure penetration. Crater depth in tiles was measured as a function of impact particle size. The relationship between coating type and crater morphology was also explored. Data obtained during this test series was used to perform a preliminary analysis of the risks to a typical orbital vehicle from the meteoroid and space debris environment.

  5. Same Chemotherapy Regimen Leads to Different Myelotoxicity in Different Malignancies: A Comparison of Chemotherapy-Associated Myelotoxicity in Patients With Advanced Ovarian and Non-Small-Cell Lung Cancer.

    PubMed

    Tas, Faruk; Yildiz, Ibrahim; Kilic, Leyla; Ciftci, Rumeysa; Keskin, Serkan; Sen, Fatma

    2016-01-01

    Carboplatin-paclitaxel chemotherapy combination is the standard first-line treatment of advanced ovarian cancer and is the most commonly used treatment combination shown to be effective in advanced non-small-cell lung cancer (NSCLC). The most important dose-limiting side effect is hematologic toxicity. In this study, the severity of treatment-related myelotoxicity is compared in patients with advanced ovarian and lung cancers who received same schedule of carboplatin-paclitaxel. The study was prospectively performed from February 2009 to July 2011 and involved 103 patients with stages Ic-IV ovarian (n = 51) and advanced NSCLC (n = 52) who were administered a maximum of 6 cycles of carboplatin-paclitaxel as a first-line treatment. Full blood counts were measured before treatment, before each chemotherapy cycle during therapy, and at the first and sixth month after therapy. The median ages were 59 years (range, 35-77 years) for patients with NSCLC and 56 years (range, 38-75 years) for patients with ovarian cancer. The frequencies of anemia were 17% and 28.6% before the initiation of chemotherapy, 39.2% and 68.0% at the third cycle of treatment, and 44.2% and 45.2% at the sixth cycle of treatment in patients with NSCLC and ovarian cancer, respectively. Initial leukopenia rates were 3.4% and 0%; at the third cycle 46.0% and 41.2%; and at the sixth cycle 41.9% and 48.8% in patients with NSCLC and ovarian cancer, respectively. At the third cycle, 2.5% of the patients with NSCLC and 10.4% of the patients with ovarian cancer had thrombocytopenia, and at the sixth cycle, 23.3% of the patients with NSCLC and 25% of the patients with ovarian cancer had thrombocytopenia. Hemoglobin, leukocyte, and platelet values at the third cycle were significantly lower than those at admission in both cancer groups. Declines in hemoglobin levels in patients with NSCLC and in platelets in patients with ovarian cancer at the sixth cycle were statistically significant compared with the third

  6. Circulating Tumor DNA Detection in Early-Stage Non-Small Cell Lung Cancer Patients by Targeted Sequencing

    PubMed Central

    Chen, Ke-Zhong; Lou, Feng; Yang, Fan; Zhang, Jing-Bo; Ye, Hua; Chen, Wei; Guan, Tian; Zhao, Ming-Yu; Su, Xue-Xia; Shi, Rong; Jones, Lindsey; Huang, Xue F.; Chen, Si-Yi; Wang, Jun

    2016-01-01

    Circulating tumor DNA (ctDNA) isolated from peripheral blood has recently been shown to be an alternative source to detect gene mutations in primary tumors; however, most previous studies have focused on advanced stage cancers, and few have evaluated ctDNA detection in early-stage lung cancer. In the present study, blood and tumor samples were collected prospectively from 58 early-stage non-small lung cancer (NSCLC) patients (stages IA, IB, and IIA) and a targeted sequencing approach was used to detect somatic driver mutations in matched tumor DNA (tDNA) and plasma ctDNA. We identified frequent driver mutations in plasma ctDNA and tDNA in EGFR, KRAS, PIK3CA, and TP53, and less frequent mutations in other genes, with an overall study concordance of 50.4% and sensitivity and specificity of 53.8% and 47.3%, respectively. Cell-free (cfDNA) concentrations were found to be significantly associated with some clinical features, including tumor stage and subtype. Importantly, the presence of cfDNA had a higher positive predictive value than that of currently used protein tumor biomarkers. This study demonstrates the feasibility of identifying plasma ctDNA mutations in the earliest stage lung cancer patients via targeted sequencing, demonstrating a potential utility of targeted sequencing of ctDNA in the clinical management of NSCLC. PMID:27555497

  7. Combined therapy with thrombospondin-1 type I repeats (3TSR) and chemotherapy induces regression and significantly improves survival in a preclinical model of advanced stage epithelial ovarian cancer

    PubMed Central

    Russell, Samantha; Duquette, Mark; Liu, Joyce; Drapkin, Ronny; Lawler, Jack; Petrik, Jim

    2015-01-01

    Most women are diagnosed with epithelial ovarian cancer (EOC) at advanced stage, where therapies have limited effectiveness and the long-term survival rate is low. We evaluated the effects of combined antiangiogenic and chemotherapy treatments on advanced stage EOC. Treatment of EOC cells with a recombinant version of the thrombospondin-1 type I repeats (3TSR) induced more apoptotic cell death (36.5 ± 9.6%) in vitro compared to untreated controls (4.1 ± 1.4). In vivo, tumors were induced in an orthotopic, syngeneic mouse model of advanced stage EOC. Mice were treated with 3TSR (4 mg/kg per day) alone or in combination with chemotherapy drugs delivered with maximum tolerated dose or metronomic scheduling. Pretreatment with 3TSR induced tumor regression, normalized tumor vasculature, and improved uptake of chemotherapy drugs. Combination 3TSR and metronomic chemotherapy induced the greatest tumor regression (6.2-fold reduction in size compared to PBS-treated controls) and highest survival when treatment was initiated at advanced stage. 3TSR binding to its receptor, CD36 (cluster of differentiation 36), increased binding of CD36 and SHP-1, which significantly inhibited phosphorylation of the VEGF receptor. In this study, we describe a novel treatment approach and mechanism of action with 3TSR and chemotherapy that induces regression of advanced stage EOC and significantly improves survival.—Russell, S., Duquette, M., Liu, J., Drapkin, R., Lawler, J., Petrik, J. Combined therapy with thrombospondin-1 type I repeats (3TSR) and chemotherapy induces regression and significantly improves survival in a preclinical model of advanced stage epithelial ovarian cancer. PMID:25395453

  8. Bioinformatics Analysis Reveals Distinct Molecular Characteristics of Hepatitis B-Related Hepatocellular Carcinomas from Very Early to Advanced Barcelona Clinic Liver Cancer Stages

    PubMed Central

    Hu, Wei; Kou, Yan-Bo; You, Hong-Juan; Liu, Xiao-Mei; Zheng, Kui-Yang; Tang, Ren-Xian

    2016-01-01

    Hepatocellular carcinoma (HCC)is the fifth most common malignancy associated with high mortality. One of the risk factors for HCC is chronic hepatitis B virus (HBV) infection. The treatment strategy for the disease is dependent on the stage of HCC, and the Barcelona clinic liver cancer (BCLC) staging system is used in most HCC cases. However, the molecular characteristics of HBV-related HCC in different BCLC stages are still unknown. Using GSE14520 microarray data from HBV-related HCC cases with BCLC stages from 0 (very early stage) to C (advanced stage) in the gene expression omnibus (GEO) database, differentially expressed genes (DEGs), including common DEGs and unique DEGs in different BCLC stages, were identified. These DEGs were located on different chromosomes. The molecular functions and biology pathways of DEGs were identified by gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and the interactome networks of DEGs were constructed using the NetVenn online tool. The results revealed that both common DEGs and stage-specific DEGs were associated with various molecular functions and were involved in special biological pathways. In addition, several hub genes were found in the interactome networks of DEGs. The identified DEGs and hub genes promote our understanding of the molecular mechanisms underlying the development of HBV-related HCC through the different BCLC stages, and might be used as staging biomarkers or molecular targets for the treatment of HCC with HBV infection. PMID:27454179

  9. Tail-flick test response in 3×Tg-AD mice at early and advanced stages of disease.

    PubMed

    Baeta-Corral, Raquel; Defrin, Ruti; Pick, Chagi G; Giménez-Llort, Lydia

    2015-07-23

    Despite the impact of pain in cognitive dysfunctions and affective disorders has been largely studied, the research that examines pain dimensions in cognitive impairment or dementia is still scarce. In patients with Alzheimer's disease (AD) and related dementias, management of pain is challenging. While the sensory-discriminative dimension of pain is preserved, the cognitive-evaluative and the affective-motivational pain dimensions are affected. Due to the complexity of the disease and the poor self-reports, pain is underdiagnosed and undertreated. In confluence with an impaired thermoregulatory behavior, the patients' ability to confront environmental stressors such as cold temperature can put them at risk of fatal accidental hypothermia. Here, 3xTg-AD mice demonstrate that the sensorial-discriminative threshold to a noxious cold stimulus, as measured by the latency of tail-flicking, was preserved at early and advances stages of disease (7 and 11 month-old, respectively) as compared to age-matched (adulthood and middle aged, respectively) non-transgenic mice (NTg). In both genotypes, the sensory deterioration and poor thermoregulatory behavior associated to age was observed as an increase of tail-flick response and poor sensorimotor performance. At both stages studied, 3xTg-AD mice exhibited BPSD (Behavioral and Psychological Symptoms of Dementia)-like alterations in the corner, open-field, dark-light box and the T-maze tests. In the adult NTg mice, this nociceptive withdrawal response was correlated with copying with stress-related behaviors. This integrative behavioral profile was lost in both groups of 3xTg-AD mice and middle aged controls, suggesting derangements in their subjacent networks and the complex interplay between the pain dimensions in the elderly with dementia. PMID:26091881

  10. The Minority Report: Targeting the Rare Oncogenes in NSCLC

    PubMed Central

    McCoach, Caroline E.

    2014-01-01

    Lung cancer is still responsible for the highest number of cancer deaths worldwide. Despite this fact, significant progress has been made in the treatment of non-small cell lung cancer (NSCLC). Specifically, efforts to identify and treat genetic alterations (gene mutations, gene fusions, gene amplification events, etc.) that result in oncogenic drivers are now standard of care (EGFR and ALK) or an intense area of research. The most prevalent oncogenic drivers have likely already been identified; thus, there is now a focus on subgroups of tumors with less common genetic alterations. Interestingly, as we explore these less common mutations, we are discovering that many occur across other tumor types (i.e., non-lung cancer), further justifying their study. Furthermore, many studies have demonstrated that by searching broadly for multiple genetic alterations in large subsets of patients they are able to identify potentially targetable alterations in the majority of patients. Although individually, the rare oncogenic drivers subgroups may seem to occur too infrequently to justify their exploration, the fact that the majority of patients with NSCLC harbor a potentially actionable driver mutation within their tumors and the fact that different types of cancers often have the same oncogenic driver justifies this approach. PMID:25228144

  11. 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.

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

    PubMed

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

    2012-05-01

    Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC. PMID:22117197

  13. Stage-by-Stage and Parallel Flow Path Compressor Modeling for a Variable Cycle Engine, NASA Advanced Air Vehicles Program - Commercial Supersonic Technology Project - AeroServoElasticity

    NASA Technical Reports Server (NTRS)

    Kopasakis, George; Connolly, Joseph W.; Cheng, Larry

    2015-01-01

    This paper covers the development of stage-by-stage and parallel flow path compressor modeling approaches for a Variable Cycle Engine. The stage-by-stage compressor modeling approach is an extension of a technique for lumped volume dynamics and performance characteristic modeling. It was developed to improve the accuracy of axial compressor dynamics over lumped volume dynamics modeling. The stage-by-stage compressor model presented here is formulated into a parallel flow path model that includes both axial and rotational dynamics. This is done to enable the study of compressor and propulsion system dynamic performance under flow distortion conditions. The approaches utilized here are generic and should be applicable for the modeling of any axial flow compressor design accurate time domain simulations. The objective of this work is as follows. Given the parameters describing the conditions of atmospheric disturbances, and utilizing the derived formulations, directly compute the transfer function poles and zeros describing these disturbances for acoustic velocity, temperature, pressure, and density. Time domain simulations of representative atmospheric turbulence can then be developed by utilizing these computed transfer functions together with the disturbance frequencies of interest.

  14. Phase II Trial of Combined Modality Therapy With Concurrent Topotecan Plus Radiotherapy Followed by Consolidation Chemotherapy for Unresectable Stage III and Selected Stage IV Non-Small-Lung Cancer

    SciTech Connect

    Seung, Steven K. Ross, Helen J.

    2009-03-01

    Purpose: The optimal combination of chemotherapy and radiotherapy (RT) and the role of consolidation chemotherapy in patients with locally advanced non-small-cell lung cancer (NSCLC) are unknown. Topotecan is active against NSCLC, can safely be combined with RT at effective systemic doses, and can be given by continuous infusion, making it an attractive study agent against locally advanced NSCLC. Methods and Materials: In this pilot study, 20 patients were treated with infusion topotecan 0.4 mg/m{sup 2}/d with three-dimensional conformal RT to 63 Gy both delivered Monday through Friday for 7 weeks. Patients without progression underwent consolidation chemotherapy with etoposide and a platinum agent for one cycle followed by two cycles of docetaxel. The study endpoints were treatment response, time to progression, survival, and toxicity. Results: Of the 20 patients, 19 completed induction chemoradiotherapy and 13 completed consolidation. Of the 20 patients, 18 had a partial response and 1 had stable disease after induction chemoradiotherapy. The 3-year overall survival rate was 32% (median, 18 months). The local and distant progression-free survival rate was 30% (median, 21 months) and 58% (median, not reached), respectively. Three patients developed central nervous system metastases, 1 within 228 days, 1 within 252 days, and 1 within 588 days. Three patients had pulmonary emboli. Therapy was well tolerated with 1 of 20 developing Grade 4 lymphopenia. Grade 3 hematologic toxicity was seen in 17 of 20 patients but was not clinically significant. Other Grade 3 toxicities included esophagitis in 3, esophageal stricture in 2, fatigue in 8, and weight loss in 1. Grade 3 pneumonitis occurred in 6 of 20 patients. Conclusion: Continuous infusion topotecan with RT was well tolerated and active in the treatment of poor-risk patients with unresectable Stage III NSCLC.

  15. 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

  16. Report From the International Atomic Energy Agency (IAEA) Consultants' Meeting on Elective Nodal Irradiation in Lung Cancer: Non-Small-Cell Lung Cancer (NSCLC)

    SciTech Connect

    Belderbos, Jose; Martel, Mary K.; Videtic, Gregory; Jeremic, Branislav

    2008-10-01

    Lymphatic spread is an important pathway of progression in non-small-cell lung cancer (NSCLC), along with local spread and distant metastasis. The probability of lymph node (LN) involvement is dependent on the site of the primary tumor, stage, and histology. Elective nodal irradiation (ENI) is the irradiation of clinical and radiological uninvolved LN to account for microscopic tumor invasion in these LNs because we have not been able to determine the extent of LN spread accurately. The clinical value of ENI is uncertain. The impact of ENI is dependent on many (staging-, treatment-, and patient-related) factors. The purpose of this report is to analyze the current status of ENI and to provide comprehensive in-depth analysis and guidance on how to generally approach this issue in NSCLC.

  17. Design and overall performance of four highly loaded, high speed inlet stages for an advanced high-pressure-ratio core compressor

    NASA Technical Reports Server (NTRS)

    Reid, L.; Moore, R. D.

    1978-01-01

    The detailed design and overall performances of four inlet stages for an advanced core compressor are presented. These four stages represent two levels of design total pressure ratio (1.82 and 2.05), two levels of rotor aspect ratio (1.19 and 1.63), and two levels of stator aspect ratio (1.26 and 1.78). The individual stages were tested over the stable operating flow range at 70, 90, and 100 percent of design speeds. The performances of the low aspect ratio configurations were substantially better than those of the high aspect ratio configurations. The two low aspect ratio configurations achieved peak efficiencies of 0.876 and 0.872 and corresponding stage efficiencies of 0.845 and 0.840. The high aspect ratio configurations achieved peak ratio efficiencies of 0.851 and 0.849 and corresponding stage efficiencies of 0.821 and 0.831.

  18. Results of an Advanced Fan Stage Operating Over a Wide Range of Speed and Bypass Ratio. Part 1; Fan Stage Design and Experimental Results

    NASA Technical Reports Server (NTRS)

    Suder, Kenneth L.; Prahst, Patricia S.; Thorp, Scott A.

    2011-01-01

    NASA s Fundamental Aeronautics Program is investigating turbine-based combined cycle (TBCC) propulsion systems for access to space because it provides the potential for aircraft-like, space-launch operations that may significantly reduce launch costs and improve safety. To this end, National Aeronautics and Space Administration (NASA) and General Electric (GE) teamed to design a Mach 4 variable cycle turbofan/ramjet engine for access to space. To enable the wide operating range of a Mach 4+ variable cycle turbofan ramjet required the development of a unique fan stage design capable of multi-point operation to accommodate variations in bypass ratio (10 ), fan speed (7 ), inlet mass flow (3.5 ), inlet pressure (8 ), and inlet temperature (3 ). In this paper, NASA has set out to characterize a TBCC engine fan stage aerodynamic performance and stability limits over a wide operating range including power-on and hypersonic-unique "windmill" operation. Herein, we will present the fan stage design, and the experimental test results of the fan stage operating from 15 to 100 percent corrected design speed. Whereas, in the companion paper, we will provide an assessment of NASA s APNASA code s ability to predict the fan stage performance and operability over a wide range of speed and bypass ratio.

  19. Cachexia Index in Advanced Non-Small-Cell Lung Cancer Patients

    PubMed Central

    Jafri, Syed Hasan Raza; Previgliano, Carlos; Khandelwal, Keerti; Shi, Runhua

    2015-01-01

    INTRODUCTION Cancer cachexia affects many advanced non-small-cell lung cancer (NSCLC) patients. Cachexia index (CXI) was developed to assess the degree of cachexia in these patients. METHODS Patients with metastatic NSCLC diagnosed between January 1, 2000, and June 30, 2011, at our institution were retrospectively studied. Abdominal computed tomography scans done within 1 month of diagnosis were reviewed to estimate skeletal muscle area (SMA) and skeletal muscle index (SMI) at the L3 level. CXI was developed as follows: CXI=SMI×AlbNLR where SMI is the skeletal muscle index, Alb is the serum albumin, and NLR is the neutrophil-to-lymphocyte ratio. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Survival among various factors was calculated using the log-rank test. Multivariate Cox regression was used to perform survival analysis in order to estimate the effects of various factors. RESULTS Patients were divided into two groups around the median into stage I cachexia (CXI ≥35, n = 56) and stage II cachexia (CXI <35, n = 56). Groups did not differ in age, gender, ethnicity, or histology of cancer. Patients with stage II cachexia had significantly worse PFS (2.45 vs 5.43 months, P < 0.0001) and OS (3.45 vs 8.8 months, P = 0.0001) than those with stage I cachexia. On multivariate analysis adjusting for gender, race, and histology, patients with stage II cachexia were found to have worse PFS (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.27–2.95) and OS (HR 1.53, 95% CI 1.0009–2.34). CONCLUSION The CXI is a novel index for estimating cachexia that also correlates with prognosis in both men and women with advanced NSCLC. PMID:26604850

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

    PubMed Central

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

    2015-01-01

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

  1. Differences in the efficacy of S-1 monotherapy according to histological type in pretreated patients with advanced non-small cell lung cancer

    PubMed Central

    Hisamatsu, Yasushi; Murakami, Haruyasu; Akamatsu, Hiroaki; Kimura, Madoka; Mori, Keita; Imai, Hisao; Ono, Akira; Shukuya, Takehito; Taira, Tetsuhiko; Kenmotsu, Hirotsugu; Naito, Tateaki; Endo, Masahiro; Nakajima, Takashi; Takahashi, Toshiaki; Yamamoto, Nobuyuki

    2014-01-01

    Background S-1 is a novel antimetabolic agent that inhibits thymidylate synthase. The expression of thymidylate synthase is higher in squamous (Sq) non-small cell lung cancer (NSCLC) than in non-Sq NSCLC. The aim of this retrospective study was to assess the efficacy of S-1 monotherapy for advanced NSCLC according to the histological subtype. Methods We reviewed the clinical records of patients with advanced NSCLC treated with S-1 monotherapy as second- or third-line therapy between May 2005 and July 2012 at the Shizuoka Cancer Center. Results A total of 71 patients were included in this retrospective study. Patient characteristics were similar in the Sq NSCLC (n = 15) and non-Sq NSCLC (n = 56) groups, except with regard to gender and smoking status. The overall response rates were 0% (95% confidence interval [CI] 0–17%) for Sq NSCLC and 11% (95% CI 3–19%) for non-Sq NSCLC (P = 0.33). For Sq NSCLC and non-Sq NSCLC, the median progression-free survival times were 2.1 and 2.8 months (P = 0.02), respectively, and the median overall survival times were 6.1 and 10.1 months (P = 0.01), respectively. Conclusion S-1 monotherapy may be more effective in patients with non-Sq NSCLC than in those with Sq NSCLC. PMID:26766988

  2. A Multi-institutional Investigation of the Prognostic Value of Lymph Nodal Yield in Advanced Stage Oral Cavity Squamous Cell Carcinoma (OCSCC)

    PubMed Central

    Jaber, James J.; Zender, Chad A.; Mehta, Vikas; Davis, Kara; Ferris, Robert L.; Lavertu, Pierre; Rezaee, Rod; Feustel, Paul J.

    2014-01-01

    Background Although existing literature provides surgical recommendations for treating occult disease (cN0) in early stage oral cavity squamous cell carcinoma, a focus on late stage OCSCC is less pervasive. Methods The records of 162 late stage OCSCC pN0 individuals that underwent primary neck dissections were reviewed. Lymph node yield (LNY) as a prognosticator was examined. Results Despite being staged pN0, patients that had a higher LNY had an improved regional/distant control rates, DFS, DSS, and OS. LNY consistently outperformed all other standard variables as being the single best prognostic factor with a tight risk ratio range (RR = 0.95–0.98) even when correcting for the number of lymph nodes examined. Conclusion The results of this study showed that lower regional recurrence rates and improved survival outcomes were seen as lymph node yield increased for advanced T-stage OCSCC pN0. This suggests that increasing lymph node yield with an extended cervical lymphadenectomy may result in lower recurrence rates and improved survival outcomes for this advanced stage group. PMID:24038739

  3. 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

  4. High expression of CAI2, a 9p21-embedded long non-coding RNA, contributes to advanced stage neuroblastoma

    PubMed Central

    Barnhill, Lisa M.; Williams, Richard T.; Cohen, Olga; Kim, Youngjin; Batova, Ayse; Mielke, Jenna A.; Messer, Karen; Pu, Minya; Bao, Lei; Yu, Alice L.; Diccianni, Mitchell B.

    2014-01-01

    Neuroblastoma is a pediatric cancer with significant genomic and biological heterogeneity. p16 and ARF, two important tumor suppressor genes on chromosome 9p21, are inactivated commonly in most cancers but paradoxically overexpressed in neuroblastoma. Here we report that exon γ in p16 is also part of an undescribed long non-coding RNA (lncRNA) that we have termed CAI2 (CDKN2A/ARF Intron 2 lncRNA). CAI2 is a single exon gene with a poly A signal located in but independent of the p16/ARF exon 3. CAI2 is expressed at very low levels in normal tissue but is highly expressed in most tumor cell lines with an intact 9p21 locus. Concordant expression of CAI2 with p16 and ARF in normal tissue along with the ability of CAI2 to induce p16 expression suggested that CAI2 may regulate p16 and/or ARF. In neuroblastoma cells transformed by serial passage in vitro, leading to more rapid proliferation, CAI2, p16 and ARF expression all increased dramatically. A similar relationship was also observed in primary neuroblastomas where CAI2 expression was significantly higher in advanced stage neuroblastoma, independently of MYCN amplification. Consistent with its association with high risk disease, CAI2 expression was also significantly associated with poor clinical outcomes, although this effect was reduced when adjusted for MYCN amplification. Taken together, our findings suggested that CAI2 contributes to the paradoxical overexpression of p16 in neuroblastoma, where CAI2 may offer a useful biomarker of high-risk disease. PMID:25028366

  5. Progenitor Hematopoietic Cells Implantation Improves Functional Capacity of End Stage Coronary Artery Disease Patients with Advanced Heart Failure

    PubMed Central

    Yuniadi, Yoga; Kusnadi, Yuyus; Sandhow, Lakshmi; Erika, Rendra; Hanafy, Dicky A.; Sardjono, Caroline; Kaligis, R. W. M.; Kasim, Manoefris; Harimurti, Ganesja M.

    2016-01-01

    Background. Proangiogenic Hematopoietic Cells (PHC) which comprise diverse mixture of cell types are able to secrete proangiogenic factors and interesting candidate for cell therapy. The aim of this study was to seek for benefit in implantation of PHC on functional improvement in end stage coronary artery disease patients with advanced heart failure. Methods. Patients with symptomatic heart failure despite guideline directed medical therapy and LVEF less than 35% were included. Peripheral blood mononuclear cells were isolated, cultivated for 5 days, and then harvested. Flow cytometry and cell surface markers were used to characterize PHC. The PHC were delivered retrogradely via sinus coronarius. Echocardiography, myocardial perfusion, and clinical and functional data were analyzed up to 1-year observation. Results. Of 30 patients (56.4 ± 7.40 yo) preimplant NT proBNP level is 5124.5 ± 4682.50 pmol/L. Harvested cells characterized with CD133, CD34, CD45, and KDR showed 0.87 ± 0.41, 0.63 ± 0.66, 99.00 ± 2.60, and 3.22 ± 3.79%, respectively. LVEF was improved (22 ± 5.68 versus 26.8 ± 7.93, p < 0.001) during short and long term observation. Myocardial perfusion significantly improved 6 months after treatment. NYHA Class and six-minute walk test are improved during short term and long term follow-up. Conclusion. Expanded peripheral blood PHC implantation using retrograde delivery approach improved LV systolic function, myocardial perfusion, and functional capacity. PMID:27148465

  6. Impedance-Matching Hearing in Paleozoic Reptiles: Evidence of Advanced Sensory Perception at an Early Stage of Amniote Evolution

    PubMed Central

    Müller, Johannes; Tsuji, Linda A.

    2007-01-01

    Background Insights into the onset of evolutionary novelties are key to the understanding of amniote origins and diversification. The possession of an impedance-matching tympanic middle ear is characteristic of all terrestrial vertebrates with a sophisticated hearing sense and an adaptively important feature of many modern terrestrial vertebrates. Whereas tympanic ears seem to have evolved multiple times within tetrapods, especially among crown-group members such as frogs, mammals, squamates, turtles, crocodiles, and birds, the presence of true tympanic ears has never been recorded in a Paleozoic amniote, suggesting they evolved fairly recently in amniote history. Methodology/Principal Findings In the present study, we performed a morphological examination and a phylogenetic analysis of poorly known parareptiles from the Middle Permian of the Mezen River Basin in Russia. We recovered a well-supported clade that is characterized by a unique cheek morphology indicative of a tympanum stretching across large parts of the temporal region to an extent not seen in other amniotes, fossil or extant, and a braincase specialized in showing modifications clearly related to an increase in auditory function, unlike the braincase of any other Paleozoic tetrapod. In addition, we estimated the ratio of the tympanum area relative to the stapedial footplate for the basalmost taxon of the clade, which, at 23∶1, is in close correspondence to that of modern amniotes capable of efficient impedance-matching hearing. Conclusions/Significance Using modern amniotes as analogues, the possession of an impedance-matching middle ear in these parareptiles suggests unique ecological adaptations potentially related to living in dim-light environments. More importantly, our results demonstrate that already at an early stage of amniote diversification, and prior to the Permo-Triassic extinction event, the complexity of terrestrial vertebrate ecosystems had reached a level that proved advanced

  7. 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

  8. 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

  9. Fluid biopsy for Circulating Tumor Cell identification in Patients with early and late stage Non-Small Cell Lung Cancer; a glimpse into lung cancer biology

    PubMed Central

    Wendel, Marco; Bazhenova, Lyudmila; Boshuizen, Rogier; Kolatkar, Anand; Honnatti, Meghana; Cho, Edward H.; Marrinucci, Dena; Sandhu, Ajay; Perricone, Anthony; Thistlethwaite, Patricia; Bethel, Kelly; Nieva, Jorge; van den Heuvel, Michel; Kuhn, Peter

    2012-01-01

    Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast, and colorectal cancer, and recent data suggests a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there is little published data about CTC prevalence rates and morphologic heterogeneity in early stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology, and aggregation in early stage, locally advanced, and metastatic NSCLC patients by using a fluid phase biopsy approach that identifies CTCs without relying on surface receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (> 0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs/mL (range 0–515.6) and a mean of 44.7 (±95.2) HD-CTCs/mL. No significant difference in the medians of HD-CTC counts was detected between stage IV (n=31, range 0–178.2), stage III (n=34, range 0–515.6) and stages I/II (n=13, range 0–442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that, despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early and late stage lung cancer CTCs. Larger studies are warranted to investigate the prognostic value of CTC profiling in early stage lung cancer. This finding has implications for the design of larger studies examining screening, therapy, and surveillance in

  10. Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology

    NASA Astrophysics Data System (ADS)

    Wendel, Marco; Bazhenova, Lyudmila; Boshuizen, Rogier; Kolatkar, Anand; Honnatti, Meghana; Cho, Edward H.; Marrinucci, Dena; Sandhu, Ajay; Perricone, Anthony; Thistlethwaite, Patricia; Bethel, Kelly; Nieva, Jorge; van den Heuvel, Michel; Kuhn, Peter

    2012-02-01

    Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast and colorectal cancer, and recent data suggest a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there are few published data about CTC prevalence rates and morphologic heterogeneity in early-stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology and aggregation in early stage, locally advanced and metastatic NSCLC patients by using a fluid-phase biopsy approach that identifies CTCs without relying on surface-receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (>0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs mL-1 (range 0-515.6) and a mean of 44.7 (±95.2) HD-CTCs mL-1. No significant difference in the medians of HD-CTC counts was detected between stage IV (n = 31, range 0-178.2), stage III (n = 34, range 0-515.6) and stages I/II (n = 13, range 0-442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early- and late-stage lung cancer CTCs. Extensive studies are warranted to investigate the prognostic value of CTC profiling in early-stage lung cancer. This finding has implications for the design of extensive studies examining screening, therapy and surveillance in

  11. Dichloroacetate should be considered with platinum-based chemotherapy in hypoxic tumors rather than as a single agent in advanced non-small cell lung cancer

    PubMed Central

    Garon, Edward B.; Christofk, Heather R.; Hosmer, Wylie; Britten, Carolyn D; Bahng, Agnes; Crabtree, Matthew J; Hong, Candice Sun; Kamranpour, Naeimeh; Pitts, Sharon; Kabbinavar, Fairooz; Patel, Cecil; von Euw, Erika; Black, Alexander; Michelakis, Evangelos D.; Dubinett, Steven M.; Slamon, Dennis J.

    2014-01-01

    Objectives Dichloroacetate (DCA) is a highly bioavailable small molecule that inhibits pyruvate dehydrogenase kinase, promoting glucose oxidation and reversing the glycolytic phenotype in preclinical cancer studies. We designed this open label phase II trial to determine the response rate, safety, and tolerability of oral DCA in patients with metastatic breast cancer and advanced stage NSCLC. Materials and Methods This trial was conducted with DCA 6.25 mg/kg orally twice daily in previously treated stage IIIB/IV non-small cell lung cancer (NSCLC) or stage IV breast cancer. Growth inhibition by DCA was also evaluated in a panel of 54 NSCLC cell lines with and without cytotoxic chemotherapeutics (cisplatin and docetaxel) in normoxic and hypoxic conditions. Results and Conclusions Under normoxic conditions in vitro, single agent IC50 was > 2 mM for all evaluated cell lines. Synergy with cisplatin was seen in some cell lines under hypoxic conditions. In the clinical trial, after seven patients were enrolled, the study was closed based on safety concerns. The only breast cancer patient had stable disease after 8 weeks, quickly followed by progression in the brain. Two patients withdrew consent within a week of enrollment. Two patients had disease progression prior to the first scheduled scans. Within one week of initiating DCA, one patient died suddenly of unknown cause, and one experienced a fatal pulmonary embolism. We conclude that patients with previously treated advanced NSCLC did not benefit from oral DCA. In the absence of a larger controlled trial, firm conclusions regarding the association between these adverse events and DCA are unclear. Further development of DCA should be in patients with longer life expectancy, in whom sustained therapeutic levels can be achieved, and potentially in combination with cisplatin. PMID:24442098

  12. Neoadjuvant Chemoradiation With Paclitaxel/Carboplatin for Selected Stage III Non-Small-Cell Lung Cancer: Long-Term Results of a Trimodality Phase II Protocol

    SciTech Connect

    Hehr, Thomas; Friedel, Godehard; Steger, Volker; Spengler, Werner; Eschmann, Susanne M.; Bamberg, Michael; Budach, Wilfried

    2010-04-15

    Purpose: To evaluate, in a Phase II trial conducted August 1998 through January 2001, the efficacy of neoadjuvant chemotherapy followed by chemoradiotherapy and definitive surgery in patients with locally advanced non-small-cell lung cancer (LA-NSCLC), Stages IIIA bulky and selected Stage IIIB. Patients and Methods: Staging of LA-NSCLC included computed tomography of cranium, thorax, and abdomen, whole-body positron emission tomography, and video mediastinoscopy. Induction chemotherapy with weekly paclitaxel and carboplatin was followed by hyperfractionated accelerated thoracic radiotherapy (45 Gy) with simultaneous weekly paclitaxel and carboplatin. Four to six weeks after completion of induction therapy, restaging and resection of primary tumor and lymph nodes was intended. Results: A total of 59 consecutive patients were enrolled, 25% with Stage IIIA bulky disease, 65% with Stage IIIB, and 10% with Stage IV (excluded from further analysis). Forty-one patients completed induction therapy; in 52.4% a functional (positron emission tomography) downstaging was proven. Thirty-two patients (59.3%) underwent complete tumor resection, and 5 patients had an exploratory thoracotomy only. Histopathologic downstaging was proven in 59.4% and complete response in 21.9%. Hospital mortality was 5.4%. Median duration of follow-up for living patients was 62.1 months. Overall median survival was 22.6 months, 58.2 months for completely resected patients. During induction chemotherapy, Grade 3/4 granulocytopenia occurred in 8% of patients; the most common Grade 3/4 toxicity of chemoradiation was esophagitis, in 26.4% of patients. Conclusions: Induction paclitaxel/carboplatin with hyperfractionated accelerated chemoradiotherapy followed by complete tumor resection demonstrates high efficacy in LA-NSCLC and offers a promising chance of long-term survival.

  13. Coping with an Advanced Stage Lung Cancer Diagnosis: Patient, Caregiver, and Provider Perspectives on the Role of the Health Care System.

    PubMed

    Islam, K M; Opoku, Samuel T; Apenteng, Bettye A; Fetrick, Ann; Ryan, June; Copur, M; Tolentino, Addison; Vaziri, Irfan; Ganti, Apar K

    2016-09-01

    Although lung cancer is the leading cause of cancer death in the USA, there have been few studies on patient-centered advanced lung cancer treatment practices. As part of a larger research study on how to use a patient-inclusive approach in late-stage lung cancer treatment, this present study describes patient, caregiver, and provider perspectives on the role of the health care system in helping patients cope with an advanced stage lung cancer diagnosis. Four focus group sessions were conducted with six to eleven participants per group for a total of 36 participants. Two focus groups were held with patients and family members/caregivers and two with physicians and nurses. A major theme that emerged concerned coping with an advanced lung cancer diagnosis, which is the subject of this paper. The patients, caregivers, and providers spoke passionately about interactions with the health care system and volunteered examples of supportive and non-supportive relationships between patients and clinicians. They advocated for better patient-provider communication practices as well as the expanded use of patient navigation and new patient orientation programs. This study contributes additional knowledge by including the perspectives of caregivers and providers who live and work closely with patients with advanced lung cancer. The findings can inform the development of comprehensive patient-centered care plans for patients living with an advanced lung cancer diagnosis. PMID:25900672

  14. First Human Treatment With Investigational rhGUS Enzyme Replacement Therapy in an Advanced Stage MPS VII Patient

    PubMed Central

    Fox, Joyce E; Volpe, Linda; Bullaro, Josephine; Kakkis, Emil D; Sly, William S

    2015-01-01

    Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is a very rare lysosomal storage disease caused by a deficiency of the enzyme β-glucuronidase (GUS), which is required for the degradation of three glycosaminoglycans (GAGs): dermatan sulfate, heparan sulfate and chondroitin sulfate. Progressive accumulation of these GAGs in lysosomes leads to increasing dysfunction in numerous tissues and organs. Enzyme replacement therapy (ERT) has been used successfully for other MPS disorders, but there is no approved treatment for MPS VII. Here we describe the first human treatment with recombinant human GUS (rhGUS), an investigational therapy for MPS VII, in a 12-year old boy with advanced stage MPS VII. Despite a tracheostomy, nocturnal continuous positive airway pressure, and oxygen therapy, significant pulmonary restriction and obstruction led to oxygen dependence and end-tidal carbon dioxide (ETCO2) levels in the 60-80 mmHg range, eventually approaching respiratory failure (ETCO2 of 100 mmHg) and the need for full-time ventilation. Since no additional medical measures could improve his function, we implemented experimental ERT by infusing rhGUS at 2 mg/kg over 4 hours every 2 weeks for 24 weeks. Safety was evaluated by standard assessments and observance for any infusion associated reactions (IARs). Urinary GAG (uGAG) levels, pulmonary function, oxygen dependence, CO2 levels, cardiac valve function, liver and spleen size, and growth velocity were assessed to evaluate response to therapy. rhGUS infusions were well tolerated. No serious adverse events (SAEs) or IARs were observed. After initiation of rhGUS infusions, the patient's uGAG excretion decreased by more than 50%. Liver and spleen size were reduced within 2 weeks of the first infusion and reached normal size by 24 weeks. Pulmonary function appeared to improve during the course of treatment based on reduced changes in ETCO2 after off-ventilator challenges and a reduced oxygen requirement. The patient regained

  15. First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient.

    PubMed

    Fox, Joyce E; Volpe, Linda; Bullaro, Josephine; Kakkis, Emil D; Sly, William S

    2015-02-01

    Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is a very rare lysosomal storage disease caused by a deficiency of the enzyme β-glucuronidase (GUS), which is required for the degradation of three glycosaminoglycans (GAGs): dermatan sulfate, heparan sulfate, and chondroitin sulfate. Progressive accumulation of these GAGs in lysosomes leads to increasing dysfunction in numerous tissues and organs. Enzyme replacement therapy (ERT) has been used successfully for other MPS disorders, but there is no approved treatment for MPS VII. Here we describe the first human treatment with recombinant human GUS (rhGUS), an investigational therapy for MPS VII, in a 12-year old boy with advanced stage MPS VII. Despite a tracheostomy, nocturnal continuous positive airway pressure, and oxygen therapy, significant pulmonary restriction and obstruction led to oxygen dependence and end-tidal carbon dioxide (ETCO2) levels in the 60-80mmHg range, eventually approaching respiratory failure (ETCO2 of 100mmHg) and the need for full-time ventilation. Since no additional medical measures could improve his function, we implemented experimental ERT by infusing rhGUS at 2mg/kg over 4h every 2 weeks for 24 weeks. Safety was evaluated by standard assessments and observance for any infusion associated reactions (IARs). Urinary GAG (uGAG) levels, pulmonary function, oxygen dependence, CO2 levels, cardiac valve function, liver and spleen size, and growth velocity were assessed to evaluate response to therapy. rhGUS infusions were well tolerated. No serious adverse events (SAEs) or IARs were observed. After initiation of rhGUS infusions, the patient's uGAG excretion decreased by more than 50%. Liver and spleen size were reduced within 2 weeks of the first infusion and reached normal size by 24 weeks. Pulmonary function appeared to improve during the course of treatment based on reduced changes in ETCO2 after off-ventilator challenges and a reduced oxygen requirement. The patient regained the

  16. Feasibility Of Administering Adjuvant Chemotherapy Of Pemetrexed Followed By Pemetrexed/oxaliplatin Immediately Post-VATS In Patients With Completely Resected NSCLC

    PubMed Central

    He, Jianxing; Shao, Wenlong; Li, Shuben; Chen, Manyin; Chen, Hanzhang; Liu, Jun; Wang, Wei; Qiu, Yuan; Wang, Daoyuan

    2009-01-01

    Non-small cell lung cancer (NSCLC) accounts for the largest number of cancer deaths annually, worldwide. It seems reasonable to test a less toxic regimen also in early stages after complete (R0) resection of the tumor, where reduced toxicities might improve the feasibility of drug delivery, compliance and the convenience of treatment for the patient and hence perhaps improve survival. The main purpose of this phase II trial is to evaluate the clinical feasibility-in terms of patients without dose limiting toxicities or premature treatment withdrawal or death-of administering adjuvant chemotherapy of pemetrexed followed by pemetrexed/oxaliplatin immediately post-VATS (video-assisted thoracic surgery) in patients with completely resected NSCLC. PMID:22263005

  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. Assessment of cytology based molecular analysis to guide targeted therapy in advanced non-small-cell lung cancer

    PubMed Central

    Guo, Lei; Qiu, Tian; Ling, Yun; Cao, Jian; Guo, Huiqin; Zhao, Huan; Li, Lin; Ying, Jianming

    2016-01-01

    To investigate the use of molecular testing on cytological specimens in selecting advanced non-small cell lung cancer (NSCLC) patients who are adequate for targeted treatment, a total of 137 NSCLC cases were analyzed by fluorescence in situ hybridization (FISH) for anaplastic lymphoma kinase (ALK) rearrangements, and Epidermal growth factor receptor (EGFR), kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were evaluated by quantitative real-time PCR (qRT-PCR) platform combining amplification refractory mutation system (ARMS) primers and TaqMan probes. Cytological specimens included 91 fine-needle aspirates, 5 fibreoptic bronchoscopic derived samples and 41 pleural effusions. Among 137 NSCLCs analyzed for ALK FISH, 16 (11.7%, of 137) were detected to harbor ALK rearrangement. FISH positive cases were all defined as adenocarcinoma (ADC) histologic subtype and the FNA samples showed the highest ALK positive rate (13.2%, 12/91). Of the 9 ALK FISH positive patients who received crizotinib treatment, 8 (88.9%) patients exhibited tumor regression. In addition, 60 (44.8%, of 134) cases were found to harbor EGFR mutations and 22 patients with EGFR sensitive mutations who received gefitinib or erlotinib treatment showed a median PFS of 16.0 months. Mutations of KRAS occurred in 8 (6.0%, of 134) cases and this was mutually exclusive from EGFR mutation. Our results demonstrated that ALK FISH and EGFR, KRAS mutational analysis on cytological specimens are sensitive methods for screening advanced stage NSCLC patients who are adequate for targeted treatment. PMID:26789109

  19. Clinical efficacy of percutaneous vertebroplasty combined with intensity-modulated radiotherapy for spinal metastases in patients with NSCLC

    PubMed Central

    Li, Yi; Qing, Yi; Zhang, Zhimin; Li, Mengxia; Xie, Jiaying; Wang, Ge; Wang, Dong

    2015-01-01

    Objective This study aimed to evaluate the safety and efficacy of percutaneous vertebroplasty (PVP) combined with intensity-modulated radiotherapy (IMRT) for metastatic lesions of patients with non-small-cell lung cancer (NSCLC) at centrum vertebrae. Methods A total of 39 patients with spinal metastatic NSCLC (stage IV) were treated with PVP followed by IMRT (30 Gy/10F/2 W) for metastatic lesion at centrum vertebrae under local anesthesia. Retrospective analysis was done with medical records and radiological data. The change of visual analog scale (VAS), activities of daily living, and kyphotic angle was measured preoperatively. The presence of complications was assessed preoperatively (baseline) at 24 hours, 1 week, and 1, 3, 6, 12, and 24 months postoperatively, or until the patient died or was lost to follow-up. Survival was assessed in the group. Results A total of 39 consecutive patients were successfully treated with PVP via a translateral approach and IMRT. Their mean VAS score decreased from 7.93±1.09 preoperatively to 4.14±1.15 by the 24-hour postoperative time point and was 3.92±1.23 at 1 week, 4.27±1.93 at 1 month, 3.24±1.35 at 3 months, 2.27±0.96 at 6 months, and 2.59±1.55 at 12 months after the procedure. The mean VAS score at all of the postoperative time points was decreased significantly from the preoperative baseline score (P<0.05). Activities of daily living evaluation showed that the patients had a significantly high life quality after the combined approach (50.9±11.7 vs 82.3±9.9, P<0.05). No severe complications were observed. Mild complications included two cases (5.13%) of asymptomatic cement leakage into the epidural space and one case (2.56%) of paravertebral leakage. Median survival time was extended to 13 months. Conclusion The safety and efficacy of PVP combined with IMRT in patients with NSCLC with metastatic lesions at centrum vertebrae and the ability to prevent the diseased vertebrae from further deformation and tumor

  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. A Broadly Adaptive Array of Dose-Constraint Templates for Planning of Intensity-Modulated Radiation Therapy for Advanced T-Stage Nasopharyngeal Carcinoma

    SciTech Connect

    Chau, R.M.-C. Leung, S.-F.; Kam, M.K.-M.; Cheung, K.-Y.; Kwan, W.-H.; Yu, K.-H.; Chiu, K.-W.; Cheung, M.L.-M.; Chan, A.T.-C.

    2009-05-01

    Purpose: To develop and validate adaptive dose-constraint templates in intensity-modulated radiotherapy (IMRT) planning for advanced T-stage nasopharyngeal carcinoma (NPC). Method and Materials: Dose-volume histograms of clinically approved plans for 20 patients with advanced T-stage NPC were analyzed, and the pattern of distribution in relation to the degree of overlap between targets and organs at risk (OARs) was explored. An adaptive dose constraint template (ADCT) was developed based on the degree of overlap. Another set of 10 patients with advanced T-stage NPC was selected for validation. Results of the manual arm optimization protocol and the ADCT optimization protocol were compared with respect to dose optimization time, conformity indices, multiple-dose end points, tumor control probability, and normal tissue complication probability. Results: For the ADCT protocol, average time required to achieve an acceptable plan was 9 minutes, with one optimization compared with 94 minutes with more than two optimizations of the manual arm protocol. Target coverage was similar between the manual arm and ADCT plans. A more desirable dose distribution in the region of overlap between planning target volume and OARs was achieved in the ADCT plan. Dose end points of OARs were similar between the manual arm and ADCT plans. Conclusions: With the developed ADCT, IMRT treatment planning becomes more efficient and less dependent on the planner's experience on dose optimization. The developed ADCT is applicable to a wide range of advanced T-stage NPC treatment and has the potential to be applied in a broader context to IMRT planning for other cancer sites.

  2. Advanced Stage T-Cell Non-Hodgkin lymphoma in an 11-Month-Old Infant and Related Superior Vena Cava Syndrome: Importance of Transthoracic Echocardiography.

    PubMed

    Yilmaz, Osman; Karabag, Kezban; Keskin Yildirim, Zuhal; Calik, Muhammet; Kilic, Omer

    2014-01-01

    Superior vena cava syndrome (SVCS) is rare in infants. Non-Hodgkin lymphoma is the most common cause of SVCS in children. Swelling in the face and neck are the most common clinical symptoms associated with this syndrome. However, these clinical findings are also observed in allergic diseases, which therefore often leads to misdiagnosis. Here, we reported the importance of echocardiography in diagnosing SVCS in an infant with advanced stage non-Hodgkin lymphoma. PMID:24639614

  3. Comparison of five models for end-stage liver disease in predicting the survival rate of patients with advanced hepatocellular carcinoma.

    PubMed

    Hong, Ying-Fen; Chen, Zhan-Hong; Ma, Xiao-Kun; Li, Xing; Wu, Dong-Hao; Chen, Jie; Dong, Min; Wei, Li; Wang, Tian-Tian; Ruan, Dan-Yun; Lin, Ze-Xiao; Wen, Jing-Yun; Lin, Qu; Jia, Chang-Chang; Wu, Xiang-Yuan

    2016-04-01

    Prognosis of patients with advanced hepatocellular carcinoma (HCC) is under expectation. Life expectancy more than 3 months is one inclusion criteria for molecular targeted drugs in clinical trials. The main purpose of this research is to compare Model for End-Stage Liver Disease (MELD) and four MELD-based prognostic models in predicting the survival rate of advanced HCC patients. One hundred eighty-three patients with advanced HCC who were not amendable to standard anti-tumor therapy were retrospectively analyzed. Data were collected to classify patients according to MELD, Model for End-Stage Liver Disease with the incorporation of serum sodium (MELD-NA), Model for End-Stage Liver Disease to ascites and sodium (MELD-AS), integrated Model for End-Stage Liver Disease (iMELD), and Model for End-Stage Liver Disease to sodium (MESO) scores at diagnosis. 1-, 3-, and 6-month survivals were the end points used in the analysis. When predicting 1-month survival, MELD-AS, MELD, and MESO were the top 3 ranking staging systems. When predicting 3-month survival, area under the receiver operating characteristic curve (AUC) of MELD-AS is significantly higher than that of the other models (P < 0.05). When predicting 6-month survival, AUCs of MELD-AS and MELD-NA are significantly higher than those of the other models (P < 0.05). Cutoff point of MELD-AS is 23.11 with 40.5 % sensitivity and 93.8 % specificity at 1 month, 9.5 with 76.9 % sensitivity and 59.5 % specificity at 3 months, and 18.5 with 27.0 % sensitivity and 89.1 % specificity at 6 months. MELD-based scores of death group are significantly higher than those of survivors within 1 and 3 months (P < 0.001). Independent prognostic factors identified by multivariate analysis included persistent ascites, serum sodium, and thrombosis. MELD-AS is the best model in the prediction of short and intermediate survival among the five models for end-stage liver disease analyzed for Chinese advanced HCC patients

  4. Diminished production of interleukin-6 in chronic lymphocytic leukaemia (B-CLL) cells from patients at advanced stages of disease. Tampere CLL Group.

    PubMed

    Hulkkonen, J; Vilpo, J; Vilpo, L; Hurme, M

    1998-03-01

    The production of the cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in B-CLL cells from 24 patients at different stages of chronic lymphocytic B-cell leukaemia (B-CLL) was investigated in vitro. In the majority of these cases, low spontaneous IL-6 production was measured. Mitogenic stimulation with phorbol 12-myristate 13-acetate (PMA) or PMA plus interleukin-2 (IL-2) resulted in a tremendous increase in TNF-alpha and IL-6 production in cells representing early stage (Binet A) disease. In contrast, very little, if any, production took place in cells from patients with advanced stage (Binet C) B-CLL. The results from stage B patients were intermediate. The most remarkable difference was recorded in PMA-stimulated (1 ng/ml) IL-6 production. In stimulated 72 h cultures, IL-6 concentrations were 1280 +/- 1080 pg/ml for Binet A (n = 11), 757 +/- 597 pg/ml for Binet B (n = 8) and 46.0 +/- 84.0 pg/ml for Binet C (n = 5). The differences in IL-6 production between stage C v B and stage C v A were both statistically significant (P=0.025). Similar effects, but to a lesser extent, were observed in TNF-alpha production. These results suggest that the varying capacity to produce IL-6 and TNF-alpha may play a role in B-CLL progression and in clinical manifestations of the disease. PMID:9504629

  5. 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

    Purpose: Several surgical series have identified subcarinal, contralateral, and multilevel nodal involvement as predictors of poor overall survival in patients with Stage III non-small-cell lung cancer (NSCLC) treated with definitive resection. This retrospective study evaluates the impact of extent and location of mediastinal lymph node (LN) involvement on survival in patients with Stage III NSCLC treated with definitive radiotherapy. Methods and Materials: We analyzed 106 consecutive patients with T1-4 N2-3 Stage III NSCLC treated with definitive radiotherapy at University of Pennsylvania between January 2003 and February 2009. For this analysis, mediastinal LN stations were divided into four mutually exclusive groups: supraclavicular, ipsilateral mediastinum, contralateral mediastinum, and subcarinal. Patients' conditions were then analyzed according to the extent of involvement and location of mediastinal LN stations. Results: The majority (88%) of patients received sequential or concurrent chemotherapy. The median follow-up time for survivors was 32.6 months. By multivariable Cox modeling, chemotherapy use (hazard ratio [HR]: 0.21 [95% confidence interval (CI): 0.07-0.63]) was associated with improved overall survival. Increasing primary tumor [18F]-fluoro-2-deoxy-glucose avidity (HR: 1.11 [CI: 1.06-1.19]), and subcarinal involvement (HR: 2.29 [CI: 1.11-4.73]) were significant negative predictors of overall survival. On univariate analysis, contralateral nodal involvement (HR: 0.70 [CI: 0.33-1.47]), supraclavicular nodal involvement (HR: 0.78 [CI: 0.38-1.67]), multilevel nodal involvement (HR: 0.97 [CI: 0.58-1.61]), and tumor size (HR: 1.04 [CI: 0.94-1.14]) did not predict for overall survival. Patients with subcarinal involvement also had lower rates of 2-year nodal control (51.2% vs. 74.9%, p = 0.047) and 2-year distant control (28.4% vs. 61.2%, p = 0.043). Conclusions: These data suggest that the factors that determine oncologic outcome in Stage III NSCLC

  6. The microRNA miR-34a inhibits non-small cell lung cancer (NSCLC) growth and the CD44hi stem-like NSCLC cells.

    PubMed

    Shi, Yang; Liu, Can; Liu, Xin; Tang, Dean G; Wang, Junchen

    2014-01-01

    Lung cancer is among the most lethal malignancies with a high metastasis and recurrence rate, which is probably due to the existence of lung cancer stem cells (CSCs). CSCs in many tumors including non-small cell lung cancer (NSCLC) have been identified using adhesion molecular CD44, either individually or in combination with other marker(s). MicroRNAs (miRNAs) regulate both normal stem cells and CSCs and dysregulation of miRNAs has been implicated in tumorigenesis. Recently, miR-34a was found to be downregulated in NSCLC cells but the biological functions of miR-34a in regulating NSCLC cell behavior have not been extensively studied. Here we show that transfection of synthetic miR-34a, but not the negative control (NC) miRNA oligonucleotides (oligos) in three NSCLC cell lines, i.e., A549, H460, and H1299, inhibited their holoclone formation, clonogenic expansion, and tumor regeneration in vivo. Furthermore, the lentiviral vector-mediated overexpression of miR-34a in purified CD44hi H460 cells also inhibited tumor outgrowth. In contrast, expression of miR-34a antagomirs (i.e., antisense oligos) in the CD44lo H460 cells promoted tumor development. Our study shows that miR-34a is a negative regulator of the tumorigenic properties of NSCLC cells and CD44hi lung CSCs, and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against NSCLC. PMID:24595209

  7. Once-Weekly, High-Dose Stereotactic Body Radiotherapy for Lung Cancer: 6-Year Analysis of 60 Early-Stage, 42 Locally Advanced, and 7 Metastatic Lung Cancers

    SciTech Connect

    Salazar, Omar M. Sandhu, Taljit S.; Lattin, Paul B.; Chang, Jung H.; Lee, Choon K.; Groshko, Gayle A.; Lattin, Cheryl J.

    2008-11-01

    Purpose: To explore once-weekly stereotactic body radiotherapy (SBRT) in nonoperable patients with localized, locally advanced, or metastatic lung cancer. Methods and Materials: A total of 102 primary (89 untreated plus 13 recurrent) and 7 metastatic tumors were studied. The median follow-up was 38 months, the average patient age was 75 years. Of the 109 tumors studied, 60 were Stage I (45 IA and 15 IB), 9 were Stage II, 30 were Stage III, 3 were Stage IV, and 7 were metastases. SBRT only was given in 73% (40 Gy in four fractions to the planning target volume to a total dose of 53 Gy to the isocenter for a biologically effective dose of 120 Gy{sub 10}). SBRT was given as a boost in 27% (22.5 Gy in three fractions once weekly for a dose of 32 Gy at the isocenter) after 45 Gy in 25 fractions to the primary plus the mediastinum. The total biologically effective dose was 120 Gy{sub 10}. Respiration gating was used in 46%. Results: The overall response rate was 75%; 33% had a complete response. The overall response rate was 89% for Stage IA patients (40% had a complete response). The local control rate was 82%; it was 100% and 93% for Stage IA and IB patients, respectively. The failure rate was 37%, with 17% within the planning target volume. No Grade 3-4 acute toxicities developed in any patient; 12% and 7% of patients developed Grade 1 and 2 toxicities, respectively. Late toxicity, all Grade 2, developed in 3% of patients. The 5-year cause-specific survival rate for Stage I was 70% and was 74% and 64% for Stage IA and IB patients, respectively. The 3-year Stage III cause-specific survival rate was 30%. The patients with metastatic lung cancer had a 57% response rate, a 27% complete response rate, an 86% local control rate, a median survival time of 19 months, and 23% 3-year survival rate. Conclusions: SBRT is noninvasive, convenient, fast, and economically attractive; it achieves results similar to surgery for early or metastatic lung cancer patients who are older

  8. A phase I study of nimotuzumab plus docetaxel in chemotherapy-refractory/resistant patients with advanced non-small-cell lung cancer

    PubMed Central

    Zhao, Jun; Zhuo, Minglei; Wang, Zhijie; Duan, Jianchun; Wang, Yuyan; Wang, Shuhang; An, Tongtong; Wu, Meina

    2016-01-01

    Background To determine the safety and therapeutic efficacy of nimotuzumab (h-R3) combined with docetaxel in advanced non-small-cell lung cancer (NSCLC) patients who have failed to respond to prior first-line chemotherapy. Methods In this single-center, open-label, dose-escalating phase I trial, patients with epidermal growth factor receptor (EGFR)-expressing stage IV NSCLC were treated with nimotuzumab plus docetaxel according to a dose escalation schedule. The safety and efficacy of the combination treatment were observed and analyzed. Results There were 12 patients with EGFR-expressing stage IV NSCLC enrolled. The dose of nimotuzumab was escalated from 200 to 600 mg/week. The longest administration of study drug was 40 weeks at the 600 mg/week dose level. Grade III–IV toxicities included neutropenia and fatigue, and other toxicities included rash. Dose-limiting toxicity occurred with Grade 3 fatigue at the 200 mg dose level of nimotuzumab and Grade 4 neutropenia with pneumonia at the 600 mg dose level of nimotuzumab. No objective responses were observed, and stable disease was observed in eight patients (66.7%). The median progression-free survival (PFS) was 4.4 months in all patients, 1.3 months in patients with the EGFR mutation, and 4.4 months in those with wild type EGFR (EGFR WT). The median survival time (MST) was 21.1 months in all patients, 21.1 months in patients with EGFR mutation, and 26.4 months in patients with EGFR WT. Conclusions Nimotuzumab and docetaxel combination therapy was found to be well tolerated and efficacious. Further study of nimotuzumab is warranted in advanced NSCLC patients. PMID:27041923

  9. A prospective evaluation of the impact of 18-F-fluoro-deoxy-D-glucose positron emission tomography staging on survival for patients with locally advanced esophageal cancer

    SciTech Connect

    Blackstock, A. William . E-mail: ablackst@wfubmc.edu; Farmer, Michael R.; Lovato, James; Mishra, Girish; Melin, Susan A.; Oaks, Timothy; Aklilu, Mabea; Clark, Paige B.; Levine, Edward A.

    2006-02-01

    Purpose: To determine the impact of 18-F-fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the staging and prognosis of patients with locally advanced esophageal cancer (LAEC). Methods and Materials: Between January 2000 and October 2004, all patients with LAEC evaluated in the Department of Radiation Oncology were considered for enrollment into a Phase II trial of preoperative chemoradiation. Entry required a staging whole-body FDG-PET scan. Results: One hundred ten consecutive patients were evaluated; 38 were ineligible for reasons including treatment elsewhere, prior malignancy, or refusal of treatment. After conventional staging (clinical examination, endoscopic ultrasound, and chest/abdominal computerized tomography), 33 patients were ineligible because of metastatic disease or poor performance status. Of the remaining 39 patients, 23 were confirmed to have LAEC after FDG-PET staging and were treated in the Phase II trial (Cohort I). Sixteen patients, however, had FDG-PET findings consistent with occult metastatic disease and were deemed ineligible for the trial but were treated with curative intent (Cohort II). The 2-year survival rate for the 23 patients in Cohort I was 64%, compared with 17% (p = 0.003) for patients in Cohort II (FDG-PET positive). Conclusions: More than one-third of patients determined to have LAEC with conventional staging were upstaged with the use of FDG-PET. Despite comparable therapy, upstaging with FDG-PET predicts poor 2-year survival.

  10. Gefitinib in Combination With Irradiation With or Without Cisplatin in Patients With Inoperable Stage III Non-Small Cell Lung Cancer: A Phase I Trial

    SciTech Connect

    Rothschild, Sacha; Bucher, Stephan E.; Bernier, Jacques; Aebersold, Daniel M.; Zouhair, Aberrahim; Ries, Gerhard; Lombrieser, Norbert; Lippuner, Thomas; Luetolf, Urs M.; Glanzmann, Christoph; Ciernik, I. Frank

    2011-05-01

    Purpose: To establish the feasibility and tolerability of gefitinib (ZD1839, Iressa) with radiation (RT) or concurrent chemoradiation (CRT) with cisplatin (CDDP) in patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: In this multicenter Phase I study, 5 patients with unresectable NSCLC received 250 mg gefitinib daily starting 1 week before RT at a dose of 63 Gy (Step 1). After a first safety analysis, 9 patients were treated daily with 250 mg gefitinib plus CRT in the form of RT and weekly CDDP 35 mg/m{sup 2} (Step 2). Gefitinib was maintained for up to 2 years until disease progression or toxicity. Results: Fourteen patients were assessed in the two steps. In Step 1 (five patients were administered only gefitinib and RT), no lung toxicities were seen, and there was no dose-limiting toxicity (DLT). Adverse events were skin and subcutaneous tissue reactions, limited to Grade 1-2. In Step 2, two of nine patients (22.2%) had DLT. One patient suffered from dyspnea and dehydration associated with neutropenic pneumonia, and another showed elevated liver enzymes. In both steps combined, 5 of 14 patients (35.7%) experienced one or more treatment interruptions. Conclusions: Gefitinib (250 mg daily) in combination with RT and CDDP in patients with Stage III NSCLC is feasible, but CDDP likely enhances toxicity. The impact of gefitinib on survival and disease control as a first-line treatment in combination with RT remains to be determined.

  11. Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report

    PubMed Central

    YEO, SEUNG-GU

    2015-01-01

    Hyperthermia enhances the susceptibility of tumors to radiotherapy (RT) and chemotherapy. Oncothermia, also known as electro-hyperthermia, is a new treatment modality developed to overcome the problems of traditional hyperthermia by selectively delivering energy to the malignant tissues. The present study reports the outcome of combined oncothermia and RT in a 75-year-old patient with stage IIIB non-small-cell lung cancer (NSCLC). Due to the advanced age and the performance status of the patient, the combination of systemic chemotherapy and RT was deemed infeasible; therefore, the patient instead decided to undergo oncothermia concurrently with definitive RT. The RT was administered at a dose of 64.8 Gy in 36 fractions using a three-dimensional conformal plan technique. Oncothermia was started concomitantly with RT and was performed for 60 min per session, two sessions per week, for a total of 12 sessions. No severe toxicities developed, with the exception of mild odynophagia, which resolved soon after the treatments. Follow-up computed tomography showed complete tumor response, and the patient was alive with no evidence of the disease 18 months after the completion of the treatment. In conclusion, the present case report suggests that oncothermia combined with RT, with the former possessing radiosensitizing potential and no additional toxicities, may be a promising alternative for advanced-age and/or frail patients with locally advanced NSCLC. PMID:26622391

  12. Efficacy Comparison Between Total Laryngectomy and Nonsurgical Organ-Preservation Modalities in Treatment of Advanced Stage Laryngeal Cancer: A Meta-Analysis.

    PubMed

    Fu, Xiaoyuan; Zhou, Qi; Zhang, Xianquan

    2016-04-01

    It remains unclear whether the efficacy of nonsurgical organ-preservation modalities (NOP) in the treatment of advanced-stage laryngeal cancer was noninferiority compared with that of total laryngectomy (TL). The objective of this study was to compare the curative effects between TL and NOP in the treatment of advanced-stage laryngeal cancer through a meta-analysis.Clinical studies were retrieved from the electronic databases of PubMed, Embase, Wanfang, and Chinese National Knowledge infrastructure. A meta-analysis was performed to investigate the differences in the curative efficacy of advanced-stage laryngeal cancer between TL and the nonsurgical method. Two reviewers screened all titles and abstracts, and independently assessed all articles. All identified studies were retrospective.Sixteen retrospective studies involving 8308 patients (4478 in the TL group and 3701 in the nonsurgical group) were included in this meta-analysis. The analysis results displayed the advantage of TL for 2-year and 5-year overall survival (OS)(OR 2.79, 95% CI 1.85-4.23 and OR 1.52, 95% CI 1.09-2.14) as well as in 5-year disease-specific survival (DSS)(OR 1.79, 95% CI 1.61-1.98), but no significant difference in 2-year DSS was detected between the 2 groups (OR = 2.09,95% CI0.69-6.40). Additionally, there were no significant differences between TL and NOP for 5-year local control (LC) either (OR = 1.75, 95% CI 0.87-3.53). When we carried out subgroup analyses, the advantage of TL was especially obvious in T4 subgroups, but not in T3 subgroups.This is the first study to compare the curative effects on advanced-stage laryngeal cancer using meta-analytic methodology. Although there was a trend in favor of TL for OS and DSS, there is no clear difference in oncologic outcome between TL and NOP. Therefore, other factors such as tumor T-stage and size, lymph node metastasis, and physical condition are also important indicators for treatment choice. PMID:27057837

  13. Testing of polyimide second-stage rod seals for single-state applications in advanced aircraft hydraulic systems

    NASA Technical Reports Server (NTRS)

    Waterman, A. W.

    1977-01-01

    Machined polyimide second-stage rod seals were evaluated to determine their suitability for single-stage applications where full system pressure acts on the upstream side of the seal. The 6.35-cm (2.5-in.) K-section seal was tested in impulse screening tests where peak pressure was increased in 3.448-MPa (500-psi) increments each 20,000 cycles. Seal failure occurred at 37.92 MPa (5,500 psi), indicating a potential for acceptability in a 27.58-MPa (4,000-psi) system. Static pressurization for 600 sec at pressures in excess of 10.34 MPa (1,500 psi) revealed structural inadequacy of the seal cross section to resist fracture and extrusion. Endurance testing showed the seals capable of at least 65,000 1.27-cm (0.5-in.) cycles at 450 K (350 F) without leakage. It was concluded that the second-stage seals were proven to be exceptional in the 1.379-MPa (200-psi) applications for which they were designed, but polyimide material properties are not adequate for use in this design at pressure loading equivalent to that present in single-stage applications.

  14. Association between polymorphisms of BAG-1 and XPD and chemotherapy sensitivity in advanced non-small-cell lung cancer patients treated with vinorelbine combined cisplatin regimen.

    PubMed

    Li, Ping; Wang, Ya-Di; Cheng, Jian; Chen, Jun-Chen; Ha, Min-Wen

    2015-12-01

    BCL-2 Associated athanogene 1 (BAG-1) and Xeroderma pigmentosum group D (XPD) are involved in the nucleotide excision repair pathway and DNA repair. We aimed to investigate whether polymorphisms in BAG-1 and XPD have effects on chemotherapy sensitivity and survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with vinorelbine combined cisplatin (NP) regimen. A total of 142 patients with diagnosed advanced NSCLC were recruited in the current study. NP regimen was applied for all eligible patients. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for BAG-1 (codon 324) and XPD (codons 312 and 751) genotyping. The treatment response was evaluated according to the RECIST guidelines. Progression-free survival (PFS) and overall survival (OS) were record as median and end point, respectively. As for BAG-1 codon 324, the chemotherapy sensitivity in NSCLC patients with CT genotype was 0.383 times of those with CC genotype (P < 0.05). With respect to XPD codon 751, the chemotherapy sensitivity in NSCLC patients with Lys/Gln genotype was 0.400 times of those with Lys/Lys genotype (P < 0.05). In addition, NSCLC patients carrying combined C/C genotype at codon 324 in BAG-1, Asp/Asp of XPD codon 312, and Lys/Lys of XPD codon 751 produced a higher efficacy of NP chemotherapy compared to those carrying mutation genotypes (all P < 0.05). Further, there were significant differences in PFS between patients with combined C/C genotype of BAG-1 codon 324, Lys/Lys genotype of XPD codon 751, and Asp/Asp genotype of XPD codon 312 and patients carrying BAG-1 codon 324 C/T genotype, XPD codon751 Lys/Gln genotype, and XPD codon312 Asp/Asn genotype (P < 0.05). Multivariate Cox regression analysis indicated that the combined wild-type of codon 324 XPD, codon 751 XPD, and codon 312 BAG-1 is the protective factor for OS and PFS, and clinical stages is the risk factor for OS and PFS. In conclusion, our research

  15. Outcome of active anti-cancer treatment in elderly patients with advanced non-small cell lung cancer: A single center experience

    PubMed Central

    Kim, Ji Hye; Ryu, Min Sun; Ryu, Yon Ju; Lee, Jin Hwa; Shim, Sung Shine; Kim, Yookyung; Chang, Jung Hyun

    2014-01-01

    Background This study aimed to evaluate the characteristics of active anti-cancer treatment (AAT) compared with best supportive care (BSC) in elderly patients with advanced non-small cell lung cancer (NSCLC). Methods A retrospective analysis of 144 patients, aged 70 or older, with stage IIIb/IV NSCLC from 672 patients with confirmed lung cancer, was conducted. Results Median age at diagnosis was 77 years and median survival time was five months. On multivariate analysis, AAT independently contributed to a decreased hazard ratio of death (P = 0.04), whereas male gender (P = 0.004), a body mass index of less than 18.5 (P = 0.004), and a poor performance score were associated with an increased risk of death (P < 0.001). The 52 subjects receiving AAT experienced longer survival than the 92 subjects receiving BSC (median seven months [AAT] versus three months [BSC]; P < 0.001). When sub-classified into five-year age intervals, AAT was a significant advantage in overall survival (OS) to patients aged 70–74, but not to those ≥75 years old. Conclusions AAT for patients ≥70 years old with advanced NSCLC extended OS. However, care should be taken in decisions on active anti-cancer treatments for patients over 75 years old. A prospective multicenter trial is required in the near future. PMID:26766990

  16. Impact of TG4010 Vaccine on Health-Related Quality of Life in Advanced Non-Small-Cell Lung Cancer: Results of a Phase IIB Clinical Trial

    PubMed Central

    Rotonda, Christine; Anota, Amélie; Mercier, Mariette; Bastien, Bérangère; Lacoste, Gisèle; Limacher, Jean-Marc; Quoix, Elisabeth; Bonnetain, Franck

    2015-01-01

    Background This study describes the effect of TG4010 vaccine on Health related Quality of Life (HRQOL) in patients with stage IIIb and IV non–small-cell lung cancer (NSCLC). Methods 148 patients with advanced NSCLC expressing MUC1 were randomly assigned to receive TG4010 plus chemotherapy or chemotherapy alone. HRQOL was assessed with the Functional Assessment of Cancer Therapy-Lung (FACT-L) at baseline and every 6 weeks until disease progression. Time until definitive deterioration (TUDD) of the four well-being dimensions of the FACT-L physical (PWB), functional (FWB), emotional (EWB) and social well-being (SWB) and the Lung Cancer Subscale (LCS) domains were analyzed for a 5-point minimal clinically important difference. Results No difference of TUDD of HRQOL has been found between treatment arms. No prognostic factors have been found to have a significant impact on the TUDD of PWB, SWB and LCS domains. The gender, the performance status and the smoking habits seemed to be associated with a shorter TUDD of EWB domain. The smokers and the former smokers seemed to present a shorter TUDD of FWB domain. Conclusion This study suggests that adding therapeutic vaccination with TG4010 to standard chemotherapy in patients with advanced NSCLC is associated with a similar evolution in HRQOL compared to chemotherapy alone. PMID:26207902

  17. Initial Stage Affects Survival Even After Complete Pathologic Remission is Achieved in Locally Advanced Esophageal Cancer: Analysis of 70 Patients With Pathologic Major Response After Preoperative Chemoradiotherapy

    SciTech Connect

    Kim, Min Kyoung; Cho, Kyung-Ja; Park, Seung-Il; Kim, Yong Hee; Kim, Jong Hoon; Song, Ho-Young; Shin, Ji Hoon; Jung, Hwoon Yong; Lee, Gin Hyug; Choi, Kee Don; Song, Ho June; Ryu, Jin-Sook; Kim, Sung-Bae

    2009-09-01

    Purpose: To analyze outcomes and factors predictive for recurrence and survival in patients with operable esophageal carcinoma who achieved pathologic complete response (PCR) or microscopic residual disease (MRD) after preoperative chemoradiotherapy (CRT). Materials and Methods: Outcomes were assessed in 70 patients with locally advanced esophageal cancer who achieved pathologic major response (53 with PCR and 17 with MRD) after preoperative CRT. Results: At a median follow-up of 38.6 months for surviving patients, 17 of 70 patients (24.3%) experienced disease recurrence and 31 (44.3%) died. Clinical stage (II vs III; p = 0.013) and pathologic response (PCR vs. MRD; p = 0.014) were independent predictors of disease recurrence. Median overall survival (OS) was 99.6 months (95% CI, 44.1-155.1 months) and the 5-year OS rate was 57%. Median recurrence-free survival (RFS) was 71.5 months (95% CI, 39.5-103.6 months) and the 5-year RFS rate was 51.3%. Median OS of patients with Stage II and Stage III disease was 108.8 months and 39.9 months, respectively, and the 5-year OS rates were 68.2% and 27.0%, respectively (p = 0.0003). In a subgroup of patients with PCR, median OS and RFS were also significantly different according to clinical stage. Multivariate analysis showed that clinical stage was an independent predictor of RFS (p = 0.01) and OS (p = 0.008). Conclusions: Even though patients achieved major response after preoperative CRT, pretreatment clinical stage is an important prognostic marker for recurrence and survival. Patients with MRD have an increased recurrence risk but similar survival compared with patients achieved PCR.

  18. 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

  19. SU-E-J-87: Ventilation Weighting Effect On Mean Doses of Both Side Lungs for Patients with Advanced Stage Lung Cancer

    SciTech Connect

    Qu, H; Xia, P; Yu, N

    2015-06-15

    Purpose: To study ventilation weighting effect on radiation doses to both side lungs for patients with advanced stage lung cancer. Methods: Fourteen patients with advanced stage lung cancer were included in this retrospective study. Proprietary software was developed to calculate the lung ventilation map based on 4DCT images acquired for radiation therapy. Two phases of inhale (0%) and exhale (50%) were used for the lung ventilation calculations. For each patient, the CT images were resampled to the same dose calculation resolution of 3mmx3mmx3mm. The ventilation distribution was then normalized by the mean value of the ventilation. The ventilation weighted dose was calculated by applying linearly weighted ventilation to the dose of each pixel. The lung contours were automatically delineated from patient CT image with lung window, excluding the tumor and high density tissues. For contralateral and ipsilateral lungs, the mean lung doses from the original plan and ventilation weighted mean lung doses were compared using two tail t-Test. Results: The average of mean dose was 6.1 ±3.8Gy for the contralateral lungs, and 26.2 ± 14.0Gy for the ipsilateral lungs. The average of ventilation weighted dose was 6.3± 3.8Gy for the contralateral lungs and 24.6 ± 13.1Gy for the ipsilateral lungs. The statistics analysis shows the significance of the mean dose increase (p<0.015) for the contralateral lungs and decrease (p<0.005) for the ipsilateral lungs. Conclusion: Ventilation weighted doses were greater than the un-weighted doses for contralateral lungs and smaller for ipsilateral lungs. This Result may be helpful to understand the radiation dosimetric effect on the lung function and provide planning guidance for patients with advance stage lung cancer.

  20. Randomized clinical trial of adenosine 5'-triphosphate on tumor growth and survival in advanced lung cancer patients.

    PubMed

    Agteresch, Hendrik J; Burgers, Sjaak A; van der Gaast, Ate; Wilson, J H Paul; Dagnelie, Pieter C

    2003-09-01

    We recently reported that regular infusions of adenosine 5'-triphosphate (ATP) inhibited loss of body weight and quality of life in patients with non-small cell lung cancer (NSCLC). In the present paper we investigated whether ATP affects tumor growth and survival in the same group of patients. Fifty-eight NSCLC patients (stage IIIB or IV) were randomly assigned to receive either 10 i.v. 30-h ATP infusions every 2-4 weeks over a 24-week period (n = 28) or no ATP (control patients, n = 30). ATP was given for a median of 6.5 infusions. Differences in time to progression and survival between patients in both groups were tested by means of the log-rank test and Cox regression analysis. Forty-nine patients were evaluable for tumor response. None of the evaluable patients showed a complete or partial response. Median time to progression was 3.9 months [95% confidence interval (CI) = 2.3-5.5] in the ATP group compared to 3.0 months (95% CI = 2.4-3.7) in the control group (p = 0.71). Median survival was 5.6 months (95% CI = 1.1-10.1) for the ATP group and 4.7 months (95% CI = 2.6-6.8) for the control group (p = 0.68). ATP treatment was associated with a significant increase in survival in the subgroup of weight-losing patients with stage IIIB NSCLC: in this subgroup, median survival was 9.3 months (95% CI = 2.1-16.5) for ATP-treated patients versus 3.5 months (95% CI = 2.3-4.7) for control patients (between-group difference: p = 0.009). No significant effect of ATP was observed for weight-losing patients with stage IV NSCLC or for weight-stable NSCLC patients. Although ATP as a single therapy does not lead to tumor regression or increased survival in patients with advanced lung cancer, it may prolong survival in weight-losing patients with stage IIIB lung cancer. The latter finding is intriguing, but requires confirmation in larger clinical trials. PMID:14501386

  1. Analysis of the characteristics and prognosis of advanced non-small-cell lung cancer in older patients

    PubMed Central

    Gao, Ying; Gao, Fei; Ma, Jin-lu; Zhang, Xiao-zhi; Li, Yi; Song, Li-ping; Zhao, Dong-li

    2015-01-01

    Objective Lung cancer is still the leading cause of cancer-related deaths worldwide. However, most elderly patients with advanced non-small-cell lung cancer (NSCLC) have been undertreated and the outcome related to age is controversial. A retrospective analysis was conducted for advanced NSCLC in order to investigate the characteristics and prognosis of older patients. Methods Medical records were collected from 165 patients with NSCLC (stages IIIA–IIIB) who had been treated with concurrent chemoradiotherapy (CRT) or radiotherapy from January 2009 to January 2011. The cases were divided into two age groups 1) patients ≥70 years old; 2) patients <70 years old. There were 73 patients in group I, 92 in group II. Patient characteristics, treatment toxicities, and prognosis were evaluated. Results Of the 165 patients analyzed, 34 patients (34/73) in group I received concurrent CRT while 47 (47/92) in group II completed that treatment. No significant difference was observed in the reason for patients who discontinued CRT in two groups (P>0.05). In the patients with adenocarcinoma, more cases were found in group II than that in group I; the more squamous cell carcinoma and the more smokers with squamous cell carcinoma were seen in older group (P<0.05). With a median follow-up of 20.5 months, the 1-year survival for group I and II were 49.3% and 40.2% respectively (P=0.243). Two-year survival for the two groups was 20.5% and 16.3% (P=0.483); 3-year survival was 9.6% and 9.8% (P=0.967). There was no significant difference between two groups statistically in survival by univariate analysis (P>0.05). The therapy-related toxicities in group I seem to be similar to the group II (P>0.05). Conclusion More adenocarcinoma patients were found in youthful lung cancer and the more smokers with squamous cell carcinoma were seen in older group. Age is not the important factor for the selection and allocation of treatment in advanced NSCLC. The same prognosis and toxicities had been

  2. Large-Scale Liquid Hydrogen Tank Rapid Chill and Fill Testing for the Advanced Shuttle Upper Stage Concept

    NASA Technical Reports Server (NTRS)

    Flachbart, R. H.; Hedayat, A.; Holt, K. A.; Sims, J.; Johnson, E. F.; Hastings, L. J.; Lak, T.

    2013-01-01

    Cryogenic upper stages in the Space Shuttle program were prohibited primarily due to a safety risk of a 'return to launch site' abort. An upper stage concept addressed this concern by proposing that the stage be launched empty and filled using shuttle external tank residuals after the atmospheric pressure could no longer sustain an explosion. However, only about 5 minutes was allowed for tank fill. Liquid hydrogen testing was conducted within a near-ambient environment using the multipurpose hydrogen test bed 638.5 ft3 (18m3) cylindrical tank with a spray bar mounted longitudinally inside. Although the tank was filled within 5 minutes, chilldown of the tank structure was incomplete, and excessive tank pressures occurred upon vent valve closure. Elevated tank wall temperatures below the liquid level were clearly characteristic of film boiling. The test results have substantial implications for on-orbit cryogen transfer since the formation of a vapor film would be much less inhibited due to the reduced gravity. However, the heavy tank walls could become an asset in normal gravity testing for on-orbit transfer, i.e., if film boiling in a nonflight weight tank can be inhibited in normal gravity, then analytical modeling anchored with the data could be applied to reduced gravity environments with increased confidence.

  3. CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance.

    PubMed

    Park, Kang-Seo; Raffeld, Mark; Moon, Yong Wha; Xi, Liqiang; Bianco, Caterina; Pham, Trung; Lee, Liam C; Mitsudomi, Tetsuya; Yatabe, Yasushi; Okamoto, Isamu; Subramaniam, Deepa; Mok, Tony; Rosell, Rafael; Luo, Ji; Salomon, David S; Wang, Yisong; Giaccone, Giuseppe

    2014-07-01

    The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC. PMID:24911146

  4. CRIPTO1 expression in EGFR-mutant NSCLC elicits intrinsic EGFR-inhibitor resistance

    PubMed Central

    Park, Kang-Seo; Raffeld, Mark; Moon, Yong Wha; Xi, Liqiang; Bianco, Caterina; Pham, Trung; Lee, Liam C.; Mitsudomi, Tetsuya; Yatabe, Yasushi; Okamoto, Isamu; Subramaniam, Deepa; Mok, Tony; Rosell, Rafael; Luo, Ji; Salomon, David S.; Wang, Yisong; Giaccone, Giuseppe

    2014-01-01

    The majority of non–small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI–sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC. PMID:24911146

  5. A two stage launch vehicle for use as an advanced space transportation system for logistics support of the space station

    NASA Technical Reports Server (NTRS)

    1987-01-01

    This report describes the preliminary design specifications for an Advanced Space Transportation System consisting of a fully reusable flyback booster, an intermediate-orbit cargo vehicle, and a shuttle-type orbiter with an enlarged cargo bay. It provides a comprehensive overview of mission profile, aerodynamics, structural design, and cost analyses. These areas are related to the overall feasibility and usefullness of the proposed system.

  6. Dose escalation with stereotactic body radiation therapy boost for locally advanced non small cell lung cancer

    PubMed Central

    2013-01-01

    Introduction Low survival outcomes have been reported for the treatment of locally advanced non small cell lung cancer (LA-NSCLC) with the standard of care treatment of concurrent chemoradiation (cCRT). We present our experience of dose escalation using stereotactic body radiosurgery (SBRT) following conventional cCRT for patients with LA-NSCLC. Methods Sixteen patients with a median age of 67.5 treated with fractionated SBRT from 2010 to 2012 were retrospectively analyzed. Nine (56%) of the patients had stage IIIB, 6 (38%) has stage IIIA, and 1 (6%) had recurrent disease. Majority of the patients (63%) presented with N2 disease. All patients had a PET CT for treatment planning. Patients received conventional cCRT to a median dose of 50.40 Gy (range 45–60) followed by an SBRT boost with an average dose of 25 Gy (range 20–30) given over 5 fractions. Results With a median follow-up of 14 months (range, 1–14 months), 1-year overall survival (OS), progression free survival (PFS), local control (LC), regional control (RC), and distant control (DC) rates were, 78%, 42%, 76%, 79%, and 71%, respectively. Median times to disease progression and regional failure were 10 months and 18 months, respectively. On univariate analysis, advanced age and nodal status were worse prognostic factors of PFS (p < 0.05). Four patients developed radiation pneumonitis and one developed hemoptysis. Treatment was interrupted in one patient who required hospitalization due to arrhythmias and pneumonia. Conclusion Risk adaptive dose escalation with SBRT following external beam radiotherapy is possible and generally tolerated treatment option for patients with LA-NSCLC. PMID:23842112

  7. Phase II trial of S-1 and cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer

    PubMed Central

    Ohyanagi, F; Yamamoto, N; Horiike, A; Harada, H; Kozuka, T; Murakami, H; Gomi, K; Takahashi, T; Morota, M; Nishimura, T; Endo, M; Nakamura, Y; Tsuya, A; Horai, T; Nishio, M

    2009-01-01

    Background: To assess the efficacy and safety of S-1 and cisplatin with concurrent thoracic radiation for unresectable stage III non-small-cell lung cancer (NSCLC). Methods: Eligible patients were 20–74 years old and had histologically or cytologically confirmed NSCLC, a performance status of 0–1, and no prior chemotherapy. Patients were treated with cisplatin (60 mg m−2 on day 1) and S-1 (orally at 40 mg m−2 per dose, b.i.d., on days 1–14), with the treatment repeated every 4 weeks for four cycles. Beginning on day 2, a 60-Gy thoracic radiation dose was delivered in 30 fractions. Results: Of 50 patients, 48 were eligible. Partial response was observed in 42 patients (87.5%; 95% CI: 79.1–96.9%). This regimen was well tolerated. Common toxicities included grade 3/4 neutropenia (32%), grade 3/4 leukopenia (32%), grade 3/4 thrombocytopenia (4%), grade 3 febrile neutropenia (6%), grade 3 oesophagitis (10%), and grade 3 pneumonitis (5%). Median progression-free survival was 12.0 months and median overall survival was 33.1 months. The 1- and 2-year survival rates were 89.5 and 56%, respectively. Conclusion: This chemotherapy regimen with concomitant radiotherapy is a promising treatment for locally advanced NSCLC because of its high response rates, good survival rates, and mild toxicities. PMID:19603031

  8. Effective avoidance of a functional spect-perfused lung using intensity modulated radiotherapy (IMRT) for non-small cell lung cancer (NSCLC): an update of a planning study.

    PubMed

    Lavrenkov, Konstantin; Singh, Shalini; Christian, Judith A; Partridge, Mike; Nioutsikou, Elena; Cook, Gary; Bedford, James L; Brada, Michael

    2009-06-01

    IMRT and 3-dimensional conformal radiotherapy (3-DCRT) plans of 25 patients with non-small cell lung (NSCLC) were compared in terms of planning target volume (PTV) coverage and sparing of functional lung (FL) defined by a SPECT perfusion scan. IMRT resulted in significant reduction of functional V(20) and mean lung dose in stage III patients with inhomogeneous hypoperfusion. If the dose to FL is shown to be the determinant of lung toxicity, IMRT would allow for effective dose escalation by specific avoidance of functional lung. PMID:18995919

  9. Granulocyte colony-stimulating factor in secondary prophylaxis for advanced-stage Hodgkin lymphoma treated with ABVD chemotherapy: a cost-effectiveness analysis.

    PubMed

    Cheung, M C; Prica, A; Graczyk, J; Buckstein, R; Chan, K K W

    2016-08-01

    Granulocyte colony-stimulating factor (G-CSF) is commonly administered to patients with Hodgkin lymphoma (HL) with neutropenia. We constructed a decision-analytic model to compare the cost-effectiveness of secondary prophylaxis with G-CSF to a strategy of 'no G-CSF' in response to severe neutropenia for adults with advanced-stage HL treated with ABVD. A Canadian public health payer's perspective was considered and costs were presented in 2013 Canadian dollars. The quality-adjusted life years (QALYs) attained with the G-CSF and 'no G-CSF' strategies were 1.403 and 1.416, respectively. Costs for the strategies with and without G-CSF were $38,971 and $33,982, respectively. In the base case analysis, the 'no G-CSF' strategy was associated with cost savings and improved QALYs; therefore, 'no G-CSF' was the dominant approach. For patients with severe neutropenia during ABVD chemotherapy for advanced-stage HL, a strategy without G-CSF support is associated with improved quality-adjusted outcomes, cost savings, and is the preferred approach. PMID:26758765

  10. Single stage, low noise, advanced technology fan. Volume 5: Fan acoustics. Section 2: One-third octave data tabulations and selected narrowband traces

    NASA Technical Reports Server (NTRS)

    Jutras, R. R.

    1976-01-01

    The raw-acoustic data corrected to standard day, from acoustic tests performed on a 0.508-scale fan vehicle of a 111,300 newton thrust, full-size engine, which has application on an advanced transport aircraft, are presented. The single-stage advanced technology fan was designed to a pressure ratio of 1.8 at a tip speed of 503 m/sec to achieve the desired pressure ratio in a single-stage fan with low radius ratio, and to maintain adequate stall margin. The two basic approaches taken in the acoustic design were: (1) minimization of noise at the source, and (2) suppression of the generated noise in the inlet and bypass exhaust duct. Suppression of the generated noise was accomplished in the inlet through use of the hybrid concept (wall acoustic treatment plus airflow acceleration suppression) and in the exhaust duct with extensive acoustic treatment including a splitter. The goal of the design was attainment of twenty effective perceived noise decibels. The suppression goal of FAR 36-20 was not reached, but improvements in the technology of both front and aft fan-noise suppression were realized.

  11. Knockdown of ANXA1 suppresses the biological behavior of human NSCLC cells in vitro

    PubMed Central

    FANG, YING; GUAN, XIAOYING; CAI, TONGHUI; LONG, JIE; WANG, HONGYAN; XIE, XIAOBIN; ZHANG, YAJIE

    2016-01-01

    Annexin A1 (ANXA1) is a member of the annexin superfamily. Previous studies have reported that ANXA1 is highly expressed in various types of malignant tumor; however, its role in the progression of non-small cell lung cancer (NSCLC) remains to be fully clarified. The present study aimed to investigate the oncogenic role of ANXA1 in NSCLC cells in vitro. RNA interference was used to down-regulate ANXA1 expression in A549 and H1299 cells using a small interfering RNA lentiviral vector. Subsequently, cell proliferation and migration were detected using Cell Counting kit-8, clone formation, wound healing and Transwell chamber assays. Successful transfection was confirmed using fluorescence microscopy, which demonstrated that ANXA1 had been efficiently inhibited. ANXA1 knockdown suppressed the proliferation, migration and invasion of NSCLC cells. In conclusion, the present study provided evidence suggesting that ANXA1 may contribute to the growth and invasion of NSCLC cell lines, and ANXA1 may be exploited as an in vitro therapeutic target for the treatment of NSCLC. PMID:27035116

  12. Knockdown of ANXA1 suppresses the biological behavior of human NSCLC cells in vitro.

    PubMed

    Fang, Ying; Guan, Xiaoying; Cai, Tonghui; Long, Jie; Wang, Hongyan; Xie, Xiaobin; Zhang, Yajie

    2016-05-01

    Annexin A1 (ANXA1) is a member of the annexin superfamily. Previous studies have reported that ANXA1 is highly expressed in various types of malignant tumor; however, its role in the progression of non‑small cell lung cancer (NSCLC) remains to be fully clarified. The present study aimed to investigate the oncogenic role of ANXA1 in NSCLC cells in vitro. RNA interference was used to downregulate ANXA1 expression in A549 and H1299 cells using a small interfering RNA lentiviral vector. Subsequently, cell proliferation and migration were detected using Cell Counting kit‑8, clone formation, wound healing and Transwell chamber assays. Successful transfection was confirmed using fluorescence microscopy, which demonstrated that ANXA1 had been efficiently inhibited. ANXA1 knockdown suppressed the proliferation, migration and invasion of NSCLC cells. In conclusion, the present study provided evidence suggesting that ANXA1 may contribute to the growth and invasion of NSCLC cell lines, and ANXA1 may be exploited as an in vitro therapeutic target for the treatment of NSCLC. PMID:27035116

  13. Advanced space engine preliminary design. [liquid hydrogen/liquid oxygen upper stage engine for space tug application

    NASA Technical Reports Server (NTRS)

    Zachary, A. T.

    1973-01-01

    Analysis and design of an optimum LO2/LH2, combustion topping cycle, 88,964 Newtons (20,000-pound) thrust, liquid rocket engine was conducted. The design selected is well suited to high-energy, upper-stage engine applications such as the Space Tug and embodies features directed toward optimization of vehicle performance. A configuration selection was conducted based on prior Air Force Contracts, and additional criteria for optimum stage performance. Following configuration selection, analyses and design of the major components and engine systems were conducted to sufficient depth to provide layout drawings suitable for subsequent detailing. In addition, engine packaging to a common interface and a retractable nozzle concept were defined. Alternative development plans and related costs were also established. The design embodies high-performance, low-weight, low NPSH requirements (saturated propellant inlet conditions at start), idle-mode operation, and autogenous pressurization. The design is the result of the significant past and current LO2/LH2 technology efforts of the NASA centers and the Air Force, as well as company-funded programs.

  14. Treatment of liver cancer of middle and advanced stages using ultrasound-guided percutaneous ethanol injection combined with radiofrequency ablation: A clinical analysis

    PubMed Central

    SUN, XUE; LI, RU; ZHANG, BOTAO; YANG, YUEJIE; CUI, ZHIFEI

    2016-01-01

    Liver cancer is a malignancy of the digestive system and has a high morbidity and mortality rate. Local intervention has become a viable option in identifying liver treatment. The aim of the present study was to analyze the clinical effects of treating liver cancer in middle and advanced stages using ultrasound-guided percutaneous ethanol injection (PEI) in tumors combined with radiofrequency ablation (RFA). A total of 100 patients with stage III–IV liver cancers were selected to participate in the study. Patients were divided into groups. In group A, treatment was initiated with PEI and after 1–2 weeks RFA was applied while in group B treatment was initiated with RFA and after 1–2 weeks PEI was applied. Patients in group C received PEI and RFA simultaneously. The clinical effects in the 3 groups were compared after 6-month follow ups. The volume of tumor ablation necrosis in group A was significantly greater than that in the groups B and C, while the size was significantly smaller compared to groups B and C after ablation. For group A, the complete ablation rate was significantly higher than that in groups B and C, and the differences were statistically significant (P<0.05). Liver damage indices, including raising levels of glutamic-pyruvic transaminase and total bilirubin, were significantly decreased in group A (P<0.05). The survival rate in group A was also significantly higher than in groups B and C (P<0.05). In conclusion, for patients with liver cancer in middle and advanced stages, the treatment method using PEI followed by RFA was more beneficial in terms of improving the tumor ablation rate, alleviating liver damages and increasing survival rates. PMID:26998128

  15. Radiochemotherapy plus 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in Advanced-Stage Cervical and Vaginal Cancers

    PubMed Central

    Kunos, Charles A.; Radivoyevitch, Tomas; Waggoner, Steven; Debernardo, Robert; Zanotti, Kristine; Resnick, Kimberly; Fusco, Nancy; Adams, Ramon; Redline, Raymond; Faulhaber, Peter; Dowlati, Afshin

    2013-01-01

    Objective Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. Methods We conducted a phase II study evaluating 3x weekly 2-hour intravenous 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m2) co-administered with 1x weekly intravenous cisplatin (40 mg/m2) and daily pelvic radiation (45 Gy) in women with stage IB2-IVB cervical (n = 22) or stage II-IV vaginal (n = 3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (PET/CT) and clinical examination. Results 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. Conclusions The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted. PMID:23603372

  16. Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model

    PubMed Central

    Scarisbrick, Julia J.; Prince, H. Miles; Vermeer, Maarten H.; Quaglino, Pietro; Horwitz, Steven; Porcu, Pierluigi; Stadler, Rudolf; Wood, Gary S.; Beylot-Barry, Marie; Pham-Ledard, Anne; Foss, Francine; Girardi, Michael; Bagot, Martine; Michel, Laurence; Battistella, Maxime; Guitart, Joan; Kuzel, Timothy M.; Martinez-Escala, Maria Estela; Estrach, Teresa; Papadavid, Evangelia; Antoniou, Christina; Rigopoulos, Dimitis; Nikolaou, Vassilki; Sugaya, Makoto; Miyagaki, Tomomitsu; Gniadecki, Robert; Sanches, José Antonio; Cury-Martins, Jade; Miyashiro, Denis; Servitje, Octavio; Muniesa, Cristina; Berti, Emilio; Onida, Francesco; Corti, Laura; Hodak, Emilia; Amitay-Laish, Iris; Ortiz-Romero, Pablo L.; Rodríguez-Peralto, Jose L.; Knobler, Robert; Porkert, Stefanie; Bauer, Wolfgang; Pimpinelli, Nicola; Grandi, Vieri; Cowan, Richard; Rook, Alain; Kim, Ellen; Pileri, Alessandro; Patrizi, Annalisa; Pujol, Ramon M.; Wong, Henry; Tyler, Kelly; Stranzenbach, Rene; Querfeld, Christiane; Fava, Paolo; Maule, Milena; Willemze, Rein; Evison, Felicity; Morris, Stephen; Twigger, Robert; Talpur, Rakhshandra; Kim, Jinah; Ognibene, Grant; Li, Shufeng; Tavallaee, Mahkam; Hoppe, Richard T.; Duvic, Madeleine; Whittaker, Sean J.; Kim, Youn H.

    2015-01-01

    Purpose Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. Patients and Methods Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). Results Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). Conclusion To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and

  17. Studies of Advanced Stages of Meditation in the Tibetan Buddhist and Vedic Traditions. I: A Comparison of General Changes

    PubMed Central

    Hankey, Alex

    2006-01-01

    This article is the first of two comparing findings of studies of advanced practitioners of Tibetan Buddhist meditation in remote regions of the Himalayas, with established results on long-term practitioners of the Transcendental Meditation programs. Many parallel levels of improvement were found, in sensory acuity, perceptual style and cognitive function, indicating stabilization of aspects of attentional awareness. Together with observed increases in EEG coherence and aspects of brain function, such changes are consistent with growth towards a state of total brain functioning, i.e. development of full mental potential. They are usually accompanied by improved health parameters. How they may be seen to be consistent with growth of enlightenment will be the subject of a second article. PMID:17173116

  18. 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

  19. MiR-449c targets c-Myc and inhibits NSCLC cell progression.

    PubMed

    Miao, Li-Jun; Huang, Shi-Fu; Sun, Zhen-Tao; Gao, Zeng-Yan; Zhang, Rui-Xia; Liu, Ying; Wang, Jing

    2013-05-01

    MicroRNAs (miRNA) play an important role in tumorigenesis, proliferation, and differentiation. Altered miRNA expression in cancer indicates that miRNAs can function as tumor suppressors or oncogenes. MiR-449c downregulation in non-small cell lung cancer (NSCLC) compared with normal lung tissues was investigated in this study. NSCLC cell proliferation and invasion assays indicate that transfection of miR-449c expression plasmid inhibits the proliferation and invasion ability of NCI-H23 and NCI-H838 cells. In addition, miR-449c overexpression could suppress tumor growth in vivo. Morever, c-Myc was identified as a direct target gene of miR-449c. These findings clearly suggest that miR-449c downregulation and c-Myc amplification may be involved in the development of NSCLC. PMID:23507140

  20. Tumor deposits counted as positive lymph nodes in TNM staging for advanced colorectal cancer: a retrospective multicenter study

    PubMed Central

    Li, Jun; Yang, Shengke; Hu, Junjie; Liu, Hao; Du, Feng; Yin, Jie; Liu, Sai; Li, Ci; Xing, Shasha; Yuan, Jiatian; Lv, Bo; Fan, Jun; Leng, Shusheng; Zhang, Xin; Wang, Bing

    2016-01-01

    We investigated the possibility of counting tumor deposits (TDs) as positive lymph nodes (pLNs) in the pN category and evaluated its prognostic value for colorectal cancer (CRC) patients. A new pN category (npN category) was calculated using the numbers of pLNs plus TDs. The npN category included 4 tiers: npN1a (1 tumor node), npN1b (2-3 tumor nodes), npN2a (4-6 tumor nodes), and npN2b (≥7 tumor nodes). We identified 4,121 locally advanced CRC patients, including 717 (11.02%) cases with TDs. Univariate and multivariate analyses were performed to evaluate the disease-free and overall survival (DFS and OS) for npN and pN categories. Multivariate analysis showed that the npN and pN categories were both independent prognostic factors for DFS (HR 1.614, 95% CI 1.541 to 1.673; HR 1.604, 95% CI 1.533 to 1.679) and OS (HR 1.633, 95% CI 1.550 to 1.720; HR 1.470, 95% CI 1.410 to 1.532). However, the npN category was superior to the pN category by Harrell's C statistic. We conclude that it is thus feasible to consider TDs as positive lymph nodes in the pN category when evaluating the prognoses of CRC patients, and the npN category is potentially superior to the TNM (7th edition) pN category for predicting DFS and OS among advanced CRC patients. PMID:26934317

  1. The Latest in Surgical Management of Stage IIIA Non-Small Cell Lung Cancer: Video-Assisted Thoracic Surgery and Tumor Molecular Profiling.

    PubMed

    Woodard, Gavitt A; Jablons, David M

    2015-01-01

    Stage IIIA non-small cell lung cancer (NSCLC) remains a treatment challenge and requires a multidisciplinary care team to optimize survival outcomes. Thoracic surgeons play an important role in selecting operative candidates and assisting with pathologic mediastinal staging via cervical mediastinoscopy, endobronchial ultrasound, or esophageal ultrasound with fine needle aspiration. The majority of patients with stage IIIA disease will receive induction therapy followed by repeat staging before undergoing lobectomy or pneumonectomy; occasionally, a patient with an incidentally found, single-station microscopic IIIA tumor will undergo resection as the primary initial therapy. Multiple large clinical trials, including SWOG-8805, EORTC-8941, INT-0139, and ANITA, have shown 5-year overall survival rates of up to 30% to 40% using triple-modality treatments, and the best outcomes repeatedly are seen among patients who respond to induction treatment or who have tumors amenable to lobectomy instead of pneumonectomy. The need for a pneumonectomy is not a reason to deny patients an operation, because current operative mortality and morbidity rates are acceptably low at 5% and 30%, respectively. In select patients with stage IIIA disease, video-assisted thoracic surgery and open resections have been shown to have comparable rates of local recurrence and long-term survival. New developments in genetic profiling and personalized medicine are exciting areas of research, and early data suggest that molecular profiling of stage IIIA NSCLC tumors can accurately stratify patients by risk within this stage and predict survival outcomes. Future advances in treating stage IIIA disease will involve developing better systemic therapies and customizing treatment plans on the basis of an individual tumor's genetic profile. PMID:25993207

  2. Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status

    PubMed Central

    Xiao, Zhiguang; Sperl, Bianca; Ullrich, Axel; Knyazev, Pjotr

    2014-01-01

    The presence of cancer stem cells (CSCs) is linked to preexisting or acquired drug resistance and tumor relapse. Therefore, targeting both differentiated tumor cells and CSCs was suggested as an effective approach for non-small cell lung cancer (NSCLC) treatment. After screening of chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) or monoclonal antibody in combination with the putative stem cell killer Salinomycin (SAL), we found Metformin (METF), which modestly exerted a growth inhibitory effect on monolayer cells and alveospheres/CSCs of 5 NSCLC cell lines regardless of their EGFR, KRAS, EML4/ALK and LKB1 status, interacted synergistically with SAL to effectively promote cell death. Inhibition of EGFR (AKT, ERK1/2) and mTOR (p70 s6k) signaling with the combination of METF and SAL can be augmented beyond that achieved using each agent individually. Phospho-kinase assay further suggested the multiple roles of this combination in reducing oncogenic effects of modules, such as ß-catenin, Src family kinases (Src, Lyn, Yes), Chk-2 and FAK. Remarkably, significant reduction of sphere formation was seen under combinatorial treatment in all investigated NSCLC cell lines. In conclusion, METF in combination with SAL could be a promising treatment option for patients with advanced NSCLC irrespective of their EGFR, KRAS, EML4/ALK and LKB1 status. PMID:25375092

  3. Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status.

    PubMed

    Xiao, Zhiguang; Sperl, Bianca; Ullrich, Axel; Knyazev, Pjotr

    2014-12-30

    The presence of cancer stem cells (CSCs) is linked to preexisting or acquired drug resistance and tumor relapse. Therefore, targeting both differentiated tumor cells and CSCs was suggested as an effective approach for non-small cell lung cancer (NSCLC) treatment. After screening of chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) or monoclonal antibody in combination with the putative stem cell killer Salinomycin (SAL), we found Metformin (METF), which modestly exerted a growth inhibitory effect on monolayer cells and alveospheres/CSCs of 5 NSCLC cell lines regardless of their EGFR, KRAS, EML4/ALK and LKB1 status, interacted synergistically with SAL to effectively promote cell death. Inhibition of EGFR (AKT, ERK1/2) and mTOR (p70 s6k) signaling with the combination of METF and SAL can be augmented beyond that achieved using each agent individually. Phospho-kinase assay further suggested the multiple roles of this combination in reducing oncogenic effects of modules, such as ß-catenin, Src family kinases (Src, Lyn, Yes), Chk-2 and FAK. Remarkably, significant reduction of sphere formation was seen under combinatorial treatment in all investigated NSCLC cell lines. In conclusion, METF in combination with SAL could be a promising treatment option for patients with advanced NSCLC irrespective of their EGFR, KRAS, EML4/ALK and LKB1 status. PMID:25375092

  4. HBP1 promoter methylation augments the oncogenic β-catenin to correlate with prognosis in NSCLC

    PubMed Central

    Tseng, Ruo-Chia; Huang, Way-Ren; Lin, Su-Feng; Wu, Pei-Chen; Hsu, Han-Shui; Wang, Yi-Ching

    2014-01-01

    β-catenin nuclear accumulation is frequently identified in human non-small cell lung cancer (NSCLC). The HMG-box transcription factor 1 (HBP1) is a known repressor of β-catenin transactivation. However, the role of HBP1 in relation to β-catenin nuclear accumulation has not been addressed in human cancer patients. In addition, the mechanism of HBP1 gene alteration in NSCLC remains unclear, although HBP1 mutation and gene deletion of HBP1 are reported in breast and colon cancers. Here, we demonstrate that HBP1 acts as a tumour suppressor and serves as a prognostic biomarker in NSCLC clinical and cell models. The immunohistochemistry data indicated that 30.5% (25/82) of tumours from NSCLC patients showed absence or low expression of HBP1 protein. A significant inverse correlation between mRNA/protein expression and promoter hypermethylation suggested that promoter hypermethylation is responsible for low expression of HBP1 in NSCLC patients. Reactivation of HBP1 expression by demethylation reagent or ectopic expression of HBP1 suppressed β-catenin transactivation. Conversely, HBP1 knockdown increased β-catenin transactivation. Importantly, preserved expression of HBP1 had a significantly protective effect on prognosis in patients with β-catenin nuclear accumulation, suggesting that low expression of HBP1 in NSCLC patients with β-catenin nuclear accumulation was one of the major determinants of prognosis. Our data from cellular and clinical models suggest that HBP1 is a suppressor of cancer progression, making it a potential prognostic predictor and therapeutic target to attenuate lung cancer progression. PMID:24895061

  5. 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.

  6. 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.

  7. Predictors of Surgery Types after Neoadjuvant Therapy for Advanced Stage Breast Cancer: Analysis from Florida Population-Based Cancer Registry (1996–2009)

    PubMed Central

    Al-Azhri, Jamila; Koru-Sengul, Tulay; Miao, Feng; Saclarides, Constantine; Byrne, Margaret M.; Avisar, Eli

    2015-01-01

    PURPOSE Despite the established guidelines for breast cancer treatment, there is still variability in surgical treatment after neoadjuvant therapy (NT) for women with large breast tumors. Our objective was to identify predictors of the type of surgical treatment: mastectomy versus breast-conserving surgery (BCS) in women with T3/T4 breast cancer who received NT. METHODS Population-based Florida Cancer Data System Registry, Florida’s Agency for Health Care Administration, and US census from 1996 to 2009 were linked for women diagnosed with T3/T4 breast cancer and received NT followed by either BCS or mastectomy. Analysis of multiple variables, such as sociodemographic characteristics (race, ethnicity, socioeconomic status, age, marital status, and urban/rural residency), tumor’s characteristics (estrogen/progesterone receptor status, histology, grade, SEER stage, and regional nodes positivity), treatment facilities (hospital volume and teaching status), patients’ comorbidities, and type of NT, was performed. RESULTS Of 1,056 patients treated with NT for T3/T4 breast cancer, 107 (10%) had BCS and 949 (90%) had mastectomy. After adjusting with extensive covariables, Hispanic patients (adjusted odds ratio (aOR) = [3.50], 95% confidence interval (CI): 1.38–8.84, P = 0.008) were more likely to have mastectomy than BCS. Compared to localized SEER stage, regional stage with direct extension (aOR = [3.24], 95% CI: 1.60–6.54, P = 0.001), regional stage with direct extension and nodes (aOR = [4.35], 95% CI: 1.72–11.03, P = 0.002), and distant stage (aOR = [4.44], 95% CI: 1.81–10.88, P = 0.001) were significantly more likely to have mastectomy than BCS. Compared to patients who received both chemotherapy and hormonal therapy, patients who received hormonal NT only (aOR = [0.29], 95% CI: 0.12–0.68, P = 0.004) were less likely to receive mastectomy. CONCLUSION Our study suggests that Hispanic ethnicity, advanced SEER stage, and type of NT are significant

  8. Advances in chemical and physical properties of electric arc furnace carbon steel slag by hot stage processing and mineral mixing.

    PubMed

    Liapis, Ioannis; Papayianni, Ioanna

    2015-01-01

    Slags are recognised as a highly efficient, cost effective tool in the metal processing industry, by minimising heat losses, reducing metal oxidation through contact with air, removing metal impurities and protecting refractories and graphite electrodes. When compared to natural aggregates for use in the construction industry, slags have higher specific weight that acts as an economic deterrent. A method of altering the specific weight of EAFC slag by hot stage processing and mineral mixing, during steel production is presented in this article. The method has minimal interference with the production process of steel, even by limited additions of appropriate minerals at high temperatures. Five minerals are examined, namely perlite, ladle furnace slag, bauxite, diatomite and olivine. Measurements of specific weight are accompanied by X-ray diffraction (XRD) and fluorescence (XRF) analysis and scanning electron microscopy spectral images. It is also shown how altering the chemical composition is expected to affect the furnace refractory lining. Additionally, the process has been repeated for the most suitable mix in gas furnace and physical properties (FI, SI, LA, PSV, AAV, volume stability) examined. Alteration of the specific weight can result in tailoring slag properties for specific applications in the construction sector. PMID:25261762

  9. In vivo response of the rat's retinal pigment epithelium to azide at advanced stages of hereditary retinal dystrophy.

    PubMed

    Ando, H; Noell, W K

    1993-01-01

    Electrophysiological properties of the retinal pigment epithelium (RPE) were studied in the rat with hereditary retinal dystrophy (rdy). Transocular potential changes evoked by intravenous bolus injections of azide and thiocyanate (SCN-) are the only available indication of RPE state when degeneration of rods is in progress. Also determined were age-dependent decrease in retinal DNA content and in counts of cones that survive after degeneration of rods. The azide response in the pigmented and albino rdy rat was already reduced at the earliest age tested (60 d) and continued to decrease till the age of 2 years. The SCN-response was similarly affected but seemed to decline faster than the azide response. The azide/SCN- response ratio was significantly increased in albino mutants, especially around the age of 400 d. At the age of 10 months and later, the azide and SCN- responses became slower than those of normals. A prolonged exposure of 1,200 1x light to dystrophic rats older than 110 did not affect the azide and SCN- responses whereas the same exposure abolishes the responses of normal rats and of the dystrophic rats at early stages. In rdy rats, the electrophysiological changes were considered to correlate with structural changes of the junctional RPE complex and with abnormal membrane enzyme distribution discovered by others. These RPE changes may contribute to the decreasing cone cell number after rod cell disappearance. PMID:8230852

  10. A comparison of patients with hepatitis B- or hepatitis C-based advanced-stage hepatocellular carcinoma.

    PubMed

    Carr, Brian I; Guerra, Vito; Steel, Jennifer L; Lu, Sheng-Nan

    2015-04-01

    Hepatocellular carcinoma (HCC) is a leading cause of cancer death and has characteristic causes, epidemiology and clinical features. The leading causes include hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholism, and aflatoxin B1 dietary exposure, as well as combinations of these factors. Few cancers offer the opportunity to study the clinical and cancer phenotype that results from different causes, quite like HCC. Advantage was taken of a large cohort of advanced, unresectable and untransplantable HCCs to compare the phenotypes resulting from HBV-based compared with HCV-based HCC. The main findings were that HBV-based HCC patients were statistically significantly younger, had a higher percent of males, had larger maximum tumor sizes, and had higher blood alpha-fetoprotein (AFP) and albumin levels and platelet counts than HCV-based HCC patients. These differences partly reflect an earlier age of HBV infection and a lesser degree of cirrhosis-associated liver damage, as a result of the different biological consequences of chronic HBV compared with chronic HCV infection. PMID:25843735

  11. Pilot study of modified LMB-based therapy for children with ataxia-telangiectasia and advanced stage high grade mature b-cell malignancies

    PubMed Central

    Sandlund, J. T.; Hudson, M. M.; Kennedy, W.; Onciu, M.; Kastan, M. B.

    2014-01-01

    Children with ataxia-telangiectasia (A-T) and cancer have a poorer prognosis due in part to increased treatment-related toxicity. We piloted a curative intent approach in five children with A-T who presented with advanced stage (III, n=2; IV, n=3) B-NHL (diffuse large B-cell lymphoma, n=4; Burkitt leukemia, n=1) using a modified LMB-based protocol. Two achieved sustained CCR (one, CCR at 6 years; one, pulmonary death after 3 years in CCR). Two died from toxicity during induction and 1 failed induction with progressive disease. Novel therapeutic approaches which overcome drug resistance and are less toxic are needed for children with A-T and B-NHL. PMID:23900766

  12. Personalizing Therapy in Advanced Non–Small Cell Lung Cancer

    PubMed Central

    Villaruz, Liza C.; Burns, Timothy F.; Ramfidis, Vasilis S.; Socinski, Mark A.

    2016-01-01

    The recognition that non–small cell lung cancer (NSCLC) is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms, has permanently shifted the therapeutic landscape of NSCLC to a personalized approach. This personalization of NSCLC therapy is typified by the dramatic response rates seen in EGFR mutant NSCLC when treated with targeted tyrosine kinase inhibitor therapy and in ALK translocation–driven NSCLC when treated with ALK inhibitors. Targeted therapeutic approaches in NSCLC necessitate consideration of more invasive biopsy techniques aimed at providing sufficient tissue for both histological determination and molecular profiling in all patients with stage IV disease both at the time of diagnosis and at the time of disease progression. Comprehensive genotyping efforts have identified oncogenic drivers in 62% lung adenocarcinomas and an increasing proportion of squamous cell carcinomas of the lung. The identification of these oncogenic drivers and the triage of patients to clinical trials evaluating novel targeted therapeutic approaches will increasingly mold a landscape of personalized lung cancer therapy where each genotype has an associated targeted therapy. This review outlines the state of personalized lung cancer therapy as it pertains to individual NSCLC genotypes. PMID:24258572

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  15. Hematogenous Splenic Metastases as an Independent Negative Prognosis Factor at the Moment of Primary Cytoreduction in Advanced Stage Epithelial Ovarian Cancer--A Single Center Experience.

    PubMed

    Bacalbasa, Nicolae; Balescu, Irina; Dima, Simona; Brasoveanu, Vladislav; Popescu, Irinel

    2015-10-01

    Ovarian cancer represents an aggressive gynecological malignancy with a high capacity for dissemination. Once the tumor cells go beyond the pelvic area, upper abdominal involvement, including hepatic, diaphragmatic or even splenic, is frequently seen. The aim of the present study was to determine the impact on survival of parenchymatous versus peritoneal splenic metastases versus splenic hilum lymph node involvement at the time of primary cytoreduction for advanced-stage epithelial ovarian cancer. Sixty-six patients with a mean age of 54.12 years (range=25-80 years) were submitted to splenectomy in the context of primary cytoreduction at the Dan Setlacec Center of Gastrointestinal Disease and Liver Transplantation, Fundeni Clinical Institute, between January 2002 and May 2014. Although complete macroscopic resection was attempted in all cases, an R0 resection was achieved only in 57 out of the 66 cases. Histopathological studies confirmed the presence of serous subtype in 61 cases, while in the other five cases, the mucinous subtype was found. When studying the specimens of splenectomy, capsular invasion was found in 35 cases (53%), parenchymatous involvement was present in 19 (28.7%), and hilar involvement was present in 12 (18.1%). The overall morbidity rate was 30%, while the 30-day postoperative mortality rate was 7%. The median overall survival for cases with peritoneal seeding was 58.4 months, while that for patients with parenchymatous involvement was 24.5 months (p=0.0126); patients diagnosed with hilar involvement had a median overall survival of 40.6 months (p=0.362). In conclusion, the presence of parenchymatous splenic metastases at primary cytoreduction for advanced-stage ovarian cancer is associated with significantly poorer survival when compared to hilar or peritoneal seeding. PMID:26408738

  16. An ovary transcriptome for all maturational stages of the striped bass (Morone saxatilis), a highly advanced perciform fish

    PubMed Central

    2012-01-01

    Background The striped bass and its relatives (genus Morone) are important fisheries and aquaculture species native to estuaries and rivers of the Atlantic coast and Gulf of Mexico in North America. To open avenues of gene expression research on reproduction and breeding of striped bass, we generated a collection of expressed sequence tags (ESTs) from a complementary DNA (cDNA) library representative of their ovarian transcriptome. Results Sequences of a total of 230,151 ESTs (51,259,448 bp) were acquired by Roche 454 pyrosequencing of cDNA pooled from ovarian tissues obtained at all stages of oocyte growth, at ovulation (eggs), and during preovulatory atresia. Quality filtering of ESTs allowed assembly of 11,208 high-quality contigs ≥ 100 bp, including 2,984 contigs 500 bp or longer (average length 895 bp). Blastx comparisons revealed 5,482 gene orthologues (E-value < 10-3), of which 4,120 (36.7% of total contigs) were annotated with Gene Ontology terms (E-value < 10-6). There were 5,726 remaining unknown unique sequences (51.1% of total contigs). All of the high-quality EST sequences are available in the National Center for Biotechnology Information (NCBI) Short Read Archive (GenBank: SRX007394). Informative contigs were considered to be abundant if they were assembled from groups of ESTs comprising ≥ 0.15% of the total short read sequences (≥ 345 reads/contig). Approximately 52.5% of these abundant contigs were predicted to have predominant ovary expression through digital differential display in silico comparisons to zebrafish (Danio rerio) UniGene orthologues. Over 1,300 Gene Ontology terms from Biological Process classes of Reproduction, Reproductive process, and Developmental process were assigned to this collection of annotated contigs. Conclusions This first large reference sequence database available for the ecologically and economically important temperate basses (genus Morone) provides a foundation for gene expression studies in these species. The

  17. Evaluation of 30-Day Hospital Readmission After Surgery for Advanced-Stage Ovarian Cancer in a Medicare Population

    PubMed Central

    Eskander, Ramez N.; Chang, Jenny; Ziogas, Argyrios; Anton-Culver, Hoda; Bristow, Robert E.

    2014-01-01

    Purpose To analyze rate, risk factors, and costs associated with 30-day readmission after ovarian cancer surgery. Patients and Methods The SEER-Medicare linked database (1992 to 2010) was used to evaluate readmission rates within 30 days of index surgery in patients with stage IIIC/IV ovarian, primary peritoneal, or fallopian tube cancer. Multivariable logistic regression was used to identify factors associated with readmission. Results Of 5,152 eligible patients, 1,003 (19.5%) were readmitted within 30 days of discharge. Mean patient age was 75 years. Diagnoses associated with readmission included infection (34.7%), dehydration (34.3%), ileus/obstruction (26.2%), metabolic/electrolyte derangements (23.1%), and anemia (12.3%). In multivariable analysis, year of discharge was significantly associated with 30-day readmission (1996 to 2000: odds ratio [OR], 1.32; 95% CI, 1.01 to 1.71; 2001 to 2005: OR, 1.58; 95% CI, 1.24 to 2.0; 2006 to 2010: OR, 1.73; 95% CI, 1.35 to 2.21; referent years 1992 to 1995), as were length of index hospital stay more than 8 days (OR, 1.39; 95% CI, 1.18 to 1.64) and discharge to a skilled nursing facility (OR, 1.3; 95% CI, 1.04 to 1.63). Patients readmitted within 30 days had a significantly greater 1-year mortality rate compared with patients not readmitted (41.1% v 25.1%, respectively; P < .001). The median cost of readmission hospital stay was $9,220 in year 2010 dollars, with a total cost of $9.3 million over the study period. Conclusion Early readmission after surgery for ovarian cancer is common. There is a significant association between 30-day readmission and 1-year mortality. These findings may catalyze development of targeted interventions to decrease early readmission, improve patient outcomes, and control health care costs. PMID:25385738

  18. 6p22.3 amplification as a biomarker and potential therapeutic target of advanced stage bladder cancer

    PubMed Central

    Zhang, Jianmin; Underwood, Willie; Yang, Nuo; Frangou, Costa; Eng, Kevin; Head, Karen; Bollag, Roni J.; Kavuri, Sravan K.; Rojiani, Amyn M.; Li, Yingwei; Yan, Li; Hill, Annette; Woloszynska-Read, Anna; Wang, Jianmin; Liu, Song; Trump, Donald L.; Candace, Johnson S.

    2013-01-01

    Genetic and epigenetic alterations have been identified as to contribute directly or indirectly to the generation of transitional cell carcinoma of the urinary bladder (TCC-UB). In a comparative fashion much less is known about copy number alterations in TCC-UB, but it appears that amplification of chromosome 6p22 is one of the most frequent changes. Using fluorescence in situ hybridization (FISH) analyses, we evaluated chromosomal 6p22 amplification in a large cohort of bladder cancer patients with complete surgical staging and outcome data. We have also used shRNA knockdown candidate oncogenes in the cell based study. We found that amplification of chromosome 6p22.3 is significantly associated with the muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) (22%) in contrast to superficial TCC-UB (9%) (p=7.2-04). The rate of 6p22.3 amplification in pN>1 patients (32%) is more than twice that in pN0 (16%) patients (p=0.05). Interestingly, we found that 6p22.3 amplification is as twice as high (p=0.0201) in African American (AA) than European American (EA) TCC-UB patients. Moreover, we showed that the expression of some candidate genes (E2F3, CDKAL1 and Sox4) in the 6p22.3 region is highly correlated with the chromosomal amplification. In particular, knockdown of E2F3 inhibits cell proliferation in a 6p22.3-dependent manner, whereas knockdown of CDKAL1 and Sox4 has no effect on cell proliferation. Using gene expression profiling, we further identified some common as well as distinctive subset targets of the E2F3 family members. In summary, our data indicate that E2F3 is a key regulator of cell proliferation in a subset of bladder cancer and the 6p22.3 amplicon is a biomarker of aggressive phenotype in this tumor type. PMID:24231253

  19. R-CHOP with Iodine-131 Tositumomab Consolidation for Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG S0433

    PubMed Central

    Friedberg, Jonathan W.; Unger, Joseph M.; Burack, W. Richard; Gopal, Ajay K.; Raju, Robert N.; Nademanee, Auayporn P.; Kaminski, Mark S.; Li, Hongli; Press, Oliver W.; Miller, Thomas P.; Fisher, Richard I.

    2014-01-01

    Radiolabelled antiCD-20 antibodies have demonstrated single agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). The S0433 clinical trial enrolled patients with newly diagnosed, advanced stage or bulky stage II, histologically confirmed DLBCL. Patients received six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles of CHOP, then iodine-131 tositumomab radioimmunotherapy consolidation 30–60 days after completion of chemotherapy. The primary endpoint was two-year progression-free survival (PFS). Eighty-four eligible patients were enrolled, and 56 patients completed the entire course of protocol treatment. Of the 84 patients evaluable for treatment response, 72 (86%, 95% confidence interval [CI]: 76%–92%) achieved a partial response (n=21) or a confirmed (n=41) or unconfirmed (n=10) complete response to therapy. With a median follow-up of 3.9 years, the 2-year PFS estimate is 69% and the 2-year overall survival estimate is 77%. Rituximab levels at time of radioimmunotherapy did not correlate with toxicity or outcome. Twenty percent of patients had double hit features (MYC+; BCL2+) by immunohistochemistry, and had inferior outcome. These current results suggest that the incorporation of novel agents earlier in therapy may ultimately have greater impact in DLBCL, as early progressions, deaths and declining performance status during CHOP chemotherapy limited the number of patients who ultimately could benefit from radioimmunotherapy consolidation. PMID:24749780

  20. Modeling and Test Data Analysis of a Tank Rapid Chill and Fill System for the Advanced Shuttle Upper Stage (ASUS) Concept

    NASA Technical Reports Server (NTRS)

    Flachbart, Robin; Hedayat, Ali; Holt, Kimberly A.; Cruit, Wendy (Technical Monitor)

    2001-01-01

    The Advanced Shuttle Upper Stage (ASUS) concept addresses safety concerns associated .with cryogenic stages by launching empty, and filling on ascent. The ASUS employs a rapid chill and fill concept. A spray bar is used to completely chill the tank before fill, allowing the vent valve to be closed during the fill process. The first tests of this concept, using a flight size (not flight weight) tank. were conducted at Marshall Space Flight Center (MSFC) during the summer of 2000. The objectives of the testing were to: 1) demonstrate that a flight size tank could be filled in roughly 5 minutes to accommodate the shuttle ascent window, and 2) demonstrate a no-vent fill of the tank. A total of 12 tests were conducted. Models of the test facility fill and vent systems, as well as the tank, were constructed. The objective of achieving tank fill in 5 minutes was met during the test series. However, liquid began to accumulate in the tank before it was chilled. Since the tank was not chilled until the end of each test, vent valve closure during fill was not possible. Even though the chill and fill process did not occur as expected, reasonable model correlation with the test data was achieved.

  1. Combined processes of two-stage Fenton-biological anaerobic filter-biological aerated filter for advanced treatment of landfill leachate.

    PubMed

    Wang, Xiaojun; Han, Jijun; Chen, Zhiwei; Jian, Lei; Gu, Xiaoyang; Lin, Che-Jen

    2012-12-01

    There are numerous non-biodegradable organic materials in the mature landfill leachate. To meet the new discharge standard of China, additional advanced treatment is needed for the effluent from the biological treatment processes of leachate. In this study, a combined process including two stages of "Fenton-biological anaerobic filter (BANF)-biological aerated filter (BAF)" was evaluated to address the advanced treatment need. The Fenton oxidation was applied to reduce chemical oxygen demand (COD) and enhance biodegradability of refractory organics, and the BANF-BAF process was then applied to remove the total nitrogen (TN). The treatment achieved effluent concentrations of COD<70 mg/L, TN<40 mg/L and NH(3)-N<10 mg/L. The removal efficiency of COD and TN were 96.1% and 95.9%, respectively. The effluent quality met the new discharge standard for Pollution Control on the Landfill Site of Municipal Solid of PR China (GB16889-2008). The operation cost of these processes was about 36.1CHY/t (5.70USD/t). PMID:22841597

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

    PubMed Central

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

    2016-01-01

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

  3. Expression of caveolin-1 is correlated with disease stage and survival in lung adenocarcinomas.

    PubMed

    Zhan, Ping; Shen, Xiao-Kun; Qian, Qian; Wang, Qin; Zhu, Ji-Ping; Zhang, Yu; Xie, Hai-Yan; Xu, Chuen-Hua; Hao, Ke-Ke; Hu, Wei; Xia, Ning; Lu, Guo-Jun; Yu, Li-Ke

    2012-04-01

    Caveolin-1 (cav-1) has been implicated in the development of human cancers. However, the distribution of cav-1 in non-small cell lung cancer (NSCLC) and its significance require further study. Real-time PCR and Western blot assays were performed to detect cav-1 mRNA and protein levels in tumor tissues (TT) and matched tumor-free tissues (TF). The protein expression in 115 paraffin-embedded blocks was examined by immunohistochemical staining (IHC). Correlations between cav-1 mRNA and protein expression by IHC and clinicopathological features were statistically evaluated. For the 136 patients examined, the levels of cav-1 mRNA and protein expression were significantly lower in lung TT compared to matched TF (P<0.05). High cav-1 expression was detected in 60 of 115 (52.2%) NSCLC tissues and this level was significantly lower than cav-1 expression in non-cancerous lung tissues (15 of 19, 78.9%, P<0.05). Up-regulation of cav-1 mRNA expression in lung adenocarcinoma (AC) (29.7%) was higher than that observed in lung squamous cell carcinoma (SCC) (15.8%). Statistical analysis of the correlation between cav-1 protein expression and clinical features showed a statistical association with poorer N-stage (P=0.032) and higher pathological TNM stage (P=0.012) in lung AC patients, that was not found in lung SCC patients. Moreover, lung AC patients with higher cav-1 expression showed significantly shorter life-spans than those with lower cav-1 expression (P=0.032, log-rank test). The levels of cav-1 mRNA and protein expression were significantly lower in lung cancers when compared to matched TF or non-cancerous lung tissues. The higher protein expression correlated with the advanced pathological stage and shorter survival rates in lung AC patients. PMID:22200856

  4. Effect of Advancing Age and Multiple Chronic Conditions on Mortality in Patients with End-Stage Renal Disease after Implantable Cardioverter-Defibrillator Placement

    PubMed Central

    Krishnaswami, Ashok; Kiley, Mary-Lou; Anthony, Faith F; Chen, Yuexin; Chen, Jason; Rajagopal, Sumanth; Liu, Taylor I; Young, Charlie; Paxton, Elizabeth W

    2016-01-01

    Context: There is insufficient information on the effect that advancing age and multiple chronic conditions (MCC) have on mortality after placement of an implantable cardioverter-defibrillator in patients with end-stage renal disease (ESRD) vs non-ESRD. Objective: To assess whether a differential effect of age and MCC exists between ESRD and non-ESRD. Design: Population-based, retrospective cohort study using data from the national Kaiser Permanente Cardiac Device Registry of patients who underwent placement of an implantable cardioverter-defibrillator between January 1, 2007, and December 31, 2013. Main Outcome Measures: All-cause mortality. Results: Of 7825 patients with implantable cardioverter-defibrillator placement, ESRD-affected patients constituted 4.0% of the cohort (n = 311), were similar in age (p = 0.91), and presented with a larger comorbidity burden (3.3 ± 1.3 vs 2.4 ± 1.5, p < 0.001). The effect of advancing age (every 5 years) on mortality in the ESRD cohort (hazard ratio [HR] = 1.11, 95% confidence interval [CI] = 1.03–1.20) was less than in the non-ESRD cohort (HR = 1.28, 95% CI = 1.25–1.32). Similarly, the effect of each additional comorbidity in the ESRD cohort was less (HR = 1.04, 95% CI = 0.91–1.19) than in the non-ESRD group (HR = 1.20, 95% CI = 1.16–1.25). Lastly, ESRD was independently associated with a 3-fold greater hazard of mortality. Conclusions: Advancing age and increasing number of MCC have a differential effect on mortality risk in patients with ESRD compared with their non-ESRD counterparts. Future studies should focus on assessment of nonlinear relationships of age, MCC, and naturally occurring clusters of MCC on mortality. PMID:26562307

  5. ANGPTL4 Correlates with NSCLC Progression and Regulates Epithelial-Mesenchymal Transition via ERK Pathway.

    PubMed

    Zhu, Xiaoming; Guo, Xiaobin; Wu, Sen; Wei, Li

    2016-08-01

    Purpose Lung cancer remains the leading cause of cancer deaths with intricate mechanisms. In the present study, we evaluated the clinical significance and biological role of ANGPTL4 in non-small cell lung cancer (NSCLC), the most common lung cancer subtype. Methods Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for examining the mRNA level of ANGPTL4 in NSCLC tissues and adjacent non-tumor tissues, NSCLC cell lines, and the immortalized human bronchial epithelial cell line HBE, respectively. A tissue microarray was used for analyzing the relationship between ANGPTL4 expression and the clinicopathological parameters of NSCLC patients. Commercial lentivirus expressing shRNAs was used for silencing ANGPTL4. Cell Counting Kit-8 (CCK-8) was employed for evaluating the cell proliferation ability and transwell with or without matrigel was used for cell migration and invasion assay. Results As the result, ANGPTL4 was over-expressed in NSCLC tissues compared with benign lung tissues. Silencing ANGPTL4 expression strongly inhibited the proliferation, migration, and invasion of A549 and H520 cells, which was in accordance with the increase of epithelial marker E-cadherin and decrease of mesenchymal marker vimentin. By screening the ERK, AKT, EGFR, and STAT3 pathways, we found that cell growth, migration, and invasion arrest induced by loss of ANGPTL4 expression was partially attributable to down-regulation of ERK signaling. Conclusion These results suggested that ANGPTL4 was essential for proliferation and metastasis of lung cancer cells and might serve as a novel target for the treatment of lung cancer. PMID:27166634

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

    PubMed

    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. PMID:25981168

  7. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study

    PubMed Central

    Douillard, J-Y; Ostoros, G; Cobo, M; Ciuleanu, T; McCormack, R; Webster, A; Milenkova, T

    2014-01-01

    Background: Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Methods: Treatment: gefitinib 250 mg day−1 until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples. Results: Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8% adenocarcinoma 97.2% never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5–77.7), DCR 90.6% (95% CI 83.5–94.8), median PFS 9.7 months (95% CI 8.5–11.0), median OS 19.2 months (95% CI 17.0–NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15% SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8–74.7). Conclusion: First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable. PMID:24263064

  8. Clinical effect of pemetrexed as the first‐line treatment in Chinese patients with advanced anaplastic lymphoma kinase‐positive non‐small cell lung cancer

    PubMed Central

    Ma, Di; Hao, Xuezhi; Wang, Yan; Xing, Puyuan

    2016-01-01

    Background The efficacy of pemetrexed‐based first‐line chemotherapy in anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC) has been demonstrated in several studies; however, there is a lack of data from Chinese populations. Methods The clinicopathological characteristics and treatment outcomes of 52 patients with ALK‐positive advanced NSCLC who received pemetrexed as first‐line chemotherapy at the Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences were retrospectively reviewed. The primary end points were response rate and progression‐free survival (PFS). Results The gender proportion was balanced and the median age was 51 years (range 26–76). Of the 52 patients, 46 (88.5%) had stage IV disease, predominantly adenocarcinoma (98.1%). Sixteen patients were current/former smokers and 36 were never/light smokers. The most common sites of metastasis were the pleura (36.5%), bone (30.8%), lung (26.9%), and brain (17.3%). The median PFS was 9.5 months (95% confidence interval 7.454–11.536). At the time of analysis, partial remission was achieved in 18 (34.6%) patients, stable disease in 26 (50.0%), and progressive disease in eight (15.4%); none of the patients achieved complete remission. The objective response rate was 34.6% and the disease control rate was 84.6%. Common adverse events with pemetrexed were neutropenia (53.8%), nausea and vomiting (51.9%), leukopenia (32.7%), and fatigue (25.0%), mainly at grades 1 or 2. Conclusions Pemetrexed is efficient and tolerated as first‐line treatment for ALK‐positive NSCLC in a cohort of Chinese patients and may prove to be an alternative option for the treatment of ALK‐positive NSCLC. PMID:27385988

  9. Use of field and airborne advanced remote sensing data for the characterisation of surface erosional stages in agricultural semi-arid soils (central Spain) at various scales

    NASA Astrophysics Data System (ADS)

    Milewski, Robert; Chabrillat, Sabine; Schmid, Thomas; Rodriguez, Manuel; Schuett, Brigitta

    2014-05-01

    The interest in the use of non-invasive remote sensing methods such as visible-near infrared reflectance spectroscopy for the remote determination of mineralogical composition in soils and planetary surfaces has been demonstrated since the 1970s with the development of databases in the laboratory of minerals spectra. Nowadays, quantitative soil spectroscopy has been shown to be a powerful tool for the identification and prediction of soil properties, and has been used in many soil science applications. With the upcoming launch of the next generation of hyperspectral satellite systems such as the German EnMAP (Environmental Mapping) satellite in 2017, new potential toward the quantitative analyses of chemical and physical soil attributes of the Earth's soil surface composition based on reflectance spectroscopy will be opened. In particular, in arid and semi-arid agricultural regions sensitive to soil erosion processes, the analyses of the spatial distribution of combined varying surface soil properties based on advanced hyperspectral methodology could be used to infer erosion and deposition stages in selected areas, although it was never thoroughly demonstrated. To fully utilize the potential of this technology for the assessment of surface soil erosional stages, new adapted approaches have to be developed, providing the context for this study. This research focuses on a semi-arid, agricultural area in Central Spain near Toledo and Madrid, in which airborne hyperspectral and LiDAR data have been obtained. The study area is under the influence of a Mediterranean climate with extended agricultural rainfed uses on mostly evolved soils. There, soil erosion features can be observed that are representative for areas throughout Southern Europe. Such erosion features are associated with different soil horizons and rock outcrops with contrasted physical and chemical characteristic. They are exposed at the surface as a consequence of human induced soil erosion which is

  10. Quality of Life (QOL) Analysis of a Randomized Radiation Dose Escalation Non-Small Cell Lung Cancer (NSCLC) Study: Radiation Therapy Oncology Group (RTOG) Trial 0617

    PubMed Central

    Movsas, Benjamin; Hu, Chen; Sloan, Jeffrey; Bradley, Jeffrey; Komaki, Ritsuko; Masters, Gregory; Kavadi, Vivek; Narayan, Samir; Michalski, Jeff; Johnson, Douglas W.; Koprowski, Christopher; Curran, Walter J.; Garces, Yolanda I.; Gaur, Rakesh; Wynn, Raymond B.; Schallenkamp, John; Gelblum, Daphna Y.; MacRae, Robert M; Paulus, Rebecca; Choy, Hak

    2015-01-01

    Importance A recent randomized radiation dose escalation trial in unresectable stage III NSCLC showed a lower survival in the high-dose arm (74Gy vs. 60Gy) with concurrent chemotherapy. Quality of life (QOL), an important secondary endpoint, is presented here. Objective The primary QOL hypothesis predicted a clinically meaningful decline (CMD) in QOL via the Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS) in the high-dose RT-arm at 3 months. Design RTOG 0617 was a randomized phase III study (conducted from Nov 2007 to Nov 2011) in stage III NSCLC using a 2×2 factorial design and stratified by histology, PET staging, performance status and radiation technique (3D-conformal RT [3DCRT] vs. intensity-modulated radiation [IMRT]). Setting 185 institutions in the USA and Canada. Participants Of 424 eligible stage III NSCLC patients randomized, 360 (85%) consented to QOL, of whom 313 (88%) completed baseline QOL assessments. Intervention for Clinical Trials 74Gy vs. 60Gy with concurrent and consolidation carboplatin/paclitaxel +/− cetuximab. Main Outcomes and Measures QOL was collected prospectively via FACT-Trial Outcome Index (FACT-TOI), equaling Physical-Well-Being (PWB) + Functional-Well-Being (FWB) + Lung Cancer Subscale (LCS). Data are presented at baseline & 3 and 12 months via minimal clinically meaningful changes of >=2 points for PWB, FWB or LCS or >=5 points for TOI. Results Patient demographics and baseline QOL scores were comparable between the 74Gy and 60Gy arms. Two-hundred-nineteen (72%) of living patients who completed QOL at baseline did so at 3 months and 137 (57%) of living patients did so at 12 months. Significantly more patients on 74Gy arm had clinically meaningful decline in FACT-LCS at 3 months than on the 60Gy arm (45% vs. 30%, p=0.02). At 12 months, fewer patients who received IMRT (vs 3DCRT) had clinically meaningful decline in FACT-LCS (21% vs 46%, p=0.003). Baseline FACT-TOI was associated with overall survival in

  11. Low miR-145 silenced by DNA methylation promotes NSCLC cell proliferation, migration and invasion by targeting mucin 1

    PubMed Central

    Ye, Zhiqiang; Shen, Ning; Weng, Yimin; Li, Kai; Hu, Liu; Liao, Hongyin; An, Jun; Liu, Libao; Lao, Sen; Cai, Songwang

    2015-01-01

    MiR-145 has been implicated in the progression of non-small cell lung cancer (NSCLC); however, its exact mechanism is not well established. Here, we report that miR-145 expression is decreased in NSCLC cell lines and tumor tissues and that this low level of expression is associated with DNA methylation. MiR-145 methylation in NSCLC was correlated with a more aggressive tumor phenotype and was associated with poor survival time, as shown by Kaplan-Meier analysis. Additional multivariate Cox regression analysis indicated that miR-145 methylation was an independent prognostic factor for poor survival in patients with NSCLC. Furthermore, we found that restoration of miR-145 expression inhibited proliferation, migration and invasion of NSCLC by the direct targeting of mucin 1 by miR-145. Our results indicate that low miR-145 expression, due to methylation, promotes NSCLC cell proliferation, migration and invasion by targeting mucin 1. Therefore, miR-145 may be a valuable therapeutic target for NSCLC. PMID:25961369

  12. Increased Levels of Plasma Epstein Barr Virus DNA Identify a Poor-Risk Subset of Patients With Advanced Stage Cutaneous T-Cell Lymphoma

    PubMed Central

    Haverkos, Bradley M.; Gru, Alejandro A.; Geyer, Susan M.; Bingman, Anissa K.; Hemminger, Jessica A.; Mishra, Anjali; Wong, Henry K.; Pancholi, Preeti; Freud, Aharon G.; Caligiuri, Michael A.; Baiocchi, Robert A.; Porcu, Pierluigi

    2016-01-01

    Discovering prognostic factors that simultaneously describe tumor characteristics and improve risk stratification is a priority in cutaneous T-cell lymphoma (CTCL). More than a third of advanced stage CTCL patients in this cohort had detectable cell free plasma Epstein–Barr virus (EBV)-DNA (pEBVd) using quantitative real-time polymerase chain reaction. An increased level of pEBVd was highly concordant with EBV (ie, Epstein–Barr virus RNAs) in tumor tissue and was associated with inferior survival. Introduction Outcomes in advanced stage (AS) cutaneous T-cell lymphomas (CTCL) are poor but with great variability. Epstein–Barr virus (EBV) is associated with a subset of non-Hodgkin lymphomas. Frequency of plasma EBV-DNA (pEBVd) detection, concordance with EBV RNA (EBER) in tumor tissue, codetection of plasma cytomegalovirus DNA (pCMVd), and prognostic effect in AS CTCL are unknown. Patients and Methods Patients (n = 46; 2006–2013) with AS CTCL (≥IIB) were retrospectively studied. pEBVd and pCMVd were longitudinally measured using quantitative real-time polymerase chain reaction. EBER in situ hybridization (ISH) was performed on tumor samples. Survival from time of diagnosis (ToD) and time of progression to AS was assessed. Results Plasma EBV-DNA and pCMVd were detected in 37% (17 of 46) and 17% (8 of 46) of AS CTCL patients, respectively. pCMVd detection was significantly more frequent in pEBVd-positive (pEBVd+) than pEBVd− patients (35% vs. 7%; P = .038). Tumor tissue for EBER-ISH was available in 14 of 17 pEBVd+ and 22 of 29 pEBVd− patients; 12 of 14 (85.7%) pEBVd+ patients were EBER+ versus 0 of 22 pEBVd− patients. Frequency of large cell transformation (LCT) tended to be greater in pEBVd+ patients, but was not significant (10 of 14 pEBVd+ vs. 10 of 23 pEBVd−; P = .17). No notable differences in rates of increased levels of serum lactate dehydrogenase (LDH) were observed (17 of 17 pEBVd+ vs. 27 of 29 pEBVd−). pEBVd detection was associated with

  13. Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer.

    PubMed

    Mu, Zhaomei; Wang, Chun; Ye, Zhong; Austin, Laura; Civan, Jesse; Hyslop, Terry; Palazzo, Juan P; Jaslow, Rebecca; Li, Bingshan; Myers, Ronald E; Jiang, Juntao; Xing, Jinliang; Yang, Hushan; Cristofanilli, Massimo

    2015-12-01

    The enumeration of circulating tumor cells (CTCs) provides important prognostic values in patients with metastatic breast cancer. Recent studies indicate that individual CTCs form clusters and these CTC-clusters play an important role in tumor metastasis. We aimed to assess whether quantification of CTC-clusters provides additional prognostic value over quantification of individual CTCs alone. In 115 prospectively enrolled advanced-stage (III and IV) breast cancer patients, CTCs and CTC-clusters were counted in 7.5 ml whole blood using the CellSearch system at baseline before first-line therapy. The individual and joint effects of CTC and CTC cluster counts on patients' progression-free survival (PFS) were analyzed using Cox proportional hazards modeling. Of the 115 patients, 36 (31.3 %) had elevated baseline CTCs (≥5 CTCs/7.5 ml) and 20 (17.4 %) had CTC-clusters (≥2 CTCs/7.5 ml). Patients with elevated CTCs and CTC-clusters both had worse PFS with a hazard ratio (HR) of 2.76 [95 % confidence interval (CI) 1.57-4.86, P log-rank = 0.0005] and 2.83 (1.48-5.39, P log-rank = 0.001), respectively. In joint analysis, compared with patients with <5 CTCs and without CTC-clusters, patients with elevated CTCs but without clusters, and patients with elevated CTCs and with clusters, had an increasing trend of progression risk, with an HR of 2.21 (1.02-4.78) and 3.32 (1.68-6.55), respectively (P log-rank = 0.0006, P trend = 0.0002). The additional prognostic value of CTC-clusters appeared to be more pronounced in patients with inflammatory breast cancer (IBC), the most aggressive form of breast cancer with the poorest survival. Baseline counts of both individual CTCs and CTC-clusters were associated with PFS in advanced-stage breast cancer patients. CTC-clusters might provide additional prognostic value compared with CTC enumeration alone, in patients with elevated CTCs. PMID:26573830

  14. A randomized prospective study of comparison of reservoir ports versus conventional vascular access in advanced-stage ovarian carcinoma cases treated with chemotherapy.

    PubMed

    Sehirali, S; Inal, M M; Ozsezgin, S; Sanci, M; Atli, O; Nayki, C; Yildirim, Y; Tinar, S

    2005-01-01

    Vascular access ports were developed to overcome many of the problems associated with limited peripheral access, combined with the need for frequent venipuncture, in oncology patients receiving long-term intensive therapy. In this study, we compared the effectivity and acceptability of vascular access port with conventional needle application together with complication rates in ovarian cancer patients. Advanced-stage ovarian carcinoma cases under chemotherapy treatment were equally randomized into two groups, implantable vascular access ports applied to one group (22 cases) and conventional vascular access applied to the other (38 cases) as a control group. Anteroposterior thoracic X-rays of implantable port-applied cases were taken before and after the application. Vortex reservoir ports (Horizon Medical Products, Inc., Manchester, GA) were used in the application to the subclavian vein. Classic peripheral venipuncture method (Medikit), Mediflon(trade mark) IV cannula with PTFE radiopaque catheter and injection valve, Eastern Medikit Ltd, Gurgaon, Haryana, India) was used in the control group. Vascular accesses of all cases were controlled just after the application, 12 h after the application, and during each drug or intravenous fluid application. Mean port insertion time was 26.3 min. Total port occlusion was observed in two of the port-applied cases (11.7%) and partial port occlusion was observed in five of the port-applied cases (29%). Heparin and saline combination was used in order to open the port tip, in five cases, two with total occlusion and three with partial occlusion. Infection was observed in only one case (5%) to whom appropriate therapy was given, and the port was taken out. Ports of two cases were also taken out because of skin dehiscence. No change in port tip position was observed in any of the cases. Total occlusion was observed in 16 of the 38 cases (42.1%) with conventional vascular access. In 12 cases (31.5%), a need arose to change the

  15. Presence of tumour high-endothelial venules is an independent positive prognostic factor and stratifies patients with advanced-stage oral squamous cell carcinoma.

    PubMed

    Wirsing, Anna M; Rikardsen, Oddveig G; Steigen, Sonja E; Uhlin-Hansen, Lars; Hadler-Olsen, Elin

    2016-02-01

    Staging of oral squamous cell carcinoma is based on the tumour-node-metastasis (TNM) system, which has been deemed insufficient for prognostic purposes. Hence, better prognostic tools are needed to reflect the biological diversity of these cancers. Previously, high numbers of specialized blood vessels called high-endothelial venules have been reported to be associated with prolonged survival in patients with breast cancer. In this study, we analysed the prognostic value and morphological characteristics of tumour-associated high-endothelial venules in oral cancer. The presence of tumour-associated high-endothelial venules was evaluated by immunohistochemistry in 75 patients with oral squamous cell carcinoma and analysed with correlation to clinicopathological parameters, patients' survival and vessel morphology. Ten of the samples were analysed at multiple levels to evaluate intratumoural heterogeneity. The presence of tumour-associated high-endothelial venules was found to be associated with lower disease-specific death in multivariate regression analyses (P = 0.002). High-endothelial venules were present in all (n = 53) T1-T2 tumours, but only in two thirds (n = 14) of the T3-T4 tumours. The morphology of high-endothelial venules was heterogeneous and correlated with lymphocyte density. High-endothelial venules were found to be distributed homogeneously within the tumours. We found the presence of tumour-associated high-endothelial venules to be an easy-to-use, robust, and independent positive prognostic factor for patients with oral cancer. Absence of these vessels in advanced-stage tumours might identify patients with more aggressive disease. Evaluating the presence of tumour-associated high-endothelial venules might help to tailor the treatment of oral cancer patients to their individual needs. PMID:26383526

  16. Impact of Pretreatment Combined {sup 18}F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Staging on Radiation Therapy Treatment Decisions in Locally Advanced Breast Cancer

    SciTech Connect

    Ng, Sweet Ping; David, Steven; Alamgeer, Muhammad; Ganju, Vinod

    2015-09-01

    Purpose: To assess the diagnostic performance of pretreatment {sup 18}F-fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG PET/CT) and its impact on radiation therapy treatment decisions in patients with locally advanced breast cancer (LABC). Methods and Materials: Patients with LABC with Eastern Cooperative Oncology Group performance status <2 and no contraindication to neoadjuvant chemotherapy, surgery, and adjuvant radiation therapy were enrolled on a prospective trial. All patients had pretreatment conventional imaging (CI) performed, including bilateral breast mammography and ultrasound, bone scan, and CT chest, abdomen, and pelvis scans performed. Informed consent was obtained before enrolment. Pretreatment whole-body {sup 18}F-FDG PET/CT scans were performed on all patients, and results were compared with CI findings. Results: A total of 154 patients with LABC with no clinical or radiologic evidence of distant metastases on CI were enrolled. Median age was 49 years (range, 26-70 years). Imaging with PET/CT detected distant metastatic disease and/or locoregional disease not visualized on CI in 32 patients (20.8%). Distant metastatic disease was detected in 17 patients (11.0%): 6 had bony metastases, 5 had intrathoracic metastases (pulmonary/mediastinal), 2 had distant nodal metastases, 2 had liver metastases, 1 had pulmonary and bony metastases, and 1 had mediastinal and distant nodal metastases. Of the remaining 139 patients, nodal disease outside conventional radiation therapy fields was detected on PET/CT in 15 patients (10.8%), with involvement of ipsilateral internal mammary nodes in 13 and ipsilateral level 5 cervical nodes in 2. Conclusions: Imaging with PET/CT provides superior diagnostic and staging information in patients with LABC compared with CI, which has significant therapeutic implications with respect to radiation therapy management. Imaging with PET/CT should be considered in all patients undergoing primary

  17. Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of the chromosomal error: A population-based study

    SciTech Connect

    Yoon, P.W.; Khoury, M.J.; Freeman, S.B.

    1996-03-01

    The identification of DNA polymorphisms makes it possible to classify trisomy 21 according to the parental origin and stage (meiosis I [MI], meiosis II [MII], or postzygotic mitotic) of the chromosomal error. Studying the effect of parental age on these subgroups could shed light on parental exposures and their timing. From 1989 through 1993, 170 infants with trisomy 21 and 267 randomly selected control infants were ascertained in a population-based, case-control study in metropolitan Atlanta. Blood samples for genetic studies were obtained from case infants and their parents. Using logistic regression, we independently examined the association between maternal and paternal age and subgroups of trisomy 21 defined by parental origin and meiotic stage. The distribution of trisomy 21 by origin was 86% maternal (75% MI and 25% MII), 9% paternal (50% MI and 50% MII), and 5% mitotic. Compared with women <25 years of age, women {>=}40 years old had an odds ratio of 5.2 (95% confidence interval, 1.0-27.4) for maternal MI (MMI) errors and 51.4 (95% confidence interval, 2.3-999.0) for maternal MII (MMII) errors. Birth-prevalence rates for women {>=}40 years old were 4.2/1,000 births for MMI errors and 1.9/1,000 births for MMII errors. These results support an association between advanced maternal age and both MMI and MMII errors. The association with MI does not pinpoint the timing of the error; however, the association with MII implies that there is at least one maternal age-related mechanism acting around the time of conception. 16 refs., 1 fig., 2 tabs.

  18. Neoadjuvant chemoradiotherapy or chemotherapy followed by surgery is superior to that followed by definitive chemoradiation or radiotherapy in stage IIIA (N2) nonsmall-cell lung cancer: a meta-analysis and system review

    PubMed Central

    Xu, Xiao-Ling; Dan, Li; Chen, Wei; Zhu, Shuang-Mei; Mao, Wei-Min

    2016-01-01

    Background Approximately 30% of all cases of nonsmall-cell lung cancer (NSCLC) are of a locally advanced (IIIA or IIIB) stage. However, surgical therapy for patients with stage IIIA (N2) NSCLC is associated with a disappointing 5-year survival rate. The optimal treatment for stage IIIA (N2) NSCLC is still in dispute. Methods A literature search was performed in the PubMed, Embase, and MEDLINE databases (last search updated in March 2015), and a meta-analysis of the available data was conducted. Two authors independently extracted data from each eligible study. Results A total of nine studies, including five randomized controlled trials and four retrospective studies, were enrolled in this meta-analysis. Significant homogeneity (χ2=49.62, P=0.000, I2=81.9%) was detected between four of the studies, including a total of 11,948 selected cases. Among the nine studies that investigated overall survival, the pooled hazard ratio (HR) was 0.70 (95% confidence interval (CI): 0.56–0.87; P=0.000). Subgroup analyses were performed according to the study design and the extent of resection. We observed a statistically significant better outcome after lobectomy (pooled HR: 0.52; 95% CI: 0.47–0.58; P=0.000) than after pneumonectomy (pooled HR: 0.82; 95% CI: 0.69–0.98; P=0.028). Unfortunately, there was no significant difference between the randomized controlled studies, as the pooled HR was 0.94 (95% CI: 0.81–1.09; P=0.440). Conclusion Neoadjuvant chemoradiotherapy or chemotherapy followed by surgery (particularly lobectomy) is superior to following these therapies with definitive chemoradiation or radiotherapy, particularly in patients undergoing lobectomy. PMID:26955282

  19. A Phase II Study of Synchronous Three-Dimensional Conformal Boost to the Gross Tumor Volume for Patients With Unresectable Stage III Non-Small-Cell Lung Cancer: Results of Korean Radiation Oncology Group 0301 Study

    SciTech Connect

    Cho, Kwan Ho Ahn, Sung Ja; Pyo, Hong Ryull; Kim, Kyu-Sik; Kim, Young-Chul; Moon, Sung Ho; Han, Ji-Youn; Kim, Heung Tae; Koom, Woong Sub; Lee, Jin Soo

    2009-08-01

    Purpose: We evaluated the efficacy of synchronous three-dimensional (3D) conformal boost to the gross tumor volume (GTV) in concurrent chemoradiotherapy for patients with locally advanced non-small-cell lung cancer (NSCLC). Methods and Materials: Eligibility included unresectable Stage III NSCLC with no pleural effusion, no supraclavicular nodal metastases, and Eastern Cooperative Oncology Group performance score of 0-1. Forty-nine patients with pathologically proven NSCLC were enrolled. Eighteen patients had Stage IIIA and 31 had Stage IIIB. By using 3D conformal radiotherapy (RT) techniques, a dose of 1.8 Gy was delivered to the planning target volume with a synchronous boost of 0.6 Gy to the GTV, with a total dose of 60 Gy to the GTV and 45 Gy to the planning target volume in 25 fractions during 5 weeks. All patients received weekly chemotherapy consisting of paclitaxel and carboplatin during RT. Results: With a median follow-up of 36.8 months (range, 29.0-45.5 months) for surviving patients, median survival was 28.1 months. One-, 2- and 3-year overall survival rates were 77%, 56.4%, and 43.8%, respectively. Corresponding local progression-free survival rates were 71.2%, 53.7%, and 53.7%. Compliance was 90% for RT and 88% for chemotherapy. Acute esophagitis of Grade 2 or higher occurred in 29 patients. Two patients with T4 lesions died of massive bleeding and hemoptysis during treatment (Grade 5). Overall late toxicity was acceptable. Conclusions: Based on the favorable outcome with acceptable toxicity, the acceleration scheme using 3D conformal GTV boost in this trial is warranted to compare with conventional fractionation in a Phase III trial.

  20. Validation of a Computational Model for the SLS Core Stage Oxygen Tank Diffuser Concept and the Low Profile Diffuser - An Advanced Development Design for the SLS

    NASA Technical Reports Server (NTRS)

    Brodnick, Jacob; Richardson, Brian; Ramachandran, Narayanan

    2015-01-01

    The Low Profile Diffuser (LPD) project originated as an award from the Marshall Space Flight Center (MSFC) Advanced Development (ADO) office to the Main Propulsion Systems Branch (ER22). The task was created to develop and test an LPD concept that could produce comparable performance to a larger, traditionally designed, ullage gas diffuser while occupying a smaller volume envelope. Historically, ullage gas diffusers have been large, bulky devices that occupy a significant portion of the propellant tank, decreasing the tank volume available for propellant. Ullage pressurization of spacecraft propellant tanks is required to prevent boil-off of cryogenic propellants and to provide a positive pressure for propellant extraction. To achieve this, ullage gas diffusers must slow hot, high-pressure gas entering a propellant tank from supersonic speeds to only a few meters per second. Decreasing the incoming gas velocity is typically accomplished through expansion to larger areas within the diffuser which has traditionally led to large diffuser lengths. The Fluid Dynamics Branch (ER42) developed and applied advanced Computational Fluid Dynamics (CFD) analysis methods in order to mature the LPD design from and initial concept to an optimized test prototype and to provide extremely accurate pre-test predictions of diffuser performance. Additionally, the diffuser concept for the Core Stage of the Space Launch System (SLS) was analyzed in a short amount of time to guide test data collection efforts of the qualification of the device. CFD analysis of the SLS diffuser design provided new insights into the functioning of the device and was qualitatively validated against hot wire anemometry of the exterior flow field. Rigorous data analysis of the measurements was performed on static and dynamic pressure data, data from two microphones, accelerometers and hot wire anemometry with automated traverse. Feasibility of the LPD concept and validation of the computational model were

  1. Clinical results of high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation in children with advanced stage rhabdomyosarcoma.

    PubMed

    Kim, Nam Kyun; Kim, Hyo Sun; Suh, Chang-Ok; Kim, Hyun Ok; Lyu, Chuhl Joo

    2012-09-01

    Regardless of improvement in cure of Rhabdomyosarcoma (RMS), the results in treatment of advanced stage of RMS in children are still dismal. Recently, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (HDC/APBSCT) has been tried to manage the advanced high-risk RMS patients. We investigated the effectiveness of HDC/APBSCT by reviewing the clinical records of high-risk pediatric RMS patients in single institute database. Over twenty years, 37 patients were diagnosed as RMS with high-risk at the time of first diagnosis. These patients were classified as two groups according to treatment method. The first group was HDC/APBSCT and the other was conventional multi-agent chemotherapy group. Differences of clinical results between the two groups were analyzed. The median age of patients was 5 yr, ranging from 6 months to 15 yr. The 5-yr event free survival rate (EFS) of all patients was 24.8% ± 4.8%. HDC/APBSCT group and conventional multi-agent chemotherapy group were 41.3% ± 17.8% and 16.7% ± 7.6% for 5-yr EFS, respectively (P = 0.023). There was a significant difference in the result of HDC/APBSCT between complete remission or very good partial response group and poor response group (50% ± 20.4% vs 37.5% ± 28.6%, P = 0.018). HDC/APBSCT can be a promising treatment modality in high-risk RMS patients. PMID:22969254

  2. Stereotactic body radiation therapy in stage I inoperable lung cancer: from palliative to curative options.

    PubMed

    Boujelbene, Noureddine; Elloumi, Fatma; Kamel, Mohamed E; Abeidi, Hamdi; Matzinger, Oscar; Mirimanoff, René-Olivier; Khanfir, Kaouthar

    2013-01-01

    Surgery has historically been the standard of care for operable stage I non-small cell lung cancer (NSCLC). However, nearly one-quarter of patients with stage I NSCLC will not undergo surgery because of medical comorbidity or other factors. Stereotactic ablative radiotherapy (SABR) is the new standard of care for these patients. SABR offers high local tumour control rates rivalling the historical results of surgery and is generally well tolerated by patients with both peripheral and centrally located tumours. This article reviews the history of SABR for stage I NSCLC, summarises the currently available data on efficacy and toxicity, and describes some of the currently controversial aspects of this treatment. PMID:23740331

  3. Activity of muscarinic, galanin and cannabinoid receptors in the prodromal and advanced stages in the triple transgenic mice model of Alzheimer's disease.

    PubMed

    Manuel, Iván; Lombardero, Laura; LaFerla, Frank M; Giménez-Llort, Lydia; Rodríguez-Puertas, Rafael

    2016-08-01

    Neurochemical alterations in Alzheimer's disease (AD) include cholinergic neuronal loss in the nucleus basalis of Meynert (nbM) and a decrease in densities of the M2 muscarinic receptor subtype in areas related to learning and memory. Neuromodulators present in the cholinergic pathways, such as neuropeptides and neurolipids, control these cognitive processes and have become targets of research in order to understand and treat the pathophysiological and clinical stages of the disease. This is the case of the endocannabinoid and galaninergic systems, which have been found to be up-regulated in AD, and could therefore have a neuroprotective role. In the present study, the functional coupling of Gi/o protein-coupled receptors to GalR1, and the CB1 receptor subtype for endocannabinoids were analyzed in the 3xTg-AD mice model of AD. In addition, the activity mediated by Gi/o protein-coupled M2/4 muscarinic receptor subtypes was also analyzed in brain areas involved in anxiety and cognition. Thus, male mice were studied at 4 and 15months of age (prodromal and advanced stages, respectively) and compared to age-matched non-transgenic (NTg) mice (adult and old, respectively). In 4-month-old 3xTg-AD mice, the [(35)S]GTPγS binding stimulated by galanin was significantly increased in the hypothalamus, but a decrease of functional M2/4 receptors was observed in the posterior amygdala. The CB1 cannabinoid receptor activity was up-regulated in the anterior thalamus at that age. In 15-month-old 3xTg-AD mice, muscarinic receptor activity was found to be increased in motor cortex, while CB1 activity was decreased in nbM. No changes were found in GalR1-mediated activity at this age. Our results provide further evidence of the relevance of limbic areas in the prodromal stage of AD, the profile of which is characterized by anxiety. The up-regulation of galaninergic and endocannabinoid systems support the hypothesis of their neuroprotective roles, and these are established prior to the

  4. Evaluation of 29 indicators for the prognosis of advanced non-small cell lung cancer with cytokine-induced killer cell therapy combined with chemotherapy

    PubMed Central

    JIA, HEJIN; TIAN, YAPING; JIANG, CHAO GUANG; HAN, WEIDONG

    2016-01-01

    The aim of the present study was to evaluate 29 whole blood or serum indicators to identify factors able to predict clinical outcome following cytokine-induced killer (CIK) cell therapy combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC), and to evaluate the 5-year prognosis of the patients. From March 2008 to October 2013, 42 patients with advanced NSCLC (stages III and IV) were enrolled in the study. These patients were from a single hospital, and had been treated with CIK therapy combined with chemotherapy. Evaluation of the correlation between prognosis and age, gender, tumor stage, surgery resection status, number of CIK therapy cycles, tumor subtype, and the differential whole blood or serum indicators were analyzed by Kaplan-Meier methods and the log-rank test. The prognostic factors were analyzed by Cox proportional models. The median progression-free survival (mPFS) time of patients with high expression levels of albumin [20.0 months; 95% confidence interval (CI): 17.4–22.6 months] was significantly longer than the mPFS for patients with low expression levels of albumin (36.0 months; 95% CI: 24.7–47.3 months) (P=0.034). Other factors demonstrated no significant difference. Following analysis using the Cox proportional hazards regression model, the number of CIK therapy cycles (P=0.041) and the expression level of albumin (P=0.038) were revealed to be independent prognostic factors following the use of CIK cell therapy combined with chemotherapy for patients with advanced NSCLC. The risk of adverse outcomes in patients receiving ≥4 CIK therapy cycles and in patients with increased expression levels of albumin were 0.38 (95% CI: 0.14–1.13) and 0.32 (95% CI: 0.10–1.24)-fold those of patients receiving <4 CIK therapy cycles and with decreased expression levels of albumin, respectively. The serum albumin concentration may therefore be a predictor of the 5-year survival rate of patients with advanced NSCLC treated

  5. Transient terahertz photoconductivity measurements of minority-carrier lifetime in tin sulfide thin films: Advanced metrology for an early stage photovoltaic material

    NASA Astrophysics Data System (ADS)

    Jaramillo, R.; Sher, Meng-Ju; Ofori-Okai, Benjamin K.; Steinmann, V.; Yang, Chuanxi; Hartman, Katy; Nelson, Keith A.; Lindenberg, Aaron M.; Gordon, Roy G.; Buonassisi, T.

    2016-01-01

    Materials research with a focus on enhancing the minority-carrier lifetime of the light-absorbing semiconductor is key to advancing solar energy technology for both early stage and mature material platforms alike. Tin sulfide (SnS) is an absorber material with several clear advantages for manufacturing and deployment, but the record power conversion efficiency remains below 5%. We report measurements of bulk and interface minority-carrier recombination rates in SnS thin films using optical-pump, terahertz-probe transient photoconductivity (TPC) measurements. Post-growth thermal annealing in H2S gas increases the minority-carrier lifetime, and oxidation of the surface reduces the surface recombination velocity. However, the minority-carrier lifetime remains below 100 ps for all tested combinations of growth technique and post-growth processing. Significant improvement in SnS solar cell performance will hinge on finding and mitigating as-yet-unknown recombination-active defects. We describe in detail our methodology for TPC experiments, and we share our data analysis routines in the form freely available software.

  6. The interweaving of pharmaceutical and medical expectations as dynamics of micro-pharmaceuticalisation: advanced-stage cancer patients' hope in medicines alongside trust in professionals.

    PubMed

    Brown, Patrick; de Graaf, Sabine; Hillen, Marij; Smets, Ellen; van Laarhoven, Hanneke

    2015-04-01

    Existing pharmaceuticalisation research denotes the salience of expectations in novel medicines and in the medical contexts through which these may be accessed. Specific processes of expectation such as hope and trust, alongside their shaping of patients' lifeworlds around pharmaceutical use, remain neglected however. Considering data from in-depth interviews and observations involving thirteen patients with advanced-stage cancer diagnoses who were or had recently been involved in clinical trials, we develop an interpretative phenomenological analysis of the influence of hope and trust upon the accessing of novel medicines through trials, illuminating the depth and texture of pharmaceuticalisation at the micro-level. Trust in clinicians and hope in trial medicines, for self and future patients, were important in the reconfiguring of patients' horizon of possibilities when accessing new medicines. Interwoven processes of trust and hope, embedded within heightened vulnerability, sustained the bracketing out of doubts regarding medicines, trials and professionals. The need to maintain hopes, and trusting relations with professionals who facilitated these hopes, generated meaning and momentum of medicines use which inhibited disengagement from trials. Findings indicate the taken-for-granted, as well as more reflexive, pursuit of solutions through medicines, which in this case-study enabled the generation of evidence through trial involvement. Analyses of micro-level dynamics within both downstream-consumption and upstream-substantiation of pharmaceutical solutions assist more nuanced accounts of interests, agency and expectations within pharmaceuticalisation. PMID:25465500

  7. A voice that wraps around the body--communication problems in the advanced stages of non-small cell lung cancer.

    PubMed Central

    Moore, R. J.; Chamberlain, R. M.; Khuri, F. R.

    2001-01-01

    INTRODUCTION: Significant problems in clinician-patient communication have been described in the oncology literatures. Advanced stage non-small lung cancer a devastating disease, can cause the communication between survivors, significant others, and clinicians to falter. To date, however, no studies have used qualitative methods to examine experiential aspects of living with non-small cell lung cancer. Nor have any studies evaluated the tools survivors might use to repair some of the damage caused by living with this disease. METHODS: Exploratory, two-part qualitative design. RESULTS: Survivors of non-small cell lung cancer live with multiple fears and losses. These include a diminished sense of self, the loss of health, fears of pain in a future tainted by the threat of death, and increased feelings of alienation due to the loss of previous sources of meaning in life. These experiences significantly affect cancer survivors abilities to communicate with clinicians and significant others. CONCLUSIONS: Survivors of non-small cell lung cancer often have difficulty sharing their experiences with others not suffering a similar affliction. Through their narratives with other survivors, however, patients are better able to initiate a biopsychosocial mechanism which enables them to create a cognitive map. This cognitive map helps survivors share their experiences with others, thereby repairing some of the damage caused by this disease, including the harm done to their communication with other people. PMID:11922184

  8. NSCLC subtype prediction using cytologic fluid specimens from needle aspiration biopsies.

    PubMed

    Cho, Arthur; Hur, Jin; Hong, Yoo Jin; Lee, Hye-Jeong; Kim, Young Jin; Kim, Hee Yeong; Lee, Ji Won; Shim, Hyo Sup; Choi, Byoung Wook

    2013-03-01

    This study evaluated the diagnostic usefulness of tumor marker concentrations in cytologic fluids (CF) for subtyping non-small cell lung cancer (NSCLC) and assessed the relationship between fluorine-18-fluorodeoxyglucose ((18)F-FDG) uptake with serum and CF tumor marker levels. This prospective study included 88 patients diagnosed with adenocarcinoma or squamous cell carcinoma (SCC). Cytokeratin-19 fragment (CYFRA 21-1), carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCCA) concentrations in the CF samples were correlated with serum tumor marker concentrations, (18)F-FDG uptake, and NSCLC subtype. Fifty-eight patients were diagnosed with adenocarcinoma. Multivariate analysis revealed higher CF and serum SCCA levels; smoking status predicted SCC from adenocarcinoma. CF SCCA showed the highest accuracy (83%) in distinguishing between SCC and adenocarcinoma. CF samples obtained during routine needle aspiration biopsy procedure contain tumor marker levels sufficient to distinguish between SCC and adenocarcinoma; CF SCCA had the highest diagnostic accuracy. PMID:23429366

  9. MiR-15a-16 represses Cripto and inhibits NSCLC cell progression.

    PubMed

    Chen, Feng; Hou, Shi-ke; Fan, Hao-jun; Liu, Ying-fu

    2014-06-01

    MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in cancer. The altered expressions of miRNAs and their target genes are frequently detected in various tumors. In this study, downregulation of miR-15a-16 in nonsmall cell lung cancer (NSCLC) was found to be inversely correlated with Cripto. Results from the Luciferase reporter assay and Western blot analysis also confirmed that Cripto is a direct target of miR-15a-16. In addition, transfection of miR-15a-16 expression plasmid inhibited the invasion ability and promoted the apoptosis of NCI-H23 and NCI-H358 cells. Moreover, miR-15a-16 overexpression suppressed tumor growth in vivo. These findings clearly suggest that the downregulation of miR-15a-16 with Cripto amplification may be involved in the development of NSCLC. PMID:24500260

  10. KRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach

    PubMed Central

    Belda-Iniesta, Cristóbal

    2013-01-01

    K-RAS accounts for 90% of RAS mutations in lung adenocarcinomas, the most commonly mutated oncogene in NSCLC, with mutations detected in about 25% of all tumors. Direct inhibition of KRAS has proven clinically challenging. So far, no successful targeted therapy has been developed and remains an elusive target for cancer therapy. Despite significant efforts, currently there are no drugs directly targeting mutated KRAS. Thus, new strategies have emerged for targeting RAS including the use of synthetic lethality. A specific knowledge of individual tumor molecular abnormalities that result in oncogene-specific “synthetic lethal” interactions will allow the rationale to combine promising targeted therapies for KRAS-mutated NSCLC. In this article, we review the new approach based on testing drugs or combinations of agents that work downstream of activated K-RAS. PMID:25806225

  11. KRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach.

    PubMed

    de Castro Carpeño, Javier; Belda-Iniesta, Cristóbal

    2013-04-01

    K-RAS accounts for 90% of RAS mutations in lung adenocarcinomas, the most commonly mutated oncogene in NSCLC, with mutations detected in about 25% of all tumors. Direct inhibition of KRAS has proven clinically challenging. So far, no successful targeted therapy has been developed and remains an elusive target for cancer therapy. Despite significant efforts, currently there are no drugs directly targeting mutated KRAS. Thus, new strategies have emerged for targeting RAS including the use of synthetic lethality. A specific knowledge of individual tumor molecular abnormalities that result in oncogene-specific "synthetic lethal" interactions will allow the rationale to combine promising targeted therapies for KRAS-mutated NSCLC. In this article, we review the new approach based on testing drugs or combinations of agents that work downstream of activated K-RAS. PMID:25806225

  12. Rates of cardiovascular events and deaths are associated with advanced stages of HIV-infection: results of the HIV HEART study 7, 5 year follow-up

    PubMed Central

    Esser, Stefan; Eisele, Lewin; Schwarz, Birte; Schulze, Christina; Holzendorf, Volker; Brockmeyer, Nobert H; Hower, Martin; Kwirant, Friedhelm; Rudolph, Roland; Neumann, Till; Reinsch, Nico

    2014-01-01

    Introduction Cardiovascular diseases are increasing in aging HIV-positive patients (HIV+). Impact of traditional cardiovascular risk factors, HIV-specific parameters and antiretroviral therapy (ART) on the incidence of cardiovascular events (CVE) and on the mortality rate are investigated in different HIV+ cohorts. Methods The HIV HEART (HIVH) study is an ongoing prospective observational cohort study in the German Ruhr area to assess the frequency and clinical course of cardiac disorders in 1481 HIV+ by standardized non-invasive cardiovascular screening. CVE were defined as diagnosed or documented myocardial infarction, coronary heart disease, arterial coronary intervention, stent implantation, bypass operation and stroke. Results 1481 HIV+ subjects (mean age: 49.3±10.7 years (y), female: 15.6%) were included. 130 CVE and 90 deaths were documented until the end of 7, 5 year follow-up of HIVH. Mean duration of the HIV-infection was 12.9±6.8 y. HIV+ were treated with ART on average for 8.6±6.8 y. According to the CDC classification of the HIV-infection, HIV+ were distributed over the clinical categories (A:34.6%; B:31.4% and C:33.9%) while more than the half had an advanced immunodeficiency (I:8.3%; II:41.1%; III:50.7%). Advanced clinical and immunological stages were significantly (p<0.001) associated with higher incidences of deaths (A:16.7%; B:26.7%; C:56.7% and I:6.7%; II:27.7%; III:65.6%) and CVE (A:17.7%; B:33.1%; C:49.2% and I:3.1%; II:32.3%; III:64.6%) but not with the duration of HIV-infection (per y: Hazard ratio (HR): 0.91 [0.88–0.94]) and ART (per y: HR: 0.81 [0.79–0.84]) adjusted for age. The proportion of deceased HIV+ with HIV-RNA ≥50 copies/mL and lower CD4-cell counts at their last visit is significantly higher compared with living HIV+ without CVE (HIV-RNA ≥50 copies/mL: 25.6% vs 14.7%). Median CD4-cells: 286.5 cells/µL (IQR: 168.8–482.8) versus 574 cells/µL (IQR: 406–786). 96.1% of the living HIV+ with CVE had HIV-RNA<50 copies

  13. 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

  14. Treatment Recommendations for Locally Advanced, Non-Small-Cell Lung Cancer: The Influence of Physician and Patient Factors

    SciTech Connect

    Lee, Irwin H.; Hayman, James A.; Landrum, Mary Beth; Tepper, Joel; Goodman, Karyn A.; Keating, Nancy L.

    2009-08-01

    Purpose: To determine the impact of patient age, comorbidity, and physician factors on treatment recommendations for locally advanced, unresectable non-small-cell lung cancer (NSCLC). Methods and Materials: We surveyed radiation oncologists regarding their recommendations for treatment (chemoradiation, radiation alone, chemotherapy alone, or no therapy) for hypothetical patients with Stage IIIB NSCLC who varied by age (55 vs. 80 years) and comorbid illness (none, moderate, or severe chronic obstructive pulmonary disease [COPD]). Multinomial logistic regression was used to assess the impact of physician and practice characteristics on radiation oncologists' treatment recommendations for three scenarios with the least agreement. Results: Of 214 radiation oncologists, nearly all (99%) recommended chemoradiation for a healthy 55 year old. However, there was substantial variability in recommendations for a 55 year old with severe COPD, an 80-year-old with moderate COPD, and an 80-year-old with severe COPD. Physicians seeing a lower volume of lung cancer patients were statistically less likely to recommend radiotherapy for younger or older patients with severe COPD (both p < 0.05), but the impact was modest. Conclusions: Nearly all radiation oncologists report following the evidence-based recommendation of chemoradiation for young, otherwise healthy patients with locally advanced, unresectable NSCLC, but there is substantial variability in treatment recommendations for older or sicker patients, probably related to the lack of clinical trial data for such patients. The physician and practice characteristics we examined only weakly affected treatment recommendations. Additional clinical trial data are necessary to guide recommendations for treatment of elderly patients and patients with poor pulmonary function to optimize their management.

  15. Treatment Recommendations for Locally Advanced, Non-small Cell Lung Cancer: The Influence of Physician and Patient Factors

    PubMed Central

    Lee, Irwin H.; Hayman, James A.; Landrum, Mary Beth; Tepper, Joel; Tao, May Lin; Goodman, Karyn A.; Keating, Nancy L.

    2011-01-01

    Purpose To determine the impact of patient age, comorbidity, and physician factors on treatment recommendations for locally-advanced, unresectable non-small cell lung cancer (NSCLC). Methods and Materials We surveyed radiation oncologists regarding their recommendations for treatment (chemoradiation, radiation alone, chemotherapy alone, or no therapy) for hypothetical patients with stage IIIB NSCLC who varied by age (55 vs. 80 years) and comorbid illness (none, moderate, or severe chronic obstructive pulmonary disease [COPD]). Multinomial logistic regression was used to assess the impact of physician and practice characteristics on radiation oncologists’ treatment recommendations for 3 scenarios with the least agreement. Results Of 214 radiation oncologists, nearly all (99%) recommended chemoradiation for a healthy 55-year-old. However, there was substantial variability in recommendations for a 55-year-old with severe COPD, an 80-year-old with moderate COPD, and an 80-year-old with severe COPD. Physicians seeing a lower volume of lung cancer patients were statistically less likely to recommend radiotherapy for younger or older patients with severe COPD (both p <0.05) but the impact was modest. Conclusions Nearly all radiation oncologists report following evidence-based recommendations of chemoradiation for young, otherwise healthy patients with locally advanced, unresectable NSCLC; but there is substantial variability in treatment recommendations for older or sicker patients, probably related to the lack of clinical trial data for such patients. The physician and practice characteristics we examined only weakly impacted treatment recommendations. Additional clinical trial data are needed to guide recommendations for treatment of elderly patients and patients with poor pulmonary function in order to optimize their management. PMID:19409730

  16. 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

  17. Lower lobe origin is a poor prognostic factor in locally advanced non-small-cell lung cancer patients treated with induction chemoradiotherapy

    PubMed Central

    SHIEN, KAZUHIKO; TOYOOKA, SHINICHI; SOH, JUNICHI; HOTTA, KATSUYUKI; KATSUI, KUNIAKI; OTO, TAKAHIRO; KANAZAWA, SUSUMU; KIURA, KATSUYUKI; DATE, HIROSHI; MIYOSHI, SHINICHIRO

    2015-01-01

    The AIM of this study was to identify prognostic factors in patients receiving trimodality therapy for locally advanced non-small-cell lung cancer (NSCLC). Among patients who underwent induction chemoradiotherapy (CRT) followed by surgery between 1999 and 2011 at our institution, 76 NSCLC patients with clinical (c) N2/3 stage III were enrolled in this retrospective study. Induction CRT consisted of docetaxel and cisplatin with concurrent 40–60 Gy radiation therapy. In total, 76 patients were assessed (53 men and 23 women) with 43 adenocarcinomas and 33 non-adenocarcinomas. Of the 76 patients, 44 had cStage IIIA and 32 had cStage IIIB disease. The primary tumors were located in the right upper lobe (N=33), right middle lobe (N=5), right lower lobe (N=11), left upper lobe (N=20s) and left lower lobe (N=7). For all 76 patients, lower lobe tumors were associated with a significantly shorter overall survival (OS) and disease-free survival (DFS) compared to non-lower lobe tumors (OS, P=0.022; and DFS, P=0.0007). When the analysis was limited to pathologically proven N2/3 disease prior to induction CRT (n=36), lower lobe location, compared to other locations, tended to be a poor prognostic factor (OS, P=0.068; and DFS, P=0.0075). Our results indicated that a lower lobe tumor origin is associated with unfavorable prognosis in NSCLC patients treated with induction CRT, strongly suggesting the significance of appropriate patient selection in order to maximize the benefits of trimodality therapy. PMID:26137291

  18. Hypofractionated radiotherapy for medically inoperable stage I non‐small cell lung cancer

    PubMed Central

    Jiang, Wei; Wang, Jian‐Yang; Wang, Jing‐Bo; Liang, Jun; Hui, Zhou‐Guang; Wang, Xiao‐Zhen; Zhou, Zong‐Mei

    2015-01-01

    Abstract Background To investigate the clinical outcomes and toxicity of hypofractionated radiotherapy for medically inoperable stage I non‐small cell lung cancer (NSCLC). Methods Patients treated with radiotherapy at a dose of 4–6 Gy per fraction using fixed‐field intensity modulated radiotherapy (IMRT) or volumetric‐modulated arc therapy (VMAT) at our hospital from June 2005 to December 2013 were analyzed. The total prescription doses ranged from 50–78 Gy with 4–6 Gy per fraction. The median follow‐up period was 24 months. Results A total of 65 patients with stage I NSCLC were analyzed, including 43 primary NSCLC patients and 22 patients with recurrent or second primary NSCLC. An objective response (complete or partial response) was achieved at six months in 84.6% of patients. The three‐year local control rate was 90.8%. Kaplan–Meier estimates of local failure‐free, progression‐free, overall, and cancer‐specific survival rates at three years were 90.3%, 64.3%, 68.9%, and 88.8%, respectively. The rate of symptomatic radiation pneumonitis was 16.9%, and no grade 4–5 toxicity was observed. Conclusion Favorable local control and outcome was achieved with hypofractionated radiotherapy in patients with inoperable stage I NSCLC with acceptable toxicity. The most common schedule of 6 Gy × 12 fractions may be a promising regimen, and a prospective study is in process. PMID:27148414

  19. The Unique Dorsal Brood Pouch of Thermosbaenacea (Crustacea, Malacostraca) and Description of an Advanced Developmental Stage of Tulumella unidens from the Yucatan Peninsula (Mexico), with a Discussion of Mouth Part Homologies to Other Malacostraca.

    PubMed

    Olesen, Jørgen; Boesgaard, Tom; Iliffe, Thomas M

    2015-01-01

    The Thermosbaenacea, a small taxon of crustaceans inhabiting subterranean waters, are unique among malacostracans as they brood their offspring dorsally under the carapace. This habit is of evolutionary interest but the last detailed report on thermosbaenacean development is more than 40 years old. Here we provide new observations on an ovigerous female of Tulumella unidens with advanced developmental stages in its brood chamber collected from an anchialine cave at the Yucatan Peninsula, which is only the third report on developmental stages of Thermosbaenacea and the first for the genus Tulumella. Significant in a wider crustacean context, we report and discuss hitherto unexplored lobate structures inside the brood chamber of the female originating at the first (maxilliped) and second thoracic segments, which are most likely modified epipods, perhaps serving as gills. At the posterior margin of carapace of the female are rows of large spines preventing the developing stages from falling out. The external morphology of the advanced developmental stages is described in much detail, providing information on e.g., carapace formation and early limb morphology. Among the hitherto unknown structures in the advanced developmental stages provided by this study are the presence of an embryonic dorsal organ and rudimentary 'naupliar processes' of the second antennae. Since most hypotheses on crustacean (and malacostracan and peracaridan) relationship rest on external limb morphology, we use early limb bud morphology of Tulumella to better establish thermosbaenacean limb homologies to those of other crustaceans, which is a necessary basis for future morphology based phylogenetic considerations. PMID:25901753

  20. The Unique Dorsal Brood Pouch of Thermosbaenacea (Crustacea, Malacostraca) and Description of an Advanced Developmental Stage of Tulumella unidens from the Yucatan Peninsula (Mexico), with a Discussion of Mouth Part Homologies to Other Malacostraca

    PubMed Central

    Olesen, Jørgen; Boesgaard, Tom; Iliffe, Thomas M.

    2015-01-01

    The Thermosbaenacea, a small taxon of crustaceans inhabiting subterranean waters, are unique among malacostracans as they brood their offspring dorsally under the carapace. This habit is of evolutionary interest but the last detailed report on thermosbaenacean development is more than 40 years old. Here we provide new observations on an ovigerous female of Tulumella unidens with advanced developmental stages in its brood chamber collected from an anchialine cave at the Yucatan Peninsula, which is only the third report on developmental stages of Thermosbaenacea and the first for the genus Tulumella. Significant in a wider crustacean context, we report and discuss hitherto unexplored lobate structures inside the brood chamber of the female originating at the first (maxilliped) and second thoracic segments, which are most likely modified epipods, perhaps serving as gills. At the posterior margin of carapace of the female are rows of large spines preventing the developing stages from falling out. The external morphology of the advanced developmental stages is described in much detail, providing information on e.g., carapace formation and early limb morphology. Among the hitherto unknown structures in the advanced developmental stages provided by this study are the presence of an embryonic dorsal organ and rudimentary ‘naupliar processes’ of the second antennae. Since most hypotheses on crustacean (and malacostracan and peracaridan) relationship rest on external limb morphology, we use early limb bud morphology of Tulumella to better establish thermosbaenacean limb homologies to those of other crustaceans, which is a necessary basis for future morphology based phylogenetic considerations. PMID:25901753

  1. Minimally invasive (robotic assisted thoracic surgery and video-assisted thoracic surgery) lobectomy for the treatment of locally advanced non-small cell lung cancer

    PubMed Central

    Yang, Hao-Xian; Woo, Kaitlin M.; Sima, Camelia S.

    2016-01-01

    Background Insufficient data exist on the results of minimally invasive surgery (MIS) for locally advanced non-small cell lung cancer (NSCLC) traditionally approached by thoracotomy. The use of telerobotic surgical systems may allow for greater utilization of MIS approaches to locally advanced disease. We will review the existing literature on MIS for locally advanced disease and briefly report on the results of a recent study conducted at our institution. Methods We performed a retrospective review of a prospective single institution database to identify patients with clinical stage II and IIIA NSCLC who underwent lobectomy following induction chemotherapy. The patients were classified into two groups (MIS and thoracotomy) and were compared for differences in outcomes and survival. Results From January 2002 to December 2013, 428 patients {397 thoracotomy, 31 MIS [17 robotic and 14 video-assisted thoracic surgery (VATS)]} underwent induction chemotherapy followed by lobectomy. The conversion rate in the MIS group was 26% (8/31) The R0 resection rate was similar between the groups (97% for MIS vs. 94% for thoracotomy; P=0.71), as was postoperative morbidity (32% for MIS vs. 33% for thoracotomy; P=0.99). The median length of hospital stay was shorter in the MIS group (4 vs. 5 days; P<0.001). The 3-year overall survival (OS) was 48.3% in the MIS group and 56.6% in the thoracotomy group (P=0.84); the corresponding 3-year DFS were 49.0% and 42.1% (P=0.19). Conclusions In appropriately selected patients with NSCLC, MIS approaches to lobectomy following induction therapy are feasible and associated with similar disease-free and OS to those following thoracotomy. PMID:27195138

  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. EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB.

    PubMed

    Lin, Kailong; Cheng, Jianan; Yang, Tao; Li, Yongsheng; Zhu, Bo

    Non-small-cell lung cancer (NSCLC) is a severe disease threatening human health. Targeted therapy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has obtained potent efficacy in the treatment of NSCLC patients. However, the effects of EGFR-TKIs on tumor immune microenvironment are unclear. In this study, we show that NSCLCs with EGFR mutation express higher programmed cell death ligand 1 (PD-L1) than NSCLCs with wild type EGFR. The EGFR activation is also associated with high expression of PD-L1. The EGFR-TKI gefitinib can reduce PD-L1 expression, via inhibiting NF-κB, in EGFR mutant NSCLC in vitro and in vivo. These findings elucidate a novel anti-tumor mechanism of EGFR-TKI and provide the possibility of combined strategy of targeted therapy and immunotherapy for EGFR mutant NSCLC patients. PMID:25998384

  4. 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

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

    SciTech Connect

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

    2012-11-01

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

  6. Factors associated with initiation of antiretroviral therapy in the advanced stages of HIV infection in six Ethiopian HIV clinics, 2012 to 2013

    PubMed Central

    Nash, Denis; Tymejczyk, Olga; Gadisa, Tsigereda; Kulkarni, Sarah Gorrell; Hoffman, Susie; Yigzaw, Muluneh; Elul, Batya; Remien, Robert H; Lahuerta, Maria; Daba, Shalo; El Sadr, Wafaa; Melaku, Zenebe

    2016-01-01

    Introduction Most HIV-positive persons in sub-Saharan Africa initiate antiretroviral therapy (ART) with advanced infection (late ART initiation). Intervening on the drivers of late ART initiation is a critical step towards achieving the full potential of HIV treatment scale-up. This study aimed to identify modifiable factors associated with late ART initiation in Ethiopia. Methods From 2012 to 2013, Ethiopian adults (n=1180) were interviewed within two weeks of ART initiation. Interview data were merged with HIV care histories to assess correlates of late ART initiation (CD4+ count <150 cells/µL or World Health Organization Stage IV). Results The median CD4 count at enrolment in HIV care was 263 cells/µL (interquartile range (IQR): 140 to 390) and 212 cells/µL (IQR: 119 to 288) at ART initiation. Overall, 31.2% of participants initiated ART late, of whom 85.1% already had advanced HIV disease at enrolment. Factors associated with higher odds of late ART initiation included male sex (vs. non-pregnant females; adjusted odds ratio (aOR): 2.02; 95% CI: 1.50 to 2.73), high levels of psychological distress (vs. low/none, aOR: 1.96; 95% CI: 1.34 to 2.87), perceived communication barriers with providers (aOR: 2.42, 95% CI: 1.24 to 4.75), diagnosis via provider initiated testing (vs. voluntary counselling and testing, aOR: 1.47, 95% CI: 1.07 to 2.04), tuberculosis (TB) treatment prior to ART initiation (aOR: 2.16, 95% CI: 1.43 to 3.25) and a gap in care of six months or more prior to ART initiation (aOR: 2.02, 95% CI: 1.10 to 3.72). Testing because of partner illness/death (aOR: 0.64, 95% CI: 0.42 to 0.95) was associated with lower odds of late ART initiation. Conclusions Programmatic initiatives promoting earlier diagnosis, engagement in pre-ART care, and integration of TB and HIV treatments may facilitate earlier ART initiation. Men and those experiencing psychological distress may also benefit from targeted support prior to ART initiation. PMID:27113335

  7. miR-204 suppresses non-small-cell lung carcinoma (NSCLC) invasion and migration by targeting JAK2.

    PubMed

    Wang, P; Lv, H Y; Zhou, D M; Zhang, E N

    2016-01-01

    Aberrant expression of microRNA is associated with the development and progression of cancers. MicroRNA-204 (miR-204) down-regulation has been previously demonstrated in non-small-cell lung carcinoma (NSCLC); however, the underlying mechanism by which miR-204 suppresses tumorigenesis in NSCLC remains elusive. In this study, miR-204 expression was found to be down-regulated, and that of Janus kinase 2 (JAK2) was found to be up-regulated in four NSCLC cell lines (A549, H1299, H1650, and H358) compared to the normal lung cell line. The overexpression of miR-204 suppressed the invasive and migratory capacities of H1299 cells. A luciferase assay confirmed that the binding of miR-124 to the -untranslated region of JAK2 inhibited the expression of JAK2 proteins in H1299 cells. JAK-2 overexpression effectively reversed miR-204-repressed NSCLC metastasis. Taken together, our findings revealed that miR-204 functions as a tumor suppressor in NSCLC by targeting JAK2, and that miR-204 may therefore serve as a biomarker for the diagnosis and treatment of NSCLC. PMID:27323056

  8. Phase I/II Study of Postoperative Adjuvant Chemoradiation for Advanced-Stage Cutaneous Squamous Cell Carcinoma of the Head and Neck (cSCCHN)

    ClinicalTrials.gov

    2014-11-17

    Recurrent Skin Cancer; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Squamous Cell Carcinoma of the Skin; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity

  9. CoMPASs: IOn programme (Care Of Memory Problems in Advanced Stages of dementia: Improving Our Knowledge): protocol for a mixed methods study

    PubMed Central

    Jones, Louise; Harrington, Jane; Scott, Sharon; Davis, Sarah; Lord, Kathryn; Vickerstaff, Victoria; Round, Jeff; Candy, Bridget; Sampson, Elizabeth L

    2012-01-01

    Introduction Approximately 700 000 people in the UK have dementia, rising to 1.2 million by 2050; one-third of people aged over 65 will die with dementia. Good end-of-life care is often neglected, and detailed UK-based research on symptom burden and needs is lacking. Our project examines these issues from multiple perspectives using a rigorous and innovative design, collecting data which will inform the development of pragmatic interventions to improve care. Methods and analysis To define in detail symptom burden, service provision and factors affecting care pathways we shall use mixed methods: prospective cohort studies of people with advanced dementia and their carers; workshops and interactive interviews with health professionals and carers, and a workshop with people with early stage dementia. Interim analyses of cohort data will inform new scenarios for workshops and interviews. Final analysis will include cohort demographics, the symptom burden and health service use over the follow-up period. We shall explore the level and nature of unmet needs, describing how comfort and quality of life change over time and differences between those living in care homes and those remaining in their own homes. Data from workshops and interviews will be analysed for thematic content assisted by textual grouping software. Findings will inform the development of a complex intervention in the next phase of the research programme. Ethics and dissemination Ethical approval was granted by National Health Service ethical committees for studies involving people with dementia and carers (REC refs. 12/EE/0003; 12/LO/0346), and by university ethics committee for work with healthcare professionals (REC ref. 3578/001). We shall present our findings at conferences, and in peer-reviewed journals, prepare detailed reports for organisations involved with end-of-life care and dementia, publicising results on the Marie Curie website. A summary of the research will be provided to participants

  10. Three-dimensional conformal radiotherapy for locally advanced (Stage II and worse) head-and-neck cancer: Dosimetric and clinical evaluation

    SciTech Connect

    Portaluri, Maurizio . E-mail: portaluri@hotmail.com; Fucilli, Fulvio I.M.; Castagna, Roberta; Bambace, Santa; Pili, Giorgio; Tramacere, Francesco; Russo, Donatella; Francavilla, Maria Carmen

    2006-11-15

    Purpose: To evaluate the dosimetric parameters of three-dimensional conformal radiotherapy (3D-CRT) in locally advanced head-and-neck tumors (Stage II and above) and the effects on xerostomia. Methods and Materials: A total of 49 patients with histologically proven squamous cell cancer of the head and neck were consecutively treated with 3D-CRT using a one-point setup technique; 17 had larynx cancer, 12 oropharynx, 12 oral cavity, and 6 nasopharynx cancer; 2 had other sites of cancer. Of the 49 patients, 41 received postoperative RT and 8 definitive treatment. Also, 13 were treated with cisplatin-based chemotherapy before and during RT; in 6 cases, 5-fluorouracil was added. The follow-up time was 484-567 days (median, 530 days). Results: One-point setup can deliver 96% of the prescribed dose to the isocenter, to the whole planning target volume, including all node levels of the neck and without overdosages. The mean dose to the primary planning target volume was 49.54 {+-} 4.82 Gy (51.53 {+-} 5.47 Gy for larynx cases). The average dose to the contralateral parotid gland was approximately 38 Gy (30 Gy for larynx cases). The maximal dose to the spinal cord was 46 Gy. A Grade 0 Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer xerostomia score corresponded to a mean dose of 30 Gy to one parotid gland. A lower xerostomia score with a lower mean parotid dose and longer follow-up seemed to give rise to a sort of functional recovery phenomenon. Conclusion: Three dimensional-CRT in head-and-neck cancers permits good coverage of the planning target volume with about 10-11 segments and one isocenter. With a mean dose of approximately 30 Gy to the contralateral parotid, we observed no or mild xerostomia.

  11. Electrochemotherapy in combination with chemoradiotherapy in the treatment of oral carcinomas in advanced stages of disease: efficacy, safety, and clinical outcomes in a small number of selected cases

    PubMed Central

    Domanico, Rossana; Trapasso, Serena; Santoro, Mariaquila; Pingitore, Domenico; Allegra, Eugenia

    2015-01-01

    Introduction Electrochemotherapy (ECT) is a new therapeutic method that is used in oncology as palliative treatment in patients with recurrent head and neck tumors and who are not candidates for standard therapeutic options. The aim of our study was to evaluate the cytoreductive effect of ECT in patients subjected to chemoradiotherapy for squamous cell carcinoma of the oral cavity. The primary endpoint of the study was to verify tumor debulking after ECT treatment as neoadjuvant, before conventional chemoradiotherapy. The secondary endpoint was to assess the safety and tolerability of ECT treatment. Materials and methods This experimental study was conducted at the Division of Otolaryngology, University of Catanzaro, Italy. From February 2013 to February 2014, four patients were enrolled, two males and two females, with a mean age of 56 years (range: 47–65 years), and with squamous cell carcinoma of the oral cavity in advanced stages of disease (T3–T4). All patients, with their informed consent, received ECT treatment in accordance with the Standard Operating Procedures defined in the European Standard Operating Procedures on Electrochemotherapy (ESOPE) study, followed by conventional chemoradiotherapy. Their response to ECT treatment was assessed after 30 days. For each patient, the following parameters were evaluated with the appropriate forms: local tumor control, control of pain (analgesia postsurgery scale [APS]), and quality of life (Short Form [36] Health Survey [SF-36]; v1). Results Three of four patients (75%) showed a partial response, whereas in one patient (25%), the disease remained stable. The treatment was well-tolerated by all patients, according to the APS and SF-36 results. Conclusion Although the study was conducted on a small number of cases, data from this study show that ECT represents a safe and effective treatment in terms of tumor cytoreduction and locoregional control of the disease. It also allows good control of postoperative pain

  12. Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer

    PubMed Central

    Leodolter, Andreas; Alonso, Sergio; González, Beatriz; Ebert, Matthias P; Vieth, Michael; Röcken, Christoph; Wex, Thomas; Peitz, Ullrich; Malfertheiner, Peter; Perucho, Manuel

    2015-01-01

    Objectives: Helicobacter pylori-related high-risk gastritis (HRG) is a severe risk factor for gastric cancer (GC). The link between HRG and long-term risk for GC may involve genetic and epigenetic alterations underlying a field defect, i.e. a region of the mucosa prone to cancer development. Global DNA hypomethylation is a pervasive alteration in GC that associates with chromosomal instability and poor prognosis. The aim of this study was to determine the chronology of this alteration along the progression of HRG to GC, to test the hypothesis that it occurs early in the chronology of this pathway and plays a mechanistic role in the long-term cancer risk. Methods: We comparatively measured the genomic methylation level in gastric biopsies from 94 GC patients and 16 of their cancer-free relatives, 38 HRG patients, and 17 GERD patients, using a quantitative enzymatic method. Results: GC biopsies were hypomethylated compared to their matching non-tumor mucosa (P=9.4 × 10−12), irrespective of the tumor location or patients' country of origin. Genome-wide hypomethylation was also found in gastric mucosa of GC (P=1.5 × 10−5) and HRG (P=0.004) patients compared with healthy donors and GC relatives, regardless of the biopsy location within the stomach or previous H. pylori eradication therapy. An enhanced hypomethylation, distinguished by a bi-slope distribution of the differences in methylation between tumor and normal tissues, associated with a more invasive (P=0.005) and advanced stage (P=0.017) type of GC. Conclusions: Universal DNA demethylation in normal gastric mucosa in GC patients appears sporadic rather than familial. Genomic hypomethylation in HRG possibly contributes to a field defect for cancerization that is not reversed by bacterial eradication. Enhanced somatic hypomethylation may stratify GC for prognostic purposes. PMID:25928808

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

    PubMed Central

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

    2015-01-01

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

  14. The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC)

    PubMed Central

    Xu, Meng; Xie, Yiqun; Ni, Songshi

    2015-01-01

    First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, produce reliable responses and survival benefits in selected patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who initially respond to first-line therapy with EGFR TKIs will experience disease progression in 1-2 years. To overcome the resistance of EGFR TKIs, the potent resistance mechanisms and novel therapeutic strategies have been developed. T790M mutation and activation of bypass signaling pathway are identified the predominant mechanisms of acquired resistance to TKIs. Several approaches have shown promise, such as next-generation EGFR TKIs, immunotherapy, and combinational therapies. And the limited clinical data suggest that all drugs are acceptable safe. Additionally, this review will also focus on the increasingly importance of re-biopsy at the time of disease progression, and the matching effective therapies is related to the identification of specific molecular types of tumors. PMID:26015938

  15. Novel EGFR mutation specific antibodies for NSCLC: Immunohistochemistry as a possible screening method for EGFR mutations

    PubMed Central

    Kato, Yasufumi; Peled, Nir; Wynes, Murry W.; Yoshida, Koichi; Pardo, Marta; Mascaux, Celine; Ohira, Tatsuo; Tsuboi, Masahiro; Matsubayashi, Jun; Nagao, Toshitaka; Ikeda, Norihiko; Hirsch, Fred R.

    2010-01-01

    Background Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict better outcome to EGFR tyrosine kinase inhibitors (TKIs). The most common mutations are exon 19 deletions (most frequently E746-A750) and L858R point mutation in exon 21. Here, we evaluated the accuracy of novel EGFR mutation specific antibodies in a Japanese cohort with NSCLC and compared to direct DNA sequencing and clinical outcome. Materials and methods Immunohistochemistry (IHC) using antibodies specific for the E746-A750 and L858R mutations in EGFR was performed on tissue microarrays of tumors from 70 gefitinib treated NSCLC patients. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21. Results DNA sequencing showed EGFR mutations in 41 patients (58.6%), and exon 19 deletions in 18 patients (25.7%), 61% (11/18) had a deletion in the range of E746-A750) and 12 (17.1%) had exon 21 mutations (L858R). IHC showed, for the E746-A750 and L858R mutations, sensitivity (81.8% and 75%), specificity (100%, 96.6%), PPV (100%, 81.8%) and NPV (96.7%, 94.9%). Analysis for objective response rates (ORR) and survival were not correlated to IHC staining, although the combined staining showed non-significant trends towards better overall survival for patients with EGFR mutations. Conclusions The mutation specific IHC antibodies have high sensitivity and specificity for pre-defined EFGR mutations and may be suitable for screening for these pre-defined mutations. However, negative IHC results require further mutation analyses prior to excluding EGFR-targeted therapy. PMID:20697298

  16. 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

  17. 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

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

    PubMed Central

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

    2016-01-01

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

  19. Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib.

    PubMed

    Hirsh, Vera

    2015-06-01

    First-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, represented an important addition to the treatment armamentarium for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, all patients inevitably develop acquired resistance to these agents, primarily due to secondary EGFR mutations, molecular aberrations affecting other signaling pathways, or transformation to small-cell histology. It was hypothesized that development of second-generation TKIs with broader inhibitory profiles could confer longer-lasting clinical activity and overcome acquired resistance to first-generation inhibitors. Here, we review the development of afatinib, an irreversible ErbB family blocker that potently inhibits signaling of all homodimers and heterodimers formed by the EGFR, human epidermal growth factor receptor (HER)-2, HER3, and HER4 receptors. In two phase III trials in patients with EGFR mutation-positive NSCLC, first-line afatinib significantly improved progression-free survival (PFS) and health-related quality of life versus standard-of-care chemotherapy. Moreover, in preplanned sub-analyses, afatinib significantly improved overall survival in patients harboring EGFR Del19 mutations. Afatinib has also demonstrated clinical activity in NSCLC patients who had progressed on erlotinib/gefitinib, particularly when combined with cetuximab, and offers 'treatment beyond progression' benefit when combined with paclitaxel versus chemotherapy alone. Furthermore, a recent phase III study demonstrated that PFS was significantly improved with afatinib versus erlotinib for the second-line treatment of patients with squamous cell carcinoma of the lung. The activity of afatinib in both first-line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members. Afatinib has a well-defined safety profile with characteristic gastrointestinal (diarrhea

  20. 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

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

    PubMed

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

    2016-01-01

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

  2. Analysis of HLA class I-II haplotype frequency and segregation in a cohort of patients with advanced stage ovarian cancer.

    PubMed

    Gamzatova, Z; Villabona, L; van der Zanden, H; Haasnoot, G W; Andersson, E; Kiessling, R; Seliger, B; Kanter, L; Dalianis, T; Bergfeldt, K; Masucci, G V

    2007-09-01

    In solid tumors, human leucocyte antigen (HLA)-A2 has been suggested to be a risk factor and a negative prognostic factor. The HLA-A2 allele in Scandinavia has a high prevalence; it decreases with latitude and also with ovarian cancer mortality in Europe. Furthermore, an association of the HLA-A2 allele with severe prognosis in serous adenocarcinoma of the ovary in stages III-IV was found. Thirty-two unrelated Swedish women with relapsing or progressive ovarian cancer were analysed for the genotypes at the HLA-A, HLA-B, HLA-Cw, and HLA-DRB1 loci by the polymerase chain reaction/sequence-specific primer method. The frequencies of HLA alleles of healthy Swedish bone marrow donors provided by the coordinating centre of the Bone Marrow Donors Worldwide Registries, Leiden, the Netherlands were used as controls. When this cohort of epithelial ovarian cancer patients was compared with healthy Swedish donors, the frequency of HLA-A1 and HLA-A2 gene/phenotype appears, although not statistically significant, to be increased in patients with ovarian carcinoma, while HLA-A3 was decreased. HLA-A2 homozygotes were twofold higher in patients. The A2-B8 haplotype was significantly increased (corrected P value). A2-B5, A2-B15, A2-DRB1*03, A2-DRB1*04, A2-B15-Cw3, and A2-B8-DRB1*03 had odds ratio as well as the level of the lower confidence interval above 1 and significant P value only when considered as single, non-corrected analysis. HLA-B15 and HLA-Cw3 were only present in HLA-A2-positive patients showing that the HLA-A2-HLA-Cw3 and HLA-B15 haplotypes were segregated. In this selected cohort with advanced disease, there are indications of an unusual overrepresentation of HLA class I and II genes/haplotypes as well as segregation for the HLA-A2-HLA-Cw3 and HLA-B15 haplotypes. These findings are presented as a descriptive analysis and need further investigations on a larger series of ovarian cancer patients to establish prognostic associations. PMID:17661908

  3. A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non–small-cell lung cancer

    PubMed Central

    Hasegawa, Takaaki; Futamura, Yohei; Horiba, Akane; Yoshida, Tsutomu; Suzuki, Toshitaka; Kato, Tatsuo; Kaito, Daizo; Ohno, Yasuhi; Iida, Takayoshi; Hayashi, Shinya; Sawa, Toshiyuki

    2016-01-01

    We investigated the efficacy and safety of albumin-bound paclitaxel (nab-PTX) and carboplatin (CBDCA) with concurrent radiotherapy for unresectable locally advanced non–small-cell lung cancer (NSCLC). Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Concurrent chemoradiotherapy consisted of weekly administration of nab-PTX (40 mg/m2) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m2 on Days 1, 8 and 15)/CBDCA (AUC 5 mg/ml/min on Day 1). Response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival were estimated using the Kaplan–Meier method. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. A total of 10 patients were enrolled in this trial between September 2013 and January 2014 from three institutes. The overall response rate was 40.0% and the median progression-free survival was 6.7 months. Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. The results of this study indicate that no further investigation is warranted into nab-PTX and CBDCA with concurrent thoracic radiation for Stage III NSCLC with V20 > 30% due to severe toxicity. PMID:26442970

  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. Prognostic value of the standardized uptake value maximum change calculated by dual-time-point 18F-fluorodeoxyglucose positron emission tomography imaging in patients with advanced non-small-cell lung cancer

    PubMed Central

    Jin, Feng; Zhu, Hui; Fu, Zheng; Kong, Li; Yu, Jinming

    2016-01-01

    Purpose The purpose of this study was to investigate the prognostic value of the standardized uptake value maximum (SUVmax) change calculated by dual-time-point 18F-fluorodeoxyglucose positron emission tomography (PET) imaging in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods We conducted a retrospective review of 115 patients with advanced NSCLC who underwent pretreatment dual-time-point 18F-fluorodeoxyglucose PET acquired at 1 and 2 hours after injection. The SUVmax from early images (SUVmax1) and SUVmax from delayed images (SUVmax2) were recorded and used to calculate the SUVmax changes, including the SUVmax increment (ΔSUVmax) and percent change of the SUVmax (%ΔSUVmax). Progression-free survival (PFS) and overall survival (OS) were determined by the Kaplan–Meier method and were compared with the studied PET parameters, and the clinicopathological prognostic factors in univariate analyses and multivariate analyses were constructed using Cox proportional hazards regression. Results One hundred and fifteen consecutive patients were reviewed, and the median follow-up time was 12.5 months. The estimated median PFS and OS were 3.8 and 9.6 months, respectively. In univariate analysis, SUVmax1, SUVmax2, ΔSUVmax, %ΔSUVmax, clinical stage, and Eastern Cooperative Oncology Group (ECOG) scores were significant prognostic factors for PFS. Similar results were significantly correlated with OS, except %ΔSUVmax. In multivariate analysis, ΔSUVmax and %ΔSUVmax were significant factors for PFS. On the other hand, ECOG scores were only identified as independent predictors of OS. Conclusion Our results demonstrated the prognostic value of the SUVmax change in predicting the PFS of patients with advanced NSCLC. However, SUVmax change could not predict OS. PMID:27284249

  6. A phase II clinical trial of gemcitabine and split dose cisplatin in advanced non-small cell lung cancer in an outpatient setting.

    PubMed

    Hussain, S A; Palmer, D H; Swinson, D E; Riley, P; Wills, A; Brown, C; Draycott, C; El-Modir, A; Peake, D R; Rea, D W; Chetiyawardana, A D; Cullen, M H

    2008-07-01

    In response to increasing pressure on inpatient services and a meta-analysis indicating that cisplatin (C) is superior to carboplatin, we report a phase II trial of gemcitabine (G) and split-dose C in advanced non-small cell lung cancer (NSCLC) in an outpatient setting. Patients with stage IIIB/IV NSCLC received: G/C 1250/40 mg/m(2); G and C were given on day (d) 1 and d8 in a 21d cycle. Patients with performance status 0-2, adequate bone marrow function and calculated glomerular filtration rate (GFR) >50 ml/min were eligible. Forty-two patients were enrolled: 25 male; median age 62 (range 37-78) years. There were 26 patients (62%) with stage IV disease. One hundred and thirty-eight cycles of chemotherapy were delivered. Chemotherapy was well tolerated, allowing maintenance of planned dose intensity (DI) with mean dose delivered of 780.1 mg/m(2) (93%) and 25.6 mg/m(2) (96%) for G and C, respectively. The overall response rate was 43%. Median survival was 12.5 months with a median follow-up of 13.5 months. One year survival rate was 51%. G plus C both given on d1 and d8 (q21d) is a very active, well tolerated and convenient outpatient schedule, which maintains DI. PMID:18575742

  7. Long-term outcome of surgical resection for residual or regrown advanced non-small cell lung carcinomas following EGFR-TKI treatment: report of four cases.

    PubMed

    Hishida, Tomoyuki; Yoshida, Junji; Aokage, Keiju; Nagai, Kanji; Tsuboi, Masahiro

    2016-07-01

    We report the long-term outcome of 4 patients who underwent pulmonary resection for residual or regrown primary lesion of non-small cell lung cancer (NSCLC) treated with a epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib. Two patients underwent surgical resection for localized regrown primary lesion after gefitinib for stage IV disease. The remaining two patients underwent surgery for localized residual primary lesion that was downstaged to N0 after gefitinib for initially inoperable cN2 (stage IIIA) disease. Three patients developed recurrence with a median progression-free period of 1.2 years (0.2-2.2), but they survived more than 5 years postoperatively with good local control. One patient who initially had cN2 disease is alive without recurrence after 4 years with continued postoperative gefitinib. Although our series is small, the relatively favorable long-term survival indicates the need for further investigation of the role of surgery during molecular-targeted therapy for advanced NSCLC. PMID:25512091

  8. 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

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

    PubMed

    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

  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. PMID:26854716

  11. Individualized Dose Prescription for Hypofractionation in Advanced Non-Small-Cell Lung Cancer Radiotherapy: An in silico Trial

    SciTech Connect

    Hoffmann, Aswin L.; Troost, Esther G.C.; Huizenga, Henk; Kaanders, Johannes H.A.M.; Bussink, Johan

    2012-08-01

    Purpose: Local tumor control and outcome remain poor in patients with advanced non-small-cell lung cancer (NSCLC) treated by external beam radiotherapy. We investigated the therapeutic gain of individualized dose prescription with dose escalation based on normal tissue dose constraints for various hypofractionation schemes delivered with intensity-modulated radiation therapy. Methods and Materials: For 38 Stage III NSCLC patients, the dose level of an existing curative treatment plan with standard fractionation (66 Gy) was rescaled based on dose constraints for the lung, spinal cord, esophagus, brachial plexus, and heart. The effect on tumor total dose (TTD) and biologic tumor effective dose in 2-Gy fractions (TED) corrected for overall treatment time (OTT) was compared for isotoxic and maximally tolerable schemes given in 15, 20, and 33 fractions. Rescaling was accomplished by altering the dose per fraction and/or the number of fractions while keeping the relative dose distribution of the original treatment plan. Results: For 30 of the 38 patients, dose escalation by individualized hypofractionation yielded therapeutic gain. For the maximally tolerable dose scheme in 33 fractions (MTD{sub 33}), individualized dose escalation resulted in a 2.5-21% gain in TTD. In the isotoxic schemes, the number of fractions could be reduced with a marginal increase in TED. For the maximally tolerable dose schemes, the TED could be escalated up to 36.6%, and for all patients beyond the level of the isotoxic and the MTD{sub 33} schemes (range, 3.3-36.6%). Reduction of the OTT contributed to the therapeutic gain of the shortened schemes. For the maximally tolerable schemes, the maximum esophageal dose was the dominant dose-limiting constraint in most patients. Conclusions: This modeling study showed that individualized dose prescription for hypofractionation in NSCLC radiotherapy, based on scaling of existing treatment plans up to normal tissue dose constraints, enables dose

  12. Second-line erlotinib in patients with advanced non-small-cell lung cancer: subgroup analyses from the TRUST study.

    PubMed

    Heigener, David F; Wu, Yi-Long; van Zandwijk, Nico; Mali, Pekka; Horwood, Keith; Reck, Martin

    2011-11-01

    Erlotinib is a highly potent inhibitor of epidermal growth factor receptor tyrosine-kinase activity that significantly prolongs overall survival in patients with non-small-cell lung cancer (NSCLC), and improves symptom control and quality of life compared with placebo. The safety and efficacy of erlotinib has been investigated in a large, international, phase IV, open-label study (TRUST) in patients (n=6665) with advanced stage IIIB/IV NSCLC. An analysis of efficacy and safety outcomes is reported for patients receiving erlotinib as second-line therapy in TRUST (n=3224). Best response data were available for all 3224 patients. Complete response, partial response and stable disease were achieved in 25 (<1%), 368 (14%) and 1444 (54%) patients, respectively, for a disease control rate of 68%. Median progression-free and overall survivals were 13.6 weeks and 8.6 months, respectively; 1-year survival was 39.4%. Safety data were available for all patients. Of these, 389 patients (12%) had an erlotinib-related adverse event (AE) other than pre-specified AEs defined in the protocol; only 96 patients (3%) had an erlotinib-related AE ≥ grade 3. Of 1376 patients (43%) with serious AEs (SAEs), only 122 (4%) had treatment-related SAEs and most were gastrointestinal disorders (mainly diarrhoea and nausea). No treatment-related SAE occurred in ≥ 1% of patients. Data on the incidence of erlotinib-related rash were collected for all patients, 2302 (71%) of whom experienced rash. Of these rash events, 83% were of grade 1/2. These data confirm the good efficacy and tolerability of second-line erlotinib in a broad range of patients with NSCLC. PMID:21439671

  13. Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study

    PubMed Central

    2011-01-01

    Background Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. Methods Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5 × 107 DC cells administered subcutaneous and intravenously two times at two week intervals. The immunologic response, safety and tolerability to the vaccine were evaluated by the lymphoproliferation assay and clinical and laboratorial evolution, respectively. Results The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.005). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. Conclusion Despite the small sample size, the results on the immune response, safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment. Trial Registration Current Controlled Trials: ISRCTN45563569 PMID:21682877

  14. 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

  15. Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC

    PubMed Central

    Che, Ting-Fang; Lin, Ching-Wen; Wu, Yi-Ying; Chen, Yu-Ju; Han, Chia-Li; Chang, Yih-leong; Wu, Chen-Tu; Hsiao, Tzu-Hung

    2015-01-01

    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. PMID:26497368

  16. Rebiopsy during disease progression in patients treated by TKI for oncogene-addicted NSCLC.

    PubMed

    Bosc, Cecile; Ferretti, Gilbert R; Cadranel, Jacques; Audigier-Valette, Clarisse; Besse, Benjamin; Barlesi, Fabrice; Decroisette, Chantal; Lantuejoul, Sylvie; Arbib, François; Moro-Sibilot, Denis

    2015-06-01

    All lung cancer patients with mutant epidermal growth factor receptor (EGFR) or rearranged EML4-ALK eventually develop acquired resistance to treatment. Rebiopsy may give insight into the resistance mechanisms and direct further lines of treatment. Here, we evaluate the potential interest and limitations of rebiopsy. Patients with mutant EGFR or rearranged EML4-ALK non-small cell lung cancer (NSCLC) and acquired resistance to tyrosine kinase inhibitors were included in a retrospective study to determine the percentage of patients who underwent rebiopsy and whether rebiopsy would have been possible, or not, in the remaining patients. In a cohort of 84 patients from 6 institutions, a biopsy had been performed in 39 cases. Biopsy samples were sufficient for histopathological or cytological examination in 35 cases (89.7 %). Complete or partial response had been observed in 84.5 % of patients whose cancer further progressed and who underwent rebiopsy. A biopsy could have been considered in 30 of the 45 remaining patients. Those with brain (N = 9) and bone (N = 2) metastases and/or with contraindications (N = 6) were excluded (two patients had both brain metastases and a contraindication). The rebiopsy target was thoracic in 62 % of cases and on distant metastases in 38 % of cases. Patients with NSCLC and an activating mutation could undergo a rebiopsy in 72 % of cases. A response to treatment does not preclude the possibility of rebiopsy at the time of progression. PMID:25119973

  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. [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

  19. [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

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

    PubMed Central

    Velazquez, Emmanuel Rios; Parmar, Chintan; Jermoumi, Mohammed; Mak, Raymond H.; van Baardwijk, Angela; Fennessy, Fiona M.; Lewis, John H.; De Ruysscher, Dirk; Kikinis, Ron; Lambin, Philippe; Aerts, Hugo J. W. L.

    2013-01-01

    Accurate volumetric assessment in non-small cell lung cancer (NSCLC) is critical for adequately informing treatments. In this study we assessed the clinical relevance of a semiautomatic computed tomography (CT)-based segmentation method using the competitive region-growing based algorithm, implemented in the free and public available 3D-Slicer software platform. We compared the 3D-Slicer segmented volumes by three independent observers, who segmented the primary tumour of 20 NSCLC patients twice, to manual slice-by-slice delineations of five physicians. Furthermore, we compared all tumour contours to the macroscopic diameter of the tumour in pathology, considered as the “gold standard”. The 3D-Slicer segmented volumes demonstrated high agreement (overlap fractions > 0.90), lower volume variability (p = 0.0003) and smaller uncertainty areas (p = 0.0002), compared to manual slice-by-slice delineations. Furthermore, 3D-Slicer segmentations showed a strong correlation to pathology (r = 0.89, 95%CI, 0.81–0.94). Our results show that semiautomatic 3D-Slicer segmentations can be used for accurate contouring and are more stable than manual delineations. Therefore, 3D-Slicer can be employed as a starting point for treatment decisions or for high-throughput data mining research, such as Radiomics, where manual delineating often represent a time-consuming bottleneck. PMID:24346241

  1. 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

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

    PubMed Central

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

    2014-01-01

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

  3. Nuclear Cryogenic Propulsion Stage

    NASA Technical Reports Server (NTRS)

    Houts, Michael G.; Borowski, S. K.; George, J. A.; Kim, T.; Emrich, W. J.; Hickman, R. R.; Broadway, J. W.; Gerrish, H. P.; Adams, R. B.

    2012-01-01

    The fundamental capability of Nuclear Thermal Propulsion (NTP) is game changing for space exploration. A first generation Nuclear Cryogenic Propulsion Stage (NCPS) based on NTP could provide high thrust at a specific impulse above 900 s, roughly double that of state of the art chemical engines. Characteristics of fission and NTP indicate that useful first generation systems will provide a foundation for future systems with extremely high performance. The role of the NCPS in the development of advanced nuclear propulsion systems could be analogous to the role of the DC-3 in the development of advanced aviation. Progress made under the NCPS project could help enable both advanced NTP and advanced NEP.

  4. Long-term outcomes after video-assisted thoracic surgery (VATS) lobectomy versus lobectomy via open thoracotomy for clinical stage IA non-small cell lung cancer

    PubMed Central

    2014-01-01

    Background Video-assisted thoracic surgery (VATS) lobectomy is a standard treatment for lung cancer. This study retrospectively compared long-term outcomes after VATS lobectomy versus lobectomy via open thoracotomy for clinical stage IA non-small cell lung cancer (NSCLC). Methods From July 2002 to June 2012, 160 patients were diagnosed with clinical stage IA NSCLC and underwent lobectomy. Of these, 114 underwent VATS lobectomy and 46 underwent lobectomy via open thoracotomy. Results The 5-year disease-free survival (DFS) rate was 88.0% in the VATS group and 77.1% in the thoracotomy group for clinical stage IA NSCLC (p = 0.1504), and 91.5% in the VATS group and 93.8% in the thoracotomy group for pathological stage IA NSCLC (p = 0.2662). The 5-year overall survival (OS) rate was 94.1% in the VATS group and 81.8% in the thoracotomy group for clinical stage IA NSCLC (p = 0.0268), and 94.8% in the VATS group and 96.2% in the thoracotomy group for pathological stage IA NSCLC (p = 0.5545). The rate of accurate preoperative staging was 71.9% in the VATS group and 56.5% in the thoracotomy group (p = 0.2611). Inconsistencies between the clinical and pathological stages were mainly related to tumor size, nodal status, and pleural invasion. Local recurrence occurred for one lesion in the VATS group and six lesions (five patients) in the thoracotomy group (p = 0.0495). Conclusions The DFS and OS were not inferior after VATS compared with thoracotomy. Local control was significantly better after VATS than after thoracotomy. Preoperative staging lacked sufficient accuracy. PMID:24886655

  5. Neoadjuvant Radiotherapy/Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Yalman, Deniz

    2015-01-01

    Locally advanced non-small cell lung cancer (NSCLC) consists of a heterogeneous group of patients, and the optimal treatment is still controversial. The current standard of care is concurrent chemoradiotherapy. The prognosis is still poor, with high rates of local and distant failure despite multimodality treatment. One of the efforts to improve outcomes in these patients is to use neoadjuvant treatment to improve resectability, and downstaging the nodal disease, which has a clear impact on prognosis. Radiotherapy as the sole neoadjuvant modality has been used historically without any survival benefit, but with increased toxicity. After the demonstrating a survival benefit by combining radiotherapy and chemotherapy, phase II studies were started to determine the neoadjuvant administration of these two modalities together. Although the results of these studies revealed a heterogeneous postinduction pathologic complete response, tumor and nodal down-staging can be achieved at the cost of a slightly higher morbidity and mortality. Subsequent phase III trials also failed to show a survival benefit to surgery, but indicated that there may be a subset of patients with locally advanced disease who can benefit from resection unless pneumonectomy is not provided. In order to increase the efficacy of radiotherapy, hyperfractionated-accelerated schedules have been used with promising complete pathologic response rates, which might improve prognosis. Recently, studies applying high radiotherapy doses in the neoadjuvant setting demonstrated the safety of resection after radiotherapy, with high nodal clearance rates and encouraging long-term survival results. In conclusion, neoadjuvant treatment of locally advanced NSCLC is one of the most challenging issues in the treatment of this disease, but it can be offered to appropriately selected patients, and should be done by a multidisciplinary team. Individual risk profiles, definite role of radiotherapy with optimal timing, and

  6. Results of an Advanced Fan Stage Operating Over a Wide Range of Speed and Bypass Ratio. Part 2; Comparison of CFD and Experimental Results

    NASA Technical Reports Server (NTRS)

    Celestina, Mark L.; Suder, Kenneth L.; Kulkarni, Sameer

    2010-01-01

    NASA and GE teamed to design and build a 57 percent engine scaled fan stage for a Mach 4 variable cycle turbofan/ramjet engine for access to space with multipoint operations. This fan stage was tested in NASA's transonic compressor facility. The objectives of this test were to assess the aerodynamic and aero mechanic performance and operability characteristics of the fan stage over the entire range of engine operation including: 1) sea level static take-off; 2) transition over large swings in fan bypass ratio; 3) transition from turbofan to ramjet; and 4) fan wind-milling operation at high Mach flight conditions. This paper will focus on an assessment of APNASA, a multistage turbomachinery analysis code developed by NASA, to predict the fan stage performance and operability over a wide range of speeds (37 to 100 percent) and bypass ratios.

  7. 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. PMID:26235195

  8. Inhibition of non-small cell lung cancer (NSCLC) growth by a novel small molecular inhibitor of EGFR

    PubMed Central

    Fang, Yuanzhang; Vaughn, Amanda; Cai, Xiaopan; Xu, Leqin; Wan, Wei; Li, Zhenxi; Chen, Shijie; Yang, Xinghai; Wu, Song; Xiao, Jianru

    2015-01-01

    The epidermal growth factor receptor (EGFR) is a therapeutic target (oncotarget) in NSCLC. Using in vitro EGFR kinase activity system, we identified a novel small molecule, WB-308, as an inhibitor of EGFR. WB-308 decreased NSCLC cell proliferation and colony formation, by causing G2/M arrest and apoptosis. Furthermore, WB-308 inhibited the engraft tumor growths in two animal models in vivo (lung orthotopic transplantation model and patient-derived engraft mouse model). WB-308 impaired the phosphorylation of EGFR, AKT, and ERK1/2 protein. WB-308 was less cytotoxic than Gefitinib. Our study suggests that WB-308 is a novel EGFR-TKI and may be considered to substitute for Gefitinib in clinical therapy for NSCLC. PMID:25730907

  9. PD-1 and PD-L1 Expression in NSCLC Indicate a Favorable Prognosis in Defined Subgroups

    PubMed Central

    Schmidt, Lars Henning; Kümmel, Andreas; Görlich, Dennis; Mohr, Michael; Bröckling, Sebastian; Mikesch, Jan Henrik; Grünewald, Inga; Marra, Alessandro; Schultheis, Anne M.; Wardelmann, Eva; Müller-Tidow, Carsten; Spieker, Tilmann; Schliemann, Christoph; Berdel, Wolfgang E.

    2015-01-01

    Background Immunotherapy can become a crucial therapeutic option to improve prognosis for lung cancer patients. First clinical trials with therapies targeting the programmed cell death receptor PD-1 and its ligand PD-L1 have shown promising results in several solid tumors. However, in lung cancer the diagnostic, prognostic and predictive value of these immunologic factors remains unclear. Method The impact of both factors was evaluated in a study collective of 321 clinically well-annotated patients with non-small lung cancer (NSCLC) using immunohistochemistry. Results PD-1 expression by tumor infiltrating lymphocytes (TILs) was found in 22%, whereas tumor cell associated PD-L1 expression was observed in 24% of the NSCLC tumors. In Fisher’s exact test a positive correlation was found for PD-L1 and Bcl-xl protein expression (p = 0.013). Interestingly, PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas (SCC, p = 0.042, log rank test), with adjuvant therapy (p = 0.017), with increased tumor size (pT2-4, p = 0.039) and with positive lymph node status (pN1-3, p = 0.010). These observations were confirmed by multivariate cox regression models. Conclusion One major finding of our study is the identification of a prognostic implication of PD-L1 in subsets of NSCLC patients with pulmonary SCC, with increased tumor size, with a positive lymph node status and NSCLC patients who received adjuvant therapies. This study provides first data for immune-context related risk stratification of NSCLC patients. Further studies are necessary both to confirm this observation and to evaluate the predictive value of PD-1 and PD-L1 in NSCLC in the context of PD-1 inhibition. PMID:26313362

  10. 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

  11. Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition.

    PubMed

    Soucheray, Margaret; Capelletti, Marzia; Pulido, Inés; Kuang, Yanan; Paweletz, Cloud P; Becker, Jeffrey H; Kikuchi, Eiki; Xu, Chunxiao; Patel, Tarun B; Al-Shahrour, Fatima; Carretero, Julián; Wong, Kwok-Kin; Jänne, Pasi A; Shapiro, Geoffrey I; Shimamura, Takeshi

    2015-10-15

    Non-small cell lung cancers (NSCLC) that have developed resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI), including gefitinib and erlotinib, are clinically linked to an epithelial-to-mesenchymal transition (EMT) phenotype. Here, we examined whether modulating EMT maintains the responsiveness of EGFR-mutated NSCLCs to EGFR TKI therapy. Using human NSCLC cell lines harboring mutated EGFR and a transgenic mouse model of lung cancer driven by mutant EGFR (EGFR-Del19-T790M), we demonstrate that EGFR inhibition induces TGFβ secretion followed by SMAD pathway activation, an event that promotes EMT. Chronic exposure of EGFR-mutated NSCLC cells to TGFβ was sufficient to induce EMT and resistance to EGFR TKI treatment. Furthermore, NSCLC HCC4006 cells with acquired resistance to gefitinib were characterized by a mesenchymal phenotype and displayed a higher prevalence of the EGFR T790M mutated allele. Notably, combined inhibition of EGFR and the TGFβ receptor in HCC4006 cells prevented EMT but was not sufficient to prevent acquired gefitinib resistance because of an increased emergence of the EGFR T790M allele compared with cells treated with gefitinib alone. Conversely, another independent NSCLC cell line, PC9, reproducibly developed EGFR T790M mutations as the primary mechanism underlying EGFR TKI resistance, even though the prevalence of the mutant allele was lower than that in HCC4006 cells. Thus, our findings underscore heterogeneity within NSCLC cells lines harboring EGFR kinase domain mutations that give rise to divergent resistance mechanisms in response to treatment and anticipate the complexity of EMT suppression as a therapeutic strategy. PMID:26282169

  12. Impact of Weight Change During the Course of Concurrent Chemoradiation Therapy on Outcomes in Stage IIIB Non-Small Cell Lung Cancer Patients: Retrospective Analysis of 425 Patients

    SciTech Connect

    Topkan, Erkan; Parlak, Cem; Selek, Ugur

    2013-11-15

    Purpose: We retrospectively investigated the impact of weight change (WC) during concurrent chemoradiation therapy (C-CRT) on clinical outcomes of stage 3B non-small cell lung cancer (NSCLC) patients. Methods and Materials: A total of 425 patients treated with C-CRT were included. All patients received 60 to 66 Gy of thoracic radiation therapy concurrently with 1 to 3 cycles of platinum-based chemotherapy. Pre- and posttreatment weight measurements on first and last days of C-CRT were used for WC. Patients were divided into 2 groups: group 1 = weight loss (WL); group 2 = weight preservation/gain (WP) for comparative analyses. Results: Following C-CRT, 252 patients (59.3%) experienced WL, while 89 patients (20.9%) and 84 patients (19.8%) showed WP or WG. At median 24.2 months of follow-up, 142 patients (33.4%) were alive (84 WP [48.6%] and 58 WL [23.0%]), and 58 (13.6%) of them were free of disease progression (41 [23.7%] for WP and 17 [6.7%] for WL). Median overall survival (OS), locoregional progression-free survival (LRPFS), progression-free survival (PFS), and distant metastases-free survival (DMFS) for the entire population were 22.8, 14.4, 10.6, and 11.7 months, respectively. Intergroup comparisons between WP and WL cohorts revealed significantly superior OS, LRPFS, PFS, and DMFS in WP patients (P<.05 for each). On multivariate analyses, only WL and advanced T stage were associated with poor prognosis (P<.05). Conclusions: Present results in 425 stage 3B NSCLC patients demonstrated that WL during C-CRT is strongly associated with inferior survival outcomes compared to WP. This emerging finding might be useful by forming an encouraging basis for future investigations in facilitating a way to improve the outcomes of these patients experiencing WL during C-CRT.

  13. Locally Advanced Stage IV Squamous Cell Carcinoma of the Head and Neck: Impact of Pre-Radiotherapy Hemoglobin Level and Interruptions During Radiotherapy

    SciTech Connect

    Rades, Dirk Stoehr, Monika; Kazic, Nadja; Hakim, Samer G.; Walz, Annette; Schild, Steven E.; Dunst, Juergen

    2008-03-15

    Purpose: Stage IV head and neck cancer patients carry a poor prognosis. Clear understanding of prognostic factors can help to optimize care for the individual patient. This study investigated 11 potential prognostic factors including pre-radiotherapy hemoglobin level and interruptions during radiotherapy for overall survival (OS), metastases-free survival (MFS), and locoregional control (LC) after radiochemotherapy. Methods and Materials: Eleven factors were investigated in 153 patients receiving radiochemotherapy for Stage IV squamous cell head and neck cancer: age, gender, Karnofsky performance score (KPS), tumor site, grading, T stage, N stage, pre-radiotherapy hemoglobin level, surgery, chemotherapy type, and interruptions during radiotherapy >1 week. Results: On multivariate analysis, improved OS was associated with KPS 90-100 (relative risk [RR], 2.36; 95% confidence interval [CI], 1.20-4.93; p = .012), hemoglobin {>=}12 g/dL (RR, 1.88; 95% CI, 1.01-3.53; p = .048), and no radiotherapy interruptions (RR, 2.59; 95% CI, 1.15-5.78; p = .021). Improved LC was significantly associated with lower T stage (RR, 2.17; 95% CI, 1.16-4.63; p = .013), hemoglobin {>=}12 g/dL (RR, 4.12; 95% CI, 1.92-9.09; p < .001), surgery (RR, 2.67; 95% CI, 1.28-5.88; p = .008), and no radiotherapy interruptions (RR, 3.32; 95% CI, 1.26-8.79; p = .015). Improved MFS was associated with KPS 90-100 (RR, 3.41; 95% CI, 1.46-8.85; p = .012). Conclusions: Significant predictors for outcome in Stage IV head and neck cancer were performance status, stage, surgery, pre-radiotherapy hemoglobin level, and interruptions during radiotherapy >1 week. It appears important to avoid anemia and radiotherapy interruptions to achieve the best treatment results.

  14. Inferring Growth Control Mechanisms in Growing Multi-cellular Spheroids of NSCLC Cells from Spatial-Temporal Image Data

    PubMed Central

    Müller, Margareta; Vignon-Clementel, Irene E.; Drasdo, Dirk

    2016-01-01

    We develop a quantitative single cell-based mathematical model for multi-cellular tumor spheroids (MCTS) of SK-MES-1 cells, a non-small cell lung cancer (NSCLC) cell line, growing under various nutrient conditions: we confront the simulations performed with this model with data on the growth kinetics and spatial labeling patterns for cell proliferation, extracellular matrix (ECM), cell distribution and cell death. We start with a simple model capturing part of the experimental observations. We then show, by performing a sensitivity analysis at each development stage of the model that its complexity needs to be stepwise increased to account for further experimental growth conditions. We thus ultimately arrive at a model that mimics the MCTS growth under multiple conditions to a great extent. Interestingly, the final model, is a minimal model capable of explaining all data simultaneously in the sense, that the number of mechanisms it contains is sufficient to explain the data and missing out any of its mechanisms did not permit fit between all data and the model within physiological parameter ranges. Nevertheless, compared to earlier models it is quite complex i.e., it includes a wide range of mechanisms discussed in biological literature. In this model, the cells lacking oxygen switch from aerobe to anaerobe glycolysis and produce lactate. Too high concentrations of lactate or too low concentrations of ATP promote cell death. Only if the extracellular matrix density overcomes a certain threshold, cells are able to enter the cell cycle. Dying cells produce a diffusive growth inhibitor. Missing out the spatial information would not permit to infer the mechanisms at work. Our findings suggest that this iterative data integration together with intermediate model sensitivity analysis at each model development stage, provide a promising strategy to infer predictive yet minimal (in the above sense) quantitative models of tumor growth, as prospectively of other tissue

  15. Inferring Growth Control Mechanisms in Growing Multi-cellular Spheroids of NSCLC Cells from Spatial-Temporal Image Data.

    PubMed

    Jagiella, Nick; Müller, Benedikt; Müller, Margareta; Vignon-Clementel, Irene E; Drasdo, Dirk

    2016-02-01

    We develop a quantitative single cell-based mathematical model for multi-cellular tumor spheroids (MCTS) of SK-MES-1 cells, a non-small cell lung cancer (NSCLC) cell line, growing under various nutrient conditions: we confront the simulations performed with this model with data on the growth kinetics and spatial labeling patterns for cell proliferation, extracellular matrix (ECM), cell distribution and cell death. We start with a simple model capturing part of the experimental observations. We then show, by performing a sensitivity analysis at each development stage of the model that its complexity needs to be stepwise increased to account for further experimental growth conditions. We thus ultimately arrive at a model that mimics the MCTS growth under multiple conditions to a great extent. Interestingly, the final model, is a minimal model capable of explaining all data simultaneously in the sense, that the number of mechanisms it contains is sufficient to explain the data and missing out any of its mechanisms did not permit fit between all data and the model within physiological parameter ranges. Nevertheless, compared to earlier models it is quite complex i.e., it includes a wide range of mechanisms discussed in biological literature. In this model, the cells lacking oxygen switch from aerobe to anaerobe glycolysis and produce lactate. Too high concentrations of lactate or too low concentrations of ATP promote cell death. Only if the extracellular matrix density overcomes a certain threshold, cells are able to enter the cell cycle. Dying cells produce a diffusive growth inhibitor. Missing out the spatial information would not permit to infer the mechanisms at work. Our findings suggest that this iterative data integration together with intermediate model sensitivity analysis at each model development stage, provide a promising strategy to infer predictive yet minimal (in the above sense) quantitative models of tumor growth, as prospectively of other tissue

  16. PD-L1 and Tumor Infiltrating Lymphocytes as Prognostic Markers in Resected NSCLC

    PubMed Central

    Ameratunga, Malaka; Asadi, Khashayar; Lin, Xihui; Walkiewicz, Marzena; Murone, Carmel; Knight, Simon; Mitchell, Paul; Boutros, Paul; John, Thomas

    2016-01-01

    Introduction Immune checkpoint inhibition has shifted treatment paradigms in non-small cell lung cancer (NSCLC). Conflicting results have been reported regarding the immune infiltrate and programmed death-ligand 1 (PD-L1) as a prognostic marker. We correlated the immune infiltrate and PD-L1 expression with clinicopathologic characteristics in a cohort of resected NSCLC. Methods A tissue microarray was constructed using triplicate cores from consecutive resected NSCLC. Immunohistochemistry was performed for CD8, FOXP3 and PD-L1. Strong PD-L1 expression was predefined as greater than 50% tumor cell positivity. Matched nodal samples were assessed for concordance of PD-L1 expression. Results Of 522 patients, 346 were node-negative (N0), 72 N1 and 109 N2; 265 were adenocarcinomas (AC), 182 squamous cell cancers (SCC) and 75 other. Strong PD-L1 expression was found in 24% cases. In the overall cohort, PD-L1 expression was not associated with survival. In patients with N2 disease, strong PD-L1 expression was associated with significantly improved disease-free (DFS) and overall survival (OS) in multivariate analysis (HR 0.49, 95%CI 0.36–0.94, p = 0.031; HR 0.46, 95%CI 0.26–0.80, p = 0.006). In this resected cohort only 5% harboured EGFR mutations, whereas 19% harboured KRAS and 23% other. KRAS mutated tumors were more likely to highly express PD-L1 compared to EGFR (22% vs 3%). A stromal CD8 infiltrate was associated with significantly improved DFS in SCC (HR 0.70, 95%CI 0.50–0.97, p = 0.034), but not AC, whereas FOXP3 was not prognostic. Matched nodal specimens (N = 53) were highly concordant for PD-L1 expression (89%). Conclusion PD-L1 expression was not prognostic in the overall cohort. PD-L1 expression in primary tumor and matched nodal specimens were highly concordant. The observed survival benefit in N2 disease requires confirmation. PMID:27104612

  17. 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

  18. Stage Acquisition and Stage Use. An Appraisal of Stage Displacement Explanations of Variation in Moral Reasoning.

    ERIC Educational Resources Information Center

    Levine, Charles G.

    1979-01-01

    Evaluates the differing perspectives of Kohlberg and Turiel on moral reasoning. Both perspectives use stage displacement models to depict moral development and assume that as ontogenesis proceeds, the role played by earleir acquired moral stages becomes increasingly insignificant in comparison with the role played by more advanced stages. The…

  19. Expression of DNA repair and replication genes in non-small cell lung cancer (NSCLC): a role for thymidylate synthetase (TYMS)

    PubMed Central

    2012-01-01

    stage, and treatment with Tax/Plat doublets independently predicted for prolonged OS in patients who received only one line of treatment (adjuvant or 1st line). Conclusion Classifying intratumoral B, E, R, T mRNA expression in comparison to normal lung may facilitate standardization of these parameters for prospective studies. With this approach, NSCLC patients with aberrant intratumoral TYMS expression will probably fare better with platinum-based treatments. PMID:22866924

  20. 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

  1. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer.

    PubMed

    Khambata-Ford, Shirin; Harbison, Christopher T; Hart, Lowell L; Awad, Melissa; Xu, Li-An; Horak, Christine E; Dakhil, Shaker; Hermann, Robert C; Lynch, Thomas J; Weber, Martin R

    2010-02-20

    PURPOSE The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is efficacious in multiple tumor types. Patient selection with markers predictive of benefit may enhance its therapeutic index. This retrospective, correlative analysis of the phase III trial BMS099 of cetuximab in advanced non-small-cell lung cancer (NSCLC) was conducted to identify molecular markers for the selection of patients most likely to benefit from cetuximab. METHODS In BMS099, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC of any histology or EGFR expression status were randomly assigned to taxane/carboplatin (T/C) with or without cetuximab. Biomarkers analyzed included K-Ras and EGFR mutations by direct sequencing, EGFR protein expression by immunohistochemistry (IHC), and EGFR gene copy number by fluorescent in situ hybridization (FISH). Relationships between biomarker status and progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) were assessed by log-rank tests per treatment arm for treatment-specific effects and across the total evaluable population. Results Tumor samples were available from 225 randomly assigned patients. K-Ras mutations were found in 17% of evaluable patients (35 of 202 patients), EGFR mutations were found in 10% (17 of 166 patients), EGFR positivity by IHC was found in 89% (131 of 148 patients), and FISH positivity was found in 52% (54 of 104 patients). No significant associations were found between biomarker status and PFS, OS, and ORR in the treatment-specific analyses. CONCLUSION In contrast with colorectal cancer, and within the limitations of the data set, efficacy parameters did not appear to correlate with K-Ras mutation status or with any of the EGFR-related biomarkers evaluated. Additional exploratory analyses are essential to identify predictive markers and to optimize patient selection for cetuximab therapy in NSCLC. PMID:20100958

  2. Overall survival should be the primary endpoint in clinical trials for advanced non-small-cell lung cancer

    PubMed Central

    Cheema, P.K.; Burkes, R.L.

    2013-01-01

    An article in a recent edition of Current Oncology explored the validation of progression-free survival (pfs) as an endpoint in clinical trials of antineoplastic agents for metastatic colorectal cancer, metastatic renal cell carcinoma, and ovarian cancer. The support for pfs as a surrogate endpoint for overall survival (os) was elucidated. As with the aforementioned tumour types, advanced non-small-cell lung cancer (nsclc) has seen a rise in active agents since the year 2000. Those agents range from improved cytotoxics such as pemetrexed, to targeted therapies such as tyrosine kinase inhibitors of the epidermal growth factor receptor and agents that target the EML4–ALK gene mutation. More recently, it has also become apparent that histology plays an important role in the response to and outcomes of treatment. With the therapeutic options for patients with advanced nsclc increasing, concerns are being raised that the efficacy of drugs measured by os may be diluted in clinical trials, thereby underestimating their true clinical benefit. That possibility, together with the need to have efficacious drugs available to patients earlier, has resulted in the search for a surrogate to the os endpoint in advanced nsclc. The present article follows up the recent article on pfs as a surrogate. Although advances in identifying pfs as a valid surrogate endpoint for os have been made in other tumour types, in advanced nsclc, such surrogacy has not been formally validated. Until it has, os should remain the primary endpoint of clinical trials in advanced nsclc. PMID:23559882

  3. Wilsonville Advanced Coal Liquefaction Research and Development Facility, Wilsonville, Alabama. Topical report No. 14. Catalyst activity trends in two-stage coal liquefaction

    SciTech Connect

    Not Available

    1984-02-01

    The Two Stage Coal Liquefaction process became operational at Wilsonville in May 1981, with the inclusion of an H-OIL ebullated-bed catalytic reactor. The two stage process was initially operated in a nonintegrated mode and has recently been reconfigurated to fully integrate the thermal and the catalytic stages. This report focuses on catalyst activity trends observed in both modes of operation. A literature review of relevant catalyst screening studies in bench-scale and PDU units is presented. Existing kinetic and deactivation models were used to analyze process data over an extensive data base. Based on the analysis, three separate, application studies have been conducted. The first study seeks to elucidate the dependence of catalyst deactivation rate on type of coal feedstock used. A second study focuses on the significance of catalyst type and integration mode on SRC hydrotreatment. The third study presents characteristic deactivation trends observed in integrated operation with different first-stage thermal severities. In-depth analytical work was conducted at different research laboratories on aged catalyst samples from Run 242. Model hydrogenation and denitrogenation activity trends are compared with process activity trends and with changes observed in catalyst porosimetric properties. The accumulation of metals and coke deposits with increasing catalyst age, as well as their distribution across a pellet cross-section, are discussed. The effect of catalyst age and reactor temperature on the chemical composition of flashed bottoms product is addressed. Results from regenerating spent catalysts are also presented. 35 references, 31 figures, 18 tables.

  4. Randomized, Phase III Trial of First-Line Figitumumab in Combination With Paclitaxel and Carboplatin Versus Paclitaxel and Carboplatin Alone in Patients With Advanced Non–Small-Cell Lung Cancer

    PubMed Central

    Langer, Corey J.; Novello, Silvia; Park, Keunchil; Krzakowski, Maciej; Karp, Daniel D.; Mok, Tony; Benner, Rebecca J.; Scranton, Judith R.; Olszanski, Anthony J.; Jassem, Jacek

    2014-01-01

    Purpose Figitumumab (CP-751,871), a fully human immunoglobulin G2 monoclonal antibody, inhibits the insulin-like growth factor 1 receptor (IGF-1R). Our multicenter, randomized, phase III study compared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB/IV or recurrent NSCLC disease with nonadenocarcinoma histology received open-label figitumumab (20 mg/kg) plus paclitaxel (200 mg/m2) and carboplatin (area under the concentration-time curve, 6 mg · min/mL) or paclitaxel and carboplatin alone once every 3 weeks for up to six cycles. The primary end point was overall survival (OS). Results Of 681 randomly assigned patients, 671 received treatment. The study was closed early by an independent Data Safety Monitoring Committee because of futility and an increased incidence of serious adverse events (SAEs) and treatment-related deaths with figitumumab. Median OS was 8.6 months for figitumumab plus chemotherapy and 9.8 months for chemotherapy alone (hazard ratio [HR], 1.18; 95% CI, 0.99 to 1.40; P = .06); median progression-free survival was 4.7 months (95% CI, 4.2 to 5.4) and 4.6 months (95% CI, 4.2 to 5.4), respectively (HR, 1.10; P = .27); the objective response rates were 33% and 35%, respectively. The respective rates of all-causality SAEs were 66% and 51%; P < .01). Treatment-related grade 5 adverse events were also more common with figitumumab (5% v 1%; P < .01). Conclusion Adding figitumumab to standard chemotherapy failed to increase OS in patients with advanced nonadenocarcinoma NSCLC. Further clinical development of figitumumab is not being pursued. PMID:24888810

  5. Stage design

    DOEpatents

    Shacter, J.

    1975-12-01

    A method is described of cycling gases through a plurality of diffusion stages comprising the steps of admitting the diffused gases from a first diffusion stage into an axial compressor, simultaneously admitting the undiffused gases from a second diffusion stage into an intermediate pressure zone of said compressor corresponding in pressure to the pressure of said undiffused gases, and then admitting the resulting compressed mixture of diffused and undiffused gases into a third diffusion stage.

  6. Effectiveness of a thoracic multidisciplinary clinic in the treatment of stage III non-small-cell lung cancer

    PubMed Central

    Friedman, Eliot L; Kruklitis, Robert J; Patson, Brian J; Sopka, Dennis M; Weiss, Michael J

    2016-01-01

    Introduction The Institute of Medicine, the American Society of Clinical Oncology, and the European Society of Medical Oncology promote a multidisciplinary approach for the treatment of cancer. Stage III non-small-cell lung cancer (NSCLC) represents a heterogeneous group of diseases necessitating coordination of care among medical, radiation, and surgical oncology. The optimal care of stage III NSCLC underscores the need for a multidisciplinary approach. Methods From tumor registry data, we identified all cases of stage III NSCLC seen at Lehigh Valley Health Network between March 2010 and March 2013. The care received by patients when seen in the thoracic multidisciplinary clinic (MDC) was compared with the care received when not seen in the thoracic MDC. Results All patients seen in the MDC, compared to <50% of patients seen outside the MDC, were evaluated by more than one physician prior to beginning the treatment. Time to initiate treatment was shorter in MDC patients than in non-MDC patients. Patients seen in the MDC had a greater concordance with clinical pathways. A greater percentage of patients seen in the thoracic MDC had pathologic staging of their mediastinum. Patients seen in the MDC were more likely to receive all of their care at Lehigh Valley Health Network. Conclusion Multidisciplinary care is essential in the treatment of patients with stage III NSCLC. Greater utilization of MDCs for this complex group of patients will result in more efficient coordination of care, pretreatment evaluation, and therapy, which in turn should translate to improve patients’ outcomes. PMID:27358568

  7. 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

  8. Metformin Enhances the Therapy Effects of Anti-IGF-1R mAb Figitumumab to NSCLC.

    PubMed

    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

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

    PubMed Central

    Barnett, Reagan; Bachaboina, Lavanya; Scalici, Jennifer; Rocconi, Rodney P.; Owen, Laurie B.; Piazza, Gary A.

    2015-01-01

    Allyl isothiocyanate (AITC), a constituent of many cruciferous vegetables exhibits significant anticancer activities in many cancer models. Our studies provide novel insights into AITC-induced anticancer mechanisms in human A549 and H1299 non-small cell lung cancer (NSCLC) cells. AITC exposure induced replication stress in NSCLC cells as evidenced by γH2AX and FANCD2 foci, ATM/ATR-mediated checkpoint responses and S and G2/M cell cycle arrest. Furthermore, AITC-induced FANCD2 foci displayed co-localization with BrdU foci, indicating stalled or collapsed replication forks in these cells. Although PITC (phenyl isothiocyanate) exhibited concentration-dependent cytotoxic effects, treatment was less effective compared to AITC. Previously, agents that induce cell cycle arrest in S and G2/M phases were shown to sensitize tumor cells to radiation. Similar to these observations, combination therapy involving AITC followed by radiation treatment exhibited increased DDR and cell killing in NSCLC cells compared to single agent treatment. Combination index (CI) analysis revealed synergistic effects at multiple doses of AITC and radiation, resulting in CI values of less than 0.7 at Fa of 0.5 (50% reduction in survival). Collectively, these studies identify an important anticancer mechanism displayed by AITC, and suggest that the combination of AITC and radiation could be an effective therapy for NSCLC. PMID:25742788

  10. 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

  11. 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

  12. Moderate dose escalation for advanced stage Hodgkin's disease using the bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone scheme and adjuvant radiotherapy: a study of the German Hodgkin's Lymphoma Study Group.

    PubMed

    Tesch, H; Diehl, V; Lathan, B; Hasenclever, D; Sieber, M; Rüffer, U; Engert, A; Franklin, J; Pfreundschuh, M; Schalk, K P; Schwieder, G; Wulf, G; Dölken, G; Worst, P; Koch, P; Schmitz, N; Bruntsch, U; Tirier, C; Müller, U; Loeffler, M

    1998-12-15

    The BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen, a rearranged and accelerated version of the standard COPP/adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, has been shown to be effective and safe in a previous pilot study for advanced stage Hodgkin's disease (HD). The present study aimed to determine a maximum practicable dose of three drugs, ie, etoposide, adriamycin, and cyclophosphamide, for which acute toxicities were acceptable and to assess the feasibility of the escalated scheme. Sixty untreated patients with advanced stage HD were enrolled in this study. Radiotherapy was given in 44 patients (73%) after chemotherapy to initial bulk lesions and residual disease. Granulocyte-colony stimulating factor (G-CSF) was given from day 8 to prevent prolonged neutrocytopenia and severe infections. The intended doses of adriamycin, etoposide, and cyclophosphamide in the BEACOPP schedule could be substantially escalated: adriamycin from 25 to 35, cyclophosphamide from 650 to 1,200, and etoposide from 100 to 200 mg/m2. The major toxicities were leukocytopenia and thrombocytopenia with considerable heterogeneity between individual patients. Of 60 patients, 56 (93%) achieved a complete remission (CR). At a median observation of 32 months, the rates of survival and freedom from treatment failure (FFTF) were estimated to be 91% (95% confidence interval 83% to 99%) and 90% (82% to 98%). These results show that a moderate dose escalation of adriamycin, cyclophosphamide, and etoposide of the baseline BEACOPP regimen is feasible. The escalated BEACOPP regimen shows very encouraging results in advanced stage HD and is now being compared in a randomized phase III study with BEACOPP at baseline dose level. PMID:9845521

  13. Mutation of the epidermal growth factor receptor gene and its impact on the efficacy of gefitinib in advanced non-small cell lung cance.

    PubMed

    Li, Xiang-Nan; Qiu, Dong; Pan, Xue; Hou, Xiao-Xu

    2015-01-01

    Mutations in the epidermal growth factor receptor (EGFR) gene are associated with subsets of non-small cell lung cancer (NSCLC). Some patients with EGFR mutations are responsive to targeted therapy with the EGFR tyrosine kinase inhibitor gefitinib. Here, the mutation status of EGFR was assessed in advanced-stage NSCLC patients to determine how mutation status influences the clinical efficacy of gefitinib. The study included 106 patients with advanced NSCLC who were treated with gefitinib. Exons 19 and 21 of EGFR were sequenced from tumor tissues samples by PCR, and patient clinical characteristics, short-term outcomes (partial response, stable disease, progressive disease), and survival [overall survival (OS) and progression-free survival (PFS)] were compared. EGFR mutations in either exon 19 or exon 21 were detected in 54.7% of cases. The EGFR gene mutation rate was significantly different in patients with different pathological types (χ(2)=6.612, P<0.05). The distribution of short-term outcomes differed significantly by EGFR gene mutation status, history of smoking, and bone metastasis (χ(2)=6.481~35.938, P<0.05). Further, OS and PFS was significantly higher following gefitinib in patients with EGFR mutations than those without EGFR mutation (χ(2)=19.135, 6.953, P<0.05). OS was also significantly higher in patients with an exon 19 deletion mutation than in those with the exon 21 point mutation (χ(2)=8.575, P<0.05). Cox multivariate regression analysis indicated that OS was correlated with the pathological type of the tumor (HR=4.877), US Eastern Cooperative Oncology Group Physical Status (ECOG PS) score (HR=3.087), and EGFR mutation status (HR=1.876) (all P<0.05), while PFS was correlated with ECOG PS score (HR=2.218), cycles of chemotherapy (HR=1.829), and EGFR mutation status (HR=1.840) (all P<0.05). Only mild adverse events were reported during gefitinib treatment. The findings indicate that gefitinib treatment can improve the clinical outcomes of NSCL