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Sample records for lung derived tumors

  1. Tumor-Derived CXCL1 Promotes Lung Cancer Growth via Recruitment of Tumor-Associated Neutrophils

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    Ming Yuan

    2016-01-01

    Full Text Available Neutrophils have a traditional role in inflammatory process and act as the first line of defense against infections. Although their contribution to tumorigenesis and progression is still controversial, accumulating evidence recently has demonstrated that tumor-associated neutrophils (TANs play a key role in multiple aspects of cancer biology. Here, we detected that chemokine CXCL1 was dramatically elevated in serum from 3LL tumor-bearing mice. In vitro, 3LL cells constitutively expressed and secreted higher level of CXCL1. Furthermore, knocking down CXCL1 expression in 3LL cells significantly hindered tumor growth by inhibiting recruitment of neutrophils from peripheral blood into tumor tissues. Additionally, tumor-infiltrated neutrophils expressed higher levels of MPO and Fas/FasL, which may be involved in TAN-mediated inhibition of CD4+ and CD8+ T cells. These results demonstrate that tumor-derived CXCL1 contributes to TANs infiltration in lung cancer which promotes tumor growth.

  2. Spheres derived from lung adenocarcinoma pleural effusions: molecular characterization and tumor engraftment.

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    Rita Mancini

    Full Text Available Malignant pleural effusions (MPEs could represent an excellent source to culture a wide variety of cancer cells from different donors. In this study, we set up culture conditions for cancer cells deriving from MPEs of several patients affected by the most frequent form of lung cancer, namely the subset of non small cell lung cancers (NSCLC classified as Lung Adenocarcinomas (AdenoCa which account for approximately 40% of lung cancer cases. AdenoCa malignant pleural effusions gave rise to in vitro cultures both in adherent and/or in spheroid conditions in almost all cases analyzed. We characterized in greater detail two samples which showed the most efficient propagation in vitro. In these samples we also compared gene profiles of spheroid vs adherent cultures and identified a set of differentially expressed genes. Finally we achieved efficient tumor engraftment in recipient NOD/SCID mice, also upon inoculation of small number of cells, thus suggesting indirectly the presence of tumor initiating cells.

  3. Tumor-Derived Tissue Factor Aberrantly Activates Complement and Facilitates Lung Tumor Progression via Recruitment of Myeloid-Derived Suppressor Cells

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    Xiao Han; Haoran Zha; Fei Yang; Bo Guo; Bo Zhu

    2017-01-01

    The initiator of extrinsic coagulation, tissue factor (TF), and its non-coagulant isoform alternatively spliced TF (asTF) are closely associated with tumor development. In the tumor microenvironment, the role of TF-induced coagulation in tumor progression remains to be fully elucidated. Using TF-knockdown lung tumor cells, we showed that TF is the dominant component of procoagulant activity but is dispensable in the cellular biology of tumor cells. In a xenograft model, using immunohistochemi...

  4. Pigment epithelium-derived factor enhances tumor response to radiation through vasculature normalization in allografted lung cancer in mice.

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    Xu, Z; Dong, Y; Peng, F; Yu, Z; Zuo, Y; Dai, Z; Chen, Y; Wang, J; Hu, X; Zhou, Q; Ma, H; Bao, Y; Gao, G; Chen, M

    2015-03-01

    This study aimed to explore the potential therapeutic effects of the combination of pigment epithelium-derived factor (PEDF) and radiation on lung cancer. The Lewis lung cancer (LLC) allografts in nude mice were treated with radiation, PEDF and PEDF combined with radiation. The morphologic changes of tumor vasculature and the hypoxic fraction of tumor tissues were evaluated. Significant inhibition of tumor growth was observed when radiation was applied between the 3rd and 7th day (the vasculature normalization window) after the initiation of PEDF treatment. During the vasculature normalization window, the tumor blood vessels in PEDF-treated mice were less tortuous and more uniform than those in the LLC allograft tumor treated with phosphate-buffered saline. Meanwhile, the thickness of the basement membrane was remarkably reduced and pericyte coverage was significantly increased with the PEDF treatment. We also found that tumor hypoxic fraction decreased during the 3rd to the 7th day after PEDF treatment, suggesting improved intratumoral oxygenation. Taken together, our results show that PEDF improved the effects of radiation therapy on LLC allografts by inducing a vascular normalization window from the 3rd to the 7th day after PEDF treatment. Our findings provide a basis for treating lung cancer with the combination of PEDF and radiation.

  5. Reductions in Myeloid-Derived Suppressor Cells and Lung Metastases using AZD4547 Treatment of a Metastatic Murine Breast Tumor Model

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    Li Liu

    2014-03-01

    Full Text Available Background: AZD4547, a small-molecule inhibitor targeting the tyrosine kinase of Fibroblast Growth Factor Receptors (FGFRs, is currently under phase II clinical study for human subjects having breast cancer, while the underlying mechanism remains elusive. The aim of this study is to explore the potential mechanism by which AZD4547 inhibits breast tumor lung metastases at the level of the tumor microenvironment. Methods: First, through in vitro experiments, we investigated the efficacy of the FGFRs inhibitor AZD4547 on 4T1 tumor cells for their proliferation, apoptosis, migration, and invasion. Second, by in vivo animal experiments, we evaluated the effects of AZD4547 on tumor growth and lung metastases in 4T1 tumor-bearing mice. Finally, we examined the impact of AZD4547 on the infiltration of myeloid-derived suppressor cells (MDSCs in lung, spleens, peripheral blood and tumor. Results: Through this study we found that AZD4547 could efficiently suppress tumor 4T1 cells through restraining their proliferation, blocking migration and invasion, and inducing apoptosis in vitro. In animal model we also demonstrated that AZD4547 was able to inhibit tumor growth and lung metastases, consistent with the decreased MDSCs accumulation in the tumor and lung tissues, respectively. Moreover, the reduced number of MDSCs in peripheral blood and spleens were also observed in the AZD4547-treated mice. Importantly, through the AZD4547 treatment, the CD4+ and CD8+ T-cells were significantly increased in tumor and spleens. Conclusion: Our studies showed that AZD4547 can inhibit breast cancer cell proliferation, induce its apoptosis and block migration and invasion in vitro and suppress tumor growth and lung metastases by modulating the tumor immunologic microenvironment in vivo.

  6. Patient-Derived Antibody Targets Tumor Cells

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    An NCI Cancer Currents blog on an antibody derived from patients that killed tumor cells in cell lines of several cancer types and slowed tumor growth in mouse models of brain and lung cancer without evidence of side effects.

  7. Low or undetectable TPO receptor expression in malignant tissue and cell lines derived from breast, lung, and ovarian tumors

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    Erickson-Miller Connie L

    2012-09-01

    Full Text Available Abstract Background Numerous efficacious chemotherapy regimens may cause thrombocytopenia. Thrombopoietin receptor (TPO-R agonists, such as eltrombopag, represent a novel approach for the treatment of chemotherapy-induced thrombocytopenia. The TPO-R MPL is expressed on megakaryocytes and megakaryocyte precursors, although little is known about its expression on other tissues. Methods Breast, lung, and ovarian tumor samples were analyzed for MPL expression by microarray and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR, and for TPO-R protein expression by immunohistochemistry (IHC. Cell line proliferation assays were used to analyze the in vitro effect of eltrombopag on breast, lung, and ovarian tumor cell proliferation. The lung carcinoma cell lines were also analyzed for TPO-R protein expression by Western blot. Results MPL mRNA was not detectable in 118 breast tumors and was detectable at only very low levels in 48% of 29 lung tumors studied by microarray analysis. By qRT-PCR, low but detectable levels of MPL mRNA were detectable in some normal (14-43% and malignant (3-17% breast, lung, and ovarian tissues. A comparison of MPL to EPOR, ERBB2, and IGF1R mRNA demonstrates that MPL mRNA levels were far lower than those of EPOR and ERBB2 mRNA in the same tissues. IHC analysis showed negligible TPO-R protein expression in tumor tissues, confirming mRNA analysis. Culture of breast, lung, and ovarian carcinoma cell lines showed no increase, and in fact, showed a decrease in proliferation following incubation with eltrombopag. Western blot analyses revealed no detectable TPO-R protein expression in the lung carcinoma cell lines. Conclusions Multiple analyses of breast, lung, and ovarian tumor samples and/or cell lines show no evidence of MPL mRNA or TPO-R protein expression. Eltrombopag does not stimulate growth of breast, lung, or ovarian tumor cell lines at doses likely to exert their actions on megakaryocytes and

  8. Lung Carcinoid Tumor: Surgery

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    ... the sleeve above and below the stain and sewing the cuff back onto the shortened sleeve. A ... because it requires a great deal of technical skill. Possible risks and side effects of lung surgery ...

  9. TU-AB-303-04: Characterizing CT-Derived Mass Change of Non-Tumor Pathology During Lung Radiotherapy

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    Guy, C; Weiss, E; Jan, N; Hugo, G [Virginia Commonwealth University, Richmond, VA (United States); Christensen, G [University of Iowa, Iowa City, IA (United States)

    2015-06-15

    Purpose: Atelectasis and other commonly-observed non-tumor lung pathologies (NTPs) can change during thoracic radiotherapy altering normal anatomy and inducing large changes in tumor position. However, the characteristics of these changes are not well understood. This study investigates longitudinal NTP tissue mass change during radiotherapy. Methods: Delineation of corresponding atelectatic regions before and after re-aeration is challenging since it is difficult to detect atelectatic-region boundaries after re-aeration. Therefore, individual lobes were delineated and analyzed instead. A radiation oncologist contoured the tumor and individual lobes in the planning and mid-treatment CTs for 7 patients. Each lobe was eroded by 2–4 voxels, which was found to reduce effects of inadvertent chest wall in the lobe delineation but still preserve the mean density of the lobe. The mass of each lobe was calculated after removing the tumor region. The uninvolved lobes were used as controls. Results: Mean mass change for contralateral, ipsilateral without NTP, and NTP lobes were +2.1 (18.0) %, −9.4 (18.2) %, and −13.4 (40.1) %, respectively. For NTP lobes, the degree and direction of change depended on atelectasis resolution type (full or partial), with mean mass change for full resolution of −43.1 (16.2) % and +4.5 (40.1) % for partial. The standard deviation for NTP lobes is likely higher due to actual changes in mass as well as increased delineation variability in the presence of tumor and lung consolidation. Median mean density change was −46.4% for NTP lobes, showing significant difference from contralateral (p=8.2×10−{sup 4}) and NTP-free ipsilateral lobes (p=0.006). Conclusion: No noticeable mass change occurred for pathology-free lobes. As NTP fully resolved, mass of the lobe decreased. One possible explanation is that the release of retained fluid and infiltrate commonly associated with NTP accounts for the reduced mass. This work was supported by the

  10. Adipose-Derived Stem Cells Enhance Cancer Stem Cell Property and Tumor Formation Capacity in Lewis Lung Carcinoma Cells Through an Interleukin-6 Paracrine Circuit.

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    Lu, Jui-Hua; Wei, Hong-Jian; Peng, Bou-Yue; Chou, Hsin-Hua; Chen, Wei-Hong; Liu, Hen-Yu; Deng, Win-Ping

    2016-12-01

    Adipose-derived stem cells (ADSCs) are multipotent cells that have attracted much recent attention and emerged as therapeutic approaches in several medical fields. Although current knowledge of the biological impacts of ADSCs in cancer research is greatly improved, the underlying effects of ADSCs in tumor development remain controversial and cause the safety concerns in clinical utilization. Hence, we isolated primary ADSCs from the abdominal fat of mice and conducted interaction of ADSCs with Lewis lung carcinoma cells in culture and in mice to investigate the impacts of ADSCs on tumor development. Cytokine array and neutralizing antibody were further utilized to identify the key regulator and downstream signaling pathway. In this study, we demonstrated that ADSCs enhance the malignant characteristics of LLC1 cells, including cell growth ability and especially cancer stem cell property. ADSCs were then identified to promote tumor formation and growth in mice. We further determined that ADSC interaction with LLC1 cells stimulates increased secretion of interleukin-6 mainly from ADSCs, which then act in a paracrine manner on LLC1 cells to enhance their malignant characteristics. Interleukin-6 was also identified to regulate genes related to cell proliferation and cancer stem cell, as well as to activate JAK2/STAT3, a predominant interleukin-6-activated pathway, in LLC1 cells. Collectively, we demonstrated that ADSCs play a pro-malignant role in tumor development of Lewis lung carcinoma cells by particularly promoting cancer stem cell property through interleukin-6 paracrine circuit, which is important for safety considerations regarding the clinical application of ADSCs.

  11. Comparison between target margins derived from 4DCT scans and real-time tumor motion tracking: Insights from lung tumor patients treated with robotic radiosurgery

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    Descovich, Martina, E-mail: mdescovich@radonc.ucsf.edu; McGuinness, Christopher; Kannarunimit, Danita; Chen, Josephine; Pinnaduwage, Dilini; Pouliot, Jean; Kased, Norbert; Gottschalk, Alexander R.; Yom, Sue S. [UCSF Department of Radiation Oncology, San Francisco, California 94115 (United States)

    2015-03-15

    Purpose: A unique capability of the CyberKnife system is dynamic target tracking. However, not all patients are eligible for this approach. Rather, their tumors are tracked statically using the vertebral column for alignment. When using static tracking, the internal target volume (ITV) is delineated on the four-dimensional (4D) CT scan and an additional margin is added to account for setup uncertainty [planning target volume (PTV)]. Treatment margins are difficult to estimate due to unpredictable variations in tumor motion and respiratory pattern during the course of treatment. The inability to track the target and detect changes in respiratory characteristics might result in geographic misses and local tumor recurrences. The purpose of this study is to develop a method to evaluate the adequacy of ITV-to-PTV margins for patients treated in this manner. Methods: Data from 24 patients with lesions in the upper lobe (n = 12), middle lobe (n = 3), and lower lobe (n = 9) were included in this study. Each patient was treated with dynamic tracking and underwent 4DCT scanning at the time of simulation. Data including the 3D coordinates of the target over the course of treatment were extracted from the treatment log files and used to determine actual target motion in the superior–inferior (S–I), anterior–posterior (A–P), and left–right (L–R) directions. Different approaches were used to calculate anisotropic and isotropic margins, assuming that the tumor moves as a rigid body. Anisotropic margins were calculated by separating target motion in the three anatomical directions, and a uniform margin was calculated by shifting the gross tumor volume contours in the 3D space and by computing the percentage of overlap with the PTV. The analysis was validated by means of a theoretical formulation. Results: The three methods provided consistent results. A uniform margin of 4.5 mm around the ITV was necessary to assure 95% target coverage for 95% of the fractions included

  12. Neuroendocrine Tumors of the Lung

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    Fisseler-Eckhoff, Annette, E-mail: Annette.Fisseler-Eckhoff@hsk-wiesbaden.de; Demes, Melanie [Department of Pathology und Cytology, Dr. Horst-Schmidt-Kliniken (HSK), Wiesbaden 65199 (Germany)

    2012-07-31

    Neuroendocrine tumors may develop throughout the human body with the majority being found in the gastrointestinal tract and bronchopulmonary system. Neuroendocrine tumors are classified according to the grade of biological aggressiveness (G1–G3) and the extent of differentiation (well-differentiated/poorly-differentiated). The well-differentiated neoplasms comprise typical (G1) and atypical (G2) carcinoids. Large cell neuroendocrine carcinomas as well as small cell carcinomas (G3) are poorly-differentiated. The identification and differentiation of atypical from typical carcinoids or large cell neuroendocrine carcinomas and small cell carcinomas is essential for treatment options and prognosis. Pulmonary neuroendocrine tumors are characterized according to the proportion of necrosis, the mitotic activity, palisading, rosette-like structure, trabecular pattern and organoid nesting. The given information about the histopathological assessment, classification, prognosis, genetic aberration as well as treatment options of pulmonary neuroendocrine tumors are based on own experiences and reviewing the current literature available. Most disagreements among the classification of neuroendocrine tumor entities exist in the identification of typical versus atypical carcinoids, atypical versus large cell neuroendocrine carcinomas and large cell neuroendocrine carcinomas versus small cell carcinomas. Additionally, the classification is restricted in terms of limited specificity of immunohistochemical markers and possible artifacts in small biopsies which can be compressed in cytological specimens. Until now, pulmonary neuroendocrine tumors have been increasing in incidence. As compared to NSCLCs, only little research has been done with respect to new molecular targets as well as improving the classification and differential diagnosis of neuroendocrine tumors of the lung.

  13. Autocrine Effects of Tumor-Derived Complement

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    Min Soon Cho

    2014-03-01

    Full Text Available We describe a role for the complement system in enhancing cancer growth. Cancer cells secrete complement proteins that stimulate tumor growth upon activation. Complement promotes tumor growth via a direct autocrine effect that is partially independent of tumor-infiltrating cytotoxic T cells. Activated C5aR and C3aR signal through the PI3K/AKT pathway in cancer cells, and silencing the PI3K or AKT gene in cancer cells eliminates the progrowth effects of C5aR and C3aR stimulation. In patients with ovarian or lung cancer, higher tumoral C3 or C5aR mRNA levels were associated with decreased overall survival. These data identify a role for tumor-derived complement proteins in promoting tumor growth, and they therefore have substantial clinical and therapeutic implications.

  14. EGFR mutations in patients with lung adenocarcinoma in southwest China: are G719S/A and L861Q more likely detected in tumors derived from smokers?

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    Wang QS

    2013-07-01

    Full Text Available Qiushi Wang,1 Jianghong Mou,1 Xin Yang,1 Yong He,2 Zengpeng Li,1 Qingya Luo,1 Yanqing Li,1 Li Lin,1 Yu Ma,1 Hualiang Xiao11Department of Pathology, 2Department of Respiration, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of ChinaBackground: The clinical characteristics of epidermal growth factor receptor (EGFR hotspot mutations, such as deletions in exon 19, substitution of L858R in exon 21, and mutations in exon 20, have been widely reported in nonsmall cell lung cancer. However, the clinical features of other low frequency EGFR mutations in these four exons (especially the relationship with smoking history, eg, substitutions of G719S/A/C in exon 18 and L861Q in exon 21, remain unclear. This study investigated the relationship between G719S/A/C and L861Q mutations (in exon 18 and 21 and smoking history.Methods: Specimens from 194 patients with lung adenocarcinoma were analyzed for EGFR mutations in exons 18–21 by high-resolution melting curve analysis and amplification refractory mutation technology to establish the relationship between G719S/A/C and L861Q mutations and smoking history.Results: Ninety-six of 194 tumors (49.5% were confirmed to be EGFR mutation-positive. Among these mutations, 71 of 104 (68.3% were from never smokers, six of 17 (35.3% were from former smokers, and 19 of 73 (26.0% were from current smokers (P < 0.001. The mutation rate in heavy smokers (5/23, 21.7% was significantly lower than in light smokers (20/67, 29.9% and never smokers (71/104, 68.3%, P < 0.001. Seven low frequency EGFR mutations (four substitutions of G719S, and G719 A, respectively, and three of L861Q in exon 21 were identified. Five of these mutations were derived from smokers (one former light smoker, one current heavy smoker, and three current light smokers. Four of these patients had been treated with tyrosine kinase inhibitors and all had a partial response, with median overall

  15. A rare tumor of the lung: inflammatory myofibroblastic tumor

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    Hammas Nawal

    2012-07-01

    Full Text Available Abstract Inflammatory myofibroblastic tumor is a rare benign lesion whose tumor origin is now proven. It represents 0.7% of all lung tumors. We report the case of a three-year-old child who suffered from a chronic cough with recurrent respiratory infections. Chest X-ray and computed tomography revealed the presence of a left lower lobe lung mass. After pneumonectomy, histological examination combined with immunohistochemical study discovered an inflammatory myofibroblastic tumor. The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8722069326962972.

  16. How Are Lung Carcinoid Tumors Staged?

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    ... in How Are Lung Carcinoid Tumors Diagnosed? The TNM staging system A staging system is a standard ... cancer – the American Joint Committee on Cancer (AJCC) TNM staging system. The TNM system describes 3 key ...

  17. DNA repair rate and etoposide (VP16) resistance of tumor cell subpopulations derived from a single human small cell lung cancer

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    Hansen, Lasse Tengbjerg; Lundin, Cecilia; Helleday, Thomas

    2003-01-01

    Two human small cell lung cancer (SCLC) subpopulations, CPH 54A, and CPH 54B, established from the same patient tumor by in vitro cloning, were investigated. The tumor was classified as intermediate-type SCLC. The cellular sensitivity to ionizing radiation (IR) was previously determined in the two...... sublines both in vivo and in vitro. Here we measured the etoposide (VP16) sensitivity together with the induction and repair of VP16- and IR-induced DNA double-strand breaks (DSBs). The two subpopulations were found to differ significantly in sensitivity to VP16, with the radioresistant 54B subline also...

  18. Cutaneous metastasis of primitive neuroectodermal lung tumor.

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    Garcia Romero, Diana; Hilara Sanchez, Yolanda; Perez Alvarez, Javier; Ramirez Garcia, Jose Ramon; De Pable Martin, Maria Pilar

    2013-06-15

    Primary sarcomas of the chest are rare. Although primitive neuroectodermal tumor (PNET) usually develops in the chest wall, it has been described as a primary pulmonary tumor. We present an unusual case of PNET arising in the lung of an 89-year-old man.

  19. Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors.

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    Pelosi, Giuseppe; Papotti, Mauro; Rindi, Guido; Scarpa, Aldo

    2014-06-01

    Currently, grading in lung neuroendocrine tumors (NETs) is inherently defined by the histological classification based on cell features, mitosis count, and necrosis, for which typical carcinoids (TC) are low-grade malignant tumors with long life expectation, atypical carcinoids (AC) intermediate-grade malignant tumors with more aggressive clinical behavior, and large cell NE carcinomas (LCNEC) and small cell lung carcinomas (SCLC) high-grade malignant tumors with dismal prognosis. While Ki-67 antigen labeling index, highlighting the proportion of proliferating tumor cells, has largely been used in digestive NETs for assessing prognosis and assisting therapy decisions, the same marker does not play an established role in the diagnosis, grading, and prognosis of lung NETs. Next generation sequencing techniques (NGS), thanks to their astonishing ability to process in a shorter timeframe up to billions of DNA strands, are radically revolutionizing our approach to diagnosis and therapy of tumors, including lung cancer. When applied to single genes, panels of genes, exome, or the whole genome by using either frozen or paraffin tissues, NGS techniques increase our understanding of cancer, thus realizing the bases of precision medicine. Data are emerging that TC and AC are mainly altered in chromatin remodeling genes, whereas LCNEC and SCLC are also mutated in cell cycle checkpoint and cell differentiation regulators. A common denominator to all lung NETs is a deregulation of cell proliferation, which represents a biological rationale for morphologic (mitoses and necrosis) and molecular (Ki-67 antigen) parameters to successfully serve as predictors of tumor behavior (i.e., identification of pathological entities with clinical correlation). It is envisaged that a novel grading system in lung NETs based on the combined assessment of mitoses, necrosis, and Ki-67 LI may offer a better stratification of prognostic classes, realizing a bridge between molecular alterations

  20. Metabolic heterogeneity in human lung tumors

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    Hensley, Christopher T.; Faubert, Brandon; Yuan, Qing; Lev-Cohain, Naama; Jin, Eunsook; Kim, Jiyeon; Jiang, Lei; Ko, Bookyung; Skelton, Rachael; Loudat, Laurin; Wodzak, Michelle; Klimko, Claire; McMillan, Elizabeth; Butt, Yasmeen; Ni, Min; Oliver, Dwight; Torrealba, Jose; Malloy, Craig R.; Kernstine, Kemp; Lenkinski, Robert E.; DeBerardinis, Ralph J.

    2015-01-01

    SUMMARY Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intra-operative 13C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature. PMID:26853473

  1. Radiofrequency Ablation of Lung Tumors

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    ... Rotating around you, the x-ray tube and electronic x-ray detectors are located opposite each other ... breathe is impaired, such as current or former cigarette smokers. When part of the tumor persists after ...

  2. Promotion of lung tumor growth by interleukin-17

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    Xu, Beibei; Guenther, James F.; Pociask, Derek A.; Wang, Yu; Kolls, Jay K.; You, Zongbing; Chandrasekar, Bysani; Shan, Bin; Sullivan, Deborah E.; Morris, Gilbert F.

    2014-01-01

    Recent findings demonstrate that inhaled cigarette smoke, the predominant lung carcinogen, elicits a T helper 17 (Th17) inflammatory phenotype. Interleukin-17A (IL-17), the hallmark cytokine of Th17 inflammation, displays pro- and antitumorigenic properties in a manner that varies according to tumor type and assay system. To investigate the role of IL-17 in lung tumor growth, we used an autochthonous tumor model (K-RasLA1 mice) with lung delivery of a recombinant adenovirus that expresses IL-...

  3. Quantitative analysis of tumor burden in mouse lung via MRI.

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    Tidwell, Vanessa K; Garbow, Joel R; Krupnick, Alexander S; Engelbach, John A; Nehorai, Arye

    2012-02-01

    Lung cancer is the leading cause of cancer death in the United States. Despite recent advances in screening protocols, the majority of patients still present with advanced or disseminated disease. Preclinical rodent models provide a unique opportunity to test novel therapeutic drugs for targeting lung cancer. Respiratory-gated MRI is a key tool for quantitatively measuring lung-tumor burden and monitoring the time-course progression of individual tumors in mouse models of primary and metastatic lung cancer. However, quantitative analysis of lung-tumor burden in mice by MRI presents significant challenges. Herein, a method for measuring tumor burden based upon average lung-image intensity is described and validated. The method requires accurate lung segmentation; its efficiency and throughput would be greatly aided by the ability to automatically segment the lungs. A technique for automated lung segmentation in the presence of varying tumor burden levels is presented. The method includes development of a new, two-dimensional parametric model of the mouse lungs and a multi-faceted cost function to optimally fit the model parameters to each image. Results demonstrate a strong correlation (0.93), comparable with that of fully manual expert segmentation, between the automated method's tumor-burden metric and the tumor burden measured by lung weight.

  4. Patrolling Monocytes Control Tumor Metastasis to the Lung

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    Hanna, Richard N.; Cekic, Caglar; Sag, Duygu; Tacke, Robert; Thomas, Graham D.; Nowyhed, Heba; Herrley, Erica; Rasquinha, Nicole; McArdle, Sara; Wu, Runpei; Peluso, Esther; Metzger, Daniel; Ichinose, Hiroshi; Shaked, Iftach; Chodaczek, Grzegorz; Biswas, Subhra K.; Hedrick, Catherine C.

    2016-01-01

    The immune system plays an important role in regulating tumor growth and metastasis. For example, classical monocytes promote tumorigenesis and cancer metastasis; however, how nonclassical “patrolling” monocytes interact with tumors is unknown. Here we show that patrolling monocytes are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack patrolling monocytes, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient patrolling monocytes into Nr4a1-deficient mice prevented tumor invasion in lung. Patrolling monocytes established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature and promoted natural killer cell recruitment and activation. Thus, patrolling monocytes contribute to cancer immunosurveillance and may be targets for cancer immunotherapy. PMID:26494174

  5. Fluorescence bronchoscope for lung tumor localization

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    Profio, A.E. (Univ. of California, Santa Barbara); Doiron, D.R.; Huth, G.C.

    1977-02-01

    A fluorescence bronchoscope has been developed for localization of small bronchogenic tumors at the carcinoma in situ stage. Injected hematoporphyrin-derivative is preferentially taken up or retained by a malignant tumor, and very small amounts can be detected by the red fluorescence under excitation by violet light. The target lesion is 80 ..mu..m thick, with a mass of 250 ..mu..g, containing 250 pg of hematoporphyrin-derivative. A fiberoptic bronchoscope system with a 200W high pressure mercury arc lamp, primary filter passing 405 nm light, special violet transmitting light conductor, coherent imaging bundle, red secondary filter, and three-stage electrostatic focus image intensifier tube was designed for this application. Tumors have been visualized in animals and preparations for clinical use are underway.

  6. Patrolling Monocytes Control Tumor Metastasis to the Lung

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    Hanna, Richard N.; Cekic, Caglar; Sag, Duygu; Tacke, Robert; Graham D. Thomas; Nowyhed, Heba; Herrley, Erica; Rasquinha, Nicole; McArdle, Sara; Wu, Runpei; Peluso, Esther; Metzger, Daniel; Ichinose, Hiroshi; Shaked, Iftach; Chodaczek, Grzegorz

    2015-01-01

    The immune system plays an important role in regulating tumor growth and metastasis. For example, classical monocytes promote tumorigenesis and cancer metastasis; however, how nonclassical “patrolling” monocytes interact with tumors is unknown. Here we show that patrolling monocytes are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack patrolling monocytes, showed increased ...

  7. Lung metastasis of benign giant cell tumor: a case report

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    Bosi, Thiago Carneiro da Cunha; Andrade, Fernando Coelho Goulart de; Turtelli, Celso Montenegro; Ribeiro Junior, Helio Antonio [Universidade Federal do Triangulo Mineiro (UFMT), Uberaba, MG (Brazil). Dept. of Radiology and Imaging Diagnosis]. E-mail: tccbosi@yahoo.com.br; Fatureto, Marcelo Cunha [Universidade Federal do Triangulo Mineiro (UFMT), Uberaba, MG (Brazil). Dept. of Thoracic Surgery; Etchebehere, Renata Margarida [Universidade Federal do Triangulo Mineiro (UFMT), Uberaba, MG (Brazil). Dept. of Pathology

    2008-05-15

    Giant cell tumor is the sixth most frequent primary bone neoplasm, affecting long bone metaphysis, most frequently in young adults. On radiological images, this tumor appears as a lytic, well-defined, eccentric lesion. The authors report a case of benign giant cell tumor in a patient who presented with lung metastases five years after undergoing resection of the primary tumor. (author)

  8. Inflammatory myofibroblastic tumor in lung with osteopulmonary arthropathy

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yi; DONG Zong-jun; ZHI Xiu-yi; LIU Lei; HU Mu

    2009-01-01

    @@ Inflammatory myofibroblastic tumor (IMT) is a rare disease that usually occurs in the lung. Recently, several reports have suggested that IMT is a true neoplasm rather than a reactive lesion. By definition, it is composed of spindle cells (myofibroblasts) with variable inflammatory component, hence the name is IMT. We report a patient of inflammatory myofibroblastic tumor in lung with osteopulmonary arthropathy.

  9. Patient-Derived Tumor Xenografts Are Susceptible to Formation of Human Lymphocytic Tumors

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    Gennadiy Bondarenko

    2015-09-01

    Full Text Available Patient-derived xenograft (PDX tumor models have emerged as a new approach to evaluate the effects of cancer drugs on patients’ personalized tumor grafts enabling to select the best treatment for the cancer patient and providing a new tool for oncology drug developers. Here, we report that human tumors engrafted in immunodeficient mice are susceptible to formation of B-and T-cell PDX tumors. We xenografted human primary and metastatic tumor samples into immunodeficient mice and found that a fraction of PDX tumors generated from patients’ samples of breast, colon, pancreatic, bladder and renal cancer were histologically similar to lymphocytic neoplasms. Moreover, we found that the first passage of breast and pancreatic cancer PDX tumors after initial transplantation of the tumor pieces from the same human tumor graft could grow as a lymphocytic tumor in one mouse and as an adenocarcinoma in another mouse. Whereas subcutaneous PDX tumors resembling human adenocarcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphocytic tumors were fast growing and formed large metastatic lesions in mouse lymph nodes, liver, lungs, and spleen. PDX lymphocytic tumors were comprised of B-cells which were Epstein-Barr virus positive and expressed CD45 and CD20. Because B-cells are typically present in malignant solid tumors, formation of B-cell tumor may evolve in a wide range of PDX tumor models. Although PDX tumor models show great promise in the development of personalized therapy for cancer patients, our results suggest that confidence in any given PDX tumor model requires careful screening of lymphocytic markers.

  10. IL-1α and IL-1β-producing macrophages populate lung tumor lesions in mice.

    Science.gov (United States)

    Terlizzi, Michela; Colarusso, Chiara; Popolo, Ada; Pinto, Aldo; Sorrentino, Rosalinda

    2016-09-06

    Macrophages highly populate tumour microenvironment and are referred to as tumor-associated macrophages (TAMs). The inflammasome is a multiprotein complex responsible of IL-1 like cytokines release, which biology has been widely studied by using bone-marrow-derived macrophages to mimic a physiological and/or host defense condition. To understand the role of this complex in lung tumor-associated macrophages (TAMs), we isolated and cultured broncho-alveolar lavage (BAL)-derived cells of lung tumor-bearing mice. The stimulation of lung TAMs with LPS+ATP increased the release of IL-1β. The inhibition of NLRP3 by means of glybenclamide significantly reduced IL-1β release. Similarly, C3H-derived, caspase-1 ko and caspase-11 ko TAMs released significantly reduced levels of IL-1β. Moreover, the stimulation of lung TAMs with the sole LPS induced a significant release of IL-1α, which was significantly reduced after caspase-1 pharmacological inhibition, and in TAMs genetically lacking caspase-1 and caspase-11. The inhibition of calpain I/II by means of MDL28170 did not alter IL-1α release after LPS treatment of lung TAMs. To note, the inoculation of LPS-treated bone marrow-derived macrophages into carcinogen-exposed mice increased lung tumor formation. In contrast, the depletion of TAMs by means of clodronate liposomes reduced lung tumorigenesis, associated to lower in vivo release of IL-1α and IL-1β.In conclusion, our data imply lung tumor lesions are populated by macrophages which pro-tumor activity is regulated by the activation of the NLRP3 inflammasome that leads to the release of IL-1α and IL-1β in a caspase-11/caspase-1-dependent manner.

  11. Establishment and Its Biological Characteristics of Patient-derived Lung Cancer Xenograft Modelse

    Directory of Open Access Journals (Sweden)

    Ying ZHUO

    2010-06-01

    Full Text Available Background and objective With the ongoing need to improve therapy for lung cancer, there has been an increasing interest in the development of reliable preclinical models to test novel therapeutics. The aim of this study is to establish a patient-derived lung cancer xenograft model in mice and to observe the biological characteristics of xenografts. Methods Surgically resectected tumor specimens from patients with lung cancer were implanted in the subcutaneous layer of the NOD/SCID mice. Cancer specimens of percutaneous lung biopsy by CT fluoroscopy were implanted into the subrenal capsule of nude mouse. The subcutaneous carcinoma was surgically removed when it grew to approximately 1.0 cm in diameter, and then re-transplanted into new nude mice. The growth process of transplanted tumor was observed. Expression of CEA, cytokeratin, and Ki67 were detected by immunohistochemistry. Mutations in the exons 18-21 of EGFR and exons 12,59 of K-ras of primary and xenograft tumors were examined. The cell cycle of xenograft tumor cells was analyzed by flow cytometry. Results Eleven cases were conducted for NOD/SCID mice and nude mice modelling. The patient-derived lung cancer xenografts have been established successfully, and the tumor could be passed to new nude mice, including No 2 model (adenocasinoma, No. 3 model (small cell lung cancer, and No. 5 model (squamous cell cancer. High homogeneity was found between xenograft tumors and human lung cancer in histopathology, immunohistochemical phenotype, and EGFR, K-ras mutation status . The S-phase fraction of xenograft cell cycle was prolonged, which indicated that the xenografts remains highly proliferated. Conclusion The xenotransplantation models established for patient-derived lung cancer in immune deficient mice. The success rate is 27%. This model system displayed the biological characteristics of human lung cancer, suggesting that it may provide a stable, reliable, and useful animal model in human

  12. [The new TNM classification for lung tumors : Changes and the assessment of multiple tumor foci].

    Science.gov (United States)

    Harms, A; Kriegsmann, M; Fink, L; Länger, F; Warth, A

    2017-02-01

    Recently a new TNM classification for tumors of the lung was published, encompassing some relevant changes, for example how to deal with multiple lung tumors. This article comprehensively describes respective changes. Furthermore, background information on how the new TNM classification was built and what should be done in the future to further improve prognosis and outcome prediction is reviewed.

  13. Screening study on new tumor marker periplakin for lung cancer

    Institute of Scientific and Technical Information of China (English)

    Shuqin Dai; Wei Li; Mian Kong; Yuzhen Zheng; Shuying Chen; Junye Wang; Linquan Zang

    2013-01-01

    Objective: The aim of this study was to use lung cancer targeting binding polypeptide ZS-9 to screen cDNA library of human lung cancer and obtain ZS-9 specific ligand to confirm tumor marker of non small-cell lung cancer. Methods: Artificially synthesize biotin labeled peptide ZS-9, anchored ZS-9 in the enzyme label plate coupled by avidin, used ZS-9 as probe to screen cDNA library of human lung cancer, after screening, obtained bacteriophage clone specifically binding with anchored polypeptide ZS-9. Extracted plasmid of bacteriophage and performed sequencing after amplified by PCR. Results: It was demonstrated by bioinformatic analysis on the sequence of ligand binded by lung cancer specific peptide ZS-9 that the ligand was the cytoskeletal protein periplakin on the surface of lung cancer cells, suggesting that periplakin might be a new marker for non-small-cell lung cancer in lung cancer. Conclusion: Use specific lung cancer binding peptide to screen new tumor marker periplakin in lung cancer and further studies on its biologic functions in genesis and development of lung cancer are still needed.

  14. Unusual synchronous lung tumors: mucoepidermoid carcinoma and mucinous adenocarcinoma.

    Science.gov (United States)

    Ponea, Ana M; Marak, Creticus P; Sun, Ying; Guddati, Achuta Kumar; Tibb, Amit S

    2014-01-01

    Primary mucoepidermoid tumors of the lung are rare entities. Synchronous primary malignancies of the lung involving mucoepidermoid carcinoma and mucinous adenocarcinoma are even rarer and constitute a unique set of patient population. The presentation, diagnosis and treatment strategies for this patient population are not well described. In most cases, the diagnosis of synchronous primary lung malignancy is made after pathological examination of the resected lung specimen. Molecular and genetic analysis is now being used to supplement the diagnosis of synchronous primary lung malignancies. In this work, we briefly discuss the current state of knowledge of this unique combination of primary lung malignancies and describe the clinical presentation and management of a patient with a rare combination of synchronous primary lung malignancies.

  15. Unusual Synchronous Lung Tumors: Mucoepidermoid Carcinoma and Mucinous Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Ana M. Ponea

    2014-01-01

    Full Text Available Primary mucoepidermoid tumors of the lung are rare entities. Synchronous primary malignancies of the lung involving mucoepidermoid carcinoma and mucinous adenocarcinoma are even rarer and constitute a unique set of patient population. The presentation, diagnosis and treatment strategies for this patient population are not well described. In most cases, the diagnosis of synchronous primary lung malignancy is made after pathological examination of the resected lung specimen. Molecular and genetic analysis is now being used to supplement the diagnosis of synchronous primary lung malignancies. In this work, we briefly discuss the current state of knowledge of this unique combination of primary lung malignancies and describe the clinical presentation and management of a patient with a rare combination of synchronous primary lung malignancies.

  16. Focus on treatment of lung carcinoid tumor

    Directory of Open Access Journals (Sweden)

    Noel-Savina E

    2013-10-01

    Full Text Available Elise Noel-Savina,1 Renaud Descourt2 1Pulmonary Service, 2Thoracic Oncology Service, Hospital de la Cavale Blanche, CHU – Brest, Brest, France Abstract: Bronchial typical carcinoid tumors are neuroendocrine bronchopulmonary tumors with a low-grade malignancy, and an atypical carcinoid is an intermediate form of these tumors. There is a lack of knowledge on the optimal treatment for these tumors. The surgical treatment of choice consists of a lobectomy supplemented by dissection. The benefit of chemotherapy and radiotherapy is unclear. Targeted therapy could be used in this condition, but there is a lack of research recommending it. Keywords: carcinoid tumor, neuroendocrine tumor, bronchopulmonary tumor, treatment

  17. P53 MUTATIONS IN HUMAN LUNG-TUMORS

    NARCIS (Netherlands)

    MILLER, CW; ASLO, A; KOK, K; YOKOTA, J; BUYS, CHCM; TERADA, M; KOEFFLER, HP; Simon, K.

    1992-01-01

    Mutation of one p53 allele and loss of the normal p53 allele [loss of heterozygosity (LOH)] occur in many tumors including lung cancers. These alterations apparently contribute to development of cancer by interfering with the tumor suppressor activity of p53. We directly sequenced amplified DNA in t

  18. [Kartagener syndrome with lung cancer and mediastinal tumor].

    Science.gov (United States)

    Horie, Masafumi; Arai, Hidenori; Noguchi, Satoshi; Suzuki, Masaru; Sakamoto, Yoshio; Oka, Teruaki

    2010-05-01

    A 71-year-old man was admitted to Kanto Central Hospital with hemoptysis. He had had chronic sinusitis and deafness since childhood. Situs inversus, bronchiectasia, and diffuse panbronchiolitis had been also diagnosed at the age of 59. Chest computed tomography demonstrated a 5-cm mass in the anterior mediastinum as well as a 4-cm mass in the upper lobe of the right lung. A transbronchial lung biopsy of the right lung tumor revealed squamous cell carcinoma. Electron microscopic examination of the bronchial epithelial cilia revealed a total defect of both inner and outer dynein arms, leading to a diagnosis of primary ciliary dyskinesia. Biopsy of the mediastinal tumor was not performed. After concurrent chemoradiation therapy, the lung cancer decreased in size partial remission (PR) and the mediastinal tumor disappeared complete remission (CR). Later, a cavity formed in the tumor, where a Pseudomonas aeruginosa infection occurred. He died 1 year after the diagnosis of lung cancer was established. There have been 5 reported cases of Kartagener syndrome complicated with lung cancer, but to the best of our knowledge there have been no reports of Kartagener syndrome with mediastinal tumor.

  19. Lung Tumor Segmentation Using Electric Flow Lines for Graph Cuts

    DEFF Research Database (Denmark)

    Hollensen, Christian; Cannon, George; Cannon, Donald;

    2012-01-01

    Lung cancer is the most common cause of cancer-related death. A common treatment is radiotherapy where the lung tumors are irradiated with ionizing radiation. The treatment is typically fractionated, i.e. spread out over time, allowing healthy tissue to recover between treatments and allowing tumor...... cells to be hit in their most sensitive phase. Changes in tumors over the course of treatment allows for an adaptation of the radiotherapy plan based on 3D computer tomography imaging. This paper introduces a method for segmentation of lung tumors on consecutive computed tomography images. These images...... are normally only used for correction of movements. The method uses graphs based on electric flow lines. The method offers several advantages when trying to replicate manual segmentations. The method gave a dice coefficient of 0.85 and performed better than level set methods and deformable registration....

  20. Cell-derived microparticles and the lung

    Directory of Open Access Journals (Sweden)

    Dario Nieri

    2016-09-01

    Full Text Available Cell-derived microparticles are small (0.1–1 μm vesicles shed by most eukaryotic cells upon activation or during apoptosis. Microparticles carry on their surface, and enclose within their cytoplasm, molecules derived from the parental cell, including proteins, DNA, RNA, microRNA and phospholipids. Microparticles are now considered functional units that represent a disseminated storage pool of bioactive effectors and participate both in the maintenance of homeostasis and in the pathogenesis of diseases. The mechanisms involved in microparticle generation include intracellular calcium mobilisation, cytoskeleton rearrangement, kinase phosphorylation and activation of the nuclear factor-κB. The role of microparticles in blood coagulation and inflammation, including airway inflammation, is well established in in vitro and animal models. The role of microparticles in human pulmonary diseases, both as pathogenic determinants and biomarkers, is being actively investigated. Microparticles of endothelial origin, suggestive of apoptosis, have been demonstrated in the peripheral blood of patients with emphysema, lending support to the hypothesis that endothelial dysfunction and apoptosis are involved in the pathogenesis of the disease and represent a link with cardiovascular comorbidities. Microparticles also have potential roles in patients with asthma, diffuse parenchymal lung disease, thromboembolism, lung cancer and pulmonary arterial hypertension.

  1. IMMUNOTHERAPY OF SPONTANEOUS METASTATIC LUNG CANCER WITH TUMOR ANTIGEN-PULSED, INTERLEUKIN-12 GENE-MODIFIED DENDRITIC CELLS

    Institute of Scientific and Technical Information of China (English)

    陈吉泉; 修清玉; 颜泽敏; 罗文侗

    2003-01-01

    Objective: To investigate the treatment of spontaneous metastatic lung cancer by tumor antigen-pulsed, interleukin-12 (IL-12) gene-modified dendritic cells (DC). Methods:The spontaneous metastatic lung cancer model, prepared by injection of the 3LL Lewis lung cancer cells into the footpads of C57BL/6 mice, was treated by subcutaneous vaccination with tumor antigen peptide mut1-pulsed, IL-12 gene-modified dendritic cells (DC-IL-12/mut1) derived from the normal bone morrow. After treatment, the lung weight, the number of lung metastatic nodes and the survival time of the tumor-bearing mice were observed, and the NK and CTL activity were determined respectively. The mice were divided into 8 groups with 12 mice in each group. Results: Compared with mice treated with mut1-pulsed, control LacZ gene modified DC and untreated DC, tumor-bearing mice treated with DC-IL-12/mut1 had the lightest lung weights (P<0.01), the least lung metastatic node number (P<0.01), the longest survival time (P<0.01), also with the induction of potent CTL activity (P<0.01) and NK activity (P<0.01). Conclusion: Tumor antigen-pulsed, IL-12 gene-modified dendritic cells have significant therapeutic effects on the spontaneous metastatic lung cancer, providing a new approach to treatment of lung tumors.

  2. Diaphragm as an anatomic surrogate for lung tumor motion

    CERN Document Server

    Cervino, Laura I; Sandhu, Ajay; Jiang, Steve B

    2009-01-01

    Lung tumor motion due to respiration poses a challenge in the application of modern three-dimensional conformal radiotherapy. Direct tracking of the lung tumor during radiation therapy is very difficult without implanted fiducial markers. Indirect tracking relies on the correlation of the tumor's motion and the surrogate's motion. The present paper presents an analysis of the correlation between the tumor motion and the diaphragm motion in order to evaluate the potential use of diaphragm as a surrogate for tumor motion. We have analyzed the correlation between diaphragm motion and superior-inferior lung tumor motion in 32 fluoroscopic image sequences from 10 lung cancer patients. A simple linear model and a more complex linear model that accounts for phase delays between the two motions have been used. Results show that the diaphragm is a good surrogate for tumor motion prediction for most patients, resulting in an average correlation factor of 0.94 and 0.98 with each model respectively. The model that accoun...

  3. File list: ALL.Lng.10.AllAg.Lung_tumors [Chip-atlas[Archive

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  13. Advances in Research on Circulating Tumor Cells in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yingjian SONG

    2012-10-01

    Full Text Available Metastatic and recurrent tumors have been identified as the leading attribute to the lung cancer deaths. Cancer research has demonstrated the critical role circulating tumor cells (CTCs play in the metastatic spread of carcinomas and the recurrence of lung cancer. The rapid advancement of technology in targeted therapy resolves the embarrassing situation for those late-stage patients whose tumor tissues cannot be obtained. CTCs, as a substitute for the tumor tissues, represent a decisive tool to the cancer treatment strategy. Thus, CTCs exert a fundamental role in the early detection of micro-metastasis, assisting in diagnosis, prognosis and monitoring of the recurrent tumors, and subsequently choosing an individualized approach for the therapeutic treatment. This article will review the advances, which have been made in the research area of CTCs with the aid of its applications in cancer therapy.

  14. Failure of the cultivated mushroom (Agaricus bisporus) to induce tumors in the A/J mouse lung tumor model

    DEFF Research Database (Denmark)

    Pilegaard, Kirsten; Kristiansen, E.; Meyer, Otto A.

    1997-01-01

    We studied whether the cultivated mushroom (Agaricus bisporus) or 4-(carboxy)phenylhydrazine (CP) induce lung adenomas in the A/J mouse lung tumor model. For 26 weeks female mice were fed a semisynthetic diet where 11 or 22% of the diet was replaced by freeze-dried mushrooms. The intake...... of the mushroom diets was equivalent to an intake of agaritine, the major phenylhydrazine derivative occurring in the mushroom, of 92 or 166 mg/kg body weight per day. The intake of CP was 106 mg/kg body weight per day. Neither the;freeze-dried mushroom nor CP induced statistically significant increased numbers...

  15. Assessment of lung tumor response by perfusion CT.

    Science.gov (United States)

    Coche, E

    2013-01-01

    Perfusion CT permits evaluation of lung cancer angiogenesis and response to therapy by demonstrating alterations in lung tumor vascularity. It is advocated that perfusion CT performed shortly after initiating therapy may provide a better evaluation of physiological changes rather than the conventional size assessment obtained with RECIST. The radiation dose,the volume of contrast medium delivered to the patient and the reproducibility of blood flow parameters remain an issue for this type of investigation.

  16. Lung tumor segmentation in PET images using graph cuts.

    Science.gov (United States)

    Ballangan, Cherry; Wang, Xiuying; Fulham, Michael; Eberl, Stefan; Feng, David Dagan

    2013-03-01

    The aim of segmentation of tumor regions in positron emission tomography (PET) is to provide more accurate measurements of tumor size and extension into adjacent structures, than is possible with visual assessment alone and hence improve patient management decisions. We propose a segmentation energy function for the graph cuts technique to improve lung tumor segmentation with PET. Our segmentation energy is based on an analysis of the tumor voxels in PET images combined with a standardized uptake value (SUV) cost function and a monotonic downhill SUV feature. The monotonic downhill feature avoids segmentation leakage into surrounding tissues with similar or higher PET tracer uptake than the tumor and the SUV cost function improves the boundary definition and also addresses situations where the lung tumor is heterogeneous. We evaluated the method in 42 clinical PET volumes from patients with non-small cell lung cancer (NSCLC). Our method improves segmentation and performs better than region growing approaches, the watershed technique, fuzzy-c-means, region-based active contour and tumor customized downhill.

  17. Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Trakul, Nicholas; Chang, Christine N.; Harris, Jeremy [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Chapman, Christopher [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of Michigan School of Medicine, Ann Arbor, MI (United States); Rao, Aarti [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of California, Davis, School of Medicine, Davis, CA (United States); Shen, John [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of California, Irvine, School of Medicine, Irvine, CA (United States); Quinlan-Davidson, Sean [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Department of Radiation Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, Ontario (Canada); Filion, Edith J. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Departement de Medecine, Service de Radio-Oncologie, Centre Hospitalier de l' Universite de Montreal, Montreal, Quebec (Canada); Wakelee, Heather A.; Colevas, A. Dimitrios [Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA (United States); Whyte, Richard I. [Department of Cardiothoracic Surgery, Division of General Thoracic Surgery, Stanford University School of Medicine, Stanford, CA (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA (United States); and others

    2012-09-01

    Purpose: Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. Methods and Materials: We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume {>=}12 mL) received multifraction regimens with BED {>=}100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2). Results: The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02). Conclusion: A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

  18. Classification of lung cancer tumors based on structural and physicochemical properties of proteins by bioinformatics models.

    Science.gov (United States)

    Hosseinzadeh, Faezeh; Ebrahimi, Mansour; Goliaei, Bahram; Shamabadi, Narges

    2012-01-01

    Rapid distinction between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) tumors is very important in diagnosis of this disease. Furthermore sequence-derived structural and physicochemical descriptors are very useful for machine learning prediction of protein structural and functional classes, classifying proteins and the prediction performance. Herein, in this study is the classification of lung tumors based on 1497 attributes derived from structural and physicochemical properties of protein sequences (based on genes defined by microarray analysis) investigated through a combination of attribute weighting, supervised and unsupervised clustering algorithms. Eighty percent of the weighting methods selected features such as autocorrelation, dipeptide composition and distribution of hydrophobicity as the most important protein attributes in classification of SCLC, NSCLC and COMMON classes of lung tumors. The same results were observed by most tree induction algorithms while descriptors of hydrophobicity distribution were high in protein sequences COMMON in both groups and distribution of charge in these proteins was very low; showing COMMON proteins were very hydrophobic. Furthermore, compositions of polar dipeptide in SCLC proteins were higher than NSCLC proteins. Some clustering models (alone or in combination with attribute weighting algorithms) were able to nearly classify SCLC and NSCLC proteins. Random Forest tree induction algorithm, calculated on leaves one-out and 10-fold cross validation) shows more than 86% accuracy in clustering and predicting three different lung cancer tumors. Here for the first time the application of data mining tools to effectively classify three classes of lung cancer tumors regarding the importance of dipeptide composition, autocorrelation and distribution descriptor has been reported.

  19. Classification of lung cancer tumors based on structural and physicochemical properties of proteins by bioinformatics models.

    Directory of Open Access Journals (Sweden)

    Faezeh Hosseinzadeh

    Full Text Available Rapid distinction between small cell lung cancer (SCLC and non-small cell lung cancer (NSCLC tumors is very important in diagnosis of this disease. Furthermore sequence-derived structural and physicochemical descriptors are very useful for machine learning prediction of protein structural and functional classes, classifying proteins and the prediction performance. Herein, in this study is the classification of lung tumors based on 1497 attributes derived from structural and physicochemical properties of protein sequences (based on genes defined by microarray analysis investigated through a combination of attribute weighting, supervised and unsupervised clustering algorithms. Eighty percent of the weighting methods selected features such as autocorrelation, dipeptide composition and distribution of hydrophobicity as the most important protein attributes in classification of SCLC, NSCLC and COMMON classes of lung tumors. The same results were observed by most tree induction algorithms while descriptors of hydrophobicity distribution were high in protein sequences COMMON in both groups and distribution of charge in these proteins was very low; showing COMMON proteins were very hydrophobic. Furthermore, compositions of polar dipeptide in SCLC proteins were higher than NSCLC proteins. Some clustering models (alone or in combination with attribute weighting algorithms were able to nearly classify SCLC and NSCLC proteins. Random Forest tree induction algorithm, calculated on leaves one-out and 10-fold cross validation shows more than 86% accuracy in clustering and predicting three different lung cancer tumors. Here for the first time the application of data mining tools to effectively classify three classes of lung cancer tumors regarding the importance of dipeptide composition, autocorrelation and distribution descriptor has been reported.

  20. [Huge benign lung tumor in a female smoker].

    Science.gov (United States)

    Smati, B; Ismail, O; Boudaya, M S; Baccari, S; Djilani, H; Mestiri, T; El Mezni, F; Gharbi, L; Kilani, T

    2005-12-01

    Pulmonary sclerosing hemangioma is a rare, slow-growing, benign tumor. Its potential for progression and its histiogenesis remains controversial. A routine chest X-ray revealed a right abdominal mass in 41-year-old woman. Search for a cause was negative. The patient underwent posterolateral thoracotomy for tumorectomy. Intraoperative pathology analysis revealed the benign nature of the tumor. No complication was observed postoperatively. The final pathological conclusion was sclerosing hemangioma of the lung. Pulmonary sclerosing hemangioma is a parenchymal tumor of the lung. The latest immunohistochemical studies of this lesion suggest a pneumocyte origin. Prognosis is good, but extension to lymph nodes may occur. Surgery is always required for cure, and must be associated with lymph node dissection for large tumors.

  1. Molecular pathogenesis of transplacentally induced mouse lung tumors.

    Science.gov (United States)

    Miller, M S; Leone-Kabler, S; Rollins, L A; Wessner, L L; Fan, M; Schaeffer, D O; McEntee, M F; O'Sullivan, M G

    1998-01-01

    Previous studies from this and other laboratories have shown that treatment of pregnant mice with 3-methylcholanthrene (MC) caused lung tumors in the offspring, the incidence of which correlated with fetal inducibility of Cyp1a1. Analysis of paraffin-embedded lung tissue for Ki-ras-2 mutations indicated that 79% of the lesions examined contained point mutations in codons 12 and 13 of the Ki-ras-2 gene locus, the majority of which (84%) were G-->T transversions. The mutational spectrum was dependent on the tumor stage, as both the incidence of mutation and type of mutation produced correlated with malignant progression of the tumor. Mutations occurred in 60% of the hyperplasias, 80% of the adenomas, and 100% of the adenocarcinomas. In the tumors with mutations, GLY12-->CYS12 transversions occurred in 100% of the hyperplasias, 42% of the adenomas, and 14% of the adenocarcinomas. GLY12-->VAL12 transversions were not observed in hyperplasias and occurred in 42% of the adenomas and 57% of the adenocarcinomas. The remaining ASP12 and ARG13 mutations occurred only in adenomas (17%) and adenocarcinomas (29%). The tumors were also analyzed for alterations in the structure or function of the tumor suppressor genes Rb, p53, and Cdkn2a. No mutations were observed in exons 5-8 of the p53 gene. SSCP analysis demonstrated that 2 of 15 lung tumors contained shifted bands at the Cdkn2a gene locus. Sequence analysis had identified these as mutations in exon 2, with a CAC-->TAC transition at base 301 (HIS74-->TYR74) in tumor 23-1 and GGG-->GAG transition at base 350 (GLY90-->GLU90) in tumor 36-1. Northern blot analysis of the larger tumors revealed that 14 of 14 of these large lung tumors exhibited markedly decreased expression of Rb gene transcripts. These results were confirmed by immunohistochemistry. The larger tumors, which exhibited features of adenocarcinomas, showed a marked reduction or almost complete absence of nuclear pRb staining compared with smaller adenomas and normal

  2. How Are Lung Carcinoid Tumors Diagnosed?

    Science.gov (United States)

    ... for chromogranin A (CgA), neuron-specific enolase (NSE), cortisol , and substance P . Depending on where the tumor ... Cancer Atlas Press Room Cancer Statistics Center Volunteer Learning Center Follow Us Twitter Facebook Instagram Cancer Information, ...

  3. Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice.

    Science.gov (United States)

    Hara, Toshiro; Murakami, Yoshinori; Seiki, Motoharu; Sakamoto, Takeharu

    2017-08-26

    Breast cancer is one of the most common cancers in women in the world. Although breast cancer is well treatable at the early stage, patients with distant metastases show a poor prognosis. Data from recent studies using transplantation models indicate that Mint3/APBA3 might promote breast cancer malignancy. However, whether Mint3 indeed contributes to tumor development, progression, or metastasis in vivo remains unclear. To address this, here we examined whether Mint3 depletion affects tumor malignancy in MMTV-PyMT breast cancer model mice. In MMTV-PyMT mice, Mint3 depletion did not affect tumor onset and tumor growth, but attenuated lung metastases. Experimental lung metastasis of breast cancer Met-1 cells derived from MMTV-PyMT mice also decreased in Mint3-depleted mice, indicating that host Mint3 expression affected lung metastasis of MMTV-PyMT-derived breast cancer cells. Further bone marrow transplant experiments revealed that Mint3 in bone marrow-derived cells promoted lung metastasis in MMTV-PyMT mice. Thus, targeting Mint3 in bone marrow-derived cells might be a good strategy for preventing metastasis and improving the prognosis of breast cancer patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Aptamers Selected to Postoperative Lung Adenocarcinoma Detect Circulating Tumor Cells in Human Blood

    Science.gov (United States)

    Zamay, Galina S; Kolovskaya, Olga S; Zamay, Tatiana N; Glazyrin, Yury E; Krat, Alexey V; Zubkova, Olga; Spivak, Ekaterina; Wehbe, Mohammed; Gargaun, Ana; Muharemagic, Darija; Komarova, Mariia; Grigorieva, Valentina; Savchenko, Andrey; Modestov, Andrey A; Berezovski, Maxim V; Zamay, Anna S

    2015-01-01

    Circulating tumor cells (CTCs) are rare cells and valuable clinical markers of prognosis of metastasis formation and prediction of patient survival. Most CTC analyses are based on the antibody-based detection of a few epithelial markers; therefore miss an important portion of mesenchymal cancer cells circulating in blood. In this work, we selected and identified DNA aptamers as specific affinity probes that bind to lung adenocarcinoma cells derived from postoperative tissues. The unique feature of our selection strategy is that aptamers are produced for lung cancer cell biomarkers in their native state and conformation without previous knowledge of the biomarkers. The aptamers did not bind to normal lung cells and lymphocytes, and had very low affinity to A549 lung adenocarcinoma culture. We applied these aptamers to detect CTCs, apoptotic bodies, and microemboli in clinical samples of peripheral blood of lung cancer and metastatic lung cancer patients. We identified aptamer-associated protein biomarkers for lung cancer such as vimentin, annexin A2, annexin A5, histone 2B, neutrophil defensin, and clusterin. Tumor-specific aptamers can be produced for individual patients and synthesized many times during anticancer therapy, thereby opening up the possibility of personalized diagnostics. PMID:26061649

  5. BOK displays cell death-independent tumor suppressor activity in non-small-cell lung carcinoma.

    Science.gov (United States)

    Moravcikova, Erika; Krepela, Evzen; Donnenberg, Vera S; Donnenberg, Albert D; Benkova, Kamila; Rabachini, Tatiana; Fernandez-Marrero, Yuniel; Bachmann, Daniel; Kaufmann, Thomas

    2017-11-15

    As the genomic region containing the Bcl-2-related ovarian killer (BOK) locus is frequently deleted in certain human cancers, BOK is hypothesized to have a tumor suppressor function. In the present study, we analyzed primary non-small-cell lung carcinoma (NSCLC) tumors and matched lung tissues from 102 surgically treated patients. We show that BOK protein levels are significantly downregulated in NSCLC tumors as compared to lung tissues (p < 0.001). In particular, we found BOK downregulation in NSCLC tumors of grades two (p = 0.004, n = 35) and three (p = 0.031, n = 39) as well as in tumors with metastases to hilar (pN1) (p = 0.047, n = 31) and mediastinal/subcarinal lymph nodes (pN2) (p = 0.021, n = 18) as opposed to grade one tumors (p = 0.688, n = 7) and tumors without lymph node metastases (p = 0.112, n = 51). Importantly, in lymph node-positive patients, BOK expression greater than the median value was associated with longer survival (p = 0.002, Mantel test). Using in vitro approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGFβ-induced migration and epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma-derived A549 cells. We have identified epigenetic mechanisms, in particular BOK promoter methylation, as an important means to silence BOK expression in NSCLC cells. Taken together, our data point toward a novel mechanism by which BOK acts as a tumor suppressor in NSCLC by inhibiting EMT. Consequently, the restoration of BOK levels in low-BOK-expressing tumors might favor the overall survival of NSCLC patients. © 2017 UICC.

  6. Pancoast tumor or lung tumor upper groove . Case report and literature review

    Directory of Open Access Journals (Sweden)

    R. Puma

    2015-04-01

    Full Text Available Lung cancer is the leading cause of cancer mortality in the world, both men and women. A 75% of patients at diagnosis have some degree of cough, hemoptysis and dyspnea as initial symptoms. Pancoast tumor or superior pulmonary sulcus tumor represents less than 5% of all bronchogenic carcinomas. They are located at the apex of the lung and is mainly characterized by invasion by contiguity of thoracic outlet structures and different from the usual signosintomatología: shoulder pain and / or the ipsilateral arm. We present the case of a male patient of 63 years after attend different services (such as orthopedics, neurology, and speech therapy was diagnosed with Pancoast tumor biopsy of cervical lymphadenopathy. The diagnosis of Pancoast tumor should be suspected at the persistence painful shoulder syndrome in patients over 60 years with a history of smoking. The usual clinical presentation of this type of lung cancer unnecessarily delaying diagnosis and correct treatment.

  7. Lung toxicity and tumor promotion by hydroxylated derivatives of 2,6-di-tert-butyl-4-methylphenol (BHT) and 2-tert-butyl-4-methyl-6-iso-propylphenol: correlation with quinone methide reactivity.

    Science.gov (United States)

    Kupfer, Rene; Dwyer-Nield, Lori D; Malkinson, Alvin M; Thompson, John A

    2002-08-01

    Acute pulmonary toxicity and tumor promotion by the food additive 2,6-di-tert-butyl-4-methylphenol (BHT) in mice are well documented. These effects have been attributed to either of two quinone methides, 2,6-di-tert-butyl-4-methylenecyclohexa-2,5-dienone (BHT-QM) formed through direct oxidation of BHT by pulmonary cytochrome P450 or a quinone methide formed by hydroxylation of a tert-butyl group of BHT (to form BHTOH) followed by oxidation of this metabolite to BHTOH-QM. BHTOH-QM is a more reactive electrophile compared to BHT-QM due to intramolecular interactions of the side-chain hydroxyl with the carbonyl oxygen. To further examine this bioactivation pathway, an analogue of BHTOH was prepared, 2-tert-butyl-6-(1'-hydroxy-1'-methyl)ethyl-4-methylphenol (BPPOH), that is structurally very similar to BHTOH but forms a quinone methide (BPPOH-QM) capable of more efficient intramolecular hydrogen bonding and, therefore, higher electrophilicity than BHTOH-QM. BPPOH-QM was synthesized and its reactivity with water, methanol, and glutathione determined to be >10-fold higher than that of BHTOH-QM. The conversions of BPPOH and BHTOH to quinone methides in lung microsomes from male BALB/cByJ mice were quantitatively similar, but in vivo the former was pneumotoxic at one-half of the dose required for the latter and one-eighth of the dose required for BHT, as determined by increased lung weight:body weight ratios following a single i.p. injection. Similar differences were found in the doses of BHT, BHTOH, or BPPOH required for tumor promotion after a single initiating dose of 3-methylcholanthrene followed by three weekly injections of the phenol. The downregulaton of calpain II, previously shown to accompany lung tumor promotion by BHT and BHTOH, also occurred with BPPOH. The correlation between biologic activities of these phenols and the reactivities of their corresponding quinone methides provides additional support for the role of BHTOH-QM as the principal metabolite

  8. Gamma knife radiosurgery for metastatic brain tumors from lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Serizawa, Toru; Ono, Junichi; Iuchi, Toshihiko [Chiba Cardiovascular Center, Ichihara (Japan). Chiba Cancer Center] (and others)

    2003-01-01

    The purpose of this retrospective study is to evaluate the effectiveness of gamma knife radiosurgery (GKS) alone for metastatic brain tumors from lung cancer. Two hundred thirty-one consecutive patients with metastatic brain tumors from lung cancer filling the following 4 criteria were analyzed for this study; no prior brain tumor treatment, 25 or fewer lesions, a maximum 5 tumors with diameter of 2 cm or more, no surgically inaccessible tumor 3 cm or greater in diameter. According to the same treatment protocol, large tumors ({>=} 3 cm) were surgically removed and all the other small lesions (<3 cm) were treated with GKS. New lesions were treated with repeated GKS. The tumor-progression-free, overall, neurological, lowered-QOL (quality of life)-free and new-lesion-free survivals were calculated with the Kaplan-Meier method. The poor prognostic factors for each survival were also analyzed with the Cox's proportional hazard model. The tumor control rate at 1 year was 96.5%. The estimated median overall survival time was 7.7 months. The first-year survival rates were 83.0% in neurological survival and 76.0% in lowered-QOL-free survival. The new-lesion-free survival at 1 year was 27.9%. Multivariate analysis revealed significant poor prognostic factors for neurological and lowered-QOL-free survivals were carcinomatous meningitis and >10 brain lesions. This study suggests the results of GKS for metastatic brain tumors from lung cancer are quite satisfactory considering prevention of neurological death and maintenance of QOL. But cases with carcinomatous meningitis and/or >10 brain lesions are not good candidates for GKS alone. (author)

  9. Radiographic characterization of primary lung tumors in 74 dogs.

    Science.gov (United States)

    Barrett, Laura E; Pollard, Rachel E; Zwingenberger, Allison; Zierenberg-Ripoll, Alexandra; Skorupski, Katherine A

    2014-01-01

    Primary pulmonary neoplasia is well recognized in dogs and prognosis depends upon the tumor type. The purpose of this retrospective study was to characterize the radiographic appearance of different primary lung tumors with the goal of establishing imaging criteria to separate the different types. Three-view thoracic radiographs of 74 dogs with histologically confirmed pulmonary anaplastic carcinoma (n = 2), adenocarcinoma (n = 31), bronchioalveolar carcinoma (n = 19), histiocytic sarcoma (n = 21), and squamous cell carcinoma (n = 1) were evaluated. Radiographs were assessed for tumor volume, affected lobe, location within lobe, overall pulmonary pattern, presence of cavitation, mineralization, air bronchograms, lymphadenomegaly, and pleural fluid. Histiocytic sarcomas were significantly larger than other tumor types (271 cm(3); P = 0.009) and most likely to be found in the left cranial (38%; 8/21) and right middle (43%; 9/21) lung lobes, whereas adenocarcinomas were most likely to be found in the left caudal (29%; 9/31) lung lobe. Fifty-seven percent (12/21) of histiocytic sarcomas had an internal air bronchogram. Findings indicate that a large mass in the periphery or affecting the whole lobe of the right middle or left cranial lung lobe with an internal air bronchogram is likely to be an histiocytic sarcoma.

  10. Capnocytophaga Lung Abscess in a Patient with Metastatic Neuroendocrine Tumor

    OpenAIRE

    Thirumala, Raghu; Rappo, Urania; Babady, N. Esther; Kamboj, Mini; Chawla, Mohit

    2012-01-01

    Capnocytophaga species are known commensals of the oral cavity of humans and animals (mainly dogs and cats) and are a rare cause of respiratory tract infections. We report a case of cavitary lung abscess caused by a Capnocytophaga species in a patient with a metastatic neuroendocrine tumor.

  11. A Genomics-Based Classification of Human Lung Tumors

    NARCIS (Netherlands)

    Seidel, Danila; Zander, Thomas; Heukamp, Lukas C.; Peifer, Martin; Bos, Marc; Fernandez-Cuesta, Lynnette; Leenders, Frauke; Lu, Xin; Ansen, Sascha; Gardizi, Masyar; Nguyen, Chau; Berg, Johannes; Russell, Prudence; Wainer, Zoe; Schildhaus, Hans-Ulrich; Rogers, Toni-Maree; Solomon, Benjamin; Pao, William; Carter, Scott L.; Getz, Gad; Hayes, D. Neil; Wilkerson, Matthew D.; Thunnissen, Erik; Travis, William D.; Perner, Sven; Wright, Gavin; Brambilla, Elisabeth; Buettner, Reinhard; Wolf, Juergen; Thomas, Roman; Gabler, Franziska; Wilkening, Ines; Mueller, Christian; Dahmen, Ilona; Menon, Roopika; Koenig, Katharina; Albus, Kerstin; Merkelbach-Bruse, Sabine; Fassunke, Jana; Schmitz, Katja; Kuenstlinger, Helen; Kleine, Michaela; Binot, Elke; Querings, Silvia; Altmueller, Janine; Boessmann, Ingelore; Nuemberg, Peter; Schneider, Peter; Bogus, Magdalena; Buettner, Reinhard; Perner, Sven; Russell, Prudence; Thunnissen, Erik; Travis, William D.; Brambilla, Elisabeth; Soltermann, Alex; Moch, Holger; Brustugun, Odd Terje; Solberg, Steinar; Lund-Iversen, Marius; Helland, Aslaug; Muley, Thomas; Hoffmann, Hans; Schnabel, Philipp A.; Chen, Yuan; Groen, Herman; Timens, Wim; Sietsma, Hannie; Clement, Joachim H.; Weder, Walter; Saenger, Joerg; Stoelben, Erich; Ludwig, Corinna; Engel-Riedel, Walburga; Smit, Egbert; Heideman, Danille A. M.; Snijders, Peter J. F.; Nogova, Lucia; Sos, Martin L.; Mattonet, Christian; Toepelt, Karin; Scheffler, Matthias; Goekkurt, Eray; Kappes, Rainer; Krueger, Stefan; Kambartel, Kato; Behringer, Dirk; Schulte, Wolfgang; Galetke, Wolfgang; Randerath, Winfried; Heldwein, Matthias; Schlesinger, Andreas; Serke, Monika; Hekmat, Khosro; Frank, Konrad F.; Schnell, Roland; Reiser, Marcel; Huenerlituerkoglu, Ali-Nuri; Schmitz, Stephan; Meffert, Lisa; Ko, Yon-Dschun; Litt-Lampe, Markus; Gerigk, Ulrich; Fricke, Rainer; Besse, Benjamin; Brambilla, Christian; Lantuejoul, Sylvie; Lorimier, Philippe; Moro-Sibilot, Denis; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Field, John K.; Hyde, Russell; Validire, Pierre; Girard, Philippe; Muscarella, Lucia A.; Fazio, Vito M.; Hallek, Michael; Soria, Jean-Charles; Carter, Scott L.; Getz, Gad; Hayes, D. Neil; Wilkerson, Matthew D.; Achter, Viktor; Lang, Ulrich; Seidel, Danila; Zander, Thomas; Heukamp, Lukas C.; Peifer, Martin; Bos, Marc; Pao, William; Travis, William D.; Brambilla, Elisabeth; Buettner, Reinhard; Wolf, Juergen; Thomas, Roman K.

    2013-01-01

    We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic interventi

  12. Tumor Associated Neutrophils in Human Lung Cancer

    Science.gov (United States)

    2016-10-01

    Internet site(s) Penn Medicine News Site: ▪ http://www.uphs.upenn.edu/news/News_Releases/2016/07/eruslanov/ Technologies or techniques Nothing to...determine whether the tumor microenvironment stimu- lates trafficking of neutrophils, resting PBNs were assayed for tran- swell migration in the presence of...Ray, Neutrophilic inflammatory response and oxidative stress in premenopausal women chronically exposed to indoor air pollution from biomass burning

  13. GLB prevents tumor metastasis of Lewis lung carcinoma by inhibiting tumor adhesion actions

    Institute of Scientific and Technical Information of China (English)

    Yan PAN; Qian-liu SONG; Yan-hua LIN; Ning LU; He-ming YU; Xue-jun LI

    2005-01-01

    Aim: To investigate the inhibitory effect of a new compound of GLB on tumor metastasis in vivo and analyze its actions on tumor cell adhesion to clarify its mechanism.Methods: The effect of GLB on tumor metastasis was analyzed by Lewis lung carcinoma model.The pathological morphology of lung alveolar was evaluated by hematoxylin-eosin staining.The effect of GLB on the proliferation of human prostate cancer cell (PC-3M, with a high metastatic characteristic) was studied using the MTT method, and its actions on PC-3M cell adhesion to human umbilical vein endothelial cells (HUVEC) and laminin were analyzed in vitro.Lewis lung carcinoma metastasis significantly (P<0.05).Simultaneously, GLB could mitigate the damage of lung alveolar caused by metastasic tumor deposits.In vitro, GLB inhibited dramatically the adhesion of PC-3M cells to HUVEC (P<0.01) and laminin (P<0.05), without cytotoxic or anti-proliferative action on PC-3M cells.Conclusion: GLB has anti-tumor metastatic activity, which partly depends on its inhibition of tumor adhesion.

  14. Role of tumor suppressor genes in transplacental lung carcinogenesis.

    Science.gov (United States)

    Rollins, L A; Leone-Kabler, S; O'Sullivan, M G; Miller, M S

    1998-03-01

    Most human cancers involve multiple genetic changes, including activation of oncogenes such as Ki-ras-2 (Kras2) and inactivation of any one of a number of tumor suppressor genes such as p53 and members of the retinoblastoma (Rb) regulatory axis. As part of an ongoing project to determine how in utero exposure to chemical carcinogens affects the molecular pathogenesis of murine lung tumors, the p53 and p16Cdkn2a genes were analyzed by using paraffin-embedded lung tissues from mice treated transplacentally with 3-methylcholanthrene. Single-strand conformation polymorphism analysis of exons 5-8 of the p53 gene, as well as their flanking introns, demonstrated an absence of mutations at this gene locus. However, a genetic polymorphism was identified at nt 708 in intron 4 of the DBA/2 strain of mice 5 bp downstream of a 3' branching-point splice signal. Analysis of exons 1 and 2 of the Cdkn2a gene by single-strand conformation polymorphism and sequence analyses revealed mutations in exon 2 in 7% of the tumors examined. Tumor 23-1 exhibited a CAC-->TAC transition at nt 301 (His74-->Tyr74), and tumor 36-1 exhibited a GGG-->GAG transition at nucleotide 350 (Gly90-->Glu90). Northern blot analysis of 14 of the larger tumors showed a marked decrease in the levels of Rb RNA expression. Immunohistochemical analysis revealed a spectrum of pRb expression, with the smaller adenomas showing moderate numbers of nuclei with heterogeneous staining for pRb in contrast with a highly reduced or near-complete absence of expression in the nuclei of larger tumors with features of adenocarcinomas. The low incidence of mutations at tumor suppressor loci suggested that inactivation of tumor suppressor genes was a late event in murine lung tumor pathogenesis. The identification of both mutations at the Cdkn2a gene locus and reduced levels of Rb expression combined with previous studies demonstrating a high incidence of mutated Kras2 alleles in these tumors implies that alterations of the Rb

  15. Jaagsiekte sheep retrovirus proviral clone JSRV(JS7), derived from the JS7 lung tumor cell line, induces ovine pulmonary carcinoma and is integrated into the surfactant protein A gene.

    Science.gov (United States)

    DeMartini, J C; Bishop, J V; Allen, T E; Jassim, F A; Sharp, J M; de las Heras, M; Voelker, D R; Carlson, J O

    2001-05-01

    Ovine pulmonary carcinoma (OPC) is a contagious neoplasm of alveolar epithelial type II (ATII) or Clara cells caused by a type D/B chimeric retrovirus, jaagsiekte sheep retrovirus (JSRV). Here we report the isolation, sequencing, pathogenicity, and integration site of a JSRV provirus isolated from a sheep lung tumor cell line (JS7). The sequence of the virus was 93 to 99% identical to other JSRV isolates and contained all of the expected open reading frames. To produce virions and test its infectivity, the JS7 provirus (JSRV(JS7)) was cloned into a plasmid containing a cytomegalovirus promoter and transfected into 293T cells. After intratracheal inoculation with virions from concentrated supernatant fluid, JSRV-associated OPC lesions were found in one of four lambs, confirming that JSRV(JS7) is pathogenic. In JS7-cell DNA, the viral genome was inserted in the protein-coding region for the surfactant protein A (SP-A) gene, which is highly expressed in ATII cells, in an orientation opposite to the direction of transcription of the SP-A gene. No significant transcription was detected from either the viral or the SP-A gene promoter in the JS7 cell line at passage level 170. The oncogenic significance of the JSRV proviral insertion involving the SP-A locus in the JS7 tumor cell line is unknown.

  16. Dosimetry of chimeric TNT in lung tumor patients

    Institute of Scientific and Technical Information of China (English)

    CHEN Yangchun; CHEN Shaoliang; JU Dianwen; SHI Hongcheng; YAO Zhifeng

    2007-01-01

    The purpose of this study was to assess the absorbed dose of tumor and main critical organs in 131I labeled chimeric tumor necrotic treatment (chTNT). In 9 patients, a single intravenous dose of (29.6±3.7) MBq/kg was administered. Blood samples were drawn at different time intervals, and urine was collected for up to one week. Tissue distribution of 131I -chTNT was followed for up to one week by gamma camera imaging. Absorbed doses to the whole body and to normal organs were computed according to the MIRD scheme using Mirdose-3 software. S-factors for lung tumors were estimated by comparison with lungs of similar mass and position in the body. It was found that mean serum disappearance half time values for 131I-chTNT were (4.93±9.36) h and (61.7±21.2) h for α, β respectively,while that for whole body was(99±10) h. Mean urine biological clearance half time value was (90±10) h. The absorbed dose to tumor was (8.28±2.65) Gy, and the tumor-to-nontumor dose ratio was 3.95±1.55. And the mean effective dose to patients was (1.02±0.29) mSv/MBq.

  17. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer

    DEFF Research Database (Denmark)

    Knudsen, Mie Grunnet; Sorensen, J B

    2012-01-01

    significance" and "predictive significance", a search was carried out on PubMed. Exclusion criteria was articles never published in English, articles before 1981 and articles evaluating tumor markers in lung cancer not involving CEA. Initially 217 articles were found, and 34 were left after selecting those....... Interestingly, an overweight of low stage (stage I-II) disease and adenocarcinoma (AC) patients were observed in this group. The remaining 7 studies (6 serum, 1 plasma) contained an overweight of patients with squamous carcinoma (SQ). One study found evidence for that a tumor marker index (TMI), based...

  18. Fibrocytes Regulate Wilms Tumor 1-Positive Cell Accumulation in Severe Fibrotic Lung Disease.

    Science.gov (United States)

    Sontake, Vishwaraj; Shanmukhappa, Shiva K; DiPasquale, Betsy A; Reddy, Geereddy B; Medvedovic, Mario; Hardie, William D; White, Eric S; Madala, Satish K

    2015-10-15

    Collagen-producing myofibroblast transdifferentiation is considered a crucial determinant in the formation of scar tissue in the lungs of patients with idiopathic pulmonary fibrosis. Multiple resident pulmonary cell types and bone marrow-derived fibrocytes have been implicated as contributors to fibrotic lesions because of the transdifferentiation potential of these cells into myofibroblasts. In this study, we assessed the expression of Wilms tumor 1 (WT1), a known marker of mesothelial cells, in various cell types in normal and fibrotic lungs. We demonstrate that WT1 is expressed by both mesothelial and mesenchymal cells in idiopathic pulmonary fibrosis lungs but has limited or no expression in normal human lungs. We also demonstrate that WT1(+) cells accumulate in fibrotic lung lesions, using two different mouse models of pulmonary fibrosis and WT1 promoter-driven fluorescent reporter mice. Reconstitution of bone marrow cells into a TGF-α transgenic mouse model demonstrated that fibrocytes do not transform into WT1(+) mesenchymal cells, but they do augment accumulation of WT1(+) cells in severe fibrotic lung disease. Importantly, the number of WT1(+) cells in fibrotic lesions was correlated with severity of lung disease as assessed by changes in lung function, histology, and hydroxyproline levels in mice. Finally, inhibition of WT1 expression was sufficient to attenuate collagen and other extracellular matrix gene production by mesenchymal cells from both murine and human fibrotic lungs. Thus, the results of this study demonstrate a novel association between fibrocyte-driven WT1(+) cell accumulation and severe fibrotic lung disease. Copyright © 2015 by The American Association of Immunologists, Inc.

  19. The relationship between tumor markers and pulmonary embolism in lung cancer.

    Science.gov (United States)

    Xiong, Wei; Zhao, Yunfeng; Xu, Mei; Guo, Jian; Pudasaini, Bigyan; Wu, Xueling; Liu, Jinming

    2017-06-20

    Tumor markers (TMs) and D-Dimer are both hallmarks of severity and prognosis of lung cancer. Tumor markers could be related to pulmonary embolism (PE) in lung cancer. The number of abnormal tumor markers of lung cancer patients with pulmonary embolism (3.9 ± 1.1vs1.6 ± 0.6,P 0.005) was more than that in patients without pulmonary embolism. TMs panel (P trend tumor markers, TMs panel (OR5.98, P Tumor markers were compared between lung cancer patients complicated with pulmonary embolism and those without pulmonary embolism Then the correlation between each tumor marker as well as panel of combined TMs and D-Dimer as well as pulmonary embolism were analyzed for patients with pulmonary embolism. There is a relationship between tumor markers and pulmonary embolism in patients with lung cancer. The panel of combined tumor markers is a valuable diagnostic marker for pulmonary embolism in lung cancer.

  20. TU-CD-304-06: Using FFF Beams Improves Tumor Control in Radiotherapy of Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Vassiliev, O [Mary Bird Perkins Cancer Center, Baton Rouge, LA (United States); Wang, H [UT MD Anderson Cancer Center, Houston, TX (United States)

    2015-06-15

    Purpose: Electron disequilibrium at the lung-tumor interface results in an under-dosage of tumor regions close to its surface. This under-dosage is known to be significant and can compromise tumor control. Previous studies have shown that in FFF beams, disequilibrium effects are less pronounced, which is manifested in an increased skin dose. In this study we investigate the improvement in tumor dose coverage that can be achieved with FFF beams. The significance of this improvement is evaluated by comparing tumor control probabilities of FFF beams and conventional flattened beams. Methods: The dosimetric coverage was investigated in a virtual phantom representing the chest wall, lung tissue and the tumor. A range of tumor sizes was investigated, and two tumor locations – central and adjacent to the chest wall. Calculations were performed with BEAMnrc Monte Carlo code. Parallel-opposed and multiple coplanar 6-MV beams were simulated. The tumor control probabilities were calculated using the logistic model with parameters derived from clinical data for non-small lung cancer patients. Results: FFF beams were not entirely immune to disequilibrium effects. They nevertheless consistently delivered more uniform dose distribution throughout the volume of the tumor, and eliminated up to ∼15% of under-dosage in the most affected by disequilibrium 1-mm thick surface region of the tumor. A voxel-by-voxel comparison of tumor control probabilities between FFF and conventional flattened beams showed an advantage of FFF beams that, depending on the set up, was from a few to ∼9 percent. Conclusion: A modest improvement in tumor control probability on the order of a few percent can be achieved by replacing conventional flattened beams with FFF beams. However, given the large number of lung cancer patients undergoing radiotherapy, these few percent can potentially prevent local tumor recurrence for a significant number of patients.

  1. Evaluation of lung tumor motion management in radiation therapy with dynamic MRI

    Science.gov (United States)

    Park, Seyoun; Farah, Rana; Shea, Steven M.; Tryggestad, Erik; Hales, Russell; Lee, Junghoon

    2017-03-01

    Surrogate-based tumor motion estimation and tracing methods are commonly used in radiotherapy despite the lack of continuous real time 3D tumor and surrogate data. In this study, we propose a method to simultaneously track the tumor and external surrogates with dynamic MRI, which allows us to evaluate their reproducible correlation. Four MRIcompatible fiducials are placed on the patient's chest and upper abdomen, and multi-slice 2D cine MRIs are acquired to capture the lung and whole tumor, followed by two-slice 2D cine MRIs to simultaneously track the tumor and fiducials, all in sagittal orientation. A phase-binned 4D-MRI is first reconstructed from multi-slice MR images using body area as a respiratory surrogate and group-wise registration. The 4D-MRI provides 3D template volumes for different breathing phases. 3D tumor position is calculated by 3D-2D template matching in which 3D tumor templates in 4D-MRI reconstruction and the 2D cine MRIs from the two-slice tracking dataset are registered. 3D trajectories of the external surrogates are derived via matching a 3D geometrical model to the fiducial segmentations on the 2D cine MRIs. We tested our method on five lung cancer patients. Internal target volume from 4D-CT showed average sensitivity of 86.5% compared to the actual tumor motion for 5 min. 3D tumor motion correlated with the external surrogate signal, but showed a noticeable phase mismatch. The 3D tumor trajectory showed significant cycle-to-cycle variation, while the external surrogate was not sensitive enough to capture such variations. Additionally, there was significant phase mismatch between surrogate signals obtained from fiducials at different locations.

  2. Human Organotypic Lung Tumor Models: Suitable For Preclinical 18F-FDG PET-Imaging

    OpenAIRE

    Fecher, David; Hofmann, Elisabeth; Buck, Andreas; BUNDSCHUH, RALPH; Nietzer, Sarah; Dandekar, Gudrun; Walles, Thorsten; Walles, Heike; Lückerath, Katharina; Steinke, Maria

    2016-01-01

    Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. ...

  3. IL-6 Receptor Is a Possible Target against Growth of Metastasized Lung Tumor Cells in the Brain

    Directory of Open Access Journals (Sweden)

    Mami Noda

    2012-12-01

    Full Text Available In the animal model of brain metastasis using human lung squamous cell carcinoma-derived cells (HARA-B inoculated into the left ventricle of the heart of nude mice, metastasized tumor cells and brain resident cells interact with each other. Among them, tumor cells and astrocytes have been reported to stimulate each other, releasing soluble factors from both sides, subsequently promoting tumor growth significantly. Among the receptors for soluble factors released from astrocytes, only IL-6 receptor (IL-6R on tumor cells was up-regulated during the activation with astrocytes. Application of monoclonal antibody against human IL-6R (tocilizumab to the activated HARA-B cells, the growth of HARA-B cells stimulated by the conditioned medium of HARA-B/astrocytes was significantly inhibited. Injecting tocilizumab to animal models of brain metastasis starting at three weeks of inoculation of HARA-B cells, two times a week for three weeks, significantly inhibited the size of the metastasized tumor foci. The up-regulated expression of IL-6R on metastasized lung tumor cells was also observed in the tissue from postmortem patients. These results suggest that IL-6R on metastasized lung tumor cells would be a therapeutic target to inhibit the growth of the metastasized lung tumor cells in the brain.

  4. The roles of tumor-derived exosomes in cancer pathogenesis.

    Science.gov (United States)

    Yang, Chenjie; Robbins, Paul D

    2011-01-01

    Exosomes are endosome-derived, 30-100 nm small membrane vesicles released by most cell types including tumor cells. They are enriched in a selective repertoire of proteins and nucleic acids from parental cells and are thought to be actively involved in conferring intercellular signals. Tumor-derived exosomes have been viewed as a source of tumor antigens that can be used to induce antitumor immune responses. However, tumor-derived exosomes also have been found to possess immunosuppressive properties and are able to facilitate tumor growth, metastasis, and the development of drug resistance. These different effects of tumor-derived exosomes contribute to the pathogenesis of cancer. This review will discuss the roles of tumor-derived exosomes in cancer pathogenesis, therapy, and diagnostics.

  5. The Roles of Tumor-Derived Exosomes in Cancer Pathogenesis

    Directory of Open Access Journals (Sweden)

    Chenjie Yang

    2011-01-01

    Full Text Available Exosomes are endosome-derived, 30–100 nm small membrane vesicles released by most cell types including tumor cells. They are enriched in a selective repertoire of proteins and nucleic acids from parental cells and are thought to be actively involved in conferring intercellular signals. Tumor-derived exosomes have been viewed as a source of tumor antigens that can be used to induce antitumor immune responses. However, tumor-derived exosomes also have been found to possess immunosuppressive properties and are able to facilitate tumor growth, metastasis, and the development of drug resistance. These different effects of tumor-derived exosomes contribute to the pathogenesis of cancer. This review will discuss the roles of tumor-derived exosomes in cancer pathogenesis, therapy, and diagnostics.

  6. Anti-tumor activities of CIK cells derived from lymph nodes of lung cancer patients%肺癌患者淋巴结内培养CIK细胞的抑瘤实验和临床前期研究

    Institute of Scientific and Technical Information of China (English)

    滕家俊; 周严; 刘显勋; 韩宝惠; 钟华

    2015-01-01

    Background and purpose:Cytokine-induced killer (CIK) has both the advantages of T lympho-cytes’ powerful anti-tumor activity and NK cells’ tumor killing capacity without MHC restriction. It could directly kill tumor cells, regulate and enhance immune function, without damaging the structure and functions of the immune sys-tem. Its effects on the treatment of malignant solid tumors has been widely recognized. This study aimed to evaluate the anti-proliferation effects of CIK cells obtained and cultivated from lung cancer patients’ lymph nodes. Meanwhile, the safety of clinical transfusion was observed.Methods:The peripheral blood and lymph nodes of 6 surgery patients with lung cancer from Shanghai Chest Hospital were used to cultivate CIK cells for 14 days. The phenotypes of CIK cells were detected by lfow cytometry. The anti-proliferation activities of CIK cells on A549 lung cancer cells were detected by CCK8 assay. The morphological changes of CIK cells were observed by invert microscope. The expression of CEA level and adverse events were evaluated after CIK transfusion.Results:The proportion of CD3+CD56+T lymphocyte in two groups were both more than 30%. The CCK8 assay showed that the suppression rate of lymph nodes group was higher than that of peripheral blood group at each effect/target ratio(P<0.05). The adverse effect of CIK transfusion was mild and tolerable. The expression of CEA level decreased in patients.Conclusion:Lymph nodes of surgery patients with lung cancer can be used for cultivation of CIK cells. The anti-tumor activity of CIK isolated from lymph nodes is better than that of CIK cells cultivated from peripheral blood. Preclinical experiments showed high safety.%背景与目的:细胞因子诱导的杀伤细胞(cytokine-induced killer cells,CIK)兼具T淋巴细胞强大的杀瘤活性与自然杀伤细胞(natural killer cell,NK)杀瘤的非MHC限制性。CIK细胞可直接杀伤肿瘤细胞,调节并增强免疫功能,同时不

  7. 基于PDTX模型研究原发性肺癌顺铂耐药与ERCC1 IGFBP5表达水平的关系%Relationship between cisplatin resistance of primary lung cancer and expression levels of ERCC1 and IGFBP5 in patient-derived tumor xenograft models

    Institute of Scientific and Technical Information of China (English)

    展丙香; 程龙强; 罗朋; 章菊; 王保龙

    2015-01-01

    Objective:To establish a lung cancer model of patient-derived tumor xenografts (PDTX) and to explore the relation-ship between primary cisplatin resistance and ERCC1 and IGFBP5 expression levels. Methods:Lung cancer tissues from 84 patients who underwent surgery were collected and implanted into nude mice. Patient characteristics for the first generation xenografts that were and were not engrafted were compared. Passage 3 xenografts were treated with cisplatin. The expression levels of ERCC1 and IGFBP5 in cisplatin-resistant and cisplatin-sensitive groups were detected using immunohistochemistry assay. Results:The model success rates were 32.14%(27/84) in first-generation xenografts, 88.89%(24/27) in second-generation xenografts, and 95.83%(23/24) in third-gener-ation xenografts. The tumorigenicity of first-generation xenografts was correlated with size, differentiation, clinical stage, and histologi-cal type. PDTX tumors maintain the histological type of parental tumors through serial passage in nude mice. ERCC1 expression level was significantly higher in the cisplatin-resistant group than in the cisplatin-sensitive group, whereas the IGFBP5 expression level was lower in the cisplatin-resistant group than in the cisplatin-sensitive group. Conclusion:Lung cancer PDTX models were successfully es-tablished, and histological characteristics of the primary cancers were retained. Therefore, the models may serve a function in preclini-cal research of lung tumor biology and for exploring the drug resistance mechanism of tumors. The cisplatin resistance of primary lung cancer may be correlated with the expression level of ERCC1 and IGFBP5 in lung carcinoma.%目的:构建PDTX(patient-derived tumor xenografts)肺癌模型,探索ERCC1、IGFBP5的表达水平与原发性肺癌顺铂耐药的关系.方法:取新鲜切除的84例肺癌组织移植于裸鼠(BALB/c)的皮下,构建PDTX模型,分析一代成瘤率与临床病理参数关系.三代移植瘤接受顺铂化疗,采

  8. Laser fluorescence bronchoscope for localization of occult lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Profio, A.E.; Doiron, D.R.; King, E.G.

    1979-11-01

    A system for imaging occult bronchogenic carcinoma by the fluorescence of previously-injected, tumor-specific compound hematoporphyrin-derivative has been assembled and successfully used to locate a tumor l mm thick. The violet excitation source is a krypton ion laser coupled to fused quartz fiber light conductor. An electrostatic image intensifier attached to a standard flexible fiberoptic bronchoscope provides a bright image even at relatively low irradiance. A red secondary filter rejects most reflected background and autofluorescence. Sensitivity and contrast capability of the system should permit detection of a tumor less than 0.1 mm thick.

  9. Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer.

    Science.gov (United States)

    Nurwidya, Fariz; Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal

    2016-09-01

    Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer.

  10. Interfraction variation in lung tumor position with abdominal compression during stereotactic body radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Mampuya, Wambaka Ange; Nakamura, Mitsuhiro; Matsuo, Yukinori; Ueki, Nami; Iizuka, Yusuke; Monzen, Hajime; Mizowaki, Takashi; Hiraoka, Masahiro [Department of Radiation Oncology and Image-applied Therapy, Graduate School of Medicine, Kyoto University, Kyoto 606-8507 (Japan); Fujimoto, Takahiro; Yano, Shinsuke [Division of Clinical Radiology Service, Kyoto University Hospital, Kyoto 606-8507 (Japan)

    2013-09-15

    Purpose: To assess the effect of abdominal compression on the interfraction variation in tumor position in lung stereotactic body radiotherapy (SBRT) using cone-beam computed tomography (CBCT) in a larger series of patients with large tumor motion amplitude.Methods: Thirty patients with lung tumor motion exceeding 8 mm who underwent SBRT were included in this study. After translational and rotational initial setup error was corrected based on bone anatomy, CBCT images were acquired for each fraction. The residual interfraction variation was defined as the difference between the centroid position of the visualized target in three dimensions derived from CBCT scans and those derived from averaged intensity projection images. The authors compared the magnitude of the interfraction variation in tumor position between patients treated with [n= 16 (76 fractions)] and without [n= 14 (76 fractions)] abdominal compression.Results: The mean ± standard deviation (SD) of the motion amplitude in the longitudinal direction before abdominal compression was 19.9 ± 7.3 (range, 10–40) mm and was significantly (p < 0.01) reduced to 12.4 ± 5.8 (range, 5–30) mm with compression. The greatest variance of the interfraction variation with abdominal compression was observed in the longitudinal direction, with a mean ± SD of 0.79 ± 3.05 mm, compared to −0.60 ± 2.10 mm without abdominal compression. The absolute values of the 95th percentile of the interfraction variation for one side in each direction were 3.97/6.21 mm (posterior/anterior), 4.16/3.76 mm (caudal/cranial), and 2.90/2.32 mm (right/left) without abdominal compression, and 2.14/5.03 mm (posterior/anterior), 3.93/9.23 mm (caudal/cranial), and 2.37/5.45 mm (right/left) with abdominal compression. An absolute interfraction variation greater than 5 mm was observed in six (9.2%) fractions without and 13 (17.1%) fractions with abdominal compression.Conclusions: Abdominal compression was effective for reducing the amplitude

  11. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors.

    Science.gov (United States)

    Dorantes-Heredia, Rita; Ruiz-Morales, José Manuel; Cano-García, Fernando

    2016-08-01

    Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3-15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuron-specific enolase.

  12. Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients

    Science.gov (United States)

    Prado-Garcia, Heriberto; Romero-Garcia, Susana; Aguilar-Cazares, Dolores; Meneses-Flores, Manuel; Lopez-Gonzalez, Jose Sullivan

    2012-01-01

    Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer. PMID:23118782

  13. Tumor-Induced CD8+ T-Cell Dysfunction in Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Heriberto Prado-Garcia

    2012-01-01

    Full Text Available Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.

  14. Expression of the p16{sup INK4a} tumor suppressor gene in rodent lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Swafford, D.S.; Tesfaigzi, J.; Belinsky, S.A.

    1995-12-01

    Aberrations on the short arm of chromosome 9 are among the earliest genetic changes in human cancer. p16{sup INK4a} is a candidate tumor suppressor gene that lies within human 9p21, a chromosome region associated with frequent loss of heterozygosity in human lung tumors. The p16{sup INK4a} protein functions as an inhibitor of cyclin D{sub 1}-dependent kinases that phosphorylate the retinoblastoma (Rb) tumor suppressor gene product enabling cell-cycle progression. Thus, overexpression of cyclin D{sub 1}, mutation of cyclin-dependent kinase genes, or loss of p16{sup INK4a} function, can all result in functional inactivation of Rb. Inactivation of Rb by mutation or deletion can result in an increase in p16{sup INK4a} transcription, suggesting that an increased p16{sup INK4a} expression in a tumor cell signals dysfunction of the pathway. The p16{sup (INK4a)} gene, unlike some tumor suppressor genes, is rarely inactivated by mutation. Instead, the expression of this gene is suppressed in some human cancers by hypermethylation of the CpG island within the first exon or by homozygous deletion: 686. Chromosome losses have been observed at 9p21 syntenic loci in tumors of the mouse and rat, two species often used as animal models for pulmonary carcinogenesis. Expression of p16{sup INK4a} is lost in some mouse tumor cell lines, often due to homozygous deletion. These observations indicate that p16{sup INK4a} dysfunction may play a role in the development of neoplasia in rodents as well as humans. The purpose of the current investigation was to define the extent to which p16{sup INK4a} dysfunction contributes to the development of rodent lung tumors and to determine the mechanism of inactivation of the gene. There is no evidence to suggest a loss of function of the p16{sup INK4a} tumor suppressor gene in these primary murine lung tumors by mutation, deletion, or methylation.

  15. KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer.

    Science.gov (United States)

    Yu, T; Chen, X; Zhang, W; Liu, J; Avdiushko, R; Napier, D L; Liu, A X; Neltner, J M; Wang, C; Cohen, D; Liu, C

    2016-02-01

    Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifen-induced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras(LSL-G12D/+);Klf4(fl/fl) mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

  16. Uncommon of the uncommon: Malignant Perivascular epithelioid cell tumor of the lung

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Hyun Ju; Lee, Ho Yun; Han, Joung Ho; Choi, Yong Soo; Lee, Kyung Soo [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2013-08-15

    A perivascular epithelioid cell (PEC) tumor is a rare mesenchymal tumor characterized by abundant cytoplasmic Periodic acid-Schiff positive glycogen (also called sugar tumor or clear cell tumor of the lung for this characteristic) and is mostly benign. We report a case of a 63-year-old man who presented with an enlarging mass on chest radiograph. After a thorough workup, diagnosis of malignant pulmonary PEC tumor with lung to lung metastases was established. Herein, the difficulties of diagnosis and management we confronted are described.

  17. Video-Assisted Thoracoscopic Surgery in Patients With Clinically Resectable Lung Tumors

    Directory of Open Access Journals (Sweden)

    H. Sakai

    1996-01-01

    Full Text Available To investigate the feasibility of thoracoscopic resection, a pilot study was performed in patients with clinically resectable lung tumors. In 40 patients, Video-assisted thoracic surgery (VATS was performed because of suspicion of malignancy. There were 29 men and 11 women with a median age of 54.8 years (range 18 to 78. Preoperative indications were suspected lung cancer and tumor in 27 patients, assessment of tumor resectability in 7 patients, and probability of metastatic tumors in 6 patients. The final diagnoses in the 27 patients with suspected lung cancer were 12 primary lung cancers, 6 lung metastases, and 9 benign lesions. The success rates for VATS (no conversion to thoracotomy were 1 of 12 (8.3% for resectable stage I lung cancer, 8 of 12 (66.7% for metastatic tumors, and 9 of 9 (100% for benign tumors. With VATS, 6 of 7 patients (85.7%, possible stage III non-small cell lung cancer, an explorative thoracotomy with was avoided, significantly reducing morbidity. The reasons for conversion to thoracotomy were 1 oncological (N2 lymph node dissection and prevention of tumor spillage and 2 technical (inability to locate the nodule, central localization, no anatomical fissure, or poor lung function requiring full lung ventilation. The ultimate diagnoses were 19 lung cancers, 12 metastatic lung tumors, and 9 benign lung tumors. Our data show the limitations of VATS for malignant tumors in general use. These findings, together with the fact that experience in performing thoracoscopic procedures demonstrates a learning curve, may limit the use of thoracoscopic resection as a routine surgical procedure, especially when strict oncological rules are respected.

  18. Bone marrow-derived cells contribute to NDEA-induced lung squamous cell carcinoma.

    Science.gov (United States)

    Luo, Dan; Liu, Dengqun; Zhou, Xiangdong; Yang, Shiming; Tang, Chunlan; Liu, Guoxiang

    2013-02-01

    Bone marrow-derived stem cells (BMDCs) have the ability to differentiate into lung epithelial cells in response to damage; however, their role in squamous cell carcinoma (SCC) formation is unknown. This study aimed to determine whether BMDC-derived lung epithelial cells could contribute to SCC formation. A model of lung SCC induced with N-nitrosodiethylamine (NDEA) in recipient female mice transplanted with green fluorescent protein (GFP)-positive BMDCs from male donors was established. Incorporation of BMDCs in lung tissue was determined using immunohistochemistry and immunofluorescence to detect GFP expression and fluorescence in situ hybridization to Y chromosomes. BMDC appeared at three stages of lung SCC progression: metaplasia, dysplasia, and carcinoma. There was a significantly higher proportion of GFP-positive (GFP(+)) cells within SCC than was found in metaplasia and dysplasia 16 weeks post-transplantation (both P cells in SCC were pancytokeratin-positive (PCK(+)) epithelial cells, and some exhibited proliferative activity as determined by Ki67 staining (9.7 ± 3.92 %). The presence of GFP(+)Ki67(+)PCK(+) cells within SCC nests suggested that some donor BMDCs differentiated into proliferating epithelial cells. Finally, analysis of p63 expression, a marker of SCC cells, indicated that the presence of GFP(+)p63(+) cells (green) in inner parts of the SCC. These findings strongly suggest that BMDC-derived lung epithelial cells could participate in lung SCC formation and partially contribute to tumor growth, which might have significant potential implications for both clinical cancer therapy using BMDCs.

  19. Tumor-derived circulating endothelial cell clusters in colorectal cancer.

    KAUST Repository

    Cima, Igor

    2016-06-29

    Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease.

  20. Limited Restoration of Cystic Fibrosis Lung Epithelium In Vivo with Adult Bone Marrow–derived Cells

    OpenAIRE

    Loi, Roberto; Beckett, Travis; Goncz, Kaarin K.; Suratt, Benjamin T.; Weiss, Daniel J.

    2005-01-01

    Rationale: Recent literature suggests that adult bone marrow–derived cells can localize to lung and acquire immunophenotypic characteristics of lung epithelial cells. We speculated this might be a potential therapeutic approach for correcting defective lung epithelium in cystic fibrosis.

  1. SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jia-lei [Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Lu, Fan-zhen [Department of Thoracic Surgery, The Huadong Hospital, Fudan University, Shanghai 200040 (China); Shen, Xiao-Yong, E-mail: shengxiaoyong_sh@163.com [Department of Thoracic Surgery, The Huadong Hospital, Fudan University, Shanghai 200040 (China); Wu, Yun, E-mail: WuYun_hd@163.com [Department of Thoracic Surgery, The Huadong Hospital, Fudan University, Shanghai 200040 (China); Zhao, Li-ting [Department of Thoracic Surgery, The Huadong Hospital, Fudan University, Shanghai 200040 (China)

    2014-12-12

    Highlights: • SAMHD1 expression level is down regulated in lung adenocarcinoma. • The promoter of SAMHD1 is methylated in lung adenocarcinoma. • Over expression of SAMHD1 inhibits the proliferation of lung cancer cells. - Abstract: The function of dNTP hydrolase SAMHD1 as a viral restriction factor to inhibit the replication of several viruses in human immune cells was well established. However, its regulation and function in lung cancer have been elusive. Here, we report that SAMHD1 is down regulated both on protein and mRNA levels in lung adenocarcinoma compared to adjacent normal tissue. We also found that SAMHD1 promoter is highly methylated in lung adenocarcinoma, which may inhibit its gene expression. Furthermore, over expression of the SAMHD1 reduces dNTP level and inhibits the proliferation of lung tumor cells. These results reveal the regulation and function of SAMHD1 in lung cancer, which is important for the proliferation of lung tumor cells.

  2. Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells.

    Science.gov (United States)

    Damelin, Marc; Geles, Kenneth G; Follettie, Maximillian T; Yuan, Ping; Baxter, Michelle; Golas, Jonathon; DiJoseph, John F; Karnoub, Maha; Huang, Shuguang; Diesl, Veronica; Behrens, Carmen; Choe, Sung E; Rios, Carol; Gruzas, Janet; Sridharan, Latha; Dougher, Maureen; Kunz, Arthur; Hamann, Philip R; Evans, Deborah; Armellino, Douglas; Khandke, Kiran; Marquette, Kimberly; Tchistiakova, Lioudmila; Boghaert, Erwin R; Abraham, Robert T; Wistuba, Ignacio I; Zhou, Bin-Bing S

    2011-06-15

    Poorly differentiated tumors in non-small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody-drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.

  3. The anoikis effector Bit1 displays tumor suppressive function in lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Xin Yao

    Full Text Available The mitochondrial Bit1 (Bcl-2 inhibitor of transcription 1 protein is a part of an apoptotic pathway that is uniquely regulated by integrin-mediated attachment. As an anoikis effector, Bit1 is released into the cytoplasm following loss of cell attachment and induces a caspase-independent form of apoptosis. Considering that anoikis resistance is a critical determinant of transformation, we hypothesized that cancer cells may circumvent the Bit1 apoptotic pathway to attain anchorage-independence and tumorigenic potential. Here, we provide the first evidence of the tumor suppressive effect of Bit1 through a mechanism involving anoikis induction in human lung adenocarcinoma derived A549 cells. Restitution of Bit1 in anoikis resistant A549 cells is sufficient to induce detachment induced-apoptosis despite defect in caspase activation and impairs their anchorage-independent growth. Conversely, stable downregulation of Bit1 in these cells significantly enhances their anoikis resistance and anchorage-independent growth. The Bit1 knockdown cells exhibit significantly enhanced tumorigenecity in vivo. It has been previously shown that the nuclear TLE1 corepressor is a putative oncogene in lung cancer, and we show here that TLE1 blocks Bit1 mediated anoikis in part by sequestering the pro-apoptotic partner of Bit1, the Amino-terminal Enhancer of Split (AES protein, in the nucleus. Taken together, these findings suggest a tumor suppressive role of the caspase-independent anoikis effector Bit1 in lung cancer. Consistent with its role as a tumor suppressor, we have found that Bit1 is downregulated in human non-small cell lung cancer (NSCLC tissues.

  4. The anoikis effector Bit1 displays tumor suppressive function in lung cancer cells.

    Science.gov (United States)

    Yao, Xin; Jennings, Scott; Ireland, Shubha Kale; Pham, Tri; Temple, Brandi; Davis, Mya; Chen, Renwei; Davenport, Ian; Biliran, Hector

    2014-01-01

    The mitochondrial Bit1 (Bcl-2 inhibitor of transcription 1) protein is a part of an apoptotic pathway that is uniquely regulated by integrin-mediated attachment. As an anoikis effector, Bit1 is released into the cytoplasm following loss of cell attachment and induces a caspase-independent form of apoptosis. Considering that anoikis resistance is a critical determinant of transformation, we hypothesized that cancer cells may circumvent the Bit1 apoptotic pathway to attain anchorage-independence and tumorigenic potential. Here, we provide the first evidence of the tumor suppressive effect of Bit1 through a mechanism involving anoikis induction in human lung adenocarcinoma derived A549 cells. Restitution of Bit1 in anoikis resistant A549 cells is sufficient to induce detachment induced-apoptosis despite defect in caspase activation and impairs their anchorage-independent growth. Conversely, stable downregulation of Bit1 in these cells significantly enhances their anoikis resistance and anchorage-independent growth. The Bit1 knockdown cells exhibit significantly enhanced tumorigenecity in vivo. It has been previously shown that the nuclear TLE1 corepressor is a putative oncogene in lung cancer, and we show here that TLE1 blocks Bit1 mediated anoikis in part by sequestering the pro-apoptotic partner of Bit1, the Amino-terminal Enhancer of Split (AES) protein, in the nucleus. Taken together, these findings suggest a tumor suppressive role of the caspase-independent anoikis effector Bit1 in lung cancer. Consistent with its role as a tumor suppressor, we have found that Bit1 is downregulated in human non-small cell lung cancer (NSCLC) tissues.

  5. Tumor-Induced Myeloid-Derived Suppressor Cells.

    Science.gov (United States)

    De Sanctis, Francesco; Bronte, Vincenzo; Ugel, Stefano

    2016-06-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous, immune-suppressive leukocyte population that develops systemically and infiltrates tumors. MDSCs can restrain the immune response through different mechanisms including essential metabolite consumption, reactive oxygen and nitrogen species production, as well as display of inhibitory surface molecules that alter T-cell trafficking and viability. Moreover, MDSCs play a role in tumor progression, acting directly on tumor cells and promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. Many biological and pharmaceutical drugs affect MDSC expansion and functions in preclinical tumor models and patients, often reversing host immune dysfunctions and allowing a more effective tumor immunotherapy.

  6. A GPU-based framework for modeling real-time 3D lung tumor conformal dosimetry with subject-specific lung tumor motion

    Energy Technology Data Exchange (ETDEWEB)

    Min Yugang; Santhanam, Anand; Ruddy, Bari H [University of Central Florida, FL (United States); Neelakkantan, Harini; Meeks, Sanford L [M D Anderson Cancer Center Orlando, FL (United States); Kupelian, Patrick A, E-mail: anand.santhanam@orlandohealth.co [Department of Radiation Oncology, University of California, Los Angeles, CA (United States)

    2010-09-07

    In this paper, we present a graphics processing unit (GPU)-based simulation framework to calculate the delivered dose to a 3D moving lung tumor and its surrounding normal tissues, which are undergoing subject-specific lung deformations. The GPU-based simulation framework models the motion of the 3D volumetric lung tumor and its surrounding tissues, simulates the dose delivery using the dose extracted from a treatment plan using Pinnacle Treatment Planning System, Phillips, for one of the 3DCTs of the 4DCT and predicts the amount and location of radiation doses deposited inside the lung. The 4DCT lung datasets were registered with each other using a modified optical flow algorithm. The motion of the tumor and the motion of the surrounding tissues were simulated by measuring the changes in lung volume during the radiotherapy treatment using spirometry. The real-time dose delivered to the tumor for each beam is generated by summing the dose delivered to the target volume at each increase in lung volume during the beam delivery time period. The simulation results showed the real-time capability of the framework at 20 discrete tumor motion steps per breath, which is higher than the number of 4DCT steps (approximately 12) reconstructed during multiple breathing cycles.

  7. Tumor-derived exosomes and their role in cancer progression

    Science.gov (United States)

    Whiteside, Theresa L

    2017-01-01

    Tumor cells actively produce, release and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon the contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as non-invasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation. PMID:27117662

  8. Tumor-Derived Exosomes and Their Role in Cancer Progression.

    Science.gov (United States)

    Whiteside, Theresa L

    2016-01-01

    Tumor cells actively produce, release, and utilize exosomes to promote tumor growth. Mechanisms through which tumor-derived exosomes subserve the tumor are under intense investigation. These exosomes are information carriers, conveying molecular and genetic messages from tumor cells to normal or other abnormal cells residing at close or distant sites. Tumor-derived exosomes are found in all body fluids. Upon contact with target cells, they alter phenotypic and functional attributes of recipients, reprogramming them into active contributors to angiogenesis, thrombosis, metastasis, and immunosuppression. Exosomes produced by tumors carry cargos that in part mimic contents of parent cells and are of potential interest as noninvasive biomarkers of cancer. Their role in inhibiting the host antitumor responses and in mediating drug resistance is important for cancer therapy. Tumor-derived exosomes may interfere with cancer immunotherapy, but they also could serve as adjuvants and antigenic components of antitumor vaccines. Their biological roles in cancer development or progression as well as cancer therapy suggest that tumor-derived exosomes are critical components of oncogenic transformation.

  9. Depletion of tumor associated macrophages slows the growth of chemically-induced mouse lung adenocarcinomas

    Directory of Open Access Journals (Sweden)

    Jason M. Fritz

    2014-11-01

    Full Text Available Chronic inflammation is a risk factor for lung cancer, and low dose aspirin intake reduces lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung tumors progress, and pulmonary macrophage programming changes within 2 weeks of carcinogen exposure. To examine how macrophages specifically affect lung tumor progression, they were depleted in mice bearing urethane-induced lung tumors using clodronate-encapsulated liposomes. Alveolar macrophage populations decreased to ≤ 50% of control levels after 4-6 weeks of liposomal clodronate treatment. Tumor burden decreased by 50% compared to vehicle treated mice, and tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of IGF-I, CXCL1, IL-6 and CCL2 diminished with clodronate liposome treatment. Tumor associated macrophages expressed markers of both M1 and M2 programming in vehicle and clodronate liposome treated mice. Mice lacking CCR2 (the receptor for macrophage chemotactic factor CCL2 had comparable numbers of alveolar macrophages and showed no difference in tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating lung cancer progression.

  10. Tumor lysis without syndrome in adenocarcinoma of the lung: Case report.

    Science.gov (United States)

    Chopra, Amit; Marak, Creticus; Alappan, Narendra Kumar; Alterman, Daniel; Shim, Chang

    2013-01-01

    Tumor lysis syndrome TLS is commonly seen during the treatment of rapidly proliferating. However TLS is rarely reported in Non-small cell Lung Cancer. This may because of low proliferative rate and chemo-resistant nature of NSCLC. We are reporting a case of tumor lysis without concomitant syndrome in a patient with adenocarcinoma of Lung.

  11. Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in lung cancer

    Directory of Open Access Journals (Sweden)

    Venditti Julio

    2010-09-01

    Full Text Available Abstract Background Changes in DNA methylation of crucial cancer genes including tumor suppressors can occur early in carcinogenesis, being potentially important early indicators of cancer. The objective of this study was to examine a multiplexed approach to assess the methylation of tumor suppressor genes as tumor stratification and clinical outcome prognostic biomarkers for lung cancer. Methods A multicandidate probe panel interrogated DNA for aberrant methylation status in 18 tumor suppressor genes in lung cancer using a methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA. Lung cancer cell lines (n = 7, and primary lung tumors (n = 54 were examined using MS-MLPA. Results Genes frequently methylated in lung cancer cell lines including SCGB3A1, ID4, CCND2 were found among the most commonly methylated in the lung tumors analyzed. HLTF, BNIP3, H2AFX, CACNA1G, TGIF, ID4 and CACNA1A were identified as novel tumor suppressor candidates methylated in lung tumors. The most frequently methylated genes in lung tumors were SCGB3A1 and DLC1 (both 50.0%. Methylation rates for ID4, DCL1, BNIP3, H2AFX, CACNA1G and TIMP3 were significantly different between squamous and adenocarcinomas. Methylation of RUNX3, SCGB3A1, SFRP4, and DLC1 was significantly associated with the extent of the disease when comparing localized versus metastatic tumors. Moreover, methylation of HTLF, SFRP5 and TIMP3 were significantly associated with overall survival. Conclusions MS-MLPA can be used for classification of certain types of lung tumors and clinical outcome prediction. This latter is clinically relevant by offering an adjunct strategy for the clinical management of lung cancer patients.

  12. Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema

    Energy Technology Data Exchange (ETDEWEB)

    Binkley, Michael S. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Shrager, Joseph B. [Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Leung, Ann N. [Department of Radiology, Stanford University School of Medicine, Stanford, California (United States); Popat, Rita [Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California (United States); Trakul, Nicholas [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Department of Radiation Oncology, University of Southern California Keck School of Medicine, Los Angeles, California (United States); Atwood, Todd F.; Chaudhuri, Aadel [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Maxim, Peter G. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Diehn, Maximilian, E-mail: Diehn@Stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States); Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California (United States); Loo, Billy W., E-mail: BWLoo@Stanford.edu [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California (United States)

    2014-09-01

    Purpose: Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema. Methods and Materials: We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3). Results: 27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, −0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, −3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r{sup 2}=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r{sup 2}=0.47, P<.0001). Conclusions: We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across

  13. Establishment and Quantitative Imaging of a 3D Lung Organotypic Model of Mammary Tumor Outgrowth

    OpenAIRE

    Martin, Michelle D.; Fingleton, Barbara; Lynch, Conor C.; Wells, Sam; McIntyre, J. Oliver; Piston, David W.; Matrisian, Lynn M.

    2008-01-01

    The lung is the second most common site of metastatic spread in breast cancer and experimental evidence has been provided in many systems for the importance of an organ-specific microenvironment in the development of metastasis. To better understand the interaction between tumor and host cells in this important secondary site, we have developed a 3D in vitro organotypic model of breast tumor metastatic growth in the lung. In our model, cells isolated from mouse lungs are placed in a collagen ...

  14. Expression profiles of metastatic brain tumor from lung adenocarcinomas on cDNA microarray.

    Science.gov (United States)

    Kikuchi, Takefumi; Daigo, Yataro; Ishikawa, Nobuhisa; Katagiri, Toyomasa; Tsunoda, Tatsuhiko; Yoshida, Seiichi; Nakamura, Yusuke

    2006-04-01

    Distant metastasis is one of the crucial parameters determining the type of treatment and prognosis of patients. Previous studies discovered important factors involved in multiple steps of metastasis, the precise mechanisms of metastasis still remain to be clarified. To identify genes associated with this complicated biological feature of cancer, we analyzed expression profiles of 16 metastatic brain tumors derived from primary lung adenocarcinoma (ADC) using cDNA microarray representing 23,040 genes. We applied bioinformatic algorithm to compare the expression data of these 16 brain metastatic loci with those of 37 primary NSCLCs including 22 ADCs, and found that metastatic tumor cells has very different characteristics of gene expression patterns from primary ones. Two hundred and forty-four genes that showed significantly different expression levels between the two groups included plasma membrane bounding proteins, cellular antigens, and cytoskeletal proteins that might play important roles in altering cell-cell communication, attachment, and cell motility, and enhance the metastatic ability of cancer cells. Our results provide valuable information for development of predictive markers as well as novel therapeutic target molecules for metastatic brain tumor of ADC of the lung.

  15. Failure of the cultivated mushroom (Agaricus bisporus) to induce tumors in the A/J mouse lung tumor model

    DEFF Research Database (Denmark)

    Pilegaard, Kirsten; Kristiansen, E.; Meyer, Otto A.

    1997-01-01

    We studied whether the cultivated mushroom (Agaricus bisporus) or 4-(carboxy)phenylhydrazine (CP) induce lung adenomas in the A/J mouse lung tumor model. For 26 weeks female mice were fed a semisynthetic diet where 11 or 22% of the diet was replaced by freeze-dried mushrooms. The intake...

  16. Organ heterogeneity of host-derived matrix metalloproteinase expression and its involvement in multiple-organ metastasis by lung cancer cell lines.

    Science.gov (United States)

    Shiraga, Minoru; Yano, Seiji; Yamamoto, Akihiko; Ogawa, Hirohisa; Goto, Hisatsugu; Miki, Toyokazu; Miki, Keisuke; Zhang, Helong; Sone, Saburo

    2002-10-15

    Cancer metastasis is tightly regulated by the interaction of tumor cells and host organ microenvironments. Matrix metalloproteinases (MMPs), produced by both tumor cells and host stromal cells, play a central role in tumor invasion and angiogenesis. We determined whether metastatic potential of lung cancer to multiple organs is dependent solely on the expression of MMPs by tumor cells, using two metastasis models of human lung cancer cell lines expressing various levels of MMPs and a MMP inhibitor (ONO-4817). In the lung metastasis model, tumor cells (PC14, PC14PE6, H226, A549) inoculated i.v. into nude or SCID mice metastasized only in the lung. In the multiple-organ metastasis model, tumor cells (RERF-LC-AI, SBC-3/DOX, H69/VP, which express low levels of MMPs) inoculated i.v. into natural killer cell-depleted SCID mice metastasized into the liver, kidneys, and systemic lymph nodes. Film in situ zymography analysis revealed that the nontumor parenchyma of the lung had no gelatinolytic activity, whereas gelatinolytic activity of the liver and kidney was high and low, respectively. In the lung metastasis model, gelatinolytic activity of lung nodules directly correlated with the in vitro expression of MMP-2 and MMP-9 by tumor cells. Inhibition of MMP activity by ONO-4817 suppressed lung metastasis by the cell lines that expressed MMPs, but not those that did not express MMP, via the inhibition of MMP activity of lung tumors. In the multiple-organ metastasis model, liver parenchyma, but not liver nodules, showed gelatinolytic activity. The MMP inhibition reduced metastasis to the liver, but not to the kidney or lymph nodes, via inhibition of MMP activity of liver parenchyma. These findings suggest that MMP expression varies among the host organ microenvironments and that stromal MMPs may promote metastasis of lung cancer. Therefore, antimetastatic effects based on MMP inhibition may be dependent on MMPs derived not only from tumor cells but also from organ

  17. Mesenchymal Stem Cell Derived Secretome and Extracellular Vesicles for Acute Lung Injury and Other Inflammatory Lung Diseases

    Science.gov (United States)

    Monsel, Antoine; Zhu, Ying-gang; Gudapati, Varun; Lim, Hyungsun; Lee, Jae W.

    2017-01-01

    Introduction Acute respiratory distress syndrome is a major cause of respiratory failure in critically ill patients. Despite extensive research into its pathophysiology, mortality remains high. No effective pharmacotherapy exists. Based largely on numerous preclinical studies, administration of mesenchymal stem or stromal cell (MSC) as a therapeutic for acute lung injury holds great promise, and clinical trials are currently underway. However, concern for the use of stem cells, specifically the risk of iatrogenic tumor formation, remains unresolved. Accumulating evidence now suggest that novel cell-free therapies including MSC-derived conditioned medium and extracellular vesicles released from MSCs might constitute compelling alternatives. Areas covered The current review summarizes the preclinical studies testing MSC conditioned medium and/or MSC extracellular vesicles as treatment for acute lung injury and other inflammatory lung diseases. Expert opinion While certain logistical obstacles limit the clinical applications of MSC conditioned medium such as the volume required for treatment, the therapeutic application of MSC extracellular vesicles remains promising, primarily due to ability of extracellular vesicles to maintain the functional phenotype of the parent cell. However, utilization of MSC extracellular vesicles will require large-scale production and standardization concerning identification, characterization and quantification. PMID:27011289

  18. [Autopsy case of von Recklinghausen's disease associated with lung cancer, gastrointestinal stromal tumor of the stomach, and duodenal carcinoid tumor].

    Science.gov (United States)

    Satoh, Miki; Wakabayashi, Osamu; Araya, Yoshikazu; Jinushi, Eisei; Yoshida, Fumiaki

    2009-09-01

    A 58-year-old man with von Recklinghausen's disease was admitted for further investigation of right chest pain. Chest X-ray revealed multiple emphysematous bullae in both lungs and a tumor shadow in the right upper lobe. Bronchofiberscopy was performed, but an adequate specimen was not obtained. The tumor was diagnosed as a non-small-cell lung cancer with direct invasion to the adjacent rib. Although chemotherapy and radiotherapy resulted in decrease in tumor size, the tumor subsequently increased in size and the patient died 14 months after the first admission. Autopsy revealed multiple emphysematous bullae, poorly differentiated adenosquamous cell carcinoma of the lung, gastrointestinal stromal tumor of the stomach, and duodenal carcinoid tumor. This case suggests the possibility that von Recklinghausen's disease associated with emphysematous bullae is a risk factor for lung cancer. It has also been suggested that the genetic abnormality responsible for von Recklinghausen's disease increases the risk for various types of malignancy. Although von Recklinghausen's disease is reportedly associated with various malignant tumors, it is quite rare for von Recklinghausen's disease to be associated with triple non-neurogenic tumors. Careful observation is mandatory for patients with von Recklinghausen's disease.

  19. Essential contribution of tumor-derived perlecan to epidermal tumor growth and angiogenesis

    DEFF Research Database (Denmark)

    Jiang, Xinnong; Multhaupt, Hinke; Chan, En

    2004-01-01

    As a major heparan sulfate proteoglycan (PG) in basement membranes, perlecan has been linked to tumor invasion, metastasis, and angiogenesis. Here we produced epidermal tumors in immunocompromised rats by injection of mouse RT101 tumor cells. Tumor sections stained with species-specific perlecan...... antibodies, together with immunoelectron microscopy, showed that perlecan distributed around blood vessels was of both host and tumor cell origin. Tumor-derived perlecan was also distributed throughout the tumor matrix. Blood vessels stained with rat-specific PECAM-1 antibody showed their host origin. RT101...... cells also expressed two other basement membrane heparan sulfate PGs, agrin and type XVIII collagen. Antisense targeting of perlecan inhibited tumor cell growth in vitro, while exogenous recombinant perlecan, but not heparin, restored the growth of antisense perlecan-expressing cells, suggesting...

  20. Aggressive fibromatosis (desmoid tumor) is derived from mesenchymal progenitor cells.

    Science.gov (United States)

    Wu, Colleen; Amini-Nik, Saeid; Nik-Amini, Saied; Nadesan, Puviindran; Stanford, William L; Alman, Benjamin A

    2010-10-01

    The cellular origins from which most tumors arise are poorly defined, especially in mesenchymal neoplasms. Aggressive fibromatosis, also known as desmoid tumor, is a locally invasive soft tissue tumor that has mesenchymal characteristics. We found that aggressive fibromatosis tumors express genes and cell surface markers characteristic of mesenchymal stem cells (MSC). In mice that are genetically predisposed to develop aggressive fibromatosis tumors (Apc(wt/1638N)), we found that the number of tumors formed was proportional to the number of MSCs present. Sca-1(-/-) mice, which develop fewer MSCs, were crossed with Apc(wt/1638N) mice. Doubly mutant mice deficient in Sca-1 developed substantially fewer aggressive fibromatosis tumors than wild-type (WT) littermates, but Sca-1 deficiency had no effect on the formation of epithelial-derived intestinal polyps. MSCs isolated from Apc(wt/1638N) mice (or mice expressing a stabilized form of β-catenin) induced aberrant cellular growth reminiscent of aggressive fibromatosis tumors after engraftment to immunocompromised mice, but WT cells and mature fibroblasts from the same animals did not. Taken together, our findings indicate that aggressive fibromatosis is derived from MSCs, and that β-catenin supports tumorigenesis by maintaining mesenchymal progenitor cells in a less differentiated state. Protecting this progenitor cell population might prevent tumor formation in patients harboring a germline APC mutation, where fibromatosis is currently the leading cause of mortality. © 2010 AACR.

  1. AB059. Mutant KRAS cells release tumor specific exosomes that create an immunosuppressive phenotype in lung tumor microenvironment

    Science.gov (United States)

    Petanidis, Savvas; Domvri, Kalliopi; Nikolaos, Zogas; Zarogoulidis, Paul; Kioseoglou, Efrosini; Anestakis, Doxakis; Zarogoulidis, Konstantinos; Salifoglou, Athanasios

    2016-01-01

    Background To investigate whether KRAS-secreted exosomal RNAs contribute to metastatic related-EMT phenotype, and their association with the hypoxic immunosuppressive phenotype in lung carcinoma. Methods Lung cancer patient tissues and mice were used for exosome isolation. Exosomal molecular characterization was performed using Immunofluorescence microscopy, microRNA analysis and immunohistochemistry. Results The findings reveal that mutant KRAS secreted exosomes contain high expression of oncogenic miR-31/miR-182/miR-205 which are associated with HIF-2a-related hypoxia. Furthermore, exosomal secretion in lung tumor microenvironment caused accumulation of IL-10, CTL-4 and IDO suggesting KRAS-dependent exosomal immunosuppression that drives EMT-related lung metastasis. Conclusions These findings suggest that KRAS secreted exosomal miRNAs can modulate the hypoxic immunosuppressive mechanism in lung tumor microenvironment and trigger the EMT-related metastatic niche.

  2. Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation.

    Science.gov (United States)

    Gennai, S; Monsel, A; Hao, Q; Park, J; Matthay, M A; Lee, J W

    2015-09-01

    The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells "rehabilitated" marginal donor lungs rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose-dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co-administration of microvesicles with anti-CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  3. Tumor stem cell assay for detecting metastases of human lung cancer.

    Directory of Open Access Journals (Sweden)

    Hirai,Shunkichi

    1983-04-01

    Full Text Available We applied a tumor stem cell assay using an enriched double-layered soft agar system for the detection of metastatic sites of lung cancer. Lung cancer colonies grew from 7 of 10 effusions cytologically positive for tumor cells and 7 of 10 bone marrow aspirates cytologically and histologically positive for tumor cells. Twenty-six of 29 bone marrow aspirates cytologically and histologically negative for tumor cells showed no colony growth. However, the remaining three bone marrow aspirates, which were obtained from patients with small cell lung cancer, formed colonies in soft agar. These results indicate that the tumor stem cell assay is useful for detecting metastatic sites of lung cancer.

  4. Chemoprevention with Acetylsalicylic Acid, Vitamin D and Calcium Reduces Risk of Carcinogen-induced Lung Tumors

    DEFF Research Database (Denmark)

    Pommergaard, Hans-Christian; Burcharth, Jakob; Rosenberg, J

    2013-01-01

    Background/Aim: Research has shown that chemoprevention may be effective against the development of lung cancer. The purpose of the present study was to evaluate the effect of oral chemoprevention in a mouse model of tobacco carcinogen-induced lung tumor.......Background/Aim: Research has shown that chemoprevention may be effective against the development of lung cancer. The purpose of the present study was to evaluate the effect of oral chemoprevention in a mouse model of tobacco carcinogen-induced lung tumor....

  5. v-Ha-ras oncogene insertion: A model for tumor progression of human small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mabry, M.; Nakagawa, Toshitaro; Nelkin, B.D.; McDowell, E.; Gesell, M.; Eggleston, J.C.; Casero, R.A. Jr.; Baylin, S.B.

    1988-09-01

    Small cell lung cancer (SCLC) manifests a range of phenotypes in culture that may be important in understanding its relationship to non-SCLCs and to tumor progression events in patients. Most SCLC-derived cell lines, termed classic SCLC lines, have properties similar to SCLC tumors in patients. To delineate further the relationships between these phenotypes and the molecular events involved, the authors inserted the v-Ha-ras gene in SCLC cell lines with (biochemical variant) and without (classic) an amplified c-myc gene. These two SCLC subtypes had markedly different phenotypic responses to similar levels of expression of v-Ha-ras RNA. No biochemical or morphologic changes were observed in classic SCLC cells. In contrast, in biochemical variant SCLC cells, v-Ha-ras expression induced features typical of large cell undifferentiated lung carcinoma. Expression of v-Ha-ras in biochemical variant SCLC cells directly demonstrates that important transitions can occur between phenotypes of human lung cancer cells and that these may play a critical role in tumor progression events in patients. The finding provide a model system to study molecular events involved in tumor progression steps within a series of related tumor types.

  6. Tumor-derived microparticles induce bone marrow-derived cell mobilization and tumor homing: a process regulated by osteopontin.

    Science.gov (United States)

    Fremder, Ella; Munster, Michal; Aharon, Anat; Miller, Valeria; Gingis-Velitski, Svetlana; Voloshin, Tali; Alishekevitz, Dror; Bril, Rotem; Scherer, Stefan J; Loven, David; Brenner, Benjamin; Shaked, Yuval

    2014-07-15

    Acute chemotherapy can induce rapid bone-marrow derived pro-angiogenic cell (BMDC) mobilization and tumor homing, contributing to tumor regrowth. To study the contribution of tumor cells to tumor regrowth following therapy, we focused on tumor-derived microparticles (TMPs). EMT/6 murine-mammary carcinoma cells exposed to paclitaxel chemotherapy exhibited an increased number of TMPs and significantly altered their angiogenic properties. Similarly, breast cancer patients had increased levels of plasma MUC-1(+) TMPs following chemotherapy. In addition, TMPs from cells exposed to paclitaxel induced higher BMDC mobilization and colonization, but had no increased effect on angiogenesis in Matrigel plugs and tumors than TMPs from untreated cells. Since TMPs abundantly express osteopontin, a protein known to participate in BMDC trafficking, the impact of osteopontin-depleted TMPs on BMDC mobilization, colonization, and tumor angiogenesis was examined. Although EMT/6 tumors grown in mice inoculated with osteopontin-depleted TMPs had lower numbers of BMDC infiltration and microvessel density when compared with EMT/6 tumors grown in mice inoculated with wild-type TMPs, no significant difference in tumor growth was seen between the two groups. However, when BMDCs from paclitaxel-treated mice were injected into wild-type EMT/6-bearing mice, a substantial increase in tumor growth and BMDC infiltration was detected compared to osteopontin-depleted EMT/6-bearing mice injected with BMDCs from paclitaxel-treated mice. Collectively, our results suggest that osteopontin expressed by TMPs play an important role in BMDC mobilization and colonization of tumors, but is not sufficient to enhance the angiogenic activity in tumors.

  7. Ovarian tumor-derived ectopic hyperprolactinemia.

    Science.gov (United States)

    Elms, Autumn F; Carlan, S J; Rich, Amy E; Cerezo, Lizardo

    2012-12-01

    To describe extreme hyperprolactinemia originating from a pituitary adenoma in the wall of an ovarian dermoid. This is a description of an unusual case and a review of ectopic prolactin production. Ectopic production of prolactin is a rare condition that has been reported in isolated organ system pathology including ovaries. An ovarian dermoid is a benign neoplasm that has the potential for active unregulated endocrine function. Hyperprolactinemia can result from functioning lactotrophs found in ovarian dermoids and can lead to clinical sequelae. Definitive treatment of the condition requires surgical removal of the functioning endocrine tissue. Extreme hyperprolactinemia caused by a pituitary tumor located within a dermoid has not been reported before. We present a case of profound hyperprolactinemia originating from a pituitary adenoma found in the wall of an ovarian dermoid and give a broad overview of the condition and literature. Ectopic prolactin production should always be considered in symptomatic patients found to have elevated serum levels and no findings on brain imaging.

  8. Malignant phyllodes tumor with chondro and osteosarcomatous differentiation and secondaries in lungs

    Directory of Open Access Journals (Sweden)

    Satya Narayan

    2014-01-01

    Full Text Available Phyllodes tumor is a rare breast tumor, with neoplastic epithelial and stromal components for 10 cm in size and firm in consistency. She underwent left mastectomy. The histopathology revealed a malignant phyllodes tumor with sarcomatous stromal overgrowth and heterogeneous chondro and osteosarcomatous differentiation. At 2 months after surgery, she reported to us with secondaries in bilateral lungs. We planned palliative chemotherapy in view of good general condition of the patient and lung metastasis. Chemotherapy included ifosfamide, adriamycin and cisplatin as per standard regimen every 3 weekly. After three cycles, her lung metastasis cleared completely. It was planned to continue same chemotherapy for six cycles.

  9. The Role of Neutrophil Myeloperoxidase in Models of Lung Tumor Development

    Energy Technology Data Exchange (ETDEWEB)

    Rymaszewski, Amy L.; Tate, Everett; Yimbesalu, Joannes P. [Department of Pharmacology and Toxicology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Gelman, Andrew E. [Department of Surgery, Washington University in St. Louis, St. Louis, MO 63130 (United States); Jarzembowski, Jason A. [Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Zhang, Hao; Pritchard, Kirkwood A. Jr. [Department of Surgery and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Vikis, Haris G., E-mail: hvikis@mcw.edu [Department of Pharmacology and Toxicology and MCW Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226 (United States)

    2014-05-09

    Chronic inflammation plays a key tumor-promoting role in lung cancer. Our previous studies in mice demonstrated that neutrophils are critical mediators of tumor promotion in methylcholanthrene (MCA)-initiated, butylated hydroxytoluene (BHT)-promoted lung carcinogenesis. In the present study we investigated the role of neutrophil myeloperoxidase (MPO) activity in this inflammation promoted model. Increased levels of MPO protein and activity were present in the lungs of mice administered BHT. Treatment of mice with N-acetyl lysyltyrosylcysteine amide (KYC), a novel tripeptide inhibitor of MPO, during the inflammatory stage reduced tumor burden. In a separate tumor model, KYC treatment of a Lewis Lung Carcinoma (LLC) tumor graft in mice had no effect on tumor growth, however, mice genetically deficient in MPO had significantly reduced LLC tumor growth. Our observations suggest that MPO catalytic activity is critical during the early stages of tumor development. However, during the later stages of tumor progression, MPO expression independent of catalytic activity appears to be required. Our studies advocate for the use of MPO inhibitors in a lung cancer prevention setting.

  10. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs.

    Science.gov (United States)

    Kirson, Eilon D; Giladi, Moshe; Gurvich, Zoya; Itzhaki, Aviran; Mordechovich, Daniel; Schneiderman, Rosa S; Wasserman, Yoram; Ryffel, Bernhard; Goldsher, Dorit; Palti, Yoram

    2009-01-01

    Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100-200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors.

  11. One Case of Pulmonary Chondroma, Rare Benign Tumor of the Lung

    Institute of Scientific and Technical Information of China (English)

    YANG Kun; YANG Guanghai; LI Jinsong; WANG Jianjun

    2006-01-01

    @@ Pulmonary chondroma is a rare form of benign neoplasms of the lung, of which the cartilage is the only constituent. Most of the patients with lung chondroma are asymptomatic at the time of diagnosis and the occupying lesion in lung is mostly detected in the routine health examination. The image of pulmonary chondroma is similar to the other benign solitary neoplasms of the lung and the definitive diagnosis can only be established under a microscope after the resection of the tumor. In the present report, a 33-years-old woman with chondroma in the left lower lung was described.

  12. Audiovisual Biofeedback Improves Cine-Magnetic Resonance Imaging Measured Lung Tumor Motion Consistency.

    Science.gov (United States)

    Lee, Danny; Greer, Peter B; Ludbrook, Joanna; Arm, Jameen; Hunter, Perry; Pollock, Sean; Makhija, Kuldeep; O'brien, Ricky T; Kim, Taeho; Keall, Paul

    2016-03-01

    To assess the impact of an audiovisual (AV) biofeedback on intra- and interfraction tumor motion for lung cancer patients. Lung tumor motion was investigated in 9 lung cancer patients who underwent a breathing training session with AV biofeedback before 2 3T magnetic resonance imaging (MRI) sessions. The breathing training session was performed to allow patients to become familiar with AV biofeedback, which uses a guiding wave customized for each patient according to a reference breathing pattern. In the first MRI session (pretreatment), 2-dimensional cine-MR images with (1) free breathing (FB) and (2) AV biofeedback were obtained, and the second MRI session was repeated within 3-6 weeks (mid-treatment). Lung tumors were directly measured from cine-MR images using an auto-segmentation technique; the centroid and outlier motions of the lung tumors were measured from the segmented tumors. Free breathing and AV biofeedback were compared using several metrics: intra- and interfraction tumor motion consistency in displacement and period, and the outlier motion ratio. Compared with FB, AV biofeedback improved intrafraction tumor motion consistency by 34% in displacement (P=.019) and by 73% in period (P<.001). Compared with FB, AV biofeedback improved interfraction tumor motion consistency by 42% in displacement (P<.046) and by 74% in period (P=.005). Compared with FB, AV biofeedback reduced the outlier motion ratio by 21% (P<.001). These results demonstrated that AV biofeedback significantly improved intra- and interfraction lung tumor motion consistency for lung cancer patients. These results demonstrate that AV biofeedback can facilitate consistent tumor motion, which is advantageous toward achieving more accurate medical imaging and radiation therapy procedures. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Imaging a moving lung tumor with megavoltage cone beam computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Gayou, Olivier, E-mail: ogayou@wpahs.org; Colonias, Athanasios [Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, Pennsylvania 15212 and Allegheny Campus, Temple University School of Medicine, Pittsburgh, Pennsylvania 15212 (United States)

    2015-05-15

    Purpose: Respiratory motion may affect the accuracy of image guidance of radiation treatment of lung cancer. A cone beam computed tomography (CBCT) image spans several breathing cycles, resulting in a blurred object with a theoretical size equal to the sum of tumor size and breathing motion. However, several factors may affect this theoretical relationship. The objective of this study was to analyze the effect of tumor motion on megavoltage (MV)-CBCT images, by comparing target sizes on simulation and pretreatment images of a large cohort of lung cancer patients. Methods: Ninety-three MV-CBCT images from 17 patients were analyzed. Internal target volumes were contoured on each MV-CBCT dataset [internal target volume (ITV{sub CB})]. Their extent in each dimension was compared to that of two volumes contoured on simulation 4-dimensional computed tomography (4D-CT) images: the combination of the tumor contours of each phase of the 4D-CT (ITV{sub 4D}) and the volume contoured on the average CT calculated from the 4D-CT phases (ITV{sub ave}). Tumor size and breathing amplitude were assessed by contouring the tumor on each CBCT raw projection where it could be unambiguously identified. The effect of breathing amplitude on the quality of the MV-CBCT image reconstruction was analyzed. Results: The mean differences between the sizes of ITV{sub CB} and ITV{sub 4D} were −1.6 ± 3.3 mm (p < 0.001), −2.4 ± 3.1 mm (p < 0.001), and −7.2 ± 5.3 mm (p < 0.001) in the anterior/posterior (AP), left/right (LR), and superior/inferior (SI) directions, respectively, showing that MV-CBCT underestimates the full target size. The corresponding mean differences between ITV{sub CB} and ITV{sub ave} were 0.3 ± 2.6 mm (p = 0.307), 0.0 ± 2.4 mm (p = 0.86), and −4.0 ± 4.3 mm (p < 0.001), indicating that the average CT image is more representative of what is visible on MV-CBCT in the AP and LR directions. In the SI directions, differences between ITV{sub CB} and ITV{sub ave} could be

  14. Silencing Receptor EphA2 Enhanced Sensitivity to Lipoplatin™ in Lung Tumor and MPM Cells.

    Science.gov (United States)

    Lee, Hung-Yen; Mohammed, Kamal A; Goldberg, Eugene P; Kaye, Frederic; Najmunnisa, Nasreen

    2016-08-08

    Receptor EphA2 is overexpressed in lung cancer and malignant pleural mesothelioma (MPM) which promote tumorogenesis. Lipoplatin™, a new liposomal cisplatin formulation, is used against resistant tumors. Use of cisplatin-based drugs leads to unacceptable toxicities. To improve the effectiveness of Lipoplatin, enhancing the cellular sensitivity of lung tumor and MPM cells is critical. Therefore, we targeted receptor EphA2 by silencing interference RNA (siRNA) and treated tumor cells with Lipoplatin. The combined effects of siRNA-EphA2 and Lipoplatin were determined. We report that silencing EphA2 significantly enhanced the cellular sensitivity of lung tumor and MPM cells to Lipoplatin and maybe a potential therapy for lung cancer.

  15. Impact of temporal probability in 4D dose calculation for lung tumors.

    Science.gov (United States)

    Rouabhi, Ouided; Ma, Mingyu; Bayouth, John; Xia, Junyi

    2015-11-08

    The purpose of this study was to evaluate the dosimetric uncertainty in 4D dose calculation using three temporal probability distributions: uniform distribution, sinusoidal distribution, and patient-specific distribution derived from the patient respiratory trace. Temporal probability, defined as the fraction of time a patient spends in each respiratory amplitude, was evaluated in nine lung cancer patients. Four-dimensional computed tomography (4D CT), along with deformable image registration, was used to compute 4D dose incorporating the patient's respiratory motion. First, the dose of each of 10 phase CTs was computed using the same planning parameters as those used in 3D treatment planning based on the breath-hold CT. Next, deformable image registration was used to deform the dose of each phase CT to the breath-hold CT using the deformation map between the phase CT and the breath-hold CT. Finally, the 4D dose was computed by summing the deformed phase doses using their corresponding temporal probabilities. In this study, 4D dose calculated from the patient-specific temporal probability distribution was used as the ground truth. The dosimetric evaluation matrix included: 1) 3D gamma analysis, 2) mean tumor dose (MTD), 3) mean lung dose (MLD), and 4) lung V20. For seven out of nine patients, both uniform and sinusoidal temporal probability dose distributions were found to have an average gamma passing rate > 95% for both the lung and PTV regions. Compared with 4D dose calculated using the patient respiratory trace, doses using uniform and sinusoidal distribution showed a percentage difference on average of -0.1% ± 0.6% and -0.2% ± 0.4% in MTD, -0.2% ± 1.9% and -0.2% ± 1.3% in MLD, 0.09% ± 2.8% and -0.07% ± 1.8% in lung V20, -0.1% ± 2.0% and 0.08% ± 1.34% in lung V10, 0.47% ± 1.8% and 0.19% ± 1.3% in lung V5, respectively. We concluded that four-dimensional dose computed using either a uniform or sinusoidal temporal probability distribution can

  16. MFSD2A is a novel lung tumor suppressor gene modulating cell cycle and matrix attachment

    Directory of Open Access Journals (Sweden)

    Shames David S

    2010-03-01

    Full Text Available Abstract Background MFSD2A (major facilitator superfamily domain containing 2 gene maps on chromosome 1p34 within a linkage disequilibrium block containing genetic elements associated with progression of lung cancer. Results Here we show that MFSD2A expression is strongly downregulated in non-small cell lung cancer cell lines of different histotypes and in primary lung adenocarcinomas. Experimental modulation of MFSD2A in lung cancer cells is associated with alteration of mRNA levels of genes involved in cell cycle control and interaction with the extracellular matrix. Exogenous expression of MFSD2A in lung cancer cells induced a G1 block, impaired adhesion and migration in vitro, and significantly reduced tumor colony number in vitro (4- to 27-fold, P in vivo (~3-fold, P Conclusion Together these data suggest that MFSD2A is a novel lung cancer tumor suppressor gene that regulates cell cycle progression and matrix attachment.

  17. Stereotactic body radiotherapy for stage I lung cancer and small lung metastasis: evaluation of an immobilization system for suppression of respiratory tumor movement and preliminary results

    OpenAIRE

    Ayakawa Shiho; Oda Kyota; Ikeya-Hashizume Chisa; Tomita Natsuo; Shibamoto Yuta; Baba Fumiya; Ogino Hiroyuki; Sugie Chikao

    2009-01-01

    Abstract Background In stereotactic body radiotherapy (SBRT) for lung tumors, reducing tumor movement is necessary. In this study, we evaluated changes in tumor movement and percutaneous oxygen saturation (SpO2) levels, and preliminary clinical results of SBRT using the BodyFIX immobilization system. Methods Between 2004 and 2006, 53 consecutive patients were treated for 55 lesions; 42 were stage I non-small cell lung cancer (NSCLC), 10 were metastatic lung cancers, and 3 were local recurrenc...

  18. Audiovisual biofeedback guided breath-hold improves lung tumor position reproducibility and volume consistency

    Directory of Open Access Journals (Sweden)

    Danny Lee, PhD

    2017-07-01

    Conclusions: This study demonstrated that audiovisual biofeedback can be used to improve the reproducibility and consistency of breath-hold lung tumor position and volume, respectively. These results may provide a pathway to achieve more accurate lung cancer radiation treatment in addition to improving various medical imaging and treatments by using breath-hold procedures.

  19. Chemoprevention with Acetylsalicylic Acid, Vitamin D and Calcium Reduces Risk of Carcinogen-induced Lung Tumors

    DEFF Research Database (Denmark)

    Pommergaard, Hans-Christian; Burcharth, Jakob; Rosenberg, J

    2013-01-01

    Background/Aim: Research has shown that chemoprevention may be effective against the development of lung cancer. The purpose of the present study was to evaluate the effect of oral chemoprevention in a mouse model of tobacco carcinogen-induced lung tumor....

  20. Tumor-Derived Exosomes and Their Role in Tumor-Induced Immune Suppression

    Directory of Open Access Journals (Sweden)

    Theresa L. Whiteside

    2016-10-01

    Full Text Available Tumor-derived exosomes (TEX are emerging as critical components of an intercellular information network between the tumor and the host. The tumor escapes from the host immune system by using a variety of mechanisms designed to impair or eliminate anti-tumor immunity. TEX carrying a cargo of immunoinhibitory molecules and factors represent one such mechanism. TEX, which are present in all body fluids of cancer patients, deliver negative molecular or genetic signals to immune cells re-programming their functions. Although TEX can also stimulate immune activity, in the microenvironments dominated by the tumor, TEX tend to mediate immune suppression thus promoting tumor progression. The TEX content, in part resembling that of the parent cell, may serve as a source of cancer biomarkers. TEX also interfere with immune therapies. A better understanding of TEX and their contribution to cancer progression and cancer patients’ response to immune therapies represents a challenging new field of investigation.

  1. Clinical utility of circulating tumor cells in patients with non-small-cell lung cancer.

    Science.gov (United States)

    Gallo, Marianna; De Luca, Antonella; Maiello, Monica Rosaria; D'Alessio, Amelia; Esposito, Claudia; Chicchinelli, Nicoletta; Forgione, Laura; Piccirillo, Maria Carmela; Rocco, Gaetano; Morabito, Alessandro; Botti, Gerardo; Normanno, Nicola

    2017-08-01

    Several different studies have addressed the role of the circulating tumor cells (CTC) in non-small-cell lung cancer (NSCLC). In particular, the potential of CTC analysis in the early diagnosis of NSCLC and in the prediction of the outcome of patients with early and advanced NSCLC have been explored. A major limit of these studies is that they used different techniques for CTC isolation and enumeration, they employed different thresholds to discriminate between high- and low-risk patients, and they enrolled heterogeneous and often small cohort of patients. Nevertheless, the results of many studies are concordant in indicating a correlation between high CTC count and poor prognosis in both early and advanced NSCLC. The reduction of CTC number following treatment might also represent an important indicator of sensitivity to therapy in patients with metastatic disease. Preliminary data also suggest the potential for CTC analysis in the early diagnosis of NSCLC in high-risk individuals. However, these findings need to be confirmed in large prospective trials in order to be transferred to the clinical practice. The molecular profiling of single CTC in NSCLC might provide important information on tumor biology and on the mechanisms involved in tumor dissemination and in acquired resistance to targeted therapies. In this respect, xenografts derived from CTC might represent a valuable tool to investigate these phenomena and to develop novel therapeutic strategies.

  2. Anti-tumor effect induced by exosomes derived from dendritic cells loaded with lung cancer cell lysates%肺癌细胞裂解物负载对树突状细胞分泌的exosome诱导抗肿瘤作用的影响

    Institute of Scientific and Technical Information of China (English)

    张在云; 李希德; 刘叶; 王志仑; 潘祥林

    2011-01-01

    目的 为制备高效的胞外体(exosome)肿瘤疫苗提供理论依据.方法 用细胞因子诱导培养树突状细胞(DC),将肺癌细胞裂解物负载DC,提取exosome;用exosome活化T细胞(负载组),以未负载DC的exosome(未负载组)及肺癌细胞裂解物负载DC(DC组)活化的T细胞为对照,MTT法检测三组肺癌细胞的杀伤率.结果 exosome中有HSP70、HLA及CEA表达.活化T细胞/肺癌细胞为25∶1、10∶1 、5∶1时负载组杀伤率均明显高于未负载组及DC组(P均<0.05).结论 肺癌细胞裂解物负载能增强DC分泌的exosome诱导的抗肿瘤作用;本研究为制备高效的exosome肿瘤疫苗提供了理论依据.%Objective To obtain theoretical bases for making high efficacy exosome cancer vaccine. Methods Dendritic cells (DC) were induced with cytokines and then loaded with whole lung cancer cell lysates. Exosomes were isolated from supernatant of DC, and T cells activated by the exosomes (group loaded) , T cells activated by exosomes from nonloaded DC (group non-loaded) or activated by lysate-loaded DC(group DC) were taken as control. 11k activity of T cells for killing lung cancer cells were detected by MTT method. Results HSP70, HLA and CEA protein were found in exosomes. The kill rates of activated T cells in group loaded at E: T ratio 25:1, 10= 1, 5:1 were much higher than those in group non-loaded and group DC( all P <0.05). Condnsiong Lung cancer cell lysates loading can promote the anti-tumor activity induced by DC-derived exosomes; this study can provide theoretical bases for making high efficacy exosome cancer vaccine.

  3. Evaluation of tumor localization in respiration motion-corrected cone-beam CT: Prospective study in lung

    Energy Technology Data Exchange (ETDEWEB)

    Dzyubak, Oleksandr; Kincaid, Russell; Hertanto, Agung; Hu, Yu-Chi; Pham, Hai; Yorke, Ellen; Zhang, Qinghui; Mageras, Gig S., E-mail: magerasg@mskcc.org [Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065 (United States); Rimner, Andreas [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065 (United States)

    2014-10-15

    Purpose: Target localization accuracy of cone-beam CT (CBCT) images used in radiation treatment of respiratory disease sites is affected by motion artifacts (blurring and streaking). The authors have previously reported on a method of respiratory motion correction in thoracic CBCT at end expiration (EE). The previous retrospective study was limited to examination of reducing motion artifacts in a small number of patient cases. They report here on a prospective study in a larger group of lung cancer patients to evaluate respiratory motion-corrected (RMC)-CBCT ability to improve lung tumor localization accuracy and reduce motion artifacts in Linac-mounted CBCT images. A second study goal examines whether the motion correction derived from a respiration-correlated CT (RCCT) at simulation yields similar tumor localization accuracy at treatment. Methods: In an IRB-approved study, 19 lung cancer patients (22 tumors) received a RCCT at simulation, and on one treatment day received a RCCT, a respiratory-gated CBCT at end expiration, and a 1-min CBCT. A respiration monitor of abdominal displacement was used during all scans. In addition to a CBCT reconstruction without motion correction, the motion correction method was applied to the same 1-min scan. Projection images were sorted into ten bins based on abdominal displacement, and each bin was reconstructed to produce ten intermediate CBCT images. Each intermediate CBCT was deformed to the end expiration state using a motion model derived from RCCT. The deformed intermediate CBCT images were then added to produce a final RMC-CBCT. In order to evaluate the second study goal, the CBCT was corrected in two ways, one using a model derived from the RCCT at simulation [RMC-CBCT(sim)], the other from the RCCT at treatment [RMC-CBCT(tx)]. Image evaluation compared uncorrected CBCT, RMC-CBCT(sim), and RMC-CBCT(tx). The gated CBCT at end expiration served as the criterion standard for comparison. Using automatic rigid image

  4. Circulating tumor cells in lung cancer: detection methods and clinical applications.

    Science.gov (United States)

    Yu, Na; Zhou, Jia; Cui, Fang; Tang, Xiaokui

    2015-04-01

    Circulating tumor cells (CTCs) are tumor cells that have disseminated from primary and metastatic sites, and circulate in the bloodstream. Advanced immunological and molecular-based methods can be used to detect and analyze the cells with the characteristics of tumor cells, and can be detected and analyzed in the blood of cancer patients. The most commonly used methods in lung cancer combine the processes of immunomagnetic enrichment and immunocytochemical detection, morphology-based enrichment coupled with reverse transcriptase polymerase chain reaction (RT-PCR), and RT-PCR alone. CTC analysis is considered a liquid biopsy approach for early diagnosis, risk stratification, evaluation of curative efficacy, and early detection of lung cancer relapse. In this review, we discuss the present techniques for analyzing CTCs, and the restrictions of using these methods in lung cancer. We also review the clinical studies in lung cancer and discuss the underlying associations between these studies and their future applications to this disease.

  5. Conditions for NIR fluorescence-guided tumor resectioning in preclinical lung cancer model (Conference Presentation)

    Science.gov (United States)

    Kim, Minji; Quan, Yuhua; Choi, Byeong Hyun; Choi, Yeonho; Kim, Hyun Koo; Kim, Beop-Min

    2016-03-01

    Pulmonary nodule could be identified by intraoperative fluorescence imaging system from systemic injection of indocyanine green (ICG) which achieves enhanced permeability and retention (EPR) effects. This study was performed to evaluate optimal injection time of ICG for detecting cancer during surgery in rabbit lung cancer model. VX2 carcinoma cell was injected in rabbit lung under fluoroscopic computed tomography-guidance. Solitary lung cancer was confirmed on positron emitting tomography with CT (PET/CT) 2 weeks after inoculation. ICG was administered intravenously and fluorescent intensity of lung tumor was measured using the custom-built intraoperative color and fluorescence merged imaging system (ICFIS) for 15 hours. Solitary lung cancer was resected through thoracoscopic version of ICFIS. ICG was observed in all animals. Because Lung has fast blood pulmonary circulation, Fluorescent signal showed maximum intensity earlier than previous studies in other organs. Fluorescent intensity showed maximum intensity within 6-9 hours in rabbit lung cancer. Overall, Fluorescent intensity decreased with increasing time, however, all tumors were detectable using fluorescent images until 12 hours. In conclusion, while there had been studies in other organs showed that optimal injection time was at least 24 hours before operation, this study showed shorter optimal injection time at lung cancer. Since fluorescent signal showed the maximum intensity within 6-9 hours, cancer resection could be performed during this time. This data informed us that optimal injection time of ICG should be evaluated in each different solid organ tumor for fluorescent image guided surgery.

  6. Radical stereotactic radiosurgery with real-time tumor motion tracking in the treatment of small peripheral lung tumors

    Directory of Open Access Journals (Sweden)

    Chang Thomas

    2007-10-01

    Full Text Available Abstract Background Recent developments in radiotherapeutic technology have resulted in a new approach to treating patients with localized lung cancer. We report preliminary clinical outcomes using stereotactic radiosurgery with real-time tumor motion tracking to treat small peripheral lung tumors. Methods Eligible patients were treated over a 24-month period and followed for a minimum of 6 months. Fiducials (3–5 were placed in or near tumors under CT-guidance. Non-isocentric treatment plans with 5-mm margins were generated. Patients received 45–60 Gy in 3 equal fractions delivered in less than 2 weeks. CT imaging and routine pulmonary function tests were completed at 3, 6, 12, 18, 24 and 30 months. Results Twenty-four consecutive patients were treated, 15 with stage I lung cancer and 9 with single lung metastases. Pneumothorax was a complication of fiducial placement in 7 patients, requiring tube thoracostomy in 4. All patients completed radiation treatment with minimal discomfort, few acute side effects and no procedure-related mortalities. Following treatment transient chest wall discomfort, typically lasting several weeks, developed in 7 of 11 patients with lesions within 5 mm of the pleura. Grade III pneumonitis was seen in 2 patients, one with prior conventional thoracic irradiation and the other treated with concurrent Gefitinib. A small statistically significant decline in the mean % predicted DLCO was observed at 6 and 12 months. All tumors responded to treatment at 3 months and local failure was seen in only 2 single metastases. There have been no regional lymph node recurrences. At a median follow-up of 12 months, the crude survival rate is 83%, with 3 deaths due to co-morbidities and 1 secondary to metastatic disease. Conclusion Radical stereotactic radiosurgery with real-time tumor motion tracking is a promising well-tolerated treatment option for small peripheral lung tumors.

  7. SU-E-J-185: Gated CBCT Imaging for Positioning Moving Lung Tumor in Lung SBRT Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Li, X; Li, T; Zhang, Y; Burton, S; Karlovits, B; Clump, D; Heron, D; Huq, M [University of Pittsburgh Medical Center, Pittsburgh, PA (United States)

    2014-06-01

    Purpose: Lung stereo-tactic body radiotherapy(SBRT) treatment requires high accuracy of lung tumor positioning during treatment, which is usually accomplished by free breathing Cone-Beam computerized tomography (CBCT) scan. However, respiratory motion induced image artifacts in free breathing CBCT may degrade such positioning accuracy. The purpose of this study is to investigate the feasibility of gated CBCT imaging for lung SBRT treatment. Methods: Six Lung SBRT patients were selected for this study. The respiratory motion of the tumors ranged from 1.2cm to 3.5cm, and the gating windows for all patients were set between 35% and 65% of the respiratory phases. Each Lung SBRT patient underwent free-breathing CBCT scan using half-fan scan technique. The acquired projection images were transferred out for off-line analyses. An In-house semi-automatic algorithm was developed to trace the diaphragm movement from those projection images to acquire a patient's specific respiratory motion curve, which was used to correlate respiratory phases with each projection image. Afterwards, a filtered back-projection algorithm was utilized to reconstruct the gated CBCT images based on the projection images only within the gating window. Results: Target volumes determined by free breathing CBCT images were 71.9%±72% bigger than the volume shown in gated CBCT image. On the contrary, the target volume differences between gated CBCT and planning CT images at exhale stage were 5.8%±2.4%. The center to center distance of the targets shown in free breathing CBCT and gated CBCT images were 9.2±8.1mm. For one particular case, the superior boundary of the target was shifted 15mm between free breathing CBCT and gated CBCT. Conclusion: Gated CBCT imaging provides better representation of the moving lung tumor with less motion artifacts, and has the potential to improve the positioning accuracy in lung SBRT treatment.

  8. Lung cancer perfusion at multi-detector row CT: reproducibility of whole tumor quantitative measurements.

    Science.gov (United States)

    Ng, Quan-Sing; Goh, Vicky; Fichte, Heinz; Klotz, Ernst; Fernie, Pat; Saunders, Michele I; Hoskin, Peter J; Padhani, Anwar R

    2006-05-01

    Institutional review board approval and informed consent were obtained for this study. The aim of the study was to prospectively assess, in patients with lung cancer, the reproducibility of a quantitative whole tumor perfusion computed tomographic (CT) technique. Paired CT studies were performed in 10 patients (eight men, two women; mean age, 66 years) with lung cancer. Whole tumor permeability and blood volume were measured, and reproducibility was evaluated by using Bland-Altman statistics. Coefficient of variation of 9.49% for permeability and 26.31% for blood volume and inter- and intraobserver variability ranging between 3.30% and 6.34% indicate reliable assessment with this whole tumor technique.

  9. Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.

    Science.gov (United States)

    Wang, Zhihui; Liu, Jin-Qing; Liu, Zhenzhen; Shen, Rulong; Zhang, Guoqiang; Xu, Jianping; Basu, Sujit; Feng, Youmei; Bai, Xue-Feng

    2013-03-01

    IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.

  10. Laser-induced thermotherapy of lung metastases and primary lung tumors; Laserinduzierte Thermotherapie von Lungenmetastasen und primaeren Lungentumoren

    Energy Technology Data Exchange (ETDEWEB)

    Vogl, T.J. (Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt; Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet, Theodor-Stern-Kai 7, 60590, Frankfurt); Fieguth, H.G. (Klinik fuer Thorax-, Herz- und thorakale Gefaesschirurgie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt); Eichler, K.; Straub, R.; Lehnert, T.; Zangos, S.; Mack, M. (Institut fuer Diagnostische und Interventionelle Radiologie, Klinikum der J.-W.-Goethe-Universitaet Frankfurt)

    2004-07-01

    We present laser-induced thermotherapy (LITT) of primary and secondary lung tumors analysing indications and technical concepts. Thirty patients with lung metastases of different primary tumors (n=24) as well as localized lung tumors (n=6) were prospectively treated in 41 sessions using laser-induced thermotherapy (LITT). An MR-compatible puncture system was used with direct puncture technique. The puncture was performed via CT guidance in care vision technique. Eight patients were thermoablated using MR tomographical monitoring, 22 patients using CT monitoring. Local therapy effects, tumor control rate, side effects, complications, and survival were evaluated. In 74% of cases (28/38 lesions) of 24 patients with lung metastases and in all cases of the 6 patients with lung carcinoma a complete local ablation could be achieved. The complication rate (pneumothorax) was 9,8%. One patient with bronchial carcinoma had to be thoracotomized and resected. 93% of the patients are still alive. Percutaneous LITT of lung tumors permits a complete ablation of lung metastases and lung carcinomas with a low complication rate. Indications for the procedure were defined for patients with no more than 5 metastases up to 3 cm in size. (orig.) [German] Wir stellen nachfolgend die Ergebnisse der laserinduzierten Thermotherapie (LITT) primaerer und sekundaerer Lungentumoren vor und analysieren die Indikationsstellung und die Interventionstechnik. Dreissig Patienten mit Lungenmetastasen unterschiedlicher Primaertumoren (n=24) sowie lokalisierten Bronchialkarzinomen (n=6) wurden prospektiv in 41 Sitzungen mittels MR-gesteuerter LITT therapiert. Zum Einsatz kam ein MR-kompatibles Punktionssystem in direkter Punktionstechnik; die Punktion erfolgte jeweils unter CT-Steuerung in Care-vision-Technik. Acht Patienten wurden mittels MR-tomographischem Monitoring thermoablatiert, 22 Patienten mittels CT-Monitoring. Evaluiert wurden die lokalen Therapieeffekte, Tumorkontrollrate, und die Frage von

  11. Successful and not so successful chemoprevention of tobacco smoke-induced lung tumors.

    Science.gov (United States)

    Witschi, H

    2000-12-01

    Strain A/J mice underwent whole body exposure for 6 hours a day, 5 days a week, for 5 months to a mixture of cigarette sidestream and mainstream smoke (89%-11%; total suspended particulates 80-150 mg/m3), then were kept for another 4 months in air before being killed for scoring of lung tumors. In 7 independent experiments, lung tumor multiplicity was significantly increased in all 7 trials and lung tumor incidence in 5. When animals were kept for 9 months in smoke, lung tumor multiplicity was not significantly higher than in controls, although lung tumor incidence was. The following chemopreventive agents were evaluated: green tea, phenethyl isothiocyanate (PEITC), acetylsalicylic acid (ASA), N-acetylcysteine (NAC), p-XSC (1,4-phenylenebis[methylene]selenocyanate), d-limonene (DL), and a mixture of PEITC and BITC (benzyl isothiocyanate). In animals exposed to tobacco smoke, none of these agents reduced lung tumor multiplicity or incidence. As a control, the effects of the same agents were examined in A/J mice initiated with 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK) or urethane. In mice injected with NNK, green tea and ASA did not reduce lung tumor multiplicities and NAC had no effect on urethane-induced lung tumors, whereas PEITC, p-XSC and DL reduced NNK-induced tumor multiplicities to 20% to 50% of control values. On the other hand, dietary mixture of myoinositol and dexamethasone was not only highly protective against NNK, but reduced lung tumor multiplicities and incidence in smoke-exposed animals to control values. This effect was also seen when the animals were fed the myo-inositol-dexamethasone mixture once they were removed from smoke. It is concluded that in animal studies it might be preferable to evaluate the effectiveness of putative chemopreventive agents against full tobacco smoke rather than against selected model compounds. The observations made with myo-inositol-dexamethasone suggest that people who have recently quit smoking might

  12. Rituximab efficiently depletes B cells in lung tumors and normal lung tissue [version 1; referees: 2 approved

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    Albane Joly-Battaglini

    2016-01-01

    Full Text Available Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab.

  13. Effect of interleukin 18 gene modification on anti-tumor activity induced by lung cancer cell-derived exosomes%IL-18基因修饰对肺癌细胞来源exosome诱导杀伤肿瘤细胞作用的影响

    Institute of Scientific and Technical Information of China (English)

    张在云; 李晓梅; 王涓冬; 孙建华; 姜玉华; 潘祥林

    2011-01-01

    AIM: To study the effect of interleukin 18( IL -8 ) gene modification on anti - tumor activity induced by lung cancer cell - derived exosomes.METHODS: Exosomes isolated from the supernatants of IL -18 gene -modified NCI - H460 lung cancer cells ( IL - 18/H460 ), pcDNA3.1+ vector - modified cancer cells ( DNA3.1/H460 ) and non - modified NCI - H460 lung cancer cells ( NCI - H460 ) were observed under transmission electron microscope.The expression of heat - shock protein 70( HSP70 ), human leukocyte antigen( HLA ) and IL - 18 were determined by Western blotting.T lymphocytes were activated by exosomes or exosome - pulsed dendritic cells( DCs ).The activity of T cells for killing lung cancer cells were detected by lactate dehydrogenase ( LDH ) method.The killing rates were calculated and compared.RESULTS: Exosomes showed typical morphous under transmission electron microscope.The protein levels of HSP70 and HLA were detected in the exosomes of all 3 groups, and IL - 18 protein was only observed in IL - 18/H460 group.The killing rates of exosome - activated T cells in IL - 18/H460 group with the ratio of effector cell to target cell at 25∶ 1, 10∶ 1 and 5∶ 1 were ( 38.45 ±5.42 )% , ( 25.17 ±3.94 )% and ( 11.75 ±3.22 )% , respectively.The killing rates of exosome - pulsed DC - activated T cells in this group were ( 89.05 ± 4.06 )% , ( 64.97 ± 6.02 )% and ( 40.16 ± 4.98 )% , respectively.The killing rates in IL - 18/H460 group were higher than those in DNA3.1/H460 group and NCI - H460 group.The anti - tumor efficacy of exosome - pulsed DC - activated T cells was stronger than that of exosome - activated T cells.CONCLUSION: IL -18 gene modification enhances the anti -tumor activity induced by NCI - H460 lung cancer cell - derived exosomes.%目的:研究细胞介素18(IL-18)基因修饰对肺癌细胞来源exosome诱导杀伤肿瘤细胞作用的影响,以探讨高效exosome疫苗的制备.方法:提取IL-18基因修饰的NCI-H460细胞(IL-18/H460)

  14. A synthetic manassantin a derivative inhibits hypoxia-inducible factor 1 and tumor growth.

    Science.gov (United States)

    Lang, Liwei; Liu, Xiaoyu; Li, Yan; Zhou, Qing; Xie, Ping; Yan, Chunhong; Chen, Xiaoguang

    2014-01-01

    The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1) inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006) with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1α nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers.

  15. A synthetic manassantin a derivative inhibits hypoxia-inducible factor 1 and tumor growth.

    Directory of Open Access Journals (Sweden)

    Liwei Lang

    Full Text Available The dineolignan manassantin A from Saururaceae was recently identified as a hypoxia-inducible factor 1 (HIF-1 inhibitor, but its in-vivo anti-tumor effect has not been explored. We synthesized a series of manassantin A derivatives, and found that replacing the central tetrahydrofuran moiety with a cyclopentane ring yielded a compound (LXY6006 with increased HIF-1-inhibitory activity yet decreased stereochemically complexity amenable to a simplified synthesis scheme. LXY6006 inhibited HIF-1α nuclear accumulation induced by hypoxia, and inhibited cancer cell growth as a consequence of G2/M arrest. Oral administration of LXY6006 significantly inhibited growth of breast, lung, and pancreatic tumors implanted in nude mice. These results indicate that LXY6006 represents a novel class of agents targeting a broad range of human cancers.

  16. Malignant Phyllodes Tumor Presenting in Bone, Brain, Lungs, and Lymph Nodes

    Directory of Open Access Journals (Sweden)

    Eric D. Johnson

    2016-12-01

    Full Text Available Introduction: Phyllodes tumors (PTs are rare fibroepithelial tumors of the breast which are classified as benign, borderline, or malignant. Malignant PTs account for <1% of malignant breast tumors, and borderline tumors have potential to progress to malignant tumors. Metastatic recurrences are most commonly documented in bone and lungs. We report an extremely rare presentation of recurrent malignant PTs involving the brain, lung, lymph nodes, and bone. Case: A 66-year-old female presented with a large breast mass. Biopsy identified malignant PT, treated by mastectomy. One year later she presented with acute back pain; imaging showed pathological L4 spinal compression fracture. Core biopsy confirmed PT. Staging identified additional metastases in the lymph nodes, brain, and lung. Discussion: PTs are rare and fast-growing tumors that originate from periductal stromal tissues and are composed of both epithelial and stromal components. Histologically, they are classified as benign, borderline, or malignant. The prognosis of the malignant type is poorly defined, with local recurrence occurring in 10–40% and metastases in 10%. Chemotherapy and radiotherapy are generally ineffective in this tumor type. The most common metastatic sites for malignant cases are the lung and bones, but in rare instances, PTs may metastasize elsewhere. Conclusion: We report a rare presentation of recurrent malignant PT presenting as pathological fracture of the lumbar spine with impingement on the spinal column, along with cerebellar, nodal, and pulmonary metastases. Only 1 similar case has been previously reported.

  17. Malignant Phyllodes Tumor Presenting in Bone, Brain, Lungs, and Lymph Nodes

    Science.gov (United States)

    Johnson, Eric D.; Gulbahce, Evin; McNally, Joseph; Buys, Saundra S.

    2016-01-01

    Introduction Phyllodes tumors (PTs) are rare fibroepithelial tumors of the breast which are classified as benign, borderline, or malignant. Malignant PTs account for tumors, and borderline tumors have potential to progress to malignant tumors. Metastatic recurrences are most commonly documented in bone and lungs. We report an extremely rare presentation of recurrent malignant PTs involving the brain, lung, lymph nodes, and bone. Case A 66-year-old female presented with a large breast mass. Biopsy identified malignant PT, treated by mastectomy. One year later she presented with acute back pain; imaging showed pathological L4 spinal compression fracture. Core biopsy confirmed PT. Staging identified additional metastases in the lymph nodes, brain, and lung. Discussion PTs are rare and fast-growing tumors that originate from periductal stromal tissues and are composed of both epithelial and stromal components. Histologically, they are classified as benign, borderline, or malignant. The prognosis of the malignant type is poorly defined, with local recurrence occurring in 10–40% and metastases in 10%. Chemotherapy and radiotherapy are generally ineffective in this tumor type. The most common metastatic sites for malignant cases are the lung and bones, but in rare instances, PTs may metastasize elsewhere. Conclusion We report a rare presentation of recurrent malignant PT presenting as pathological fracture of the lumbar spine with impingement on the spinal column, along with cerebellar, nodal, and pulmonary metastases. Only 1 similar case has been previously reported. PMID:28203179

  18. Cytokines from the tumor microenvironment modulate sirtinol cytotoxicity in A549 lung carcinoma cells.

    Science.gov (United States)

    Pal, Shyama; Shankar, Bhavani S; Sainis, Krishna B

    2013-10-01

    Cytokines in tumor microenvironment play an important role in the success or failure of molecular targeted therapies. We have chosen tumor necrosis factor α (TNF-α), TNF related apoptosis inducing ligand (TRAIL), insulin-like growth factor 1 (IGF-1) and transforming growth factor β (TGF-β) as representative pro-inflammatory, pro-apoptotic, anti-apoptotic and anti-inflammatory tumor derived cytokines. Analysis of Oncomine database revealed the differential expression of these cytokines in a subset of cancer patients. The effects of these cytokines on cytotoxicity of FDA approved drugs - cisplatin and taxol and inhibitors of epidermal growth factor receptor - AG658, Janus kinase - AG490 and SIRT1 - sirtinol were assessed in A549 lung cancer cells. TRAIL augmented cytotoxicity of sirtinol and IGF-1 had a sparing effect. Since TRAIL and IGF-1 differentially modulated sirtinol cytotoxicity, further studies were carried out to identify the mechanisms. Sirtinol or knockdown of SIRT1 increased the expression of death receptors DR4 and DR5 and sensitized A549 cells to TRAIL. Increased cell death in presence of TRAIL and sirtinol was caspase independent and demonstrated classical features of necroptosis. Inhibition of iNOS increased caspase activity and switched the mode of cell death to caspase mediated apoptosis. Interestingly, sirtinol or SIRT1 knockdown did not increase IGF-1R expression. Instead, it abrogated ligand induced downregulation of IGF-1R and increased cell survival through PI3K-AKT pathway. In conclusion, these findings reveal that the tumor microenvironment contributes to modulation of cytotoxicity of drugs and that combination therapy, with agents that increase TRAIL signaling and suppress IGF-1 pathway may potentiate anticancer effect.

  19. Pancreatic Neuroendocrine Tumors in Mice Deficient in Proglucagon-Derived Peptides.

    Directory of Open Access Journals (Sweden)

    Yuko Takano

    Full Text Available Animal models with defective glucagon action show hyperplasia of islet α-cells, however, the regulatory mechanisms underlying the proliferation of islet endocrine cells remain largely to be elucidated. The Gcggfp/gfp mice, which are homozygous for glucagon/green fluorescent protein knock-in allele (GCGKO, lack all proglucagon-derived peptides including glucagon and GLP-1. The present study was aimed to characterize pancreatic neuroendocrine tumors (panNETs, which develop in the GCGKO mice. At 15 months of age, macroscopic GFP-positive tumors were identified in the pancreas of all the GCGKO mice, but not in that of the control heterozygous mice. The tumor manifested several features that were consistent with pancreatic neuroendocrine tumors (panNETs, such as organoid structures with trabecular and cribriform patterns, and the expression of chromogranin A and synaptophysin. Dissemination of GFP-positive cells was observed in the liver and lungs in 100% and 95%, respectively, of 15-month-old GCGKO mice. To elucidate the regulatory mechanism for tumor growth, PanNET grafts were transplanted into subrenal capsules in GCGKO and control mice. Ki-67 positive cells were identified in panNET grafts transplanted to GCGKO mice 1 month after transplantation, but not in those to control mice. These results suggest that humoral factors or conditions specific to GCGKO mice, are involved in the proliferation of panNETs. Taken together, GCGKO mice are novel animal model for studying the development, pathogenesis, and metastasis panNETs.

  20. Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer

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    Srivastava MK

    2012-10-01

    Full Text Available Minu K Srivastava,1,2 Li Zhu,1,2 Marni Harris-White,2 Min Huang,1–3 Maie St John,1,3 Jay M Lee,1,3 Ravi Salgia,4 Robert B Cameron,1,3,5 Robert Strieter,6 Steven Dubinett,1–3 Sherven Sharma1–31Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 3Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 4Department of Medicine, University of Chicago, Chicago, IL, 5Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 6Department of Medicine, University of Virginia, Charlottesville, VA, USAAbstract: Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs. MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with

  1. SU-E-J-267: Change in Mean CT Intensity of Lung Tumors During Radiation Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Mahon, R; Tennyson, N; Weiss, E; Hugo, G [Virginia Commonwealth University, Richmond, VA (United States)

    2015-06-15

    Purpose: To evaluate CT intensity change of lung tumors during radiation therapy. Methods: Repeated 4D CT images were acquired on a CT simulator during the course of therapy for 27 lung cancer patients on IRB approved protocols. All subjects received definitive radiation treatment ± chemotherapy. CT scans were completed prior to treatment, and 2–7 times during the treatment course. Primary tumor was delineated by an experienced Radiation Oncologist. Contours were thresholded between −100 HU and 200 HU to remove airways and bone. Correlations between the change in the mean tumor intensity and initial tumor intensity, SUVmax, and tumor volume change rate were investigated. Reproducibility was assessed by evaluating the variation in mean intensity over all phases in 4DCT, for a subgroup of 19 subjects. Results: Reproducibility of tumor intensity between phases as characterized by the root mean square of standard deviation across 19 subjects was 1.8 HU. Subjects had a mean initial tumor intensity of 16.5 ± 11.6 HU and an overall reduction in HU by 10.3 ± 8.5 HU. Evaluation of the changes in tumor intensity during treatment showed a decrease of 0.3 ± 0.3 HU/day for all subjects, except three. No significant correlation was found between change in HU/day and initial HU intensity (p=0.53), initial PET SUVmax (p=0.69), or initial tumor volume (p=0.70). The rate of tumor volume change was weakly correlated (R{sup 2}=0.05) with HU change (p=0.01). Conclusion: Most lung cancer subjects showed a marked trend of decreasing mean tumor CT intensity throughout radiotherapy, including early in the treatment course. Change in HU/day is not correlated with other potential early predictors for response, such as SUV and tumor volume change. This Result supports future studies to evaluate change in tumor intensity on CT as an early predictor of response.

  2. Endoscopic photodynamic therapy with hematoporphyrin derivative in the treatment of malignant tumors: report of 120 cases

    Science.gov (United States)

    Tian, Mao-en; Liu, Fa-wen; Qian, Jia-ping; Ji, Qing; Feng, Yun-qiu

    1993-03-01

    One-hundred-twenty cases of malignant tumors treated by endoscopic photodynamic therapy with hematoporphyrin derivative from August 1982 - July 1990 are reported. Of the 120 cases, including 97 males and 23 females ages varying from 39 to 77 years old, 40 cases were primary tumors and 80 cases were local residual or recurrent after surgery or radiotherapy or chemotherapy. All cases were confirmed in pathological biopsy, including 58 squamous cell carcinoma, 28 various adenocarcinoma, and 34 transitional cell carcinoma. Twenty-four, 48 and/or 72 hours after intravenous injection of HpD 2.0 - 3.0 mg/kg, or DHE 1.5 - 2.0 mg/kg, or Y-HpD 5.0 mg/kg, the tumor was irradiated with 630 nm wavelength of argon dye laser via a quartz light fiber inserted through the forceps channel of the endoscope. Of the 120 cases treated, CR was obtained in 38 cases, PR in 25 cases, MR in 52 cases, and NR in 5 cases. Total response rate was 95.8%; significant response rate 52.5%; and tumor eradicated rate 31.7%. The 38 cases included: 14 cases of early esophageal carcinoma, 3 cases of early cardiac carcinoma, 1 case of early lung cancer, 1 case of early gastric carcinoma, 15 cases of superficial bladder carcinoma, 3 cases of local residual recurrent micro lung cancer, and 1 case of cardiac carcinoma. The longest cancer-free survival was over eight years. Endoscopic photodynamic therapy is, therefore, curative effective in the treatment of early and superficial carcinoma, and palliative effective in the treatment of advanced carcinoma. Standardized and controlled trials are required to assess its place in combined treatment of malignant tumors.

  3. Tumor-derived lactate and myeloid-derived suppressor cells: Linking metabolism to cancer immunology.

    Science.gov (United States)

    Husain, Zaheed; Seth, Pankaj; Sukhatme, Vikas P

    2013-11-01

    Many malignant cells produce increased amounts of lactate, which promotes the development of myeloid-derived suppressor cells (MDSCs). MDSCs, lactate, and a low pH in the tumor microenvironment inhibit the function of natural killer (NK) cells and T lymphocytes, hence allowing for disease progression. Ketogenic diets can deplete tumor-bearing animals from MDSCs and regulatory T cells, thereby improving their immunological profile.

  4. What Happens after Treatment for Lung Carcinoid Tumors?

    Science.gov (United States)

    ... your health. For more information on how recurrent cancer is treated, see Treatment of Lung Carcinoid, By Type and Extent of Disease . For more general information on dealing with a recurrence, you may also want to see Coping With ...

  5. Circulating tumor cells in lung cancer:Detection methods and clinical impact

    Institute of Scientific and Technical Information of China (English)

    Minghui Zhang; Decai Chi; Co-first author Shu Zhao; Yan Wang; Maopeng Yang; Yan Wang

    2014-01-01

    Circulating tumor cels (CTCs) are tumor cels that enter the blood circulation after detaching from the primary tumor and can migrate to reach distant organs, where they can give rise to aggressive metastasis. Clinical studies have revealed that the presence of CTCs in peripheral blood is correlated with disease progression in lung cancer. However, as CTCs are rare cancer cels released from tumors into the bloodstream, both enrichment and sensitive detection methods are technicaly chalenging. In order to best understand how CTCs are currently being deployed, this review mainly focuses on the diferent detection methods for CTCs. Furthermore, we wil describe the clinical impact of circulating tumor cels in lung cancer and discuss their potential use as biomarker to guide the prognosis.

  6. Bone marrow-derived cells and tumor growth : Contribution of bone marrow-derived cells to tumor micro-environments with special focus on mesenchymal stem cells

    NARCIS (Netherlands)

    Roorda, Berber D.; ter Elst, Arja; Kamps, Willem A.; de Bont, Eveline S. J. M.

    Research has provided evidence that tumor growth depends on the interaction of tumor cells with stromal cells, as already suggested in 1889 by Paget. Experimental and clinical studies have revealed that tumor stromal cells can be derived from bone marrow (BM)-derived progenitor cells, such as

  7. Automated lung tumor segmentation for whole body PET volume based on novel downhill region growing

    Science.gov (United States)

    Ballangan, Cherry; Wang, Xiuying; Eberl, Stefan; Fulham, Michael; Feng, Dagan

    2010-03-01

    We propose an automated lung tumor segmentation method for whole body PET images based on a novel downhill region growing (DRG) technique, which regards homogeneous tumor hotspots as 3D monotonically decreasing functions. The method has three major steps: thoracic slice extraction with K-means clustering of the slice features; hotspot segmentation with DRG; and decision tree analysis based hotspot classification. To overcome the common problem of leakage into adjacent hotspots in automated lung tumor segmentation, DRG employs the tumors' SUV monotonicity features. DRG also uses gradient magnitude of tumors' SUV to improve tumor boundary definition. We used 14 PET volumes from patients with primary NSCLC for validation. The thoracic region extraction step achieved good and consistent results for all patients despite marked differences in size and shape of the lungs and the presence of large tumors. The DRG technique was able to avoid the problem of leakage into adjacent hotspots and produced a volumetric overlap fraction of 0.61 +/- 0.13 which outperformed four other methods where the overlap fraction varied from 0.40 +/- 0.24 to 0.59 +/- 0.14. Of the 18 tumors in 14 NSCLC studies, 15 lesions were classified correctly, 2 were false negative and 15 were false positive.

  8. Common Diagnostic Challenges in the Histopathologic Diagnosis of Neuroendocrine Lung Tumors: A Case Report

    Directory of Open Access Journals (Sweden)

    Monica Valente

    2010-07-01

    Full Text Available Bronchopulmonary neuroendocrine tumors are an uncommon group of neoplasms, accounting for about 20% of all lung carcinomas, arising from stem cells of the bronchial epithelium known as Kulchitsky cells. In the past, these tumors were grouped among benign or less aggressive malignant pulmonary tumors. Currently, according to the 2004 World Health Organization categorization, these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade (typical carcinoid; TC, intermediate-grade (atypical carcinoid; AC and high-grade (large-cell neuroendocrine carcinoma, LCNEC, and small-cell lung carcinoma, SCLC. They differ by morphologic, immunohistochemical and structural features. At histopathologic analysis, these tumors share progressive increase in a number of mitotic figures per 10 high-power fields and in the extent of necrosis, with TC having the lowest values and SCLC having the highest. TCs and ACs make up approximately 1–2% of all primary lung tumors. Differentiating ACs from TCs or LCNEC and SCLC is clinically important because the treatment modalities and prognoses for these types of tumors are different. We report a case of misdiagnosis of bronchopulmonary neuroendocrine tumor in a young woman which has heavily influenced her clinical history.

  9. In Vivo Tagging of Lung Epithelial Cells to Define the Early Steps of Tumor Cell Dissemination

    Science.gov (United States)

    2014-10-01

    derived lung cells, only the epithelium will be tagged by this method. Prior to using these animals for our studies, we will ensure that lineage labeled...1 AWARD NUMBER: W81XWH-13-1-0184 TITLE: In Vivo Tagging of Lung Epithelial Cells To Define...REPORT TYPE Annual 3. DATES COVERED 15Sep2013-14Sep2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER In Vivo Tagging of Lung

  10. Synthesis of 2,3-diyne-1,4-naphthoquinone derivatives and evaluation of cytotoxic activity against tumor cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Mauro G.; Camara, Celso A.; Silva, Tania M.S., E-mail: ccelso@dcm.ufrpe.br [Universidade Federal Rural de Pernambuco (LSCB/UFRPE), Recife, PE (Brazil). Dept. de Ciencias Moleculares. Lab. de Sintese de Compostos Bioativos; Feitosa, Anderson C.S.; Meira, Assuero S.; Pessoa, Claudia [Universidade Federal do Ceara (LOE/UFC), Fortaleza, CE (Brazil). Dept. de Fisiologia e Farmacologia. Lab. de Oncologia Experimental

    2013-09-15

    A series of 2,3-diyne-1,4-naphthoquinone derivatives was synthesized from 2,3-dibromo- 1,4-naphthoquinone and various functionalized terminal alkynes using palladium-catalyzed Sonogashira cross-coupling reaction. The diynes were evaluated as potential cytotoxic agents against three tumor cell lines: human ovarian adenocarcinoma (OVCAR-8), human metastatic prostate cancer (PC-3M) and human bronchoalveolar lung carcinoma (NCI-H358M), presenting, in general, satisfactory results for inhibition of cell growth. (author)

  11. A case of bronchiectasis needing lung isolation for cerebello pontine angle tumor excision: Anesthetic challenges

    Directory of Open Access Journals (Sweden)

    C Srinivasan

    2016-01-01

    Full Text Available The main goals of neuroanesthesia are the maintenance of adequate cerebral perfusion pressure, avoidance of hypercarbia, hypoxemia, and to provide better brain relaxation. Providing anesthesia for a patient with bronchiectasis needing lung isolation for craniotomy can be challenging. A 56-year-old male patient, case of right lung bronchiectasis with a right cerebello pontine angle tumor underwent excision in the left lateral position. Since he had severe bronchiectasis of the right lung, we had isolated the right lung using right-sided double lumen tube to avoid spillage. Intraoperative split lung test was performed to assess the right lung contribution on carbon dioxide (CO 2 elimination and found that there was a significant contribution from the right lung. Hence, both lungs were ventilated to control CO 2 . The importance of lung isolation to prevent spillage and avoidance of one lung ventilation to control the arterial CO 2 are highlighted in this case report. By providing a balanced anesthetic keeping both, the neurosurgical and thoracic concerns are important for better postoperative outcome.

  12. Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential.

    Directory of Open Access Journals (Sweden)

    Verline Justilien

    Full Text Available Matrix metalloproteinases (Mmps stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2 in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC. Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10(-/- mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells.

  13. WE-AB-303-08: Direct Lung Tumor Tracking Using Short Imaging Arcs

    Energy Technology Data Exchange (ETDEWEB)

    Shieh, C; Huang, C; Keall, P; Feain, I [University of Sydney, Sydney (Australia)

    2015-06-15

    Purpose: Most current tumor tracking technologies rely on implanted markers, which suffer from potential toxicity of marker placement and mis-targeting due to marker migration. Several markerless tracking methods have been proposed: these are either indirect methods or have difficulties tracking lung tumors in most clinical cases due to overlapping anatomies in 2D projection images. We propose a direct lung tumor tracking algorithm robust to overlapping anatomies using short imaging arcs. Methods: The proposed algorithm tracks the tumor based on kV projections acquired within the latest six-degree imaging arc. To account for respiratory motion, an external motion surrogate is used to select projections of the same phase within the latest arc. For each arc, the pre-treatment 4D cone-beam CT (CBCT) with tumor contours are used to estimate and remove the contribution to the integral attenuation from surrounding anatomies. The position of the tumor model extracted from 4D CBCT of the same phase is then optimized to match the processed projections using the conjugate gradient method. The algorithm was retrospectively validated on two kV scans of a lung cancer patient with implanted fiducial markers. This patient was selected as the tumor is attached to the mediastinum, representing a challenging case for markerless tracking methods. The tracking results were converted to expected marker positions and compared with marker trajectories obtained via direct marker segmentation (ground truth). Results: The root-mean-squared-errors of tracking were 0.8 mm and 0.9 mm in the superior-inferior direction for the two scans. Tracking error was found to be below 2 and 3 mm for 90% and 98% of the time, respectively. Conclusions: A direct lung tumor tracking algorithm robust to overlapping anatomies was proposed and validated on two scans of a lung cancer patient. Sub-millimeter tracking accuracy was observed, indicating the potential of this algorithm for real-time guidance

  14. Potentiation of platinum antitumor effects in human lung tumor xenografts by the angiogenesis inhibitor squalamine: effects on tumor neovascularization.

    Science.gov (United States)

    Schiller, J H; Bittner, G

    1999-12-01

    Squalamine is a novel anti-angiogenic aminosterol that is postulated to inhibit neovascularization by selectively inhibiting the sodium-hydrogen antiporter exchanger. To determine how to most effectively use this agent in patients with cancer, we examined the antitumor effects of squalamine with or without cytotoxic agents in human lung cancer xenografts and correlated these observations with the degree of tumor neovascularization. No direct cytotoxic effects of squalamine against tumor cells were observed in vitro with or without cisplatin. Squalamine was effective in inhibiting the establishment of H460 human tumors in BALBc nude mice but was ineffective in inhibiting the growth of H460, CALU-6, or NL20T-A human tumor xenografts when administered i.p. to mice bearing established tumors. However, when combined with cisplatin or carboplatin, squalamine increased tumor growth delay by > or =1.5-fold in the three human lung carcinoma cell lines compared with cisplatin or carboplatin alone. No enhancement of antitumor activity was observed when squalamine was combined with paclitaxel, vinorelbine, gemcitabine, or docetaxel. Repeated cycles of squalamine plus cisplatin administration delayed H460 tumor growth >8.6-fold. Squalamine plus cisplatin reduced CD31 vessel formation by 25% compared with controls, squalamine alone, or cisplatin alone; however, no inhibition in CD31 vessel formation was observed when squalamine was combined with vinorelbine. These data demonstrate that the combination of squalamine and a platinum analog has significant preclinical antitumor activity against human lung cancer that is related to the anti-angiogenic effects of squalamine.

  15. Automatic segmentation of tumor-laden lung volumes from the LIDC database

    Science.gov (United States)

    O'Dell, Walter G.

    2012-03-01

    The segmentation of the lung parenchyma is often a critical pre-processing step prior to application of computer-aided detection of lung nodules. Segmentation of the lung volume can dramatically decrease computation time and reduce the number of false positive detections by excluding from consideration extra-pulmonary tissue. However, while many algorithms are capable of adequately segmenting the healthy lung, none have been demonstrated to work reliably well on tumor-laden lungs. Of particular challenge is to preserve tumorous masses attached to the chest wall, mediastinum or major vessels. In this role, lung volume segmentation comprises an important computational step that can adversely affect the performance of the overall CAD algorithm. An automated lung volume segmentation algorithm has been developed with the goals to maximally exclude extra-pulmonary tissue while retaining all true nodules. The algorithm comprises a series of tasks including intensity thresholding, 2-D and 3-D morphological operations, 2-D and 3-D floodfilling, and snake-based clipping of nodules attached to the chest wall. It features the ability to (1) exclude trachea and bowels, (2) snip large attached nodules using snakes, (3) snip small attached nodules using dilation, (4) preserve large masses fully internal to lung volume, (5) account for basal aspects of the lung where in a 2-D slice the lower sections appear to be disconnected from main lung, and (6) achieve separation of the right and left hemi-lungs. The algorithm was developed and trained to on the first 100 datasets of the LIDC image database.

  16. Cyclin D expression in plutonium-induced lung tumors in F344 rats

    Energy Technology Data Exchange (ETDEWEB)

    Hahn, F.F.; Kelly, G. [SouthWest Scientific Resources, Inc., Albuquerque, NM (United States)

    1995-12-01

    The genetic mechanisms responsible for {alpha}-radiation-induced lung cancer in rats following inhalation of {sup 239}Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that {alpha}-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D{sub 1} overexpression.

  17. Stereotactic Body Radiotherapy for Small Lung Tumors in the University of Tokyo Hospital

    Directory of Open Access Journals (Sweden)

    Hideomi Yamashita

    2014-01-01

    Full Text Available Our work on stereotactic body radiation therapy (SBRT for primary and metastatic lung tumors will be described. The eligibility criteria for SBRT, our previous SBRT method, the definition of target volume, heterogeneity correction, the position adjustment using four-dimensional cone-beam computed tomography (4D CBCT immediately before SBRT, volumetric modulated arc therapy (VMAT method for SBRT, verifying of tumor position within internal target volume (ITV using in-treatment 4D-CBCT during VMAT-SBRT, shortening of treatment time using flattening-filter-free (FFF techniques, delivery of 4D dose calculation for lung-VMAT patients using in-treatment CBCT and LINAC log data with agility multileaf collimator, and SBRT method for centrally located lung tumors in our institution will be shown. In our institution, these efforts have been made with the goal of raising the local control rate and decreasing adverse effects after SBRT.

  18. Serum-derived exosomes from mice with highly metastatic breast cancer transfer increased metastatic capacity to a poorly metastatic tumor.

    Science.gov (United States)

    Gorczynski, Reginald M; Erin, Nuray; Zhu, Fang

    2016-02-01

    Altered interaction between CD200 and CD200R represents an example of "checkpoint blockade" disrupting an effective, tumor-directed, host response in murine breast cancer cells. In CD200R1KO mice, long-term cure of EMT6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB/c mice. The reverse was observed with 4THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD200R1KO. We explored possible explanations for this difference. We measured the frequency of circulating tumor cells (CTCs) in peripheral blood of tumor bearers, as well as lung/liver and draining lymph nodes. In some cases mice received infusions of exosomes from nontumor controls, or tumor bearers, with/without additional infusions of anticytokine antibodies. The measured frequency of circulating tumor cells (CTCs) in peripheral blood was equivalent in the two models in WT and CD200R1KO mice. Increased metastasis in EMT6 tumor bearers was seen in vivo following adoptive transfer of serum, or serum-derived exosomes, from 4THM tumor bearers, an effect which was attenuated by anti-IL-6, and anti-IL-17, but not anti-TNFα, antibody. Anti-IL-6 also attenuated enhanced migration of EMT6 cells in vitro induced by 4THM serum or exosomes, or recombinant IL-6. Exosome cytokine proteomic profiles responses in 4THM and EMT6 tumor-bearing mice were regulated by CD200:CD200R interactions, with attenuation of both IL-6 and IL-17 in 4THM CD200(tg) mice, and enhanced levels in 4THM CD200R1KO mice. We suggest these cytokines act on the microenvironment at sites within the host, and/or directly on tumor cells themselves, to increase metastatic potential.

  19. Effects of Physalis peruviana L on Toxicity and Lung Cancer Induction by Nicotine Derived Nitrosamine Ketone in Rats.

    Science.gov (United States)

    El-Kenawy, Ayman El-Meghawry; Elshama, Said Said; Osman, Hosam-Eldin Hussein

    2015-01-01

    Nicotine-derived nitrosamine ketone (NNK) is considered a key tobacco smoke carcinogen inducing lung tumors. Physalis peruviana L (harankash) is considered one plant with marked health benefits. This study aimed to evaluate Physalis peruviana L effect on the toxic effect of NNK induced lung cancer in the rats by using pulmonary histopathological, immunohistochemical and DNA flow cytometric analyses. Sixty adult male rats were divided into four groups, each consisting of fifteen animals. The first group received saline, the second received two successive toxic doses of NNK only while the third received two successive toxic doses of NNK with a single daily dose of Physalis peruviana L. The fourth group received a single daily dose of Physalis peruviana L only. Toxic doses of NNK induced hyperplasia and adenocarcinoma in the lung and positive immunoreactivity for Ki-67 and p53 staining with disturbance of the lung DNA content. Administration of Physalis peruviana L with NNK led to a mild pulmonary hyperplasia and weak expression of Ki-67 and p53 with an improvement in the lung DNA content. Physalis peruviana L may protect against NNK induced lung carcinogenesis due to its antioxidant and anti-proliferative effects.

  20. Acceleration of lung metastasis by up-regulation of CD44 expression in osteosarcoma-derived cell transplanted mice.

    Science.gov (United States)

    Shiratori, H; Koshino, T; Uesugi, M; Nitto, H; Saito, T

    2001-09-20

    The effect of CD44-phenotypic expression on metastasis to the lung was studied using a spontaneous murine osteosarcoma-derived cell line, POS-1, stimulated with lipopolysaccharide (LPS). POS-1 cells were inoculated into the hind paws of 20 C3H/HeJ mice and produced a visible mass in all mice in 5 weeks, and these transplanted tumors resulted in lung metastasis in all mice. The number of metastatic foci in the lungs was 12.0+/-2.1 (mean+/-SD) with LPS-stimulated cells, which was significantly higher than that of unstimulated cells (5.8+/-1.4; N=10 for each; P<0.05). Hyaluronate (HA), a ligand of CD44, inhibited a number of lung metastases in a dose-dependent manner (0.5% HA, 3.0+/-1.1; 0.005% HA, 5.1+/-1.5; without HA, 8.6+/-1.7; N=10 for each; P<0.05, each group with HA versus the group without HA). Adhesion assay by coculturing POS-1 cells and lung microvascular endothelial cells on culture plate showed that the adhesion was significantly lower in HA treated POS-1 than those without HA (1.18+/-0.12 and 2.74+/-0.17, respectively, P<0.05). These results suggest that lung metastasis was accelerated by up-regulation of CD44.

  1. Therapy monitoring using dynamic MRI: Analysis of lung motion and intrathoracic tumor mobility before and after radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Plathow, Christian [Eberhard-Karls University Tuebingen, Department of Diagnostic Radiology, Tuebingen (Germany); German Cancer Research Center, Department of Radiology, Heidelberg (Germany); Hof, Holger; Kuhn, Sabine [University of Heidelberg, Department of Radiation Therapy, Clinic for Thoracic Diseases, Heidelberg (Germany); Puderbach, Michael; Ley, Sebastian; Biederer, Juergen; Kauczor, Hans-Ulrich [German Cancer Research Center, Department of Radiology, Heidelberg (Germany); Claussen, Claus D.; Schaefer, Juergen [Eberhard-Karls University Tuebingen, Department of Diagnostic Radiology, Tuebingen (Germany); Huber, Peter E. [University of Heidelberg, Department of Radiation Therapy, Clinic for Thoracic Diseases, Heidelberg (Germany); German Cancer Research Center, Department of Radiation Oncology, Heidelberg (Germany); Tuengerthal, Siegfried [University of Heidelberg, Department of Radiology, Heidelberg (Germany)

    2006-09-15

    A frequent side effect after radiotherapy of lung tumors is a decrease of pulmonary function accompanied by dyspnea due to developing lung fibrosis. The aim of this study was to monitor lung motion as a correlate of pulmonary function and intrathoracic tumor mobility before and after radiotherapy (RT) using dynamic MRI (dMRI). Thirty-five patients with stage I non-small-cell lung carcinoma were examined using dMRI (trueFISP; three images/s). Tumors were divided into T1 and T2 tumors of the upper, middle and lower lung region (LR). Maximum craniocaudal (CC) lung dimensions and tumor mobility in three dimensions were monitored. Vital capacity (VC) was measured and correlated using spirometry. Before RT, the maximum CC motion of the tumor-bearing hemithorax was 5.2{+-}0.9 cm if the tumor was located in the lower LR (middle LR: 5.5{+-}0.8 cm; upper LR: 6.0{+-}0.6 cm). After RT, lung motion was significantly reduced in the lower LR (P<0.05). Before RT, the maximum CC tumor mobility was significantly higher in tumors of the lower LR 2.5{+-}0.6 vs. 2.0{+-}0.3 cm (middle LR; P<0.05) vs. 0.7{+-}0.2 cm (upper LR; P<0.01). After RT, tumor mobility was significantly reduced in the lower LR (P<0.01) and in T2 tumor patients (P<0.05). VC showed no significant changes. dMRI is capable of monitoring changes in lung motion that were not suspected from spirometry. This might make the treatment of side effects possible at a very early stage. Changes of lung motion and tumor mobility are highly dependent on the tumor localization and tumor diameter. (orig.)

  2. Real-Time Tumor Tracking in the Lung Using an Electromagnetic Tracking System

    Energy Technology Data Exchange (ETDEWEB)

    Shah, Amish P., E-mail: Amish.Shah@orlandohealth.com [Department of Radiation Oncology, MD Anderson Cancer Center Orlando, Orlando, Florida (United States); Kupelian, Patrick A.; Waghorn, Benjamin J.; Willoughby, Twyla R.; Rineer, Justin M.; Mañon, Rafael R.; Vollenweider, Mark A.; Meeks, Sanford L. [Department of Radiation Oncology, MD Anderson Cancer Center Orlando, Orlando, Florida (United States)

    2013-07-01

    Purpose: To describe the first use of the commercially available Calypso 4D Localization System in the lung. Methods and Materials: Under an institutional review board-approved protocol and an investigational device exemption from the US Food and Drug Administration, the Calypso system was used with nonclinical methods to acquire real-time 4-dimensional lung tumor tracks for 7 lung cancer patients. The aims of the study were to investigate (1) the potential for bronchoscopic implantation; (2) the stability of smooth-surface beacon transponders (transponders) after implantation; and (3) the ability to acquire tracking information within the lung. Electromagnetic tracking was not used for any clinical decision making and could only be performed before any radiation delivery in a research setting. All motion tracks for each patient were reviewed, and values of the average displacement, amplitude of motion, period, and associated correlation to a sinusoidal model (R{sup 2}) were tabulated for all 42 tracks. Results: For all 7 patients at least 1 transponder was successfully implanted. To assist in securing the transponder at the tumor site, it was necessary to implant a secondary fiducial for most transponders owing to the transponder's smooth surface. For 3 patients, insertion into the lung proved difficult, with only 1 transponder remaining fixed during implantation. One patient developed a pneumothorax after implantation of the secondary fiducial. Once implanted, 13 of 14 transponders remained stable within the lung and were successfully tracked with the tracking system. Conclusions: Our initial experience with electromagnetic guidance within the lung demonstrates that transponder implantation and tracking is achievable though not clinically available. This research investigation proved that lung tumor motion exhibits large variations from fraction to fraction within a single patient and that improvements to both transponder and tracking system are still

  3. Quantitative Analysis of Survivin Protein Expression and Its Therapeutic Depletion by an Antisense Oligonucleotide in Human Lung Tumors

    Directory of Open Access Journals (Sweden)

    Anna L Olsen

    2012-01-01

    Full Text Available RNA-directed antisense and interference therapeutics are a promising treatment option for cancer. The demonstration of depletion of target proteins within human tumors in vivo using validated methodology will be a key to the application of this technology. Here, we present a flow cytometric-based approach to quantitatively determine protein levels in solid tumor material derived by fiber optic brushing (FOB of non-small cell lung cancer (NSCLC patients. Focusing upon the survivin protein, and its depletion by an antisense oligonucleotide (ASO (LY2181308, we show that we can robustly identify a subpopulation of survivin positive tumor cells in FOB samples, and, moreover, detect survivin depletion in tumor samples from a patient treated with LY2181308. Survivin depletion appears to be a result of treatment with this ASO, because a tumor treated with conventional cytotoxic chemotherapy did not exhibit a decreased percentage of survivin positive cells. Our approach is likely to be broadly applicable to, and useful for, the quantification of protein levels in tumor samples obtained as part of clinical trials and studies, facilitating the proof-of-principle testing of novel targeted therapies.

  4. Adaptation and applications of a realistic digital phantom based on patient lung tumor trajectories

    Science.gov (United States)

    Mishra, Pankaj; St. James, Sara; Segars, W Paul; Berbeco, Ross I; Lewis, John H

    2012-01-01

    Digital phantoms continue to play a significant role in modeling and characterizing medical imaging. The currently available XCAT phantom incorporates both the flexibility of mathematical phantoms and the realistic nature of voxelized phantoms. This phantom generates images based on a regular breathing pattern and can include arbitrary lung tumor trajectories. In this work, we present an algorithm that modifies the current XCAT phantom to generate 4D imaging data based on irregular breathing. First, a parameter is added to the existing XCAT phantom to include any arbitrary tumor motion. This modification introduces the desired tumor motion but, comes at the cost of decoupled diaphragm, chest wall and lung motion. To remedy this problem diaphragm and chest wall motion is first modified based on initial tumor location and then input to the XCAT phantom. This generates a phantom with synchronized respiratory motion. Mapping of tumor motion trajectories to diaphragm and chest wall motion is done by adaptively calculating a scale factor based on tumor to lung contour distance. The distance is calculated by projecting the initial tumor location to lung edge contours characterized by quadratic polynomials. Data from 10 patients were used to evaluate the accuracy between actual independent tumor location and the location obtained from the modified XCAT phantom. The rmse and standard deviations for 10 patients in x, y, and z directions are: (0.29 ± 0.04, 0.54 ± 0.17, and 0.39 ± 0.06) mm. To demonstrate the utility of the phantom, we use the new phantom to simulate a 4DCT acquisition as well as a recently published method for phase sorting. The modified XCAT phantom can be used to generate more realistic imaging data for enhanced testing of algorithms for CT reconstruction, tumor tracking, and dose reconstruction. PMID:22595980

  5. WE-G-BRF-06: Positron Emission Tomography (PET)-Guided Dynamic Lung Tumor Tracking for Cancer Radiotherapy: First Patient Simulations

    Energy Technology Data Exchange (ETDEWEB)

    Yang, J; Loo, B; Graves, E [Stanford University, Stanford, CA (United States); Yamamoto, T [UC Davis School of Medicine, Sacramento, CA (United States); Keall, P [University of Sydney, Camperdown (Australia)

    2014-06-15

    Purpose: PET-guided dynamic tumor tracking is a novel concept of biologically targeted image guidance for radiotherapy. A dynamic tumor tracking algorithm based on list-mode PET data has been developed and previously tested on dynamic phantom data. In this study, we investigate if dynamic tumor tracking is clinically feasible by applying the method to lung cancer patient PET data. Methods: PET-guided tumor tracking estimates the target position of a segmented volume in PET images reconstructed continuously from accumulated coincidence events correlated with external respiratory motion, simulating real-time applications, i.e., only data up to the current time point is used to estimate the target position. A target volume is segmented with a 50% threshold, consistently, of the maximum intensity in the predetermined volume of interest. Through this algorithm, the PET-estimated trajectories are quantified from four lung cancer patients who have distinct tumor location and size. The accuracy of the PET-estimated trajectories is evaluated by comparing to external respiratory motion because the ground-truth of tumor motion is not known in patients; however, previous phantom studies demonstrated sub-2mm accuracy using clinically derived 3D tumor motion. Results: The overall similarity of motion patterns between the PET-estimated trajectories and the external respiratory traces implies that the PET-guided tracking algorithm can provide an acceptable level of targeting accuracy. However, there are variations in the tracking accuracy between tumors due to the quality of the segmentation which depends on target-to-background ratio, tumor location and size. Conclusion: For the first time, a dynamic tumor tracking algorithm has been applied to lung cancer patient PET data, demonstrating clinical feasibility of real-time tumor tracking for integrated PET-linacs. The target-to-background ratio is a significant factor determining accuracy: screening during treatment planning would

  6. Vascular Basement Membrane-derived Multifunctional Peptide, a Novel Inhibitor of Angiogenesis and Tumor Growth

    Institute of Scientific and Technical Information of China (English)

    Jian-Guo CAO; Shu-Ping PENG; Li SUN; Hui LI; Li WANG; Han-Wu DENG

    2006-01-01

    Vascular basement membrane-derived multifunctional peptide (VBMDMP) gene (fusion gene of the human immunoglobulin G3 upper hinge region and two tumstatin-derived fragments) obtained by chemical synthesis was cloned into vector pUC 19, and introduced into the expression vector pGEX-4T-1 to construct a prokaryotic expression vector pGEX-4T-1-VBMDMP. Recombinant VBMDMP produced in Escherichia coli has been shown to have significant activity of antitumor growth and antimetastasis in Lewis lung carcinoma transplanted into mouse C57B1/6. In the present study, we have studied the ability of rVBMDMP to inhibit endothelial cell tube formation and proliferation, to induce apoptosis in vitro, and to suppress tumor growth in vivo. The experimental results showed that rVBMDMP potently inhibited proliferation of human endothelial (HUVEC-12) cells and human colon cancer (SW480) cells in vitro, with no inhibition of proliferation in Chinese hamster ovary (CHO-K1) cells. rVBMDMP also significantly inhibited human endothelial cell tube formation and suppressed tumor growth of SW480 cells in a mouse xenograft model. These results suggest that rVBMDMP is a powerful therapeutic agent for suppressing angiogenesis and tumor growth.

  7. Characterization of iodinated adrenomedullin derivatives suitable for lung nuclear medicine

    Energy Technology Data Exchange (ETDEWEB)

    Fu Yan; Letourneau, Myriam; Chatenet, David [Laboratoire d' etudes moleculaires et pharmacologiques des peptides, INRS-Institut Armand-Frappier, Ville de Laval, Qc, H7V 1B7 (Canada); Dupuis, Jocelyn [Research Center, Montreal Heart Institute, Montreal, Qc (Canada); Department of Medicine, University of Montreal, Montreal, Qc (Canada); Fournier, Alain, E-mail: alain.fournier@iaf.inrs.ca [Laboratoire d' etudes moleculaires et pharmacologiques des peptides, INRS-Institut Armand-Frappier, Ville de Laval, Qc, H7V 1B7 (Canada)

    2011-08-15

    Introduction: We have recently demonstrated the effectiveness of 99m-technetium adrenomedullin (AM) as a new molecular lung imaging agent that could provide significant advantages for the diagnosis and follow-up of disorders affecting the pulmonary circulation such as pulmonary embolism and pulmonary hypertension. Having the possibility to conjugate the targeting molecule with different radionuclides would offer more flexibility and potential advantages depending on clinical situations. Since various iodine isotopes are currently used in nuclear medicine and in pharmacological studies, we have evaluated which iodination method should be privileged in order to produce a good iodinated AM-derived nuclear medicine agent. Methods: Synthetic AM was labeled with iodine through chemical and lactoperoxidase oxidation methods. Position of the iodine atom on the peptide was determined by MALDI-TOF mass spectrometry analysis following cyanogen bromide cleavage and carboxypeptidase Y digestion. Binding affinity of iodinated AM analogues was evaluated by competition and saturation binding experiments on dog lung preparations. Results: In this study, we demonstrated that, upon lactoperoxidase oxidation, iodination occurred at Tyr{sup 1} and that this radioligand retained higher binding affinity and specificity over preparations obtained through chemical oxidation. Conclusions: These results emphasize the fact that even a small chemical modification, i.e. iodination, might deeply modify the pharmacological profile of a compound and support observations that the C-terminal tail of human AM plays an important role in the AM receptor binding process. Consequently, incorporation of a radionuclide to produce an AM-based nuclear medicine agent should privilege the N-terminus of the molecule.

  8. Malignant ameloblastoma (metastatic ameloblastoma) in the lung: 3 cases of misdiagnosis as primary lung tumor with a unique growth pattern.

    Science.gov (United States)

    Bi, Rui; Shen, Lei; Zhu, Xiongzeng; Xu, Xiaoli

    2015-07-25

    Malignant ameloblastoma (metastatic ameloblastoma, MA) is currently defined as a distinct pathologic entity, MA, despite its histologically benign appearance. According to the new criteria, the histological and clinical features of MA are more homogenous. Here, we report three cases of histologically confirmed pulmonary MA. Two of the three patients complained of chest pain as the primary symptom, and the other case was detected upon the evaluation of pulmonary nodules found during a health examination after a local recurrence of mandible ameloblastoma. All three patients were female with an average age of 48 years. The intervals between the primary ameloblastoma and metastasis to the lung were 14 years, 19 years and 10 years, averaging 14.3 years. Prior to metastasis to the lung, only one patient experienced local recurrences, at 5 and 19 years after the primary tumor resection, while the other two patients both remained disease-free. Computed tomography (CT) or X-ray evaluation demonstrated multiple bilateral lung nodules ranging in size from several millimeters up to 2 cm. Histologically, the pulmonary metastatic tumors showed a unique growth pattern: the tumor cells grew among the interstitial alveoli but did not appear to destructively infiltrate the surrounding tissue. Immunohistochemically, the MA cells expressed squamous differentiation markers, such as CK10/13 and p63, while the alveolar epithelial cells stained for TTF1 and PE10. In this paper, we discuss the clinical behavior, differential diagnosis and unique growth pattern of pulmonary MA.

  9. Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs.

    Science.gov (United States)

    Halvorsen, E C; Hamilton, M J; Young, A; Wadsworth, B J; LePard, N E; Lee, H N; Firmino, N; Collier, J L; Bennewith, K L

    2016-06-01

    Regulatory T cells (Tregs) play a crucial physiological role in the regulation of immune homeostasis, although recent data suggest Tregs can contribute to primary tumor growth by suppressing antitumor immune responses. Tregs may also influence the development of tumor metastases, although there is a paucity of information regarding the phenotype and function of Tregs in metastatic target organs. Herein, we demonstrate that orthotopically implanted metastatic mammary tumors induce significant Treg accumulation in the lungs, which is a site of mammary tumor metastasis. Tregs in the primary tumor and metastatic lungs express high levels of C-C chemokine receptor type 5 (CCR5) relative to Tregs in the mammary fat pad and lungs of tumor-free mice, and Tregs in the metastatic lungs are enriched for CCR5 expression in comparison to other immune cell populations. We also identify that C-C chemokine ligand 8 (CCL8), an endogenous ligand of CCR5, is produced by F4/80(+) macrophages in the lungs of mice with metastatic primary tumors. Migration of Tregs toward CCL8 ex vivo is reduced in the presence of the CCR5 inhibitor Maraviroc. Importantly, treatment of mice with Maraviroc (MVC) reduces the level of CCR5(+) Tregs and metastatic tumor burden in the lungs. This work provides evidence of a CCL8/CCR5 signaling axis driving Treg recruitment to the lungs of mice bearing metastatic primary tumors, representing a potential therapeutic target to decrease Treg accumulation and metastatic tumor growth.

  10. Automatic lung tumor segmentation on PET/CT images using fuzzy Markov random field model.

    Science.gov (United States)

    Guo, Yu; Feng, Yuanming; Sun, Jian; Zhang, Ning; Lin, Wang; Sa, Yu; Wang, Ping

    2014-01-01

    The combination of positron emission tomography (PET) and CT images provides complementary functional and anatomical information of human tissues and it has been used for better tumor volume definition of lung cancer. This paper proposed a robust method for automatic lung tumor segmentation on PET/CT images. The new method is based on fuzzy Markov random field (MRF) model. The combination of PET and CT image information is achieved by using a proper joint posterior probability distribution of observed features in the fuzzy MRF model which performs better than the commonly used Gaussian joint distribution. In this study, the PET and CT simulation images of 7 non-small cell lung cancer (NSCLC) patients were used to evaluate the proposed method. Tumor segmentations with the proposed method and manual method by an experienced radiation oncologist on the fused images were performed, respectively. Segmentation results obtained with the two methods were similar and Dice's similarity coefficient (DSC) was 0.85 ± 0.013. It has been shown that effective and automatic segmentations can be achieved with this method for lung tumors which locate near other organs with similar intensities in PET and CT images, such as when the tumors extend into chest wall or mediastinum.

  11. Automatic Lung Tumor Segmentation on PET/CT Images Using Fuzzy Markov Random Field Model

    Directory of Open Access Journals (Sweden)

    Yu Guo

    2014-01-01

    Full Text Available The combination of positron emission tomography (PET and CT images provides complementary functional and anatomical information of human tissues and it has been used for better tumor volume definition of lung cancer. This paper proposed a robust method for automatic lung tumor segmentation on PET/CT images. The new method is based on fuzzy Markov random field (MRF model. The combination of PET and CT image information is achieved by using a proper joint posterior probability distribution of observed features in the fuzzy MRF model which performs better than the commonly used Gaussian joint distribution. In this study, the PET and CT simulation images of 7 non-small cell lung cancer (NSCLC patients were used to evaluate the proposed method. Tumor segmentations with the proposed method and manual method by an experienced radiation oncologist on the fused images were performed, respectively. Segmentation results obtained with the two methods were similar and Dice’s similarity coefficient (DSC was 0.85 ± 0.013. It has been shown that effective and automatic segmentations can be achieved with this method for lung tumors which locate near other organs with similar intensities in PET and CT images, such as when the tumors extend into chest wall or mediastinum.

  12. Lung mass in a 28-year-old male: a case report of a rare tumor.

    Science.gov (United States)

    Mroz, Robert M; Korniluk, M; Swidzinska, E; Dzieciol, J; Czaban, J; Panek, B; Chyczewska, E

    2010-11-01

    A twenty eight-year-old male presented with a two week history of dyspnea, cough, hemoptysis, chest pain, and fever 38-39°C. He also complained of loss of appetite, general weakness and left leg pain for two months preceding admission. He was referred with suspicion of lung tumor to our institution. Chest X-ray showed almost total atelectasis of the right lung with compensatory overinflation of the contralateral lung. Using computed tomography (CT), a lesion of diameter of 19.3 x 14.1 x 19.1 cm in the right lung, pleuritis, Th3 osteolysis, and compensatory overinflation of the left lung was seen. Bronchoscopy revealed a total obstruction of the right main bronchus due to submucosal infiltration and compression of the right main bronchus with negative histology of bronchial biopsy specimens. Transthoracic fine needle aspiration revealed celullae suspectae probabiliter neoplasmaticae suggesting tumor fusocellularis. USG of the abdomen revealed liver with numerous heterogeneous, solid areas hypo- and hyperechogenic, some of them with features of liquid or the disintegration up to diameter of 74 mm. Subsequent fine needle aspirations of the thorax and liver revealed fibrolamellar hepatocarcinoma and carcinoma adenoides of the lung. Patient underwent chemotherapy with 5-FU/DDP/VCR with no response. This report presents a case of a rare lung metastasis from FL-HCC.

  13. Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression.

    Science.gov (United States)

    Kong, Ruirui; Yi, Fengshuang; Wen, Pushuai; Liu, Jianghong; Chen, Xiaoping; Ren, Jinqi; Li, Xiaofei; Shang, Yulong; Nie, Yongzhan; Wu, Kaichun; Fan, Daiming; Zhu, Li; Feng, Wei; Wu, Jane Y

    2015-11-03

    Emerging evidence indicates that the neuronal guidance molecule SLIT plays a role in tumor suppression, as SLIT-encoding genes are inactivated in several types of cancer, including lung cancer; however, it is not clear how SLIT functions in lung cancer. Here, our data show that SLIT inhibits cancer cell migration by activating RhoA and that myosin 9b (Myo9b) is a ROBO-interacting protein that suppresses RhoA activity in lung cancer cells. Structural analyses revealed that the RhoGAP domain of Myo9b contains a unique patch that specifically recognizes RhoA. We also determined that the ROBO intracellular domain interacts with the Myo9b RhoGAP domain and inhibits its activity; therefore, SLIT-dependent activation of RhoA is mediated by ROBO inhibition of Myo9b. In a murine model, compared with control lung cancer cells, SLIT-expressing cells had a decreased capacity for tumor formation and lung metastasis. Evaluation of human lung cancer and adjacent nontumor tissues revealed that Myo9b is upregulated in the cancer tissue. Moreover, elevated Myo9b expression was associated with lung cancer progression and poor prognosis. Together, our data identify Myo9b as a key player in lung cancer and as a ROBO-interacting protein in what is, to the best of our knowledge, a newly defined SLIT/ROBO/Myo9b/RhoA signaling pathway that restricts lung cancer progression and metastasis. Additionally, our work suggests that targeting the SLIT/ROBO/Myo9b/RhoA pathway has potential as a diagnostic and therapeutic strategy for lung cancer.

  14. Evaluation of lung tumor response to therapy: Current and emerging techniques.

    Science.gov (United States)

    Coche, E

    2016-10-01

    Lung tumor response to therapy may be evaluated in most instances by morphological criteria such as RECIST 1.1 on computed tomography (CT) or magnetic resonance imaging (MRI). However, those criteria are limited because they are based on tumoral dimensional changes and do not take into account other morphologic criteria such as density evaluation, functional or metabolic changes that may occur following conventional or targeted chemotherapy. New techniques such as dual-energy CT, PET-CT, MRI including diffusion-weighted MRI has to be considered into the new technical armamentarium for tumor response evaluation. Integration of all informations provided by the different imaging modalities has to be integrated and represents probably the future goal of tumor response evaluation. The aim of the present paper is to review the current and emerging imaging criteria used to evaluate the response of therapy in the field of lung cancer.

  15. Peptide Agonists of Vasopressin V2 Receptor Reduce Expression of Neuroendocrine Markers and Tumor Growth in Human Lung and Prostate Tumor Cells

    Science.gov (United States)

    Pifano, Marina; Garona, Juan; Capobianco, Carla S.; Gonzalez, Nazareno; Alonso, Daniel F.; Ripoll, Giselle V.

    2017-01-01

    Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that express neuropeptides as synaptophysin, chromogranin A (CgA), and specific neuronal enolase (NSE), among others. Vasopressin (AVP) is a neuropeptide with an endocrine, paracrine, and autocrine effect in normal and pathological tissues. AVP receptors are present in human lung, breast, pancreatic, colorectal, and gastrointestinal tumors. While AVP V1 receptors are associated with stimulation of cellular proliferation, AVP V2 receptor (V2r) is related to antiproliferative effects. Desmopressin (dDAVP) is a synthetic analog of AVP that acts as a selective agonist for the V2r, which shows antitumor properties in breast and colorectal cancer models. Recently, we developed a derivative of dDAVP named [V4Q5]dDAVP, which presents higher antitumor effects in a breast cancer model compared to the parental compound. The goal of present work was to explore the antitumor properties of the V2r agonist dDAVP and its novel analog [V4Q5]dDAVP on aggressive human lung (NCI-H82) and prostate cancer (PC-3) cell lines with neuroendocrine (NE) characteristics. We study the presence of specific NE markers (CgA and NSE) and V2r expression in NCI-H82 and PC-3. Both cell lines express high levels of NE markers NSE and CgA but then incubation with dDAVP diminished expression levels of both markers. DDAVP and [V4Q5]dDAVP significantly reduced proliferation, doubling time, and migration in both tumor cell cultures. [V4Q5]dDAVP analog showed a higher cytostatic effect than dDAVP, on cellular proliferation in the NCI-H82 cell line. Silencing of V2r using small interfering RNA significantly attenuated the inhibitory effects of [V4Q5]dDAVP on NCI-H82 cell proliferation. We, preliminarily, explored the in vivo effect of dDAVP and [V4Q5]dDAVP on NCI-H82 small cell lung cancer xenografts. Treated tumors (0.3 μg kg−1, thrice a week) grew slower in comparison to vehicle-treated animals. In this work, we demonstrated

  16. Lung cancer tumorigenicity and drug resistance are maintained through ALDH(hi)CD44(hi) tumor initiating cells.

    Science.gov (United States)

    Liu, Jing; Xiao, Zhijie; Wong, Sunny Kit-Man; Tin, Vicky Pui-Chi; Ho, Ka-Yan; Wang, Junwen; Sham, Mai-Har; Wong, Maria Pik

    2013-10-01

    Limited improvement in long term survival of lung cancer patients has been achieved by conventional chemotherapy or targeted therapy. To explore the potentials of tumor initiating cells (TIC)-directed therapy, it is essential to identify the cell targets and understand their maintenance mechanisms. We have analyzed the performance of ALDH/CD44 co-expression as TIC markers and treatment targets of lung cancer using well-validated in vitro and in vivo analyses in multiple established and patient-derived lung cancer cells. The ALDH(hi)CD44(hi) subset showed the highest enhancement of stem cell phenotypic properties compared to ALDH(hi)CD44(lo), ALDH(lo)CD44(hi), ALDH(lo)CD44(lo) cells and unsorted controls. They showed higher invasion capacities, pluripotency genes and epithelial-mesenchymal transition transcription factors expression, lower intercellular adhesion protein expression and higher G2/M phase cell cycle fraction. In immunosuppressed mice, the ALDH(hi)CD44(hi)xenografts showed the highest tumor induction frequency, serial transplantability, shortest latency, largest volume and highest growth rates. Inhibition of sonic Hedgehog and Notch developmental pathways reduced ALDH+CD44+ compartment. Chemotherapy and targeted therapy resulted in higher AALDH(hi)CD44(hi) subset viability and ALDH(lo)CD44(lo) subset apoptosis fraction. ALDH inhibition and CD44 knockdown led to reduced stemness gene expression and sensitization to drug treatment. In accordance, clinical lung cancers containing a higher abundance of ALDH and CD44-coexpressing cells was associated with lower recurrence-free survival. Together, results suggested theALDH(hi)CD44(hi)compartment was the cellular mediator of tumorigenicity and drug resistance. Further investigation of the regulatory mechanisms underlying ALDH(hi)CD44(hi)TIC maintenance would be beneficial for the development of long term lung cancer control.

  17. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells.

    Science.gov (United States)

    Longmire, Tyler A; Ikonomou, Laertis; Hawkins, Finn; Christodoulou, Constantina; Cao, Yuxia; Jean, J C; Kwok, Letty W; Mou, Hongmei; Rajagopal, Jayaraj; Shen, Steven S; Dowton, Anne A; Serra, Maria; Weiss, Daniel J; Green, Michael D; Snoeck, Hans-Willem; Ramirez, Maria I; Kotton, Darrell N

    2012-04-06

    Two populations of Nkx2-1(+) progenitors in the developing foregut endoderm give rise to the entire postnatal lung and thyroid epithelium, but little is known about these cells because they are difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling, can specify these cells efficiently from definitive endodermal precursors. When derived using Nkx2-1(GFP) knockin reporter ESCs, these progenitors can be purified for expansion in culture and have a transcriptome that overlaps with developing lung epithelium. Upon induction, they can express a broad repertoire of markers indicative of lung and thyroid lineages and can recellularize a 3D lung tissue scaffold. Thus, we have derived a pure population of progenitors able to recapitulate the developmental milestones of lung/thyroid development.

  18. Expression and Clinical Significance of SHP2 in the Tumor Tissues of Smokers with Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xuemei ZHAN

    2010-09-01

    Full Text Available Background and objective It has been proved that protein phosphorylation and dephosphorylation were important mechanisms in lung cancer development, and tobacco smoking is an important risk factor of lung cancer. The aim of this study is to investigate the expression and clinical significance of protein tyrosine phosphatase SHP2 in non-small cell lung cancer (NSCLC and small cell lung cancer (SCLC; the relationship between tobacco smoking and the expression of SHP2 is also studied. Methods Immunohistochemistry (Invision and fluorescence in situ hybridization (FISH were used to detect the expression of SHP2 and the augment of SHP2 mRNA in the 53 lung cancer specimens. Results The weak positive rate of SHP2 was 80% (which was also the total positive rate in normal bronchial epithelium. The weak, moderate and strong positive rates were 35.4%, 43.8% and 6.2% (total positive rate was 85.4% in 48 NSCLC patients, 0%, 80% and 20% (total positve rate was 100% in 5 SCLC patients, 40.7%, 37.4% and 3.7% (total positive rate was 81.5% in the tumor tissues of 27 NSCLC patients who didn’t smoke and 23.8%, 71.4% and 4.7% (total positive rate was 100% in the tumor tissues of 21 NSCLC patients whose smoking indexes were ≥400. Significant differences of SHP2 expression were observed between tumor tissues and normal bronchial epithelium, NSCLC and SCLC, and between different smoking indexes (P < 0.05. Conclusion The enhancement of SHP2 expression in the tumor tissues of NSCLC patients who smoke may be correlated with tobacco smoking; SHP2 may play certain role in the development of lung cancer; SHP2 prospectively provides new ideas for the drug research and development of lung cancer treatment.

  19. SU-E-J-29: Audiovisual Biofeedback Improves Tumor Motion Consistency for Lung Cancer Patients

    Energy Technology Data Exchange (ETDEWEB)

    Lee, D; Pollock, S; Makhija, K; Keall, P [The University of Sydney, Camperdown, NSW (Australia); Greer, P [The University of Newcastle, Newcastle, NSW (Australia); Calvary Mater Newcastle Hospital, Newcastle, NSW (Australia); Arm, J; Hunter, P [Calvary Mater Newcastle Hospital, Newcastle, NSW (Australia); Kim, T [The University of Sydney, Camperdown, NSW (Australia); University of Virginia Health System, Charlottesville, VA (United States)

    2014-06-01

    Purpose: To investigate whether the breathing-guidance system: audiovisual (AV) biofeedback improves tumor motion consistency for lung cancer patients. This will minimize respiratory-induced tumor motion variations across cancer imaging and radiotherapy procedues. This is the first study to investigate the impact of respiratory guidance on tumor motion. Methods: Tumor motion consistency was investigated with five lung cancer patients (age: 55 to 64), who underwent a training session to get familiarized with AV biofeedback, followed by two MRI sessions across different dates (pre and mid treatment). During the training session in a CT room, two patient specific breathing patterns were obtained before (Breathing-Pattern-1) and after (Breathing-Pattern-2) training with AV biofeedback. In each MRI session, four MRI scans were performed to obtain 2D coronal and sagittal image datasets in free breathing (FB), and with AV biofeedback utilizing Breathing-Pattern-2. Image pixel values of 2D images after the normalization of 2D images per dataset and Gaussian filter per image were used to extract tumor motion using image pixel values. The tumor motion consistency of the superior-inferior (SI) direction was evaluated in terms of an average tumor motion range and period. Results: Audiovisual biofeedback improved tumor motion consistency by 60% (p value = 0.019) from 1.0±0.6 mm (FB) to 0.4±0.4 mm (AV) in SI motion range, and by 86% (p value < 0.001) from 0.7±0.6 s (FB) to 0.1±0.2 s (AV) in period. Conclusion: This study demonstrated that audiovisual biofeedback improves both breathing pattern and tumor motion consistency for lung cancer patients. These results suggest that AV biofeedback has the potential for facilitating reproducible tumor motion towards achieving more accurate medical imaging and radiation therapy procedures.

  20. Lung metastases

    Science.gov (United States)

    Metastases to the lung; Metastatic cancer to the lung; Lung cancer - metastases ... Metastatic tumors in the lungs are cancers that developed at other places in the body (or other parts of the lungs). They then spread through ...

  1. Effect of duration of scan acquisition on CT perfusion parameter values in primary and metastatic tumors in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Ng, Chaan S., E-mail: cng@mdanderson.org [Departments of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Chandler, Adam G., E-mail: adam.chandler@mdanderson.org [Departments of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); CT research, GE Healthcare, Waukesha, Wisconsin (United States); Wei, Wei, E-mail: wwei@mdanderson.org [Departments of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Anderson, Ella F., E-mail: eanderson@mdanderson.org [Departments of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Herron, Delise H., E-mail: dherron@mdanderson.org [Departments of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kurzrock, Razelle, E-mail: rkurzrock@ucsd.edu [Departments of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Charnsangavej, Chusilp, E-mail: ccharn@mdanderson.org [Departments of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-10-01

    Objectives: To assess the effect of acquisition duration (T{sub acq}) and pre-enhancement set points (T{sub 1}) on computer tomography perfusion (CTp) parameter values in primary and metastatic tumors in the lung. Materials and methods: 24 lung CTp datasets (10 primary; 14 metastatic), acquired using a two phase protocol spanning 125 s, in 12 patients with lung tumors, were analyzed by deconvolution modeling to yield tumor blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability (PS) values. CTp analyses were undertaken for the reference dataset (i.e., T{sub 1} = t{sub 0}) with varying T{sub acq} from 12 to 125 s. This was repeated for shifts in T{sub 1} (±0.5 s, ±1.0 s, ±2.0 s relative to the reference at t{sub 0}). Resultant CTp values were plotted against T{sub acq}; values at 30 s, 50 s, 65 s and 125 s were compared using linear mixed model. Results: All CTp parameter values were noticeably influenced by T{sub acq}, with generally less marked changes beyond 50 s, and with no difference in behavior between primary and secondary tumors. Apart from BV, which attained a plateau at approximately 50 s, the other three CTp parameters did not reach steady-state values within the available 125 s of data, with values at 30 s, 50 s and 65 s significantly different from 125 s (p < 0.004). Shifts in T{sub 1} also affected the CTp parameters values, with positive shifts having greater impact on CTp values than negative shifts. Conclusion: CTp parameter values derived from deconvolution modeling can be markedly affected by T{sub acq}, and pre-enhancement set-points. 50 s acquisition may be adequate for BV, but longer than 125 s is probably required for reliable characterization of the other three CTp parameters.

  2. Tumor Imaging in Patients with Advanced Tumors Using a New 99mTc-Radiolabeled Vitamin B12 Derivative

    DEFF Research Database (Denmark)

    Sah, Bert-Ram; Schibli, Roger; Waibel, Robert

    2014-01-01

    of the lung, 3 with squamous cell carcinomas of the hypopharyngeal region, 1 with prostate adenocarcinoma, 1 with breast, and 1 with colon adenocarcinoma. RESULTS: The median age of the study group was 61 ± 11 y. Six of 10 patients showed positive tumor uptake on (99m)Tc-PAMA-cobalamin whole-body scintigraphy...... activity using SPECT/CT over the tumor region after 4 h was measured in comparison to disease-free lung parenchyma. Patients 3-10 received between 20 and 1,000 μg of cobalamin intravenously before injection of (99m)Tc-PAMA-cobalamin. The study population comprised 4 patients with adenocarcinomas....... The scan was positive in 1 patient with colon adenocarcinoma, in 3 of 4 lung adenocarcinomas, in 1 of 3 hypopharyngeal squamous cell carcinomas, and in 1 breast adenocarcinoma. Renal uptake was between 1% and 3% for the left kidney. Predosing with cobalamin increased the tumor uptake and improved blood...

  3. A chance-constrained programming level set method for longitudinal segmentation of lung tumors in CT.

    Science.gov (United States)

    Rouchdy, Youssef; Bloch, Isabelle

    2011-01-01

    This paper presents a novel stochastic level set method for the longitudinal tracking of lung tumors in computed tomography (CT). The proposed model addresses the limitations of registration based and segmentation based methods for longitudinal tumor tracking. It combines the advantages of each approach using a new probabilistic framework, namely Chance-Constrained Programming (CCP). Lung tumors can shrink or grow over time, which can be reflected in large changes of shape, appearance and volume in CT images. Traditional level set methods with a priori knowledge about shape are not suitable since the tumors are undergoing random and large changes in shape. Our CCP level set model allows to introduce a flexible prior to track structures with a highly variable shape by permitting a constraint violation of the prior up to a specified probability level. The chance constraints are computed from two given points by the user or from segmented tumors from a reference image. The reference image can be one of the images studied or an external template. We present a numerical scheme to approximate the solution of the proposed model and apply it to track lung tumors in CT. Finally, we compare our approach with a Bayesian level set. The CCP level set model gives the best results: it is more coherent with the manual segmentation.

  4. [Unilateral hyperlucent lung induced by a carcinoid tumor: comments on the differential diagnosis and mechanisms of hypoperfusion].

    Science.gov (United States)

    Schmitz, N; Bugnet, A-S; Demian, M; Massard, G; De Blay, F; Pauli, G

    2005-04-01

    We report the case of a 35-year-old woman in whom a systematic thoracic x-ray led to the diagnosis of unilateral hyperlucent lung due to a carcinoid tumor obstructing the main left bronchus almost completely. Injected computed tomography permitted diagnosis of left lung hypoperfusion and visualization of the tumor. After enlarged inferior left lobar resection, normal perfusion was observed six months later on the isotopic lung perfusion scan. Other reported causes of unilateral hyperlucent lung are discussed as well as pathophysiological mechanisms of lung hypoperfusion and hypoxic vasoconstriction.

  5. Modeling simulation and visualization of conformal 3D lung tumor dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Santhanam, Anand; Willoughby, Twyla R; Meeks, Sanford L; Kupelian, Patrick A [Department of Radiation Oncology, M D Anderson Cancer Center Orlando, 1400S Orange Ave., Orlando, FL 32806 (United States); Rolland, Jannick P [College of Optics and Photonics, University of Central Florida, 4000 Central Florida Blvd, Orlando, FL 32816 (United States)

    2009-10-21

    Lung tumors move during breathing depending on the patient's patho-physiological condition and orientation, thereby compromising the accurate deposition of the radiation dose during radiotherapy. In this paper, we present and validate a computer-based simulation framework to calculate the delivered dose to a 3D moving tumor and its surrounding normal tissues. The computer-based simulation framework models a 3D volumetric lung tumor and its surrounding tissues, simulates the tumor motion during a simulated dose delivery both as a self-reproducible motion and a random motion using the dose extracted from a treatment plan, and predicts the amount and location of radiation doses deposited. A radiation treatment plan of a small lung tumor (1-3 cm diameter) was developed in a commercial planning system (iPlan software, BrainLab, Munich, Germany) to simulate the radiation dose delivered. The dose for each radiation field was extracted from the software. The tumor motion was simulated for varying values of its rate, amplitude and direction within a single breath as well as from one breath to another. Such variations represent the variations in tumor motion induced by breathing variations. During the simulation of dose delivery, the dose on the target was summed to generate the real-time dose to the tumor for each beam independently. The simulation results show that the dose accumulated on the tumor varies significantly with both the tumor size and the tumor's motion rate, amplitude and direction. For a given tumor motion rate, amplitude and direction, the smaller the tumor size the smaller is the percentage of the radiation dose accumulated. The simulation results are validated by comparing the center plane of the 3D tumor with 2D film dosimetry measurements using a programmable 4D motion phantom moving in a self-reproducible pattern. The results also show the real-time capability of the framework at 40 discrete tumor motion steps per breath, which is higher than

  6. SHORT PEDF-DERIVED PEPTIDE INHIBITS ANGIOGENESIS AND TUMOR GROWTH

    Science.gov (United States)

    Mirochnik, Yelena; Aurora, Arin; Schulze-Hoepfner, Frank T.; Deabes, Ahmed; Shifrin, Victor; Beckmann, Richard; Polsky, Charles; Volpert, Olga V.

    2010-01-01

    Purpose Pigment epithelial-derived factor (PEDF) is a potent angiogenesis inhibitor with multiple other functions, some of which enhance tumor growth. Our previous studies mapped PEDF anti-angiogenic and pro-survival activities to distinct epitopes. This study was aimed to determine the minimal fragment of PEDF, which maintains anti-angiogenic and anti-tumor efficacy. Experimental Design We analyzed antigenicity, hydrophilicity, and charge distribution of the angioinhibitory epitope (the 34-mer) and designed three peptides covering its C-terminus, P14, P18 and P23. We analyzed their ability to block endothelial cell (EC) chemotaxis and induce apoptosis in vitro and their anti-angiogenic activity in vivo. The selected peptide was tested for the anti-tumor activity against mildly aggressive xenografted prostate carcinoma and highly aggressive renal cell carcinoma. To verify that P18 acts in the same manner as PEDF, we used immunohistochemistry to measure PEDF targets, VEGFR2 and CD95L expression in P18-treated vasculature. Results P14 and P18 blocked endothelial cell chemotaxis; P18 and P23 induced apoptosis. P18 showed the highest IC50 and blocked angiogenesis in vivo: P23 was inactive and P14 was pro-angiogenic. P18 increased the production of CD95L and reduced the expression of VEGFR-2 by the endothelial cells in vivo. In tumor studies, P18 was more effective in blocking the angiogenesis and growth of the prostate cancer then parental 34-mer; in the renal cell carcinoma P18 strongly decreased angiogenesis and halted the progression of established tumors. Conclusions P18 is a novel and potent anti-angiogenic biotherapeutic agent, which has potential to be developed for the treatment of prostate and renal cancer. PMID:19223494

  7. Cancer-associated fibroblasts from lung tumors maintain their immunosuppressive abilities after high-dose irradiation.

    Science.gov (United States)

    Gorchs, Laia; Hellevik, Turid; Bruun, Jack-Ansgar; Camilio, Ketil-Andre; Al-Saad, Samer; Stuge, Tor-Brynjar; Martinez-Zubiaurre, Inigo

    2015-01-01

    Accumulating evidence supports the notion that high-dose (>5 Gy) radiotherapy (RT) regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy) regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study, we have investigated the effects of high-dose radiotherapy (HD-RT) on the immunomodulating functions of cancer-associated fibroblasts (CAFs). Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays, and T-cell cytokine production. Additionally, CAF-secreted immunoregulatory factors were studied by multiplex protein arrays, ELISAs, and by LC-MS/MS proteomics. In all functional assays, we observed a powerful immunosuppressive effect exerted by CAF-conditioned medium on activated T-cells (p > 0.001), and this effect was sustained after a single radiation dose of 18 Gy. Relevant immunosuppressive molecules such as prostaglandin E2, interleukin-6, and -10, or transforming growth factor-β were found in CAF-conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immunosuppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.

  8. Tracking Lung Tumors in Orthogonal X-Rays

    Directory of Open Access Journals (Sweden)

    Feng Li

    2013-01-01

    Full Text Available This paper presents a computationally very efficient, robust, automatic tracking method that does not require any implanted fiducials for low-contrast tumors. First, it generates a set of motion hypotheses and computes corresponding feature vectors in local windows within orthogonal-axis X-ray images. Then, it fits a regression model that maps features to 3D tumor motions by minimizing geodesic distances on motion manifold. These hypotheses can be jointly generated in 3D to learn a single 3D regression model or in 2D through back projection to learn two 2D models separately. Tumor is tracked by applying regression to the consecutive image pairs while selecting optimal window size at every time. Evaluations are performed on orthogonal X-ray videos of 10 patients. Comparative experimental results demonstrate superior accuracy (~1 pixel average error and robustness to varying imaging artifacts and noise at the same time.

  9. Improved identification of peripheral lung tumors by using diffuse reflectance and fluorescence spectroscopy

    NARCIS (Netherlands)

    Spliethoff, J.W.; Spliethoff, Jarich; Evers, Daniel; Evers, D.J.; Klomp, H.M.; van Sandick, J.W.; Wouters, M.W.J.M.; Nachabe, R.; Lucassen, G.W.; Lucassen, Gerald; Hendriks, B.H.W.; Wesseling, J.; Ruers, Theo J.M.

    2013-01-01

    Introduction: A significant number of transthoracic diagnostic biopsy procedures for lung lesions show indeterminate results. Such failures are potentially due to inadequate recognition of vital tumor tissue. The objective of this study was to evaluate whether optical spectroscopy at the tip of a

  10. [Non-tumoral vascular disorders of the lung in the adulthood].

    Science.gov (United States)

    Orsini, B; Doddoli, C; Brioude, G; D'Journo, X-B; Trousse, D; Gaubert, J-Y; Thomas, P-A

    2012-04-01

    Non-tumoral vascular disorders of the lung are multiple, even if cases diagnosed in the adulthood are rare. They include congenital or acquired conditions, which related symptoms, if present, are non specific. This explains why their diagnosis is challenging and usually delayed. Surgery is the cornerstone of their treatment, although interventional radiology represents currently a less invasive alternative option for some of them.

  11. Desmoplastic small round cell tumor of the lung:case report

    Institute of Scientific and Technical Information of China (English)

    WANG Zhao-ming; XIAO Wen-bo; ZHENG Shu-sen

    2007-01-01

    @@ Desmoplastic small round cell tumor(DSRCT)is a clinically and morphologically well-defined neoplasm.1 This highly aggressive malignant small cell neoplasm tends to affect adolescents and young adults and occurs predominantly in the abdomen,pelvis,and omentum.1,2 DSRCT in the lung is extremely rare.

  12. Changes in tumor-antigen expression proifle as human small-cell lung cancers progress

    Institute of Scientific and Technical Information of China (English)

    Li-Sheng Ge; Neil T Hoa; Nils Lambrecht; Maria Dacosta-Iyer; Yi Ouyang; Amir Abolhoda; Martin R Jadus

    2015-01-01

    AbstrAct Objective:Our group has previously observed that in patients with small-cell lung cancers (SCLCs), the expression of a tumor antigen, glioma big potassium (gBK) ion channel, is higher at the time of death than when the cancer is ifrst treated by surgical resection. This study aimed to determine whether this dichotomy was common in other potential lung tumor antigens by examining the same patient samples using our more extensive proifle analysis of tumor-antigen precursor protein (TAPP). We then tested the hypothesis that therapeutic intervention may inadvertently cause this increased gBK production. Methods:SCLC samples (eight surgical resections and three autopsy samples) and three control lungs were examined by quantitative real-time polymerase chain reaction for 42 potential TAPPs that represent potential T-cell-mediated immunological targets. Results:Twenty-two TAPP mRNAs displayed the same profile as gBK, i.e., more mRNAs were expressed at autopsy than in their surgical counterparts. B-cyclin and mouse double minute 2, human homolog of P53-binding protein were elevated in both autopsy and surgical specimens above the normal-lung controls. When HTB119 cells were incubated with doxorubicin, gBK was strongly induced, as conifrmed by intracellular lfow cytometry with a gBK-speciifc antibody. Conclusion:Our findings suggested that more immunological targets became available as the tumor responded to chemotherapy and proceeded toward its terminal stages.

  13. Pulmonary blastoma: an ultrastructural study emphasizing intestinal differentiation in lung tumors.

    Science.gov (United States)

    Marcus, P B; Dieb, T M; Martin, J H

    1982-05-01

    Features of intestinal differentiation, including the presence of brush borders, have been described previously in a pulmonary blastoma following xenotransplantation in athymic nude mice. This paper reports similar findings in a pulmonary blastoma subjected directly to electron microscopic study. Ultrastructural manifestations of intestinal differentiation in other types of primary lung tumors are also discussed.

  14. Prognostic value of tumor volume for patients with advanced lung cancer treated with chemotherapy.

    Science.gov (United States)

    Kuo, Chung-Feng Jeffrey; Ke, Bo-Han; Wu, Nain-Ying; Kuo, Joseph; Hsu, Hsian-He

    2017-06-01

    We aim to develop a reference system utilizing computed tomography to calculate changes in tumor volume of lung cancer patients after chemotherapy to assist physicians in clinical treatment and evaluation. Image processing techniques were used to analyze the computed tomography of lung cancer, locate the tumor, and calculate the tumor volume. The medical indicator was then evaluated and analyzed. We examined the correlation between reduced tumor volume and survival duration of 88 patients after chemotherapy at Tri-Service General Hospital, Taiwan. The innovative survival prediction index was obtained by four statistical methods: receiver operating characteristic curve, Youden index, Kaplan-Meier method, and log rank test. From the image processing techniques, tumor volume from each patient were obtained within an average of 7.25 seconds. The proposed method was shown to achieve rapid positioning of lung tumors and volume reconstruction with an estimation error of 1.92% when calibrated with an irregularly shaped stone. In medical indicator evaluation and analysis, the area below the receiver operating characteristic curve is greater than 0.8, indicating good predictability of the medical index used herein. The Youden index spotted the best cut-off point of volume, and the correlation between the volume's cut-off point and survival time was confirmed again by Kaplan-Meier and log rank test. The p-values were all less than 0.05, presenting a high degree of correlation between the two, indicating that this medical indicator is highly reliable. The proposed techniques can automatically find the location of tumors in the lung, reconstruct the volume, and calculate changes in volume before and after treatment, thus obtaining an innovative survival prediction index. This will help facilitate early and accurate predictions of disease outcomes during the course of therapy, and categorize patient stratification into risk groups for more efficient therapies. Copyright © 2017

  15. A Metastatic Jejunal Tumor from Squamous Cell Carcinoma of the Lung Found in an Intestinal Perforation

    Directory of Open Access Journals (Sweden)

    Takayuki Tanaka

    2011-11-01

    Full Text Available An 85-year-old male with advanced squamous cell carcinoma of the lung, who was diagnosed about 10 years prior to his current presentation, suddenly complained of abdominal pain and underwent an abdominal computed tomography scan, which revealed free air and massive ascites. He was admitted to our hospital for acute peritonitis and emergency surgery was performed. During the surgical procedure, a perforation of the jejunum was diagnosed and repaired. He was diagnosed to have a metastatic tumor originating from a squamous cell carcinoma of the lung. He improved and was transferred to the former hospital on the 27th postoperative day. Jejunal metastasis from squamous cell carcinoma of the lung is rare, and the prognosis of peritonitis due to a perforated intestinal metastasis from lung cancer is poor. There have been 10 reports of jejunal metastasis of squamous cell carcinoma of the lung reported in Japan between 2000 and 2011. Therefore, when patients with advanced lung cancer present with acute abdomen, it is necessary to keep in mind the possibility of a gastrointestinal metastatic tumor.

  16. ENO1 Protein Levels in the Tumor Tissues and Circulating Plasma Samples of Non-small Cell Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Ying ZHANG

    2010-12-01

    Full Text Available Background and objective Proper tumor markers are useful to diagnosis, prognosis and treatment for lung cancer. The aim of this study is to examine the levels of alpha-enolase (ENO1 protein in the tumor tissues and peripheral plasma samples obtained from non-small cell lung cancer (NSCLC patients, and evaluate its potential clinical significance. Methods The ENO1 protein levels in the tumor tissues and corresponding normal tissues from 16 cases of lung squamous cell carcinoma were analyzed by Western blot. The ENO1 protein levels in the plasma samples from 42 healthy individuals, 34 patients with lung benign disease and 84 patients with NSCLC were measured by double antibody sandwich enzyme-linked immunosorbent assay. Results For 87.5% (14/16 of the patients with lung squamous cell carcinoma, the ENO1 protein level in the tumor tissues was higher than that in the corresponding normal lung tissues. The ENO1 protein level in the plasma of NSCLC patients was significantly higher than that in the plasma of healthy individuals (P=0.031 and patients with lung benign disease (P=0.019. Furthermore, the ENO1 protein level was significantly higher in the plasma of patients with lung adenocarcinoma than that of patients with lung squamous cell carcinoma. Conclusion The elevated levels of ENO1 protein in the tumor tissues and the plasma samples from NSCLC patients indicate ENO1 may be a candidate biomarker of lung cancer.

  17. The Role of Tumor Cell-Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth

    Science.gov (United States)

    Bennewith, Kevin L.; Huang, Xin; Ham, Christine M.; Graves, Edward E.; Erler, Janine T.; Kambham, Neeraja; Feazell, Jonathan; Yang, George P.; Koong, Albert

    2009-01-01

    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted subcutaneously. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by PET imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed co-localization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer. PMID:19179545

  18. Automated localization and segmentation of lung tumor from PET-CT thorax volumes based on image feature analysis.

    Science.gov (United States)

    Cui, Hui; Wang, Xiuying; Feng, Dagan

    2012-01-01

    Positron emission tomography - computed tomography (PET-CT) plays an essential role in early tumor detection, diagnosis, staging and treatment. Automated and more accurate lung tumor detection and delineation from PET-CT is challenging. In this paper, on the basis of quantitative analysis of contrast feature of PET volume in SUV (standardized uptake value), our method firstly automatically localized the lung tumor. Then based on analysing the surrounding CT features of the initial tumor definition, our decision strategy determines the tumor segmentation from CT or from PET. The algorithm has been validated on 20 PET-CT studies involving non-small cell lung cancer (NSCLC). Experimental results demonstrated that our method was able to segment the tumor when adjacent to mediastinum or chest wall, and the algorithm outperformed the other five lung segmentation methods in terms of overlapping measure.

  19. Gamma-knife radiosurgery for metastatic brain tumors from primary lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Uchiyama, Bine; Satoh, Ken; Saijo, Yasuo [Tohoku Univ., Sendai (Japan). Inst. of Development, Aging and Cancer] [and others

    1998-06-01

    Forty patients with metastatic brain tumors from primary lung cancer underwent radiosurgery ({gamma}-knife). We retrospectively compared their prior treatment history, number of metastatic foci, and performance status, to evaluate the effects of, and indications for, {gamma}-knife therapy. After both the primary and the metastatic tumors were controlled, performance status could be used as an index in the choice of {gamma}-knife therapy. Our results demonstrate that repeated {gamma}-knife radiosurgeries prolonged survival time. Gamma-knife radiosurgery improves quality of life and prognosis of patients with metastatic brain tumors. (author)

  20. Molecular characterization of radon-induced rat lung tumors; Caracterisation moleculaire de tumeurs pulmonaires radon-induites chez le rat

    Energy Technology Data Exchange (ETDEWEB)

    Guillet Bastide, K

    2008-11-15

    The radon gas is a well known lung carcinogenic factor in human at high doses but the cancer risk at low doses is not established. Indeed, epidemiological studies at low doses are difficult to conduct because of the human exposure to other lung carcinogenic factors. These data underlined the necessity to conduct experiments on lung tumors developed on animal model. The aim of this work was to characterize rat lung tumors by working on a series of radon-induced tumors that included adenocarcinomas (A.C.), squamous cell carcinomas (S.C.C.) and adeno-squamous carcinomas (A.S.C.), that are mixed tumors with both A.C. and S.C.C. cellular components. A C.G.H. analysis of the three types of tumors allowed us to define chromosomal recurrent unbalances and to target candidate genes potentially implicated in lung carcinogenesis, as p16Ink4a, p19Arf, Rb1, K-Ras or c-Myc. A more precise analysis of the p16Ink4a/Cdk4/Rb1 and p19Arf/Mdm2/Tp53 pathways was performed and indicated that the Rb1 pathway was frequently inactivated through an absence of p16{sup Ink4a} protein expression, indicating that it has a major role in rat lung carcinogenesis. Finally, a comparative transcriptomic analysis of the three types of tumors allowed us to show for the first time that the complex tumors A.S.C. have a transcriptomic profile in accordance with their mixed nature but that they also display their own expression profiles specificities. This work allowed us to find molecular characteristics common to murine and human lung tumors, indicating that the model of lung tumors in rat is pertinent to search for radiation-induced lung tumors specificities and to help for a better molecular identification of this type of tumors in human. (author)

  1. Tumor-derived exosomes in cancer progression and treatment failure.

    Science.gov (United States)

    Yu, Shaorong; Cao, Haixia; Shen, Bo; Feng, Jifeng

    2015-11-10

    Exosomes have diameter within the range of 30-100 nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy.

  2. A geometric atlas to predict lung tumor shrinkage for radiotherapy treatment planning

    Science.gov (United States)

    Zhang, Pengpeng; Rimner, Andreas; Yorke, Ellen; Hu, Yu-Chi; Kuo, Licheng; Apte, Aditya; Lockney, Natalie; Jackson, Andrew; Mageras, Gig; Deasy, Joseph O.

    2017-02-01

    To develop a geometric atlas that can predict tumor shrinkage and guide treatment planning for non-small-cell lung cancer. To evaluate the impact of the shrinkage atlas on the ability of tumor dose escalation. The creation of a geometric atlas included twelve patients with lung cancer who underwent both planning CT and weekly CBCT for radiotherapy planning and delivery. The shrinkage pattern from the original pretreatment to the residual posttreatment tumor was modeled using a principal component analysis, and used for predicting the spatial distribution of the residual tumor. A predictive map was generated by unifying predictions from each individual patient in the atlas, followed by correction for the tumor’s surrounding tissue distribution. Sensitivity, specificity, and accuracy of the predictive model for classifying voxels inside the original gross tumor volume were evaluated. In addition, a retrospective study of predictive treatment planning (PTP) escalated dose to the predicted residual tumor while maintaining the same level of predicted complication rates for a clinical plan delivering uniform dose to the entire tumor. The effect of uncertainty on the predictive model’s ability to escalate dose was also evaluated. The sensitivity, specificity and accuracy of the predictive model were 0.73, 0.76, and 0.74, respectively. The area under the receiver operating characteristic curve for voxel classification was 0.87. The Dice coefficient and mean surface distance between the predicted and actual residual tumor averaged 0.75, and 1.6 mm, respectively. The PTP approach allowed elevation of PTV D95 and mean dose to the actual residual tumor by 6.5 Gy and 10.4 Gy, respectively, relative to the clinical uniform dose approach. A geometric atlas can provide useful information on the distribution of resistant tumors and effectively guide dose escalation to the tumor without compromising the organs at risk complications. The atlas can be further refined by using

  3. Lung Tumors in Mice Receiving Different Schedules of Urethane

    Science.gov (United States)

    1967-01-01

    tumors, but this phenotypic expression did become markedly segregated. Thus, there are strains such as A, in which almost all animals develop pulmonary...urethane," Khanolkar Felicitation Volume, Bombay , Indian Cancer Research Center, 1963, pp. 158-181. [11] P. S. HENSHAW and H. L. MEYER, "Further

  4. Metastatic tumor to the iris and ciliary body as an initial sign of lung cancer: a case report

    Institute of Scientific and Technical Information of China (English)

    SUI Rui-fang; ZHAO Jia-liang; ZHANG Shun-hua; FENG Rui-e; CHENG Gang-wei; MA Jian-min; MAO Jin

    2005-01-01

    @@ The most common sites of lung cancer metastases are pleura, bone, brain, pericardium and liver.1 Tumor metastasis to the eye is a rare complication of lung cancer. Metastatic cancer to the ocular region most often involves the uveal tract, however, most uveal metastases occur in the posterior uvea, and iris metastases are relatively rare. We describe a patient with adenocarcinoma of the lung metastatic to the iris as the first clinical sign without symptoms of lung cancer.

  5. CyberKnife for hilar lung tumors: report of clinical response and toxicity

    Directory of Open Access Journals (Sweden)

    Collins Sean P

    2010-10-01

    Full Text Available Abstract Objective To report clinical efficacy and toxicity of fractionated CyberKnife radiosurgery for the treatment of hilar lung tumors. Methods Patients presenting with primary and metastatic hilar lung tumors, treated using the CyberKnife system with Synchrony fiducial tracking technology, were retrospectively reviewed. Hilar location was defined as abutting or invading a mainstem bronchus. Fiducial markers were implanted by conventional bronchoscopy within or adjacent to tumors to serve as targeting references. A prescribed dose of 30 to 40 Gy to the gross tumor volume (GTV was delivered in 5 fractions. Clinical examination and PET/CT imaging were performed at 3 to 6-month follow-up intervals. Results Twenty patients were accrued over a 4 year period. Three had primary hilar lung tumors and 17 had hilar lung metastases. The median GTV was 73 cc (range 23-324 cc. The median dose to the GTV was 35 Gy (range, 30 - 40 Gy, delivered in 5 fractions over 5 to 8 days (median, 6 days. The resulting mean maximum point doses delivered to the esophagus and mainstem bronchus were 25 Gy (range, 11 - 39 Gy and 42 Gy (range, 30 - 49 Gy, respectively. Of the 17 evaluable patients with 3 - 6 month follow-up, 4 patients had a partial response and 13 patients had stable disease. AAT t a median follow-up of 10 months, the 1-year Kaplan-Meier local control and overall survival estimates were 63% and 54%, respectively. Toxicities included one patient experiencing grade II radiation esophagitis and one patient experiencing grade III radiation pneumonitis. One patient with gross endobronchial tumor within the mainstem bronchus developed a bronchial fistula and died after receiving a maximum bronchus dose of 49 Gy. Conclusion CyberKnife radiosurgery is an effective palliative treatment option for hilar lung tumors, but local control is poor at one year. Maximum point doses to critical structures may be used as a guide for limiting toxicities. Preliminary results

  6. Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma

    Science.gov (United States)

    Lv, Yang-Fan; Yan, Guang-Ning; Meng, Gang; Zhang, Xi; Guo, Qiao-Nan

    2015-01-01

    The enhancer of zeste homolog 2 (EZH2) methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which acts as a transcription repressor via the trimethylation of lysine 27 of histone 3 (H3K27me3). EZH2 has been recognised as an oncogene in several types of tumors; however, its role in osteosarcoma has not been fully elucidated. Herein, we show that EZH2 silencing inhibits tumor growth and lung metastasis in osteosarcoma by facilitating re-expression of the imprinting gene tumor-suppressing STF cDNA 3 (TSSC3). Our previous study showed that TSSC3 acts as a tumor suppressor in osteosarcoma. In this study, we found that EZH2 was abnormally elevated in osteosarcoma, and its overexpression was associated with poor prognosis in osteosarcoma. Silencing of EZH2 resulted in tumor growth inhibition, apoptosis and chemosensitivity enhancement. Moreover, suppression of EZH2 markedly inhibited tumor growth and lung metastasis in vivo. Furthermore, EZH2 knockdown facilitated the re-expression of TSSC3 by reducing H3K27me3 in the promoter region. Cotransfection with siEZH2 and siTSSC3 could partially reverse the ability of siEZH2 alone. We have demonstrated that EZH2 plays a crucial role in tumor growth and distant metastasis in osteosarcoma; its oncogenic role is related to its regulation of the expression of TSSC3. PMID:26265454

  7. Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma.

    Science.gov (United States)

    Lv, Yang-Fan; Yan, Guang-Ning; Meng, Gang; Zhang, Xi; Guo, Qiao-Nan

    2015-08-12

    The enhancer of zeste homolog 2 (EZH2) methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which acts as a transcription repressor via the trimethylation of lysine 27 of histone 3 (H3K27me3). EZH2 has been recognised as an oncogene in several types of tumors; however, its role in osteosarcoma has not been fully elucidated. Herein, we show that EZH2 silencing inhibits tumor growth and lung metastasis in osteosarcoma by facilitating re-expression of the imprinting gene tumor-suppressing STF cDNA 3 (TSSC3). Our previous study showed that TSSC3 acts as a tumor suppressor in osteosarcoma. In this study, we found that EZH2 was abnormally elevated in osteosarcoma, and its overexpression was associated with poor prognosis in osteosarcoma. Silencing of EZH2 resulted in tumor growth inhibition, apoptosis and chemosensitivity enhancement. Moreover, suppression of EZH2 markedly inhibited tumor growth and lung metastasis in vivo. Furthermore, EZH2 knockdown facilitated the re-expression of TSSC3 by reducing H3K27me3 in the promoter region. Cotransfection with siEZH2 and siTSSC3 could partially reverse the ability of siEZH2 alone. We have demonstrated that EZH2 plays a crucial role in tumor growth and distant metastasis in osteosarcoma; its oncogenic role is related to its regulation of the expression of TSSC3.

  8. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis.

    Science.gov (United States)

    Pezzella, F; Pastorino, U; Tagliabue, E; Andreola, S; Sozzi, G; Gasparini, G; Menard, S; Gatter, K C; Harris, A L; Fox, S; Buyse, M; Pilotti, S; Pierotti, M; Rilke, F

    1997-11-01

    Neoplastic growth is usually dependent on blood supply, and it is commonly accepted that this is provided by the formation of new vessels. However, tumors may be able to grow without neovascularization if they find a suitable vascular bed available. We have investigated the pattern of vascularization in a series of 500 primary stage I non-small-cell lung carcinomas. Immunostaining of endothelial cells has highlighted four distinct patterns of vascularization. Three patterns (which we called basal, papillary, and diffuse) have in common the destruction of normal lung and the production of newly formed vessels and stroma. The fourth pattern, which we called alveolar or putative nonangiogenic, was observed in 16% (80/500) of the cases and is characterized by lack of parenchymal destruction and absence of both tumor associated stroma and new vessels. The only vessels present were the ones in the alveolar septa, and their presence highlighted, through the whole tumor, the lung alveoli filled up by the neoplastic cells. This observation suggests that, if an appropriate vascular bed is available, a tumor can exploit it and grows without inducing neo-angiogenesis. This could have implications for strategies aimed at inhibiting tumor growth by vascular targeting or inhibition of angiogenesis.

  9. A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer.

    Science.gov (United States)

    Calbo, Joaquim; van Montfort, Erwin; Proost, Natalie; van Drunen, Ellen; Beverloo, H Berna; Meuwissen, Ralph; Berns, Anton

    2011-02-15

    Small cell lung cancer (SCLC) is the lung neoplasia with the poorest prognosis, due to its high metastatic potential and chemoresistance upon relapse. Using the previously described mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells with either a neuroendocrine or a mesenchymal marker profile. These cells had a common origin because they shared specific genomic aberrations. The transition from neuroendocrine to mesenchymal phenotype could be achieved by the ectopic expression of oncogenic Ras(V12). Crosstalk between mesenchymal and neuroendocrine cells strongly influenced their behavior. When engrafted as a mixed population, the mesenchymal cells endowed the neuroendocrine cells with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating tumor properties.

  10. Up-regulation of hepatoma-derived growth factor facilitates tumor progression in malignant melanoma [corrected].

    Directory of Open Access Journals (Sweden)

    Han-En Tsai

    Full Text Available Cutaneous malignant melanoma is the fastest increasing malignancy in humans. Hepatoma-derived growth factor (HDGF is a novel growth factor identified from human hepatoma cell line. HDGF overexpression is correlated with poor prognosis in various types of cancer including melanoma. However, the underlying mechanism of HDGF overexpression in developing melanoma remains unclear. In this study, human melanoma cell lines (A375, A2058, MEL-RM and MM200 showed higher levels of HDGF gene expression, whereas human epidermal melanocytes (HEMn expressed less. Exogenous application of HDGF stimulated colony formation and invasion of human melanoma cells. Moreover, HDGF overexpression stimulated the degree of invasion and colony formation of B16-F10 melanoma cells whereas HDGF knockdown exerted opposite effects in vitro. To evaluate the effects of HDGF on tumour growth and metastasis in vivo, syngeneic mouse melanoma and metastatic melanoma models were performed by manipulating the gene expression of HDGF in melanoma cells. It was found that mice injected with HDGF-overexpressing melanoma cells had greater tumour growth and higher metastatic capability. In contrast, mice implanted with HDGF-depleted melanoma cells exhibited reduced tumor burden and lung metastasis. Histological analysis of excised tumors revealed higher degree of cell proliferation and neovascularization in HDGF-overexpressing melanoma. The present study provides evidence that HDGF promotes tumor progression of melanoma and targeting HDGF may constitute a novel strategy for the treatment of melanoma.

  11. Cumulative Intracranial Tumor Volume (CITV) Enhances the Prognostic Value of the Lung-Specific Graded Prognostic Assessment (GPA) Model.

    Science.gov (United States)

    Marcus, Logan P; Marshall, Deborah; Hirshman, Brian R; McCutcheon, Brandon A; Gonda, David D; Koiso, Takao; Hattangadi-Gluth, Jona A; Carter, Bob S; Yamamoto, Masaaki; Chen, Clark C

    2016-08-01

    Management of patients afflicted with brain metastasis requires tailoring of therapeutic strategies based on survival expectations. Therefore, the development of prognostic indices is of critical importance in this patient population. To determine whether the cumulative intracranial tumor volume (CITV) of brain metastasis augments the prognostic value of the lung-specific Graded Prognostic Assessment (GPA) index. Patient data were derived from 365 lung cancer patients with brain metastasis who were consecutively treated with stereotactic radiosurgery at the University of California, San Diego/San Diego Gamma Knife Center. CITV was analyzed to determine the volume cutoff that maximized sensitivity and specificity for 1-year survival. Multivariate Cox proportional hazard modeling was performed, and overall survival was estimated by the Kaplan-Meier method risk stratifying with or without this optimal CITV. The prognostic value of these models (lung-specific GPA ± CITV) was quantitatively compared with the use of net reclassification improvement (>0) and integrated discrimination improvement. For the University of California, San Diego/San Diego Gamma Knife Center cohort, the CITV cutoff that had the greatest survival discrimination at 1 year was 4 cm. The addition of CITV to the lung-specific GPA indexes significantly improved the prognostic value of lung-specific GPA, with net reclassification improvement >0 of 0.430 (95% confidence interval, 0.228-0.629) and integrated discrimination improvement of 0.029 (95% confidence interval, 0.004-0.073). These findings were validated in an independent cohort of 1638 lung cancer patients with brain metastasis who were treated with stereotactic radiosurgery at the Katsuta Hospital Mito Gamma House in Japan. In independent cohorts, the addition of CITV to the lung-specific GPA index significantly improved the prognostic value of this index. AUC, area under the receiver-operating characteristic curveBM, brain metastasis

  12. Claudin 3, 4, and 15 expression in solid tumors of lung adenocarcinoma versus malignant pleural mesothelioma.

    Science.gov (United States)

    Chaouche-Mazouni, Siham; Scherpereel, Arnaud; Zaamoum, Rima; Mihalache, Adriana; Amir, Zine-Charaf; Lebaïli, Nemcha; Delaire, Baptiste; Gosset, Pierre

    2015-08-01

    Epithelioid malignant pleural mesothelioma (MPM) can easily be confused with lung adenocarcinomas (ACAs). In serous effusion, claudin (cldn) 3 is shown to be useful in the diagnosis of mesothelioma vs ACAs. Cldn15 is reported to be overexpressed in epithelioid mesothelioma and absent in human airway epithelium. The aim was to assess the value of cldn3 and cldn4 compared to that of BerEp4 and thyroid transcription factor-1 (TTF1) in differentiating lung ACA from epithelioid MPM and to examine the expression of cldn15 in these tumors. The expression of cldn3, cldn4, cldn15, BerEp4, and TTF1 was examined by immunohistochemistry in a total of 62 human specimen including 28 epithelioid MPMs and 34 ACAs of the lung. In lung ACA, cldn4 was strongly expressed in all 34 (100%) specimens followed by cldn3 in 33 (97%) of 34. BerEp4 was expressed in 32 (94.1%) of 34. TTF1 reacted for only 20 (58.82%) of 34 cases of lung ACA. In MPM specimens, the expression of cldn3 and4 as well as that of TTF1 was completely absent. In contrast, BerEp4 was focally expressed in 5 (17.85%) of 28 cases of epithelioid MPM. Cldn15 was strongly expressed in 53% pf epithelioid MPMs but also in 50% of lung ACAs. Its expression was moderate in normal pleura and limited in normal lung. Cldn3 and cldn4 appear to be the best performing carcinoma markers in discriminating lung ACA from mesothelioma compared with BerEp4 and TTF1. There is no differential expression of cldn15 between the 2 pathologies. However, the limited cldn15 expression in normal tissues and high expression in tumors make it an attractive candidate for cancer therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Bone Marrow-Derived c-kit+ Cells Attenuate Neonatal Hyperoxia-Induced Lung Injury

    Science.gov (United States)

    Ramachandran, Shalini; Suguihara, Cleide; Drummond, Shelley; Chatzistergos, Konstantinos; Klim, Jammie; Torres, Eneida; Huang, Jian; Hehre, Dorothy; Rodrigues, Claudia O.; McNiece, Ian K.; Hare, Joshua M.; Young, Karen C.

    2016-01-01

    Recent studies suggest that bone marrow (BM)-derived stem cells have therapeutic efficacy in neonatal hyperoxia-induced lung injury (HILI). c-kit, a tyrosine kinase receptor that regulates angiogenesis, is expressed on several populations of BM-derived cells. Preterm infants exposed to hyperoxia have decreased lung angiogenesis. Here we tested the hypothesis that administration of BM-derived c-kit+ cells would improve angiogenesis in neonatal rats with HILI. To determine whether intratracheal (IT) administration of BM-derived c-kit+ cells attenuates neonatal HILI, rat pups exposed to either normobaric normoxia (21% O2) or hyperoxia (90% O2) from postnatal day (P) 2 to P15 were randomly assigned to receive either IT BM-derived green fluorescent protein (GFP)+ c-kit− cells (PL) or BM-derived GFP+ c-kit+ cells on P8. The effect of cell therapy on lung angiogenesis, alveolarization, pulmonary hypertension, vascular remodeling, cell proliferation, and apoptosis was determined at P15. Cell engraftment was determined by GFP immunostaining. Compared to PL, the IT administration of BM-derived c-kit+ cells to neonatal rodents with HILI improved alveolarization as evidenced by increased lung septation and decreased mean linear intercept. This was accompanied by an increase in lung vascular density, a decrease in lung apoptosis, and an increase in the secretion of proangiogenic factors. There was no difference in pulmonary vascular remodeling or the degree of pulmonary hypertension. Confocal microscopy demonstrated that 1% of total lung cells were GFP+ cells. IT administration of BM-derived c-kit+ cells improves lung alveolarization and angiogenesis in neonatal HILI, and this may be secondary to an improvement in the lung angiogenic milieu. PMID:23759597

  14. Cytosolic phospholipaseA2 inhibition with PLA-695 radiosensitizes tumors in lung cancer animal models.

    Science.gov (United States)

    Thotala, Dinesh; Craft, Jeffrey M; Ferraro, Daniel J; Kotipatruni, Rama P; Bhave, Sandeep R; Jaboin, Jerry J; Hallahan, Dennis E

    2013-01-01

    Lung cancer remains the leading cause of cancer deaths in the United States and the rest of the world. The advent of molecularly directed therapies holds promise for improvement in therapeutic efficacy. Cytosolic phospholipase A2 (cPLA2) is associated with tumor progression and radioresistance in mouse tumor models. Utilizing the cPLA2 specific inhibitor PLA-695, we determined if cPLA2 inhibition radiosensitizes non small cell lung cancer (NSCLC) cells and tumors. Treatment with PLA-695 attenuated radiation induced increases of phospho-ERK and phospho-Akt in endothelial cells. NSCLC cells (LLC and A549) co-cultured with endothelial cells (bEND3 and HUVEC) and pre-treated with PLA-695 showed radiosensitization. PLA-695 in combination with irradiation (IR) significantly reduced migration and proliferation in endothelial cells (HUVEC & bEND3) and induced cell death and attenuated invasion by tumor cells (LLC &A549). In a heterotopic tumor model, the combination of PLA-695 and radiation delayed growth in both LLC and A549 tumors. LLC and A549 tumors treated with a combination of PLA-695 and radiation displayed reduced tumor vasculature. In a dorsal skin fold model of LLC tumors, inhibition of cPLA2 in combination with radiation led to enhanced destruction of tumor blood vessels. The anti-angiogenic effects of PLA-695 and its enhancement of the efficacy of radiotherapy in mouse models of NSCLC suggest that clinical trials for its capacity to improve radiotherapy outcomes are warranted.

  15. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    OpenAIRE

    Laila C. Roudsari; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted...

  16. Differential innate immune cell signatures and effects regulated by toll-like receptor 4 during murine lung tumor promotion

    Science.gov (United States)

    Alexander, Carla-Maria; Xiong, Ka-Na; Velmurugan, Kalpana; Xiong, Julie; Osgood, Ross S.; Bauer, Alison K.

    2017-01-01

    Tumor promotion is an early and critical stage during lung adenocarcinoma (ADC). We previously demonstrated that Tlr4 mutant mice were more susceptible to butylated hydroxytoluene (BHT)-induced pulmonary inflammation and tumor promotion in comparison to Tlr4-sufficient mice. Our study objective was to elucidate the underlying differences in Tlr4 mutant mice in innate immune cell populations, their functional responses, and the influence of these cellular differences on ADC progenitor (type II) cells following BHT-treatment. BALB (Tlr4-sufficient) and C.C3-Tlr4Lps-d/J (BALBLpsd; Tlr4 mutant) mice were treated with BHT (promoter) followed by bronchoalveolar lavage (BAL) and flow cytometry processing on the lungs. ELISAs, Club cell enrichment, macrophage function and RNA isolation were also performed. Bone marrow-derived macrophages (BMDM) co-cultured with a type II cell line were used for wound healing assays. Innate immune cells significantly increased in whole lung in BHT treated BALBLpsd mice compared to BALB mice. BHT treated BALBLpsd mice demonstrated enhanced macrophage functionality, increased epithelial wound closure via BMDMs, and increased Club cell number in BALBLpsd mice, all compared to BALB BHT-treated mice. Cytokine/chemokine (Kc, Mcp1) and growth factor (Igf1) levels also significantly differed among the strains and within macrophages, gene expression and cell surface markers collectively demonstrated a more plastic phenotype in BALBLpsd mice. Therefore, these correlative studies suggest that distinct innate immune cell populations are associated with the differences observed in the Tlr4-mutant model. Future studies will investigate the macrophage origins and the utility of the pathways identified herein as indicators of immune system deficiencies and lung tumorigenesis. PMID:27093379

  17. β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer.

    Science.gov (United States)

    Yu, Xiaomu; Xu, Maoyi; Li, Na; Li, Zongjuan; Li, Hongye; Shao, Shujuan; Zou, Kun; Zou, Lijuan

    2017-08-19

    Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Clinical Evaluation and Cost-Effectiveness Analysis of Serum Tumor Markers in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Rong Wang

    2013-01-01

    Full Text Available The detection of serum tumor markers is valuable for the early diagnosis of lung cancer. Tumor markers are frequently used for the management of cancer patients. However, single markers are less efficient but marker combinations increase the cost, which is troublesome for clinics. To find an optimal serum marker combination panel that benefits the patients and the medical management system as well, four routine lung cancer serum markers (SCCA, NSE, CEA, and CYFRA21-1 were evaluated individually and in combination. Meanwhile, the costs and effects of these markers in clinical practice in China were assessed by cost-effectiveness analysis. As expected, combinations of these tumor markers improved their sensitivity for lung cancer and different combination panels had their own usefulness. NSE + CEA + CYFRA21-1 was the optimal combination panel with highest Youden’s index (0.64, higher sensitivity (75.76%, and specificity (88.57%, which can aid the clinical diagnosis of lung cancer. Nevertheless, the most cost-effective combination was SCCA + CEA, which can be used to screen the high-risk group.

  19. LUNG TUMOR KRAS AND TP53 MUTATIONS IN NON-SMOKERS REFLECT EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS

    Science.gov (United States)

    Abstract We determined the TP53 and codon 12 KRAS mutations in lung tumors from 24 nonsmokers whose tumors were associated with exposure to smoky coal. Among any tumors studied previously, these showed the highest percentage of mutations that (a) were G -+ T transver...

  20. Dynamic lung modeling and tumor tracking using deformable image registration and geometric smoothing.

    Science.gov (United States)

    Zhang, Yongjie; Jing, Yiming; Liang, Xinghua; Xu, Guoliang; Dong, Lei

    2012-09-01

    A greyscale-based fully automatic deformable image registration algorithm, based on an optical flow method together with geometric smoothing, is developed for dynamic lung modeling and tumor tracking. In our computational processing pipeline, the input data is a set of 4D CT images with 10 phases. The triangle mesh of the lung model is directly extracted from the more stable exhale phase (Phase 5). In addition, we represent the lung surface model in 3D volumetric format by applying a signed distance function and then generate tetrahedral meshes. Our registration algorithm works for both triangle and tetrahedral meshes. In CT images, the intensity value reflects the local tissue density. For each grid point, we calculate the displacement from the static image (phase 5) to match with the moving image (other phases) by using merely intensity values of the CT images. The optical flow computation is followed by a regularization of the deformation field using geometric smoothing. Lung volume change and the maximum lung tissue movement are used to evaluate the accuracy of the application. Our testing results suggest that the application of deformable registration algorithm is an effective way for delineating and tracking tumor motion in image-guided radiotherapy.

  1. Evaluation of tumor angiogenesis in patients with non-small cell lung carcinoma

    Directory of Open Access Journals (Sweden)

    Suciu B.A.

    2015-05-01

    Full Text Available The aim of this study is to evaluate tumor angiogenesis in patients with non-small cell lung carcinoma. A total of 20 patients with pulmonary adenocarinoma have been included in the study. In order to evaluate tumor angiogenesis we studied the importance of CD34 expression. Evaluation of vascular density was performed with a semiautomated method using the dedicated software called ImageJ. We introduced in our study 20 patients with lung adenocarcinoma. We were able to identify tumor angiogenesis in 19 cases (95%. Immunolabeling of CD34 positive endothelial cells provided a good overview of tumor vascularization. Immunohistochemical staining of CD34 positive endothelium cells provided a good basis for tumor vascularity assessment, and also an excellent contrast for computer assisted morphometric measurements. Also we studied the intensity of the immunohistochemical staining of CD34 in the tumoral cells. We obtained the following results: a minor expression in 4 cases (20%, a moderate expression in 9 cases (45% and an intense expression in 6 cases (30%. The histological type of adenocarcinomas influences the architecture and branching of the vessels. The density of newly developed vessels is higher in patients with papillary pulmonary adenocarcinomas, which may indicate a possible relationship between the histological type and development of vascular supply.

  2. Quantification of lung tumor rotation with automated landmark extraction using orthogonal cine MRI images

    Science.gov (United States)

    Paganelli, Chiara; Lee, Danny; Greer, Peter B.; Baroni, Guido; Riboldi, Marco; Keall, Paul

    2015-09-01

    The quantification of tumor motion in sites affected by respiratory motion is of primary importance to improve treatment accuracy. To account for motion, different studies analyzed the translational component only, without focusing on the rotational component, which was quantified in a few studies on the prostate with implanted markers. The aim of our study was to propose a tool able to quantify lung tumor rotation without the use of internal markers, thus providing accurate motion detection close to critical structures such as the heart or liver. Specifically, we propose the use of an automatic feature extraction method in combination with the acquisition of fast orthogonal cine MRI images of nine lung patients. As a preliminary test, we evaluated the performance of the feature extraction method by applying it on regions of interest around (i) the diaphragm and (ii) the tumor and comparing the estimated motion with that obtained by (i) the extraction of the diaphragm profile and (ii) the segmentation of the tumor, respectively. The results confirmed the capability of the proposed method in quantifying tumor motion. Then, a point-based rigid registration was applied to the extracted tumor features between all frames to account for rotation. The median lung rotation values were  -0.6   ±   2.3° and  -1.5   ±   2.7° in the sagittal and coronal planes respectively, confirming the need to account for tumor rotation along with translation to improve radiotherapy treatment.

  3. A rare tumoral combination, synchronous lung adenocarcinoma and mantle cell lymphoma of the pleura

    Directory of Open Access Journals (Sweden)

    Foroulis Christophoros N

    2008-12-01

    Full Text Available Abstract Background Coexistence of adenocarcinoma and mantle cell lymphoma in the same or different anatomical sites is extremely rare. We present a case of incidental discovery of primary lung adenocarcinoma and mantle cell lymphoma involving the pleura, during an axillary thoracotomy performed for a benign condition. Case presentation A 73-year old male underwent bullectomy and apical pleurectomy for persistent pneumothorax. A bulla of the lung apex was resected en bloc with a scar-like lesion of the lung, which was located in proximity with the bulla origin, by a wide wedge resection. Histologic examination of the stripped-off parietal pleura and of the bullectomy specimen revealed the synchronous occurrence of two distinct neoplasms, a lymphoma infiltrating the pleura and a primary, early lung adenocarcinoma. Immunohistochemical and fluorescence in situ hybridization assays were performed. The morphologic, immunophenotypic and genetic findings supported the diagnosis of primary lung adenocarcinoma (papillary subtype coexisting with a non-Hodgkin, B-cell lineage, mantle cell lymphoma involving both, visceral and parietal pleura and without mediastinal lymph node involvement. The neoplastic lymphoid cells showed the characteristic immunophenotype of mantle cell lymphoma and the translocation t(11;14. The patient received 6 cycles of chemotherapy, while pulmonary function tests precluded further pulmonary parenchyma resection (lobectomy for his adenocarcinoma. The patient is alive and without clinical and radiological findings of local recurrence or distant relapse from both tumors 14 months later. Conclusion This is the first reported case of a rare tumoral combination involving simultaneously lung and pleura, emphasizing at the incidental discovery of the two coexisting neoplasms during a procedure performed for a benign condition. Any tissue specimen resected during operations performed for non-tumoral conditions should be routinely sent for

  4. Targeted deletion of Nrf2 reduces urethane-induced lung tumor development in mice.

    Directory of Open Access Journals (Sweden)

    Alison K Bauer

    Full Text Available Nrf2 is a key transcription factor that regulates cellular redox and defense responses. However, permanent Nrf2 activation in human lung carcinomas promotes pulmonary malignancy and chemoresistance. We tested the hypothesis that Nrf2 has cell survival properties and lack of Nrf2 suppresses chemically-induced pulmonary neoplasia by treating Nrf2(+/+ and Nrf2(-/- mice with urethane. Airway inflammation and injury were assessed by bronchoalveolar lavage analyses and histopathology, and lung tumors were analyzed by gross and histologic analysis. We used transcriptomics to assess Nrf2-dependent changes in pulmonary gene transcripts at multiple stages of neoplasia. Lung hyperpermeability, cell death and apoptosis, and inflammatory cell infiltration were significantly higher in Nrf2(-/- mice compared to Nrf2(+/+ mice 9 and 11 wk after urethane. Significantly fewer lung adenomas were found in Nrf2(-/- mice than in Nrf2(+/+ mice at 12 and 22 wk. Nrf2 modulated expression of genes involved cell-cell signaling, glutathione metabolism and oxidative stress response, and immune responses during early stage neoplasia. In lung tumors, Nrf2-altered genes had roles in transcriptional regulation of cell cycle and proliferation, carcinogenesis, organismal injury and abnormalities, xenobiotic metabolism, and cell-cell signaling genes. Collectively, Nrf2 deficiency decreased susceptibility to urethane-induced lung tumorigenesis in mice. Cell survival properties of Nrf2 were supported, at least in part, by reduced early death of initiated cells and heightened advantage for tumor cell expansion in Nrf2(+/+ mice relative to Nrf2(-/- mice. Our results were consistent with the concept that Nrf2 over-activation is an adaptive response of cancer conferring resistance to anti-cancer drugs and promoting malignancy.

  5. Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression.

    Science.gov (United States)

    Behnan, Jinan; Isakson, Pauline; Joel, Mrinal; Cilio, Corrado; Langmoen, Iver A; Vik-Mo, Einar O; Badn, Wiaam

    2014-05-01

    The identity of the cells that contribute to brain tumor structure and progression remains unclear. Mesenchymal stem cells (MSCs) have recently been isolated from normal mouse brain. Here, we report the infiltration of MSC-like cells into the GL261 murine glioma model. These brain tumor-derived mesenchymal stem cells (BT-MSCs) are defined with the phenotype (Lin-Sca-1+CD9+CD44+CD166+/-) and have multipotent differentiation capacity. We show that the infiltration of BT-MSCs correlates to tumor progression; furthermore, BT-MSCs increased the proliferation rate of GL261 cells in vitro. For the first time, we report that the majority of GL261 cells expressed mesenchymal phenotype under both adherent and sphere culture conditions in vitro and that the non-MSC population is nontumorigenic in vivo. Although the GL261 cell line expressed mesenchymal phenotype markers in vitro, most BT-MSCs are recruited cells from host origin in both wild-type GL261 inoculated into green fluorescent protein (GFP)-transgenic mice and GL261-GFP cells inoculated into wild-type mice. We show the expression of chemokine receptors CXCR4 and CXCR6 on different recruited cell populations. In vivo, the GL261 cells change marker profile and acquire a phenotype that is more similar to cells growing in sphere culture conditions. Finally, we identify a BT-MSC population in human glioblastoma that is CD44+CD9+CD166+ both in freshly isolated and culture-expanded cells. Our data indicate that cells with MSC-like phenotype infiltrate into the tumor stroma and play an important role in tumor cell growth in vitro and in vivo. Thus, we suggest that targeting BT-MSCs could be a possible strategy for treating glioblastoma patients.

  6. Diaphragm motion characterization using chest motion data for biomechanics-based lung tumor tracking during EBRT

    Science.gov (United States)

    Karami, Elham; Gaede, Stewart; Lee, Ting-Yim; Samani, Abbas

    2016-03-01

    Despite recent advances in image-guided interventions, lung cancer External Beam Radiation Therapy (EBRT) is still very challenging due to respiration induced tumor motion. Among various proposed methods of tumor motion compensation, real-time tumor tracking is known to be one of the most effective solutions as it allows for maximum normal tissue sparing, less overall radiation exposure and a shorter treatment session. As such, we propose a biomechanics-based real-time tumor tracking method for effective lung cancer radiotherapy. In the proposed algorithm, the required boundary conditions for the lung Finite Element model, including diaphragm motion, are obtained using the chest surface motion as a surrogate signal. The primary objective of this paper is to demonstrate the feasibility of developing a function which is capable of inputting the chest surface motion data and outputting the diaphragm motion in real-time. For this purpose, after quantifying the diaphragm motion with a Principal Component Analysis (PCA) model, correlation coefficient between the model parameters of diaphragm motion and chest motion data was obtained through Partial Least Squares Regression (PLSR). Preliminary results obtained in this study indicate that the PCA coefficients representing the diaphragm motion can be obtained through chest surface motion tracking with high accuracy.

  7. Prognostic impact of cytological fluid tumor markers in non-small cell lung cancer.

    Science.gov (United States)

    Cho, Arthur; Hur, Jin; Hong, Yoo Jin; Lee, Hye-Jeong; Kim, Young Jin; Hong, Sae Rom; Suh, Young Joo; Im, Dong Jin; Kim, Yun Jung; Lee, Jae Seok; Shim, Hyo Sup; Choi, Byoung Wook

    2016-03-01

    The serum tumor markers CYFRA 21-1, carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCCA) are useful in diagnosis and prognosis of non-small cell lung cancer (NSCLC). Cytologic tumor markers obtained during needle aspiration biopsies (NAB) of lung lesions are useful for NSCLC diagnosis. This study investigated the incremental prognostic value of cytologic tumor markers compared to serum tumor markers. This prospective study included 253 patients diagnosed with NSCLC by NAB with cytologic tumor marker analysis. Levels of cytologic CYFRA 21-1, CEA, SCCA, and their serum counterparts were followed up for survival analysis. Optimal cutoff values for each tumor marker were obtained for overall survival (OS) and progression-free survival (PFS) analyses. All patients were followed up for a median of 22.8 months. Using cutoff values of 0.44 ng/ml for C-SCCA, 2.0 ng/ml for S-SCCA, and 3.3 ng/ml for S-CYFRA, a multivariate analysis revealed that high S-SCCA (hazard ratio, HR, 1.84) and high C-SCCA (HR, 1.63) were independent predictive factors of OS. The 3-year overall survival rate was 55 vs. 80 % for high and low C-SCCA, respectively. Cytologic tumor marker level detection is easily obtainable and provides prognostic information for NSCLC. Cytologic tumor markers provide comparable prognostic information relative to serum tumor markers, with C-SCCA acting as a strong prognostic factor of overall survival and PFS.

  8. Gastrointestinal stromal tumor masquerading as a lung neoplasm. A case presentation and literature review

    Directory of Open Access Journals (Sweden)

    Papagiannopoulos K

    2008-05-01

    Full Text Available Abstract Gastrointestinal stromal tumors (GISTs are rare neoplasms of the gastrointestinal tract. Their incidence in the esophagus is 1%–3%. Never has a GIST been documented to directly invade the lung. We report a primary esophageal GIST with direct invasion into the lung parenchyma, presenting predominantly with respiratory symptoms. We include a retrospective literature review. Although the principle 'common things are common' usually guides our everyday clinical practice, this case emphasizes that rare entities can mimic common pathologies and underlines the importance of having a clearly defined differential diagnostic list which should be meticulously scrutinized.

  9. YBX1 regulates tumor growth via CDC25a pathway in human lung adenocarcinoma

    Science.gov (United States)

    Yu, Wendan; Li, Jinxiu; Tang, Zhipeng; Yu, Zhenlong; Zhao, Lei; Zhang, Yixiang; Wang, Ziyi; Wang, Peng; Li, Yechi; Li, Fengzhou; Sun, Zhe; Xuan, Yang; Tang, Ranran; Deng, Wu-guo; Guo, Wei; Gu, Chundong

    2016-01-01

    Y-box binding protein 1 (YBX1) is involved in the multi-tumor occurrence and development. However, the regulation of YBX1 in lung tumorigenesis and the underlying mechanisms, especially its relationship with CDC25a, was remains unclear. In this study, we analyzed the expression and clinical significance of YBX1 and CDC25a in lung adenocarcinoma and identified their roles in the regulation of lung cancer growth. The retrospective analysis of 116 patients with lung adenocarcinoma indicated that YBX1 was positively correlated with CDC25a expression. The Cox-regression analysis showed only high-ranking TNM stage and low CDC25a expression were an independent risk factor of prognosis in enrolled patients. High expression of YBX1 or CDC25a protein was also observed in lung adenocarcinoma cells compared with HLF cells. ChIP assay demonstrated the binding of endogenous YBX1 to the CDC25a promoter region. Overexpression of exogenous YBX1 up-regulated the expression of the CDC25a promoter-driven luciferase. By contrast, inhibition of YBX1 by siRNA markedly decreased the capability of YBX1 binding to CDC25a promoter in A549 and H322 cells. Inhibition of YBX1 expression also blocked cell cycle progression, suppressed cell proliferation and induced apoptosis via the CDC25a pathway in vitro. Moreover, inhibition of YBX1 by siRNA suppressed tumorigenesis in a xenograft mouse model and down-regulated the expression of YBX1, CDC25a, Ki67 and cleaved caspase 3 in the tumor tissues of mice. Collectively, these results demonstrate inhibition of YBX1 suppressed lung cancer growth partly via the CDC25a pathway and high expression of YBX1/CDC25a predicts poor prognosis in human lung adenocarcinoma. PMID:27384875

  10. Topology polymorphism graph for lung tumor segmentation in PET-CT images

    Science.gov (United States)

    Cui, Hui; Wang, Xiuying; Zhou, Jianlong; Eberl, Stefan; Yin, Yong; Feng, Dagan; Fulham, Michael

    2015-06-01

    Accurate lung tumor segmentation is problematic when the tumor boundary or edge, which reflects the advancing edge of the tumor, is difficult to discern on chest CT or PET. We propose a ‘topo-poly’ graph model to improve identification of the tumor extent. Our model incorporates an intensity graph and a topology graph. The intensity graph provides the joint PET-CT foreground similarity to differentiate the tumor from surrounding tissues. The topology graph is defined on the basis of contour tree to reflect the inclusion and exclusion relationship of regions. By taking into account different topology relations, the edges in our model exhibit topological polymorphism. These polymorphic edges in turn affect the energy cost when crossing different topology regions under a random walk framework, and hence contribute to appropriate tumor delineation. We validated our method on 40 patients with non-small cell lung cancer where the tumors were manually delineated by a clinical expert. The studies were separated into an ‘isolated’ group (n = 20) where the lung tumor was located in the lung parenchyma and away from associated structures / tissues in the thorax and a ‘complex’ group (n = 20) where the tumor abutted / involved a variety of adjacent structures and had heterogeneous FDG uptake. The methods were validated using Dice’s similarity coefficient (DSC) to measure the spatial volume overlap and Hausdorff distance (HD) to compare shape similarity calculated as the maximum surface distance between the segmentation results and the manual delineations. Our method achieved an average DSC of 0.881  ±  0.046 and HD of 5.311  ±  3.022 mm for the isolated cases and DSC of 0.870  ±  0.038 and HD of 9.370  ±  3.169 mm for the complex cases. Student’s t-test showed that our model outperformed the other methods (p-values <0.05).

  11. Mouse mammary tumor virus-like gene sequences are present in lung patient specimens

    Directory of Open Access Journals (Sweden)

    Rodríguez-Padilla Cristina

    2011-09-01

    Full Text Available Abstract Background Previous studies have reported on the presence of Murine Mammary Tumor Virus (MMTV-like gene sequences in human cancer tissue specimens. Here, we search for MMTV-like gene sequences in lung diseases including carcinomas specimens from a Mexican population. This study was based on our previous study reporting that the INER51 lung cancer cell line, from a pleural effusion of a Mexican patient, contains MMTV-like env gene sequences. Results The MMTV-like env gene sequences have been detected in three out of 18 specimens studied, by PCR using a specific set of MMTV-like primers. The three identified MMTV-like gene sequences, which were assigned as INER6, HZ101, and HZ14, were 99%, 98%, and 97% homologous, respectively, as compared to GenBank sequence accession number AY161347. The INER6 and HZ-101 samples were isolated from lung cancer specimens, and the HZ-14 was isolated from an acute inflammatory lung infiltrate sample. Two of the env sequences exhibited disruption of the reading frame due to mutations. Conclusion In summary, we identified the presence of MMTV-like gene sequences in 2 out of 11 (18% of the lung carcinomas and 1 out of 7 (14% of acute inflamatory lung infiltrate specimens studied of a Mexican Population.

  12. The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth

    DEFF Research Database (Denmark)

    Bennewith, Kevin L; Huang, Xin; Ham, Christine M

    2009-01-01

    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2...... adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms...

  13. Retention of human bone marrow-derived cells in murine lungs following bleomycin-induced lung injury.

    Science.gov (United States)

    Liebler, Janice M; Lutzko, Carolyn; Banfalvi, Agnes; Senadheera, Dinithi; Aghamohammadi, Neema; Crandall, Edward D; Borok, Zea

    2008-08-01

    We studied the capacity of adult human bone marrow-derived cells (BMDC) to incorporate into distal lung of immunodeficient mice following lung injury. Immunodeficient NOD/SCID and NOD/SCID/beta(2) microglobulin (beta(2)M)(null) mice were administered bleomycin (bleo) or saline intranasally. One, 2, 3 and 4 days after bleo or saline, human BMDC labeled with CellTracker Green CMFDA (5-chloromethylfluorescein diacetate) were infused intravenously. Retention of CMFDA(+) cells was maximal when delivered 4 days after bleo treatment. Seven days after bleo, cells from NOD/SCID mice were CMFDA(+), which increased 10- to 100-fold in NOD/SCID/beta(2)M(null) mice. Preincubation of BMDC with Diprotin A, a reversible inhibitor of CD26 peptidase activity that enhances the stromal-derived factor-1 (SDF-1/CXCL12)/CXCR4 axis, resulted in a 30% increase in the percentage of CMFDA(+) cells retained in the lung. These data indicate that human BMDC can be identified in lungs of mice following injury, albeit at low levels, and this may be modestly enhanced by manipulation of the SDF-1/CXCR4 axis. Given the overall low number of human cells detected, methods to increase homing and retention of adult BMDC, and consideration of other stem cell populations, will likely be required to facilitate engraftment in the treatment of lung injury.

  14. cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth.

    Science.gov (United States)

    Chen, Zirong; Li, Jian-Liang; Lin, Shuibin; Cao, Chunxia; Gimbrone, Nicholas T; Yang, Rongqiang; Fu, Dongtao A; Carper, Miranda B; Haura, Eric B; Schabath, Matthew B; Lu, Jianrong; Amelio, Antonio L; Cress, W Douglas; Kaye, Frederic J; Wu, Lizi

    2016-06-01

    The LKB1 tumor suppressor gene is frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB1-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1-inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP-responsive element-binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC.

  15. Classification of 27 Tumor-Associated Antigens by Histochemical Analysis of 36 Freshly Resected Lung Cancer Tissues.

    Science.gov (United States)

    Kurosawa, Gene; Sugiura, Mototaka; Hattori, Yoshinobu; Tsuda, Hiroyuki; Kurosawa, Yoshikazu

    2016-11-08

    In previous studies, we identified 29 tumor-associated antigens (TAAs) and isolated 488 human monoclonal antibodies (mAbs) that specifically bind to one of the 29 TAAs. In the present study, we performed histochemical analysis of 36 freshly resected lung cancer tissues by using 60 mAbs against 27 TAAs. Comparison of the staining patterns of tumor cells, bronchial epithelial cells, and normal pulmonary alveolus cells and interalveolar septum allowed us to determine the type and location of cells that express target molecules, as well as the degree of expression. The patterns were classified into 7 categories. While multiple Abs were used against certain TAAs, the differences observed among them should be derived from differences in the binding activity and/or the epitope. Thus, such data indicate the versatility of respective clones as anti-cancer drugs. Although the information obtained was limited to the lung and bronchial tube, bronchial epithelial cells represent normal growing cells, and therefore, the data are informative. The results indicate that 9 of the 27 TAAs are suitable targets for therapeutic Abs. These 9 Ags include EGFR, HER2, TfR, and integrin α6β4. Based on our findings, a pharmaceutical company has started to develop anti-cancer drugs by using Abs to TfR and integrin α6β4. HGFR, PTP-LAR, CD147, CDCP1, and integrin αvβ3 are also appropriate targets for therapeutic purposes.

  16. Classification of 27 Tumor-Associated Antigens by Histochemical Analysis of 36 Freshly Resected Lung Cancer Tissues

    Directory of Open Access Journals (Sweden)

    Gene Kurosawa

    2016-11-01

    Full Text Available In previous studies, we identified 29 tumor-associated antigens (TAAs and isolated 488 human monoclonal antibodies (mAbs that specifically bind to one of the 29 TAAs. In the present study, we performed histochemical analysis of 36 freshly resected lung cancer tissues by using 60 mAbs against 27 TAAs. Comparison of the staining patterns of tumor cells, bronchial epithelial cells, and normal pulmonary alveolus cells and interalveolar septum allowed us to determine the type and location of cells that express target molecules, as well as the degree of expression. The patterns were classified into 7 categories. While multiple Abs were used against certain TAAs, the differences observed among them should be derived from differences in the binding activity and/or the epitope. Thus, such data indicate the versatility of respective clones as anti-cancer drugs. Although the information obtained was limited to the lung and bronchial tube, bronchial epithelial cells represent normal growing cells, and therefore, the data are informative. The results indicate that 9 of the 27 TAAs are suitable targets for therapeutic Abs. These 9 Ags include EGFR, HER2, TfR, and integrin α6β4. Based on our findings, a pharmaceutical company has started to develop anti-cancer drugs by using Abs to TfR and integrin α6β4. HGFR, PTP-LAR, CD147, CDCP1, and integrin αvβ3 are also appropriate targets for therapeutic purposes.

  17. Classification of 27 Tumor-Associated Antigens by Histochemical Analysis of 36 Freshly Resected Lung Cancer Tissues

    Science.gov (United States)

    Kurosawa, Gene; Sugiura, Mototaka; Hattori, Yoshinobu; Tsuda, Hiroyuki; Kurosawa, Yoshikazu

    2016-01-01

    In previous studies, we identified 29 tumor-associated antigens (TAAs) and isolated 488 human monoclonal antibodies (mAbs) that specifically bind to one of the 29 TAAs. In the present study, we performed histochemical analysis of 36 freshly resected lung cancer tissues by using 60 mAbs against 27 TAAs. Comparison of the staining patterns of tumor cells, bronchial epithelial cells, and normal pulmonary alveolus cells and interalveolar septum allowed us to determine the type and location of cells that express target molecules, as well as the degree of expression. The patterns were classified into 7 categories. While multiple Abs were used against certain TAAs, the differences observed among them should be derived from differences in the binding activity and/or the epitope. Thus, such data indicate the versatility of respective clones as anti-cancer drugs. Although the information obtained was limited to the lung and bronchial tube, bronchial epithelial cells represent normal growing cells, and therefore, the data are informative. The results indicate that 9 of the 27 TAAs are suitable targets for therapeutic Abs. These 9 Ags include EGFR, HER2, TfR, and integrin α6β4. Based on our findings, a pharmaceutical company has started to develop anti-cancer drugs by using Abs to TfR and integrin α6β4. HGFR, PTP-LAR, CD147, CDCP1, and integrin αvβ3 are also appropriate targets for therapeutic purposes. PMID:27834817

  18. Cystic fibrohistiocytic tumor of the lung presenting as a solitary lesion

    Directory of Open Access Journals (Sweden)

    gGiorgio Sgarbi

    2010-03-01

    Full Text Available Cystic fibrohistiocytic tumor of the lung is a rare neoplasm. In many cases it represents a metastasis from a benign or low-grade fibrohistiocytic tumor of the skin, but occasionally it may be primary. Radiologically it usually occurs as a cystic change of multiple pulmonary nodules, and pneumothorax is the most frequent presenting symptom. We present here a 16-year-old man with recurrent right pneumothorax. The patient had no his-tory of cutaneous fibrohistiocytic lesions. He underwent videothoracoscopic right apical segmentectomy, right lower lobe nodulectomy, and pleuroabrasion. Microscopy of the apical segmentectomy showed a cystic fibrohistio-cytic tumor, whereas the nodule of the lower lobe was an intraparenchymal lymph node. The patient is alive with no tumor recurrence. The differential diagnosis includes Langerhans cell histiocytosis, lymphangioleiomyomatosis, pleuropulmonary blastoma, and metastatic endometrial stromal sarcoma. This disease usually occurs with multiple pulmonary cysts and cavitation. This case is the first reported presenting as a single lesion.

  19. Large malignant phyllodes tumor of the breast with metastases to the lungs

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    Alexander Augustyn

    2015-05-01

    Full Text Available Phyllodes tumors of the breast account for less than 0.5% of breast cancers and present most commonly in women 45 to 49 years old. The importance in managing fibroepithelial lesions lies in distinguishing fibroadenomas, which are benign, from phyllodes tumors, which can be malignant and require complete surgical excision. We report the case of a 56-year-old female who presented with a rapidly enlarging mass in her right breast 18 cm in maximum dimension that completely effaced the breast and distorted the nipple. The patient underwent a successful total mastectomy after core biopsy revealed a diagnosis of phyllodes tumor. Surgical resection is the primary treatment modality; neoadjuvant and adjuvant therapies remain controversial. Here, we report the case of a large malignant phyllodes tumor metastatic to the lungs, review the literature, and discuss diagnostic modalities and adjunct nonsurgical therapies.

  20. Mushroom β-Glucan May Immunomodulate the Tumor-Associated Macrophages in the Lewis Lung Carcinoma

    Directory of Open Access Journals (Sweden)

    Wan-Jhen Wang

    2015-01-01

    Full Text Available The present study showed that oral mushroom beta-glucan treatment significantly increased IFN-γ mRNA expression but significantly reduced COX-2 mRNA expression within the lung. For LLC tumor model, oral Ganoderma lucidum or Antrodia camphorata polysaccharides treatments significantly reduced TGF-β production in serum. In addition, IL-12 and IFN-γ mRNA expression were significantly increased, but IL-6, IL-10, COX-2, and TGF-β mRNA expression were substantially following oral mushroom polysaccharides treatments. The study highlights the efficacious effect of mushroom polysaccharides for ameliorating the immune suppression in the tumor microenvironment. Increased M1 phenotype of tumor-associated macrophages and attenuated M2 phenotype of tumor-associated macrophages could be achieved by ingesting mushroom polysaccharides.

  1. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

    OpenAIRE

    Dorantes-Heredia, Rita; Ruiz-Morales, José Manuel; Cano-García, Fernando

    2016-01-01

    Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted...

  2. Specific Accumulation of Tumor-Derived Adhesion Factor in Tumor Blood Vessels and in Capillary Tube-Like Structures of Cultured Vascular Endothelial Cells

    Science.gov (United States)

    Akaogi, Kotaro; Okabe, Yukie; Sato, Junji; Nagashima, Yoji; Yasumitsu, Hidetaro; Sugahara, Kazuyuki; Miyazaki, Kaoru

    1996-08-01

    Tumor-derived adhesion factor (TAF) was previously identified as a cell adhesion molecule secreted by human bladder carcinoma cell line EJ-1. To elucidate the physiological function of TAF, we examined its distribution in human normal and tumor tissues. Immunochemical staining with an anti-TAF monoclonal antibody showed that TAF was specifically accumulated in small blood vessels and capillaries within and adjacent to tumor nests, but not in those in normal tissues. Tumor blood vessel-specific staining of TAF was observed in various human cancers, such as esophagus, brain, lung, and stomach cancers. Double immunofluorescent staining showed apparent colocalization of TAF and type IV collagen in the vascular basement membrane. In vitro experiments demonstrated that TAF preferentially bound to type IV collagen among various extracellular matrix components tested. In cell culture experiments, TAF promoted adhesion of human umbilical vein endothelial cells to type IV collagen substrate and induced their morphological change. Furthermore, when the endothelial cells were induced to form capillary tube-like structures by type I collagen, TAF and type IV collagen were exclusively detected on the tubular structures. The capillary tube formation in vitro was prevented by heparin, which inhibited the binding of TAF to the endothelial cells. These results strongly suggest that TAF contributes to the organization of new capillary vessels in tumor tissues by modulating the interaction of endothelial cells with type IV collagen.

  3. Overexpression of smad7 blocks primary tumor growth and lung metastasis development in osteosarcoma.

    Science.gov (United States)

    Lamora, Audrey; Talbot, Julie; Bougras, Gwenola; Amiaud, Jérôme; Leduc, Marion; Chesneau, Julie; Taurelle, Julien; Stresing, Verena; Le Deley, Marie Cécile; Heymann, Marie Françoise; Heymann, Dominique; Redini, Françoise; Verrecchia, Franck

    2014-10-01

    Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastasis is present at diagnosis. Because transforming growth factor-β (TGFβ) has been shown to promote metastasis in many solid tumors, we investigated the effect of the natural TGFβ/Smad signaling inhibitor Smad7 and the TβRI inhibitor SD-208 on osteosarcoma behavior. By using a mouse model of osteosarcoma induced by paratibial injection of cells, we assessed the impact of Smad7 overexpression or SD-208 on tumor growth, tumor microenvironment, bone remodeling, and metastasis development. First, we demonstrated that TGFβ levels are higher in serum samples from patients with osteosarcoma compared with healthy volunteers and that TGFβ/Smad3 signaling pathway is activated in clinical samples. Second, we showed that Smad7 slows the growth of the primary tumor and increases mice survival. We furthermore demonstrated that Smad7 expression does not affect in vitro osteosarcoma cell proliferation but affects the microarchitectural parameters of bone. In addition, Smad7-osteosarcoma bone tumors expressed lower levels of osteolytic factors such as RANKL, suggesting that Smad7 overexpression affects the "vicious cycle" established between tumor cells and bone cells by its ability to decrease osteoclast activity. Finally, we showed that Smad7 overexpression in osteosarcoma cells and the treatment of mice with SD208 inhibit the development of lung metastasis. Taken together, these results demonstrate that the inhibition of the TGFβ/Smad signaling pathway may be a promising therapeutic strategy against tumor progression of osteosarcoma, specifically against the development of lung metastasis. ©2014 American Association for Cancer Research.

  4. Prognostic factors of tumor recurrence in completely resected non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Tantraworasin A

    2013-06-01

    Full Text Available Apichat Tantraworasin,1 Somcharean Seateang,1 Nirush Lertprasertsuke,2 Nuttapon Arreyakajohn,3 Choosak Kasemsarn,4 Jayanton Patumanond5 1General Thoracic Unit, Department of Surgery, Faculty of Medicine, Chiang Mai University Hospital, Chiang Mai, Thailand; 2Department of Pathology, Faculty of Medicine, Chiang Mai University Hospital, Chiang Mai, Thailand; 3Cardiovascular Thoracic Unit, Department of Surgery, Lampang Hospital, Lampang, Thailand; 4Cardiovascular Thoracic Unit, Department of Surgery, Chest Institute, Nonthaburi, Thailand; 5Department of Community Medicine, Faculty of Medicine, Chiang Mai University Hospital, Chiang Mai, Thailand Background: Patients with completely resected non-small cell lung cancer (NSCLC have an excellent outcome; however tumor recurs in 30%-77% of patients. This study retrospectively analyzed the clinicopathologic features of patients with any operable stage of NSCLC to identify the prognostic factors that influence tumor recurrence, including intratumoral blood vessel invasion (IVI, tumor size, tumor necrosis, and nodal involvement. Methods: From January 2002 to December 2011, 227 consecutive patients were enrolled in this study. They were divided into two groups: the “no recurrence” group and the “recurrence” group. Recurrence-free survival was analyzed by multivariable Cox regression analysis, stratified by tumor staging, chemotherapy, and lymphatic invasion. Results: IVI, tumor necrosis, tumor diameter more than 5 cm, and nodal involvement were identified as independent prognostic factors of tumor recurrence. The hazard ratio (HR of patients with IVI was 2.1 times higher than that of patients without IVI (95% confident interval [CI]: 1.4–3.2 (P = 0.001.The HR of patients with tumor necrosis was 2.1 times higher than that of patients without tumor necrosis (95% CI: 1.3–3.4 (P = 0.001. Patients who had a maximum tumor diameter greater than 5 cm had significantly higher risk of recurrence than

  5. A statistical method for lung tumor segmentation uncertainty in PET images based on user inference.

    Science.gov (United States)

    Zheng, Chaojie; Wang, Xiuying; Feng, Dagan

    2015-01-01

    PET has been widely accepted as an effective imaging modality for lung tumor diagnosis and treatment. However, standard criteria for delineating tumor boundary from PET are yet to develop largely due to relatively low quality of PET images, uncertain tumor boundary definition, and variety of tumor characteristics. In this paper, we propose a statistical solution to segmentation uncertainty on the basis of user inference. We firstly define the uncertainty segmentation band on the basis of segmentation probability map constructed from Random Walks (RW) algorithm; and then based on the extracted features of the user inference, we use Principle Component Analysis (PCA) to formulate the statistical model for labeling the uncertainty band. We validated our method on 10 lung PET-CT phantom studies from the public RIDER collections [1] and 16 clinical PET studies where tumors were manually delineated by two experienced radiologists. The methods were validated using Dice similarity coefficient (DSC) to measure the spatial volume overlap. Our method achieved an average DSC of 0.878 ± 0.078 on phantom studies and 0.835 ± 0.039 on clinical studies.

  6. Enhancer of zeste homolog 2 silencing inhibits tumor growth and lung metastasis in osteosarcoma

    OpenAIRE

    Yang-Fan Lv; Guang-Ning Yan; Gang Meng; Xi Zhang; Qiao-Nan Guo

    2015-01-01

    The enhancer of zeste homolog 2 (EZH2) methyltransferase is the catalytic subunit of polycomb repressive complex 2 (PRC2), which acts as a transcription repressor via the trimethylation of lysine 27 of histone 3 (H3K27me3). EZH2 has been recognised as an oncogene in several types of tumors; however, its role in osteosarcoma has not been fully elucidated. Herein, we show that EZH2 silencing inhibits tumor growth and lung metastasis in osteosarcoma by facilitating re-expression of the imprintin...

  7. Detecting small lung tumors in mouse models by refractive-index microradiology

    Energy Technology Data Exchange (ETDEWEB)

    Chien, Chia-Chi; Hwu, Y. [Academia Sinica, Institute of Physics, Taipei (China); National Tsing Hua University, Department of Engineering and System Science, Hsinchu (China); Zhang, Guilin; Yue, Weisheng; Li, Yan; Xue, Hongjie [Chinese Academy of Sciences, Shanghai Institute of Applied Physics, Shanghai (China); Liu, Ping; Sun, Jianqi; Xu, Lisa X. [Shanghai Jiao Tong University, Shanghai (China); Wang, Chang Hai; Chen, Nanyow; Lu, Chien Hung; Lee, Ting-Kuo [Academia Sinica, Institute of Physics, Taipei (China); Yang, Yuh-Cheng; Lu, Yen-Ta [Mackay Memorial Hospital, Taipei City (China); Ching, Yu-Tai [National Chiao Tung University, Department of Computer Science, Hsinchu (China); Shih, T.F.; Yang, P.C. [National Taiwan University, College of Medicine, Taipei (China); Je, J.H. [Pohang University of Science and Technology Pohang, X-ray Imaging Center, Pohang CT, Kyungbuk (Korea, Republic of); Margaritondo, G. [Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne (Switzerland)

    2011-08-15

    Refractive-index (phase-contrast) radiology was able to detect lung tumors less than 1 mm in live mice. Significant micromorphology differences were observed in the microradiographs between normal, inflamed, and lung cancer tissues. This was made possible by the high phase contrast and by the fast image taking that reduces the motion blur. The detection of cancer and inflammation areas by phase contrast microradiology and microtomography was validated by bioluminescence and histopathological analysis. The smallest tumor detected is less than 1 mm{sup 3} with accuracy better than 1 x 10{sup -3} mm{sup 3}. This level of performance is currently suitable for animal studies, while further developments are required for clinical application. (orig.)

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

    Science.gov (United States)

    2013-01-15

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

  9. Intraosseous malignant peripheral nerve sheath tumor with local recurrence, lung metastases and death

    Energy Technology Data Exchange (ETDEWEB)

    Kendi, Tuba Karaguelle [Integra MR Imaging Center, Tahran Cad., No. 38, Kavaklidere, Ankara (Turkey); Center for MR Research, University of Minnesota, 2021 6th Street SE, MN 55455, Minneapolis (United States); Erakar, Aziz; Yildiz, H.Yusuf [Department of Orthopaedic Surgery, Ankara University School of Medicine, 06100, Ankara (Turkey); Saglik, Yener; Erekul, Selim [Department of Pathology, Ankara University School of Medicine, 06100, Ankara (Turkey)

    2004-04-01

    Malignant peripheral nerve sheath tumor (MPNST) is almost always seen in soft tissue. Skeletal involvement by MPNST is uncommon and usually results from secondary invasion. Primary MPNSTs are exceptionally rare. We report a surgically proven case of intraosseous MPNST, with local recurrence and lung metastasis during follow-up. The imaging and histological features of the case are described and the literature on the subject briefly reviewed. (orig.)

  10. Evaluation and comparison of New 4DCT based strategies for proton treatment planning for lung tumors.

    Science.gov (United States)

    Wang, Ning; Patyal, Baldev; Ghebremedhin, Abiel; Bush, David

    2013-03-25

    To evaluate different strategies for proton lung treatment planning based on four-dimensional CT (4DCT) scans. Twelve cases, involving only gross tumor volumes (GTV), were evaluated. Single image sets of (1) maximum intensity projection (MIP3) of end inhale (EI), middle exhale (ME) and end exhale (EE) images; (2) average intensity projection (AVG) of all phase images; and (3) EE images from 4DCT scans were selected as primary images for proton treatment planning. Internal target volumes (ITVs) outlined by a clinician were imported into MIP3, AVG, and EE images as planning targets. Initially, treatment uncertainties were not included in planning. Each plan was imported into phase images of 4DCT scans. Relative volumes of GTVs covered by 95% of prescribed dose and mean ipsilateral lung dose of a phase image obtained by averaging the dose in inspiration and expiration phases were used to evaluate the quality of a plan for a particular case. For comparing different planning strategies, the mean of the averaged relative volumes of GTVs covered by 95% of prescribed dose and its standard deviation for each planning strategy for all cases were used. Then, treatment uncertainties were included in planning. Each plan was recalculated in phase images of 4DCT scans. Same strategies were used for plan evaluation except dose-volume histograms of the planning target volumes (PTVs) instead of GTVs were used and the mean and standard deviation of the relative volumes of PTVs covered by 95% of prescribed dose and the ipsilateral lung dose were used to compare different planning strategies. MIP3 plans without treatment uncertainties yielded 96.7% of the mean relative GTV covered by 95% of prescribed dose (standard deviations of 5.7% for all cases). With treatment uncertainties, MIP3 plans yielded 99.5% of mean relative PTV covered by 95% of prescribed dose (standard deviations of 0.7%). Inclusion of treatment uncertainties improved PTV dose coverage but also increased the ipsilateral

  11. Percutaneous radiofrequency ablation for lung tumors beneath the rib under CT fluoroscopic guidance with gantry tilt

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Takanobu; Yamagami, Takuji; Tanaka, Osamu; Yoshimatsu, Rika; Miura, Hiroshi; Nishimura, Tsunehiko (Dept. of Radiology, Graduate School of Medical Science, Kyoto Prefectural Univ. of Medicine, Kamigyo, Kyoto (Japan)), e-mail: yamagami@koto.kpu-m.ac.jp

    2010-05-15

    Background: Radiofrequency (RF) ablation of lung tumors has become a treatment of choice, especially for unresectable cases. However, RF ablation of small lung lesions located just beneath the rib is difficult. Purpose: To evaluate the efficacy and safety of gantry tilting for the performance of RF ablation of peripheral lesions located beneath the rib. Material and Methods: Our study was based on 18 of 293 lesions in the lung for which RF ablation was performed under CT scan fluoroscopic guidance at our institution between October 2004 and March 2009. For these 18 lesions, RF ablation was performed with gantry tilting because a rib blocked visualization of the RF ablation route even after other attempts had been made to change the relationship between the target and the rib. Results: All RF needles, with only one exception, were successfully advanced to hit the tumor. The commonest complication was a pneumothorax, which occurred in seven procedures. No serious complications occurred. The progression-free rates were 82.4% at 6 months, 62.5% at 12 months, and 30% at 24 months. Mean local progression-free duration was 17.6+-11.6 months (range 4-36 months). Conclusion: RF ablation under CT scan fluoroscopic guidance with gantry tilt is a useful and safe technique for RF ablation of lung nodules located beneath the rib

  12. Capturing Genomic Evolution of Lung Cancers through Liquid Biopsy for Circulating Tumor DNA

    Directory of Open Access Journals (Sweden)

    Michael Offin

    2017-01-01

    Full Text Available Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the tumor’s dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intratumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of circulating tumor DNA (ctDNA analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intratumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors.

  13. The Emergent Landscape of Detecting EGFR Mutations Using Circulating Tumor DNA in Lung Cancer

    Directory of Open Access Journals (Sweden)

    Wei-Lun Huang

    2015-01-01

    Full Text Available The advances in targeted therapies for lung cancer are based on the evaluation of specific gene mutations especially the epidermal growth factor receptor (EGFR. The assays largely depend on the acquisition of tumor tissue via biopsy before the initiation of therapy or after the onset of acquired resistance. However, the limitations of tissue biopsy including tumor heterogeneity and insufficient tissues for molecular testing are impotent clinical obstacles for mutation analysis and lung cancer treatment. Due to the invasive procedure of tissue biopsy and the progressive development of drug-resistant EGFR mutations, the effective initial detection and continuous monitoring of EGFR mutations are still unmet requirements. Circulating tumor DNA (ctDNA detection is a promising biomarker for noninvasive assessment of cancer burden. Recent advancement of sensitive techniques in detecting EGFR mutations using ctDNA enables a broad range of clinical applications, including early detection of disease, prediction of treatment responses, and disease progression. This review not only introduces the biology and clinical implementations of ctDNA but also includes the updating information of recent advancement of techniques for detecting EGFR mutation using ctDNA in lung cancer.

  14. Internal-external correlation investigations of respiratory induced motion of lung tumors.

    Science.gov (United States)

    Ionascu, Dan; Jiang, Steve B; Nishioka, Seiko; Shirato, Hiroki; Berbeco, Ross I

    2007-10-01

    In gated radiation therapy procedures, the lung tumor position is used directly (by implanted radiopaque markers) or indirectly (by external surrogate methods) to decrease the volume of irradiated healthy tissue. Due to a risk of pneumothorax, many clinics do not implant fiducials, and the gated treatment is primarily based on a respiratory induced external signal. The external surrogate method relies upon the assumption that the internal tumor motion is well correlated with the external respiratory induced motion, and that this correlation is constant in time. Using a set of data that contains synchronous internal and external motion traces, we have developed a dynamic data analysis technique to study the internal-external correlation, and to quantitatively estimate its underlying time behavior. The work presented here quantifies the time dependent behavior of the correlation between external respiratory signals and lung implanted fiducial motion. The corresponding amplitude mismatch is also reported for the lung patients studied. The information obtained can be used to improve the accuracy of tumor tracking. For the ten patients in this study, the SI internal-external motion is well correlated, with small time shifts and corresponding amplitude mismatches. Although the AP internal-external motion reveals larger time shifts than along the SI direction, the corresponding amplitude mismatches are below 5 mm.

  15. Quantitative computed tomographic descriptors associate tumor shape complexity and intratumor heterogeneity with prognosis in lung adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Olya Grove

    Full Text Available Two CT features were developed to quantitatively describe lung adenocarcinomas by scoring tumor shape complexity (feature 1: convexity and intratumor density variation (feature 2: entropy ratio in routinely obtained diagnostic CT scans. The developed quantitative features were analyzed in two independent cohorts (cohort 1: n = 61; cohort 2: n = 47 of patients diagnosed with primary lung adenocarcinoma, retrospectively curated to include imaging and clinical data. Preoperative chest CTs were segmented semi-automatically. Segmented tumor regions were further subdivided into core and boundary sub-regions, to quantify intensity variations across the tumor. Reproducibility of the features was evaluated in an independent test-retest dataset of 32 patients. The proposed metrics showed high degree of reproducibility in a repeated experiment (concordance, CCC≥0.897; dynamic range, DR≥0.92. Association with overall survival was evaluated by Cox proportional hazard regression, Kaplan-Meier survival curves, and the log-rank test. Both features were associated with overall survival (convexity: p = 0.008; entropy ratio: p = 0.04 in Cohort 1 but not in Cohort 2 (convexity: p = 0.7; entropy ratio: p = 0.8. In both cohorts, these features were found to be descriptive and demonstrated the link between imaging characteristics and patient survival in lung adenocarcinoma.

  16. Relationship between tumor size and disease stage in non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Yang Fu

    2010-09-01

    Full Text Available Abstract Background Whether tumor size and stage distribution are correlated remains controversial. The objective is to assess the relationship between tumor size and disease stage distribution in non-small cell lung cancer (NSCLC. Methods We conducted a retrospective analysis of 917 cases of NSCLC that were resected in the Cancer Hospital of Fudan University and Shanghai Sixth Hospital between January 2000 and February 2009. Tumor sizes were grouped into five categories: ≤20 mm, 21 to 30 mm, 31 to 50 mm, 51 to 70 mm and ≥71 mm. Results Age and tumor size affected stage distribution: patients 60 years or older had a higher percentage of N0M0 disease than patients younger than 60 years (61.67% vs. 44.85%, p Conclusions There is a statistically significant relationship between tumor size and distribution of disease stage of primary NSCLC tumors: the smaller the tumor, the more likely the disease is N0M0 status.

  17. A Pilot Study of Circulating Tumor Cells in Stage IV Non-Small Cell Lung Carcinoma

    Directory of Open Access Journals (Sweden)

    Max Haid

    2016-08-01

    Full Text Available Purpose: Measurement of the number of circulating tumor cells (CTCs in the bloodstream has been shown to have prognostic significance in treating breast carcinoma. This pilot study was formulated to determine if stage IV non-small cell lung carcinomas similarly shed malignant cells into the circulation and if their presence has prognostic significance. Methods: Patients with stage IV non-small cell lung carcinomas were tested once for CTCs in 7.5 ml of their blood prior to receiving any treatments. A proprietary blood collection kit produced by Veridex LLC (Raritan, NJ, which manufactures the instrument that performs the immunomagnetic CELLSEARCH® CTC assay, was used. Tumor measurements were determined in three dimensions by the same radiologist using computerized axial tomography. The three-dimensional sum was used to represent tumor size. Survival from the date of the pretreatment CTC assay was monitored and recorded. Data were analyzed statistically using NCSS8 statistical software (NCSS LLC, Kaysville, UT. Results: Of 19 evaluable patients, 10 had no detectable CTCs. There was no relation between intrapulmonary primary tumor size and the number of CTCs, nor between tumor size and survival. Survival was not affected by gender or age at entry into the trial. The mean survival of those with no detectable CTCs was 536 ± 91.1 days versus 239 ± 96.0 days for those with 1 or more detectable CTCs, a statistically significant advantage (P=0.034 favoring those without CTCs. Conclusions: Patients with a CTC score of 0 survived significantly longer than those with a CTC score of ≥ 1. Survival was not correlated with gender, age or primary tumor size. Recovery of CTCs potentially provides a noninvasive source of tumor cells for genomic profiling, which may enable development of a custom treatment plan for the individual patient. Further investigations are warranted and needed.

  18. Developing Novel Therapeutic Approaches in Small Cell Lung Carcinoma Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells

    Science.gov (United States)

    2015-10-01

    Using Genetically Engineered Mouse Models and Human Circulating Tumor Cells PRINCIPAL INVESTIGATOR: Jeffrey Engelman MD PhD CONTRACTING...SUBTITLE Developiing Novel Therapeutic Approaches in Small Cell Lung 5a. CONTRACT NUMBER Carcinoma Using Genetically Engineered Mouse Models and 5b...biomarkers. 15. SUBJECT TERMS Small cell lung cancer (SCLC), Genetically engineered mouse model (GEMM), BH3 mimetic, TORC inhibitor, Apoptosis

  19. LUNG TUMOR KRAS AND TP53 MUTATIONS IN NONSMOKERS REFLECT EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS

    Science.gov (United States)

    Lung Tumor KRAS and TP53 Mutations in Nonsmokers Reflect Exposure to PAH-Rich Coal Combustion Emissions Use of smoky coal in unvented homes in Xuan Wei County, Yunnan Province, China, is associated with lung cancer among nonsmoking females. Such women have the highest...

  20. [Lung cancer molecular testing, what role for Next Generation Sequencing and circulating tumor DNA].

    Science.gov (United States)

    Pécuchet, Nicolas; Legras, Antoine; Laurent-Puig, Pierre; Blons, Hélène

    2016-01-01

    Molecular screening has become a standard of care for patients with advanced cancers and impacts on how to treat a patient. Advances in genomic technologies with the development of high throughput sequencing methods will certainly improve the possibilities to access a more accurate molecular diagnosis and to go beyond the identification of validated targets as a large number of genes can be screened for actionable changes. Moreover, accurate high throughput testing may help tumor classification in terms of prognosis and drug sensitivity. Finally, it will be possible to assess tumor heterogeneity and changes in molecular profiles during follow-up using ultra-deep sequencing technologies and circulating tumor DNA characterization. The accumulation of somatic ADN alterations is considered as the main contributing factor in carcinogenesis. The alterations can occur at different levels: mutation, copy number variations or gene translocations resulting in altered expression of the corresponding genes or impaired protein functions. Genes involved are mainly tumor suppressors, oncogenes or ADN repair genes whose modifications in tumors will impinge cell fate and proliferation from tumor initiation to metastasis. The entire genome of various tumor types, have now been sequenced. In lung cancer, the average number of mutations is very high with more than 8.9 mutations/Mb (Network TCGAR, 2014) that is to say more than 10,000 mutations/genome. These alterations need to be classified, indeed, some are true drivers that directly impact proliferation and some are passenger mutations linked to genetic instability. The development of targeted therapies relies on the identification of oncogenic drivers. The identification of genotype-phenotype associations as in the case of EGFR-TKI (Epidermal growth factor receptor-tyrosine kinase inhibitor) and EGFR mutations in lung cancer led to the restriction of drugs to patients for which tumor genotype predicts efficacy. Tumor

  1. Nonhematopoietic cells are the primary source of bone marrow-derived lung epithelial cells.

    Science.gov (United States)

    Kassmer, Susannah H; Bruscia, Emanuela M; Zhang, Ping-Xia; Krause, Diane S

    2012-03-01

    Previous studies have demonstrated that bone marrow (BM)-derived cells differentiate into nonhematopoietic cells of multiple tissues. To date, it remains unknown which population(s) of BM cells are primarily responsible for this engraftment. To test the hypothesis that nonhematopoietic stem cells in the BM are the primary source of marrow-derived lung epithelial cells, either wild-type hematopoietic or nonhematopoietic BM cells were transplanted into irradiated surfactant-protein-C (SPC)-null mice. Donor-derived, SPC-positive type 2 pneumocytes were predominantly detected in the lungs of mice receiving purified nonhematopoietic cells and were absent from mice receiving purified hematopoietic stem and progenitor cells. We conclude that cells contained in the nonhematopoietic fraction of the BM are the primary source of marrow-derived lung epithelial cells. These nonhematopoietic cells may represent a primitive stem cell population residing in adult BM.

  2. Differential Motion Between Mediastinal Lymph Nodes and Primary Tumor in Radically Irradiated Lung Cancer Patients

    Energy Technology Data Exchange (ETDEWEB)

    Schaake, Eva E. [Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam (Netherlands); Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam (Netherlands); Rossi, Maddalena M.G. [Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam (Netherlands); Buikhuisen, Wieneke A.; Burgers, Jacobus A. [Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam (Netherlands); Smit, Adrianus A.J. [Department of Pulmonary Disease, Onze Lieve Vrouwe Gasthuis, Amsterdam (Netherlands); Belderbos, José S.A. [Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam (Netherlands); Sonke, Jan-Jakob, E-mail: j.sonke@nki.nl [Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam (Netherlands)

    2014-11-15

    Purpose/Objective: In patients with locally advanced lung cancer, planning target volume margins for mediastinal lymph nodes and tumor after a correction protocol based on bony anatomy registration typically range from 1 to 1.5 cm. Detailed information about lymph node motion variability and differential motion with the primary tumor, however, is lacking from large series. In this study, lymph node and tumor position variability were analyzed in detail and correlated to the main carina to evaluate possible margin reduction. Methods and Materials: Small gold fiducial markers (0.35 × 5 mm) were placed in the mediastinal lymph nodes of 51 patients with non-small cell lung cancer during routine diagnostic esophageal or bronchial endoscopic ultrasonography. Four-dimensional (4D) planning computed tomographic (CT) and daily 4D cone beam (CB) CT scans were acquired before and during radical radiation therapy (66 Gy in 24 fractions). Each CBCT was registered in 3-dimensions (bony anatomy) and 4D (tumor, marker, and carina) to the planning CT scan. Subsequently, systematic and random residual misalignments of the time-averaged lymph node and tumor position relative to the bony anatomy and carina were determined. Additionally, tumor and lymph node respiratory amplitude variability was quantified. Finally, required margins were quantified by use of a recipe for dual targets. Results: Relative to the bony anatomy, systematic and random errors ranged from 0.16 to 0.32 cm for the markers and from 0.15 to 0.33 cm for the tumor, but despite similar ranges there was limited correlation (0.17-0.71) owing to differential motion. A large variability in lymph node amplitude between patients was observed, with an average motion of 0.56 cm in the cranial-caudal direction. Margins could be reduced by 10% (left-right), 27% (cranial-caudal), and 10% (anteroposterior) for the lymph nodes and −2%, 15%, and 7% for the tumor if an online carina registration protocol replaced a

  3. Functional EpoR pathway utilization is not detected in primary tumor cells isolated from human breast, non-small cell lung, colorectal, and ovarian tumor tissues.

    Directory of Open Access Journals (Sweden)

    Scott D Patterson

    Full Text Available Several clinical trials in oncology have reported increased mortality or disease progression associated with erythropoiesis-stimulating agents. One hypothesis proposes that erythropoiesis-stimulating agents directly stimulate tumor proliferation and/or survival through cell-surface receptors. To test this hypothesis and examine if human tumors utilize the erythropoietin receptor pathway, the response of tumor cells to human recombinant erythropoietin was investigated in disaggregated tumor cells obtained from 186 patients with colorectal, breast, lung, ovarian, head and neck, and other tumors. A cocktail of well characterized tumor growth factors (EGF, HGF, and IGF-1 were analyzed in parallel as a positive control to determine whether freshly-isolated tumor cells were able to respond to growth factor activation ex vivo. Exposing tumor cells to the growth factor cocktail resulted in stimulation of survival and proliferation pathways as measured by an increase in phosphorylation of the downstream signaling proteins AKT and ERK. In contrast, no activation by human recombinant erythropoietin was observed in isolated tumor cells. Though tumor samples exhibited a broad range of cell-surface expression of EGFR, c-Met, and IGF-1R, no cell-surface erythropoietin receptor was detected in tumor cells from the 186 tumors examined (by flow cytometry or Western blot. Erythropoiesis-stimulating agents did not act directly upon isolated tumor cells to stimulate pathways known to promote proliferation or survival of human tumor cells isolated from primary and metastatic tumor tissues.

  4. Prognosis factors for survival in cats after removal of a primary lung tumor: 21 cases (1979-1994).

    Science.gov (United States)

    Hahn, K A; McEntee, M F

    1998-01-01

    To identify possible prognostic factors for survival time in cats with a primary lung tumor after surgical excision. Retrospective clinical study. 21 cats with histologically confirmed primary lung tumors removed surgically. Medical records for cats treated between 1979 and 1994 at 14 participating veterinary referral hospitals were reviewed. After surgical resection and recovery, 18 cats died from metastatic disease with a median survival time of 115 days (range, 13 to 1,526 days). Three cats were lost to follow-up at 119 days, 251 days, and 410 days after the surgical procedure. Contingency table analysis to determine if an association existed between clinical findings (breed, age, gender, body weight, clinical signs, duration of clinical signs, and radiographic findings) or histological features and survival time was performed. Only histological morphology of the primary lung tumor showed a significant association with survival time. Twelve cats with moderately differentiated tumors had a significantly longer survival time (median, 698 days; range, 19 to 1,526 days) than the nine cats with poorly differentiated tumors (median, 75 days; range, 13 to 634 days). Surgical resection of a solitary primary lung tumor in cats is indicated. A poor prognosis for long-term survival is warranted for those cats having a poorly differentiated primary lung tumor.

  5. Protease-mediated release of chemotherapeutics from mesoporous silica nanoparticles to ex vivo human and mouse lung tumors.

    Science.gov (United States)

    van Rijt, Sabine H; Bölükbas, Deniz A; Argyo, Christian; Datz, Stefan; Lindner, Michael; Eickelberg, Oliver; Königshoff, Melanie; Bein, Thomas; Meiners, Silke

    2015-03-24

    Nanoparticles allow for controlled and targeted drug delivery to diseased tissues and therefore bypass systemic side effects. Spatiotemporal control of drug release can be achieved by nanocarriers that respond to elevated levels of disease-specific enzymes. For example, matrix metalloproteinase 9 (MMP9) is overexpressed in tumors, is known to enhance the metastatic potency of malignant cells, and has been associated with poor prognosis of lung cancer. Here, we report the synthesis of mesoporous silica nanoparticles (MSNs) tightly capped by avidin molecules via MMP9 sequence-specific linkers to allow for site-selective drug delivery in high-expressing MMP9 tumor areas. We provide proof-of-concept evidence for successful MMP9-triggered drug release from MSNs in human tumor cells and in mouse and human lung tumors using the novel technology of ex vivo 3D lung tissue cultures. This technique allows for translational testing of drug delivery strategies in diseased mouse and human tissue. Using this method we show MMP9-mediated release of cisplatin, which induced apoptotic cell death only in lung tumor regions of Kras mutant mice, without causing toxicity in tumor-free areas or in healthy mice. The MMP9-responsive nanoparticles also allowed for effective combinatorial drug delivery of cisplatin and proteasome inhibitor bortezomib, which had a synergistic effect on the (therapeutic) efficiency. Importantly, we demonstrate the feasibility of MMP9-controlled drug release in human lung tumors.

  6. An anilinoquinazoline derivative inhibits tumor growth through interaction with hCAP-G2, a subunit of condensin II.

    Directory of Open Access Journals (Sweden)

    Hirokazu Shiheido

    Full Text Available We screened 46 novel anilinoquinazoline derivatives for activity to inhibit proliferation of a panel of human cancer cell lines. Among them, Q15 showed potent in vitro growth-inhibitory activity towards cancer cell lines derived from colorectal cancer, lung cancer and multiple myeloma. It also showed antitumor activity towards multiple myeloma KMS34 tumor xenografts in lcr/scid mice in vivo. Unlike the known anilinoquinazoline derivative gefitinib, Q15 did not inhibit cytokine-mediated intracellular tyrosine phosphorylation. Using our mRNA display technology, we identified hCAP-G2, a subunit of condensin II complex, which is regarded as a key player in mitotic chromosome condensation, as a Q15 binding partner. Immunofluorescence study indicated that Q15 compromises normal segregation of chromosomes, and therefore might induce apoptosis. Thus, our results indicate that hCAP-G2 is a novel therapeutic target for development of drugs active against currently intractable neoplasms.

  7. Automated segmentation of murine lung tumors in x-ray micro-CT images

    Science.gov (United States)

    Swee, Joshua K. Y.; Sheridan, Clare; de Bruin, Elza; Downward, Julian; Lassailly, Francois; Pizarro, Luis

    2014-03-01

    Recent years have seen micro-CT emerge as a means of providing imaging analysis in pre-clinical study, with in-vivo micro-CT having been shown to be particularly applicable to the examination of murine lung tumors. Despite this, existing studies have involved substantial human intervention during the image analysis process, with the use of fully-automated aids found to be almost non-existent. We present a new approach to automate the segmentation of murine lung tumors designed specifically for in-vivo micro-CT-based pre-clinical lung cancer studies that addresses the specific requirements of such study, as well as the limitations human-centric segmentation approaches experience when applied to such micro-CT data. Our approach consists of three distinct stages, and begins by utilizing edge enhancing and vessel enhancing non-linear anisotropic diffusion filters to extract anatomy masks (lung/vessel structure) in a pre-processing stage. Initial candidate detection is then performed through ROI reduction utilizing obtained masks and a two-step automated segmentation approach that aims to extract all disconnected objects within the ROI, and consists of Otsu thresholding, mathematical morphology and marker-driven watershed. False positive reduction is finally performed on initial candidates through random-forest-driven classification using the shape, intensity, and spatial features of candidates. We provide validation of our approach using data from an associated lung cancer study, showing favorable results both in terms of detection (sensitivity=86%, specificity=89%) and structural recovery (Dice Similarity=0.88) when compared against manual specialist annotation.

  8. A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non-Small Cell Lung Cancer Cells.

    Science.gov (United States)

    Chen, Chi-Wei; Wu, Ming-Hsi; Chen, Yi-Fan; Yen, Tsai-Yi; Lin, Yi-Wen; Chao, Shu-Hsin; Tala, Satishkumar; Tsai, Tung-Hu; Su, Tsann-Long; Lee, Te-Chang

    2016-04-01

    The therapeutic effect in non-small cell lung cancer (NSCLC) patients is limited because of intrinsic and acquired resistance. Thus, an unmet need exists for the development of new drugs to improve the therapeutic efficacy in NSCLC patients. In this study, the novel small molecule indolizino[6,7-b]indole derivative BO-1978 was selected to evaluate its therapeutic effects on NSCLC and its preclinical toxicity in animal models. An in vitro cytotoxicity assay revealed that BO-1978 significantly suppressed the growth of various NSCLC cell lines with or without mutations in epidermal growth factor receptor (EGFR). Mechanistically, we demonstrated that BO-1978 exhibited multiple modes of action, including inhibition of topoisomerase I/II and induction of DNA cross-linking. Treatment of NSCLC cells with BO-1978 caused DNA damage, disturbed cell cycle progression, and triggered apoptotic cell death. Furthermore, BO-1978 significantly suppressed the growth of EGFR wild-type and mutant NSCLC tumors in xenograft tumor and orthotopic lung tumor models with negligible body weight loss. The combination of BO-1978 with gefitinib further suppressed EGFR mutant NSCLC cell growth in xenograft tumor and orthotopic lung tumor models. Preclinical toxicity studies showed that BO-1978 administration did not cause apparent toxicity in mice. Based on its significant therapeutic efficacy and low drug toxicity, BO-1978 is a potential therapeutic agent for treatment of NSCLC.

  9. A Potent Derivative of Indolizino[6,7-b]Indole for Treatment of Human Non–Small Cell Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Chi-Wei Chen

    2016-04-01

    Full Text Available The therapeutic effect in non–small cell lung cancer (NSCLC patients is limited because of intrinsic and acquired resistance. Thus, an unmet need exists for the development of new drugs to improve the therapeutic efficacy in NSCLC patients. In this study, the novel small molecule indolizino[6,7-b]indole derivative BO-1978 was selected to evaluate its therapeutic effects on NSCLC and its preclinical toxicity in animal models. An in vitro cytotoxicity assay revealed that BO-1978 significantly suppressed the growth of various NSCLC cell lines with or without mutations in epidermal growth factor receptor (EGFR. Mechanistically, we demonstrated that BO-1978 exhibited multiple modes of action, including inhibition of topoisomerase I/II and induction of DNA cross-linking. Treatment of NSCLC cells with BO-1978 caused DNA damage, disturbed cell cycle progression, and triggered apoptotic cell death. Furthermore, BO-1978 significantly suppressed the growth of EGFR wild-type and mutant NSCLC tumors in xenograft tumor and orthotopic lung tumor models with negligible body weight loss. The combination of BO-1978 with gefitinib further suppressed EGFR mutant NSCLC cell growth in xenograft tumor and orthotopic lung tumor models. Preclinical toxicity studies showed that BO-1978 administration did not cause apparent toxicity in mice. Based on its significant therapeutic efficacy and low drug toxicity, BO-1978 is a potential therapeutic agent for treatment of NSCLC.

  10. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells

    OpenAIRE

    Longmire, Tyler A.; Ikonomou, Laertis; Hawkins, Finn; Christodoulou, Constantina; Cao, Yuxia; Jean, JC; Kwok, Letty W.; Mou, Hongmei; Rajagopal, Jayaraj; Shen, Steven S.; Dowton, Anne A.; Serra, Maria; Weiss, Daniel J.; Green, Michael D.; Snoeck, Hans-Willem

    2012-01-01

    Two populations of Nkx2-1+ progenitors in the developing foregut endoderm give rise to the entire post-natal lung and thyroid epithelium, but little is known about these cells, as they are difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling can specify t...

  11. Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development.

    Science.gov (United States)

    Benjamin, John T; van der Meer, Riet; Im, Amanda M; Plosa, Erin J; Zaynagetdinov, Rinat; Burman, Ankita; Havrilla, Madeline E; Gleaves, Linda A; Polosukhin, Vasiliy V; Deutsch, Gail H; Yanagisawa, Hiromi; Davidson, Jeffrey M; Prince, Lawrence S; Young, Lisa R; Blackwell, Timothy S

    2016-07-01

    The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory κB kinase β transactivated) mice that conditionally express an activator of the NF-κB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-κB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal airspace dilation, impaired gas exchange, and perinatal lethality. Epithelial-derived inflammation resulted in disrupted elastic fiber organization and down-regulation of elastin assembly components, including fibulins 4 and 5, lysyl oxidase like-1, and fibrillin-1. Fibulin-5 expression by saccular stage lung fibroblasts was consistently inhibited by treatment with bronchoalveolar lavage fluid from inhibitory κB kinase β transactivated mice, Escherichia coli lipopolysaccharide, or tracheal aspirates from preterm infants exposed to chorioamnionitis. Expression of a dominant NF-κB inhibitor in fibroblasts restored fibulin-5 expression after lipopolysaccharide treatment, whereas reconstitution of fibulin-5 rescued extracellular elastin assembly by saccular stage lung fibroblasts. Elastin organization was disrupted in saccular stage lungs of preterm infants exposed to systemic inflammation. Our study reveals a critical window for elastin assembly during the saccular stage that is disrupted by inflammatory signaling and could be amenable to interventions that restore elastic fiber assembly in the developing lung.

  12. Cisplatin in 5% Ethanol Eradicates Cisplatin-Resistant Lung Tumor by Killing Lung Cancer Side Population (SP Cells and Non-SP Cells

    Directory of Open Access Journals (Sweden)

    Qi eNiu

    2013-08-01

    Full Text Available Cancer side population (SP cells with cancer stem cell-like properties are thought to be responsible for lung cancer chemotherapy resistance and currently no drug can efficiently target them. Breast cancer resistance protein (BRCP/ABCG2 is a major drug transporter in protecting lung cancer SP cells from cytotoxic agents. We showed that a low concentration of ethanol, which inhibits many membrane proteins, inhibits ABCG2 in lung cancer SP cells. Furthermore, cytotoxic cisplatin (DDP in 5% (vol/vol ethanol kills SP plus non-SP cancer cells better than either treatment alone in eradicating chemoresistant lung tumors. We found that 5% ethanol did not reduce ABCG2 protein levels, but significantly reduced ABCG2 protein function by a Hoechst 33342 extrusion assay, an ATPase activity assay, and transmission electron microscopy. Further, DDP in 5% ethanol (5% ethanol-DDP induced apoptosis of the SP plus non-SP cancer cells both in vitro and in vivo. In DDP-resistant A549/DDP lung tumor-bearing Balb/C nude mice, intratumoral injection of 5% ethanol-DDP regressed tumors and significantly improved survivals compared with 5% ethanol, DDP alone, or control. Intratumoral injection of 5% ethanol-DDP helped eradicate tumors in 30% (3/10 of the mice after 4 weeks treatment. By killing SP and non-SP cancer cells, 5% ethanol-DDP could eradicate DDP-resistant lung tumor and extend survival, providing a novel way to improve chemoresistant lung cancer survival for clinic.

  13. TH-E-17A-10: Markerless Lung Tumor Tracking Based On Beams Eye View EPID Images

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, T; Kearney, V; Liu, H; Jiang, L; Foster, R; Mao, W [UT Southwestern Medical Center, Dallas, Texas (United States); Rozario, T; Bereg, S [University of Texas at Dallas, Richardson, Texas (United States); Klash, S [Premier Cancer Centers, Dallas, TX (United States)

    2014-06-15

    Purpose: Dynamic tumor tracking or motion compensation techniques have proposed to modify beam delivery following lung tumor motion on the flight. Conventional treatment plan QA could be performed in advance since every delivery may be different. Markerless lung tumor tracking using beams eye view EPID images provides a best treatment evaluation mechanism. The purpose of this study is to improve the accuracy of the online markerless lung tumor motion tracking method. Methods: The lung tumor could be located on every frame of MV images during radiation therapy treatment by comparing with corresponding digitally reconstructed radiograph (DRR). A kV-MV CT corresponding curve is applied on planning kV CT to generate MV CT images for patients in order to enhance the similarity between DRRs and MV treatment images. This kV-MV CT corresponding curve was obtained by scanning a same CT electron density phantom by a kV CT scanner and MV scanner (Tomotherapy) or MV CBCT. Two sets of MV DRRs were then generated for tumor and anatomy without tumor as the references to tracking the tumor on beams eye view EPID images. Results: Phantom studies were performed on a Varian TrueBeam linac. MV treatment images were acquired continuously during each treatment beam delivery at 12 gantry angles by iTools. Markerless tumor tracking was applied with DRRs generated from simulated MVCT. Tumors were tracked on every frame of images and compared with expected positions based on programed phantom motion. It was found that the average tracking error were 2.3 mm. Conclusion: This algorithm is capable of detecting lung tumors at complicated environment without implanting markers. It should be noted that the CT data has a slice thickness of 3 mm. This shows the statistical accuracy is better than the spatial accuracy. This project has been supported by a Varian Research Grant.

  14. Sellar collision tumor involving metastatic lung cancer and pituitary adenoma: radiologic-pathologic correlation and review of the literature.

    Science.gov (United States)

    Sogani, Julie; Yang, Wanhua; Lavi, Ehud; Zimmerman, Robert D; Gupta, Ajay

    2014-01-01

    Collision tumors of the sella turcica involving metastases to pituitary adenomas are rare. We report a case of a collision tumor involving metastatic lung cancer with an emphasis on the neuroimaging and histopathological studies. A review of the literature including the diagnostic and management implications as well as pathogenetic mechanisms is also discussed.

  15. Tumor-derived microvesicles in the tumor microenvironment: How vesicle heterogeneity can shape the future of a rapidly expanding field.

    Science.gov (United States)

    Clancy, James W; Tricarico, Christopher J; D'Souza-Schorey, Crislyn

    2015-12-01

    Information transmission from tumor cells to non-tumor cells in the surrounding microenvironment via microvesicles is a more recently studied form of intercellular signaling that can have a marked impact on the tumor microenvironment. Tumor-derived microvesicles (TMVs) are packed with information including signaling proteins and nucleic acids, and can be taken up by target cells, enabling paracrine signaling. While previous research has focused on how vesicles released from pathologic cells differ from normal cells, the heterogeneity that exists within the TMV population itself is not fully characterized, and only beginning to be appreciated. In this review, we summarize current understanding of the biogenesis and roles of shed TMVs in the tumor microenvironment, and speculate on the consequences for tumor cell signaling in light of the hypothesis that there exists variance within the TMV population. The analysis of differential signaling upon cell-TMV interactions provides insights into potential mechanisms of intercellular communication. © 2015 WILEY Periodicals, Inc.

  16. A role for platelet-derived growth factor-BB in rat postpneumonectomy compensatory lung growth.

    Science.gov (United States)

    Yuan, Shizeng; Hannam, Vicky; Belcastro, Rosetta; Cartel, Nicholas; Cabacungan, Judy; Wang, Jinxia; Diambomba, Yenge; Johnstone, Leslie; Post, Martin; Tanswell, A Keith

    2002-07-01

    Unilateral pneumonectomy leads to compensatory growth in the residual lung, the mediators of which are largely unknown. We hypothesized, based on its other known roles in lung cell growth, that platelet-derived growth factor (PDGF)-BB would be an essential mediator of postpneumonectomy compensatory lung growth. Left-sided pneumonectomies were performed on 21-d-old rats, for comparison with sham-operated or unoperated control animals. Body weights were not different between groups. Right lung weights and DNA content were significantly increased (p < 0.05), compared with controls, by 10 d after pneumonectomy. The rate of DNA synthesis was maximal on d 5 postpneumonectomy. Total right lung PDGF-B mRNA and PDGF-BB protein increased after pneumonectomy, but were apparently tightly regulated, relative to total right lung beta-actin mRNA and protein content, respectively. However, PDGF-BB expression after pneumonectomy was apparently not purely constitutive, in that daily i.p. injections of a truncated soluble PDGF beta-receptor both reduced activation of the native PDGF beta-receptor, and attenuated increased lung DNA synthesis on d 3 after pneumonectomy. These findings are consistent with a critical role for PDGF-BB in postpneumonectomy lung growth.

  17. Overexpression of CARMA3 in non-small-cell lung cancer is linked for tumor progression.

    Directory of Open Access Journals (Sweden)

    Zixuan Li

    Full Text Available We aimed to investigate the clinical significance of the expression of novel scaffold protein CARMA3 in non-small-cell lung cancer (NSCLC and the biological function of CARMA3 in NSCLC cell lines. We observed moderate to high CARMA3 staining in 68.8% of 141 NSCLC specimens compared to corresponding normal tissues. The overexpression of CARMA3 was significantly correlated with TNM stage (P = 0.022 and tumor status (P = 0.013. CARMA3 upregulation also correlated with a shorter survival rate of patients of nodal status N0 (P = 0.042as well as the expression of epidermal growth factor receptor (EGFR (P = 0.009. In EGFR mutation positive cases, CARMA3 expression was much higher (87.5% compared to non-mutation cases (66.1%. In addition, we observed that knockdown of CARMA3 inhibits tumor cell proliferation and invasion, and induces cell cycle arrest at the boundary between the G1 and S phase. We further demonstrated a direct link between CARMA3 and NF-κB activation. The change of biological behavior in CARMA3 knockdown cells may be NF-κB-related. Our findings demonstrated, for the first time, that CARMA3 was overexpressed in NSCLC and correlated with lung cancer progression, EGFR expression, and EGFR mutation. CARMA3 could serve as a potential companion drug target, along with NF-kB and EGFR in EGFR-mutant lung cancers.

  18. Stereotactic ablative radiotherapy for small lung tumors with a moderate dose. Favorable results and low toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Duncker-Rohr, V.; Nestle, U. [Universitaetsklinikum Freiburg (Germany); Momm, F. [Ortenau Klinikum Offenburg (Germany)] [and others

    2013-01-15

    Background: Stereotactic ablative body radiotherapy (SBRT, SABR) is being increasingly applied because of its high local efficacy, e.g., for small lung tumors. However, the optimum dosage is still under discussion. Here, we report data on 45 lung lesions [non-small cell lung cancer (NSCLC) or metastases] in 39 patients treated between 2009 and 2010 by SABR. Patients and methods: SABR was performed with total doses of 35 Gy (5 fractions) or 37.5 Gy (3 fractions) prescribed to the 60% isodose line encompassing the planning target volume. Three-monthly follow-up CT scans were supplemented by FDG-PET/CT if clinically indicated. Results: The median follow-up was 17 months. Local progression-free survival rates were 90.5% (all patients), 95.0% (NSCLC), and 81.8% (metastases) at 1 year. At 2 years, the respective local progression-free survival rates were 80.5%, 95.0%, and 59.7%. Overall survival rates were 71.1% (all patients), 65.4% (NSCLC), and 83.3% (metastases) at 1 year. Overall survival rates at 2 years were 52.7%, 45.9%, and 66.7%, respectively. Acute side effects were mild. Conclusion: With the moderate dose schedule used, well-tolerated SABR led to favorable local tumor control as in other published series. Standardization in reporting the dose prescription for SABR is needed to allow comparison of different series in order to determine optimum dosage. (orig.)

  19. CHARACTER OF TUMOR ASSOCIATED PROTEIN RECOGNIZED BY MONOCLONAL ANTIBODY AGAINST YUNNAN GEJIU LUNG CANCER

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objectives: To identify and characterize lung cancer associated protein N35 and attempt to learn the prospective possibility of the clinical application of the protein N35. Methods: Immunoprecipitation, immunoblotting, differential centrifigation and subcellular assay, immunohistochemistry, N-glycanase digestion, mitotic cell immunoflourescence and multiple methods of affinity chromatography have been used with the monoclonal antibody N-35 to detect the distribution of the protein N35 among the various cancer cell lines and normal human tissue, the relationship between the protein N35 and glycoprotein, the location of the subcellular structure and chromosomal domain of the protein N35,the most effective way of purification of tumor associated protein N35. Results: The protein N35 is a glycoprotein, distributes to the human lung cancer cell line GLC-82, human cervical cancer cell line Hela, human hepatic cancer cell line HepG-2 and human breast cancer cell line PMC with different relative molecular mass(Mr), but no expression of the protein ingredient in normal human fresh tissue; concentrates at the nuclei significantly ,much more than at the mitochondrail and membrane, locates at the centriole of the chromosomal domain. Conclusions: The lung cancer associated protein N35 might be expressed only by the cancer cells and related with the proliferation of cancer cells as a role of tumor cell growth regulator.

  20. Sella turcica atypical teratoid/rhabdoid tumor complicated with lung metastasis in an adult female.

    Science.gov (United States)

    Moretti, Costanzo; Lupoi, Domenico; Spasaro, Francesca; Chioma, Laura; Di Giacinto, Paola; Colicchia, Martina; Frajoli, Mario; Mocini, Renzo; Ulisse, Salvatore; Antonelli, Manila; Giangaspero, Felice; Gnessi, Lucio

    2013-01-01

    Here we present the case of a 60-year-old woman with a rare sellar region atypical teratoid/rhabdoid tumor (AT/RT), complicated by lung metastasis and treated with neurosurgery, radiotherapy, and chemotherapy. The patient had recurrent headache associated with left cavernous sinus syndrome after a previous endonasal transsphenoidal resection for a presumptive pituitary macroadenoma. Pituitary magnetic resonance imaging showed a tumor regrowth in the original location with a haemorrhagic component involving the left cavernous sinus. A near complete transsphenoidal resection of the sellar mass was performed followed by 3 months of stereotactic radiotherapy. Because of a worsening of the general clinical conditions, respiratory failure, and asthenia, the patient underwent a contrast enhanced computer tomography of the whole body which showed the presence of lung metastasis. The histopathological diagnosis on samples from pituitary and lung tissues was AT/RT. The patient survived 30 months after diagnosis regardless chemotherapy. In the adult, the AT/RT should be considered as a possible rare, aggressive, and malignant neoplasm localized in the sella turcica.

  1. The tumor suppressor gene RBM5 inhibits lung adenocarcinoma cell growth and induces apoptosis

    Directory of Open Access Journals (Sweden)

    Shao Chen

    2012-08-01

    Full Text Available Abstract Background The loss of tumor suppressor gene (TSG function is a critical step in the pathogenesis of human lung cancer. RBM5 (RNA-binding motif protein 5, also named H37/LUCA-15 gene from chromosome 3p21.3 demonstrated tumor suppressor activity. However, the role of RBM5 played in the occurrence and development of lung cancer is still not well understood. Method Paired non-tumor and tumor tissues were obtained from 30 adenocarcinomas. The expression of RBM5 mRNA and protein was examined by RT-PCR and Western blot. A549 cell line was used to determine the apoptotic function of RBM5 in vitro. A549 cells were transiently transfected with pcDNA3.1-RBM5. AnnexinV analysis was performed by flow cytometry. Expression of Bcl-2, cleaved caspase-3, caspase-9 and PAPP proteins in A549 lung cancer cells and the A549 xenograft BALB/c nude mice model was determined by Western blot. Tumor suppressor activity of RBM5 was also examined in the A549 xenograft model treated with pcDNA3.1-RBM5 plasmid carried by attenuated Salmonella typhi Ty21a. Result The expression of RBM5 mRNA and protein was decreased significantly in adenocarcinoma tissues compared to that in the non-tumor tissues. In addition, as compared to the vector control, a significant growth inhibition of A549 lung cancer cells was observed when transfected with pcDNA3.1-RBM5 as determined by cell proliferation assay. We also found that overexpression of RBM5 induced both early and late apoptosis in A549 cells using AnnexinV/PI staining as determined by flow cytometry. Furthermore, the expression of Bcl-2 protein was decreased, whereas the expression of cleaved caspase-3, caspase-9 and PARP proteins was significantly increased in the RBM5 transfected cells; similarly, expression of decreased Bcl-2 and increased cleaved caspase-3 proteins was also examined in the A549 xenograft model. More importantly, we showed that accumulative and stable overexpression of RBM5 in the A549 xenograft BALB

  2. Quantitation of Murine Stroma and Selective Purification of the Human Tumor Component of Patient-Derived Xenografts for Genomic Analysis.

    Science.gov (United States)

    Schneeberger, Valentina E; Allaj, Viola; Gardner, Eric E; Poirier, J T; Rudin, Charles M

    2016-01-01

    Patient-derived xenograft (PDX) mouse models are increasingly used for preclinical therapeutic testing of human cancer. A limitation in molecular and genetic characterization of PDX tumors is the presence of integral murine stroma. This is particularly problematic for genomic sequencing of PDX models. Rapid and dependable approaches for quantitating stromal content and purifying the malignant human component of these tumors are needed. We used a recently developed technique exploiting species-specific polymerase chain reaction (PCR) amplicon length (ssPAL) differences to define the fractional composition of murine and human DNA, which was proportional to the fractional composition of cells in a series of lung cancer PDX lines. We compared four methods of human cancer cell isolation: fluorescence-activated cell sorting (FACS), an immunomagnetic mouse cell depletion (MCD) approach, and two distinct EpCAM-based immunomagnetic positive selection methods. We further analyzed DNA extracted from the resulting enriched human cancer cells by targeted sequencing using a clinically validated multi-gene panel. Stromal content varied widely among tumors of similar histology, but appeared stable over multiple serial tumor passages of an individual model. FACS and MCD were superior to either positive selection approach, especially in cases of high stromal content, and consistently allowed high quality human-specific genomic profiling. ssPAL is a dependable approach to quantitation of murine stromal content, and MCD is a simple, efficient, and high yield approach to human cancer cell isolation for genomic analysis of PDX tumors.

  3. WE-G-BRD-01: Diffusion Weighted MRI for Response Assessment of Inoperable Lung Tumors for Patients Undergoing SBRT Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Tyagi, N; Wengler, K; Yorke, E; Hunt, M; Deasy, J; Rimner, A [Memorial Sloan-Kettering Cancer Center, New York, NY (United States)

    2014-06-15

    Purpose: To investigate early changes in tumor Apparent Diffusion Coefficients derived from diffusion weighted (DW)-MRI of lung cancer patients undergoing SBRT, as a possible early predictor of treatment response. Methods: DW-MRI scans were performed in this prospective phase I IRB-approved study of inoperable lung tumors at various time-points during the course of SBRT treatments. Axial DW scan using multi b-values ranging from 0–1000 s/mm{sup 2} were acquired in treatment position on a 3T Philips MR scanner during simulation, one hour after the first fraction (8 Gy), after a total of 5 fractions (40 Gy) and 4 weeks after SBRT delivery. A monoexponential model based on a least square fit from all b values was performed on a pixel-by-pixel basis and ADC was calculated. GTVs drawn on 4DCT for planning were mapped on the T2w MRI (acquired at exhale) after deformable registration. These volumes were then mapped on DWI scan for ADC calculation after rigid registration between the anatomical scan and diffusion scan. T2w scan on followup time points were deformably registered to the pretreatment T2 scan. Results: The first two patients in this study were analyzed. Median ADC values were 1.48, 1.48, 1.62 and 1.83 (10{sup −3}×) mm{sup 2}/s at pretreatment, after 8 Gy, after 40 Gy and 4 weeks posttreatment for the first patient and 1.57, 1.53, 1.66 and 1.72 (10{sup −3}×) mm{sup 2}/s for the second patient. ADC increased more significantly after 4 weeks of treatment rather than immediately post treatment, implying that late ADC value may be a better predictor of tumor response for SBRT treatment. The fraction of tumor pixels at high ADC values increased at 4 weeks post treatment. Conclusion: The observed increase in ADC values before the end of radiotherapy may be a surrogate for tumor response, but further patient accrual will be necessary to determine its value.

  4. Effect of dietary green tea extract and aerosolized difluoromethylornithine during lung tumor progression in A/J strain mice.

    Science.gov (United States)

    Anderson, Marshall W; Goodin, Colleen; Zhang, Yu; Kim, Sangmi; Estensen, Richard D; Wiedmann, Timothy S; Sekar, Padmini; Buncher, C Ralph; Khoury, Jane C; Garbow, Joel R; You, Ming; Tichelaar, Jay W

    2008-08-01

    Chemoprevention strategies to prevent the development of lung cancer in at-risk individuals are a key component in disease management. In addition to being highly effective, an ideal chemopreventive agent will require low toxicity as patients are likely to require treatment for several years before their risk of cancer is lowered to background levels. In principle, a combination of safe agents that work through distinct mechanisms will improve efficacy while simultaneously maintaining a favorable safety profile. Here, we describe the use of the decaffeinated green tea extract Polyphenon E (Poly E) (1% in diet) and aerosolized difluoromethylornithine (DFMO) (20 mg/kg/day, 5 days/week) in a mouse lung cancer chemoprevention study using a progression protocol. Female A/J mice were injected with benzo[a]pyrene (B[a]P) at 8 weeks of age and precancerous lesions allowed to form over a period of 21 weeks before chemoprevention treatment for an additional 25 weeks. Poly E treatment did not significantly inhibit average tumor multiplicity but reduced per animal tumor load. Analysis of tumor pathology revealed a specific inhibition of carcinomas, with the largest carcinomas significantly decreased in Poly E-treated animals. Aerosolized DFMO did not have a significant effect on lung tumor progression. Magnetic resonance imaging of B[a]P-induced lung tumors confirmed the presence of a subset of large, rapidly growing tumors in untreated mice. Our results suggest a potential role for green tea extracts in preventing the progression of large, aggressive lung adenocarcinomas.

  5. In Vitro Efficient Expansion of Tumor Cells Deriving from Different Types of Human Tumor Samples

    Directory of Open Access Journals (Sweden)

    Ilaria Turin

    2014-03-01

    Full Text Available Obtaining human tumor cell lines from fresh tumors is essential to advance our understanding of antitumor immune surveillance mechanisms and to develop new ex vivo strategies to generate an efficient anti-tumor response. The present study delineates a simple and rapid method for efficiently establishing primary cultures starting from tumor samples of different types, while maintaining the immuno-histochemical characteristics of the original tumor. We compared two different strategies to disaggregate tumor specimens. After short or long term in vitro expansion, cells analyzed for the presence of malignant cells demonstrated their neoplastic origin. Considering that tumor cells may be isolated in a closed system with high efficiency, we propose this methodology for the ex vivo expansion of tumor cells to be used to evaluate suitable new drugs or to generate tumor-specific cytotoxic T lymphocytes or vaccines.

  6. SUSD2 is frequently downregulated and functions as a tumor suppressor in RCC and lung cancer.

    Science.gov (United States)

    Cheng, Yingying; Wang, Xiaolin; Wang, Pingzhang; Li, Ting; Hu, Fengzhan; Liu, Qiang; Yang, Fan; Wang, Jun; Xu, Tao; Han, Wenling

    2016-07-01

    Sushi domain containing 2 (SUSD2) is type I membrane protein containing domains inherent to adhesion molecules. There have been few reported studies on SUSD2, and they have mainly focused on breast cancer, colon cancer, and HeLa cells. However, the expression and function of SUSD2 in other cancers remain unclear. In the present study, we conducted an integrated bioinformatics analysis based on the array data from the GEO database and found a significant downregulation of SUSD2 in renal cell carcinoma (RCC) and lung cancer. Western blotting and quantitative RT-PCR (qRT-PCR) confirmed that SUSD2 was frequently decreased in RCC and lung cancer tissues compared with the corresponding levels in normal adjacent tissues. The restoration of SUSD2 expression inhibited the proliferation and clonogenicity of RCC and lung cancer cells, whereas the knockdown of SUSD2 promoted A549 cell growth. Our findings suggested that SUSD2 functions as a tumor suppressor gene (TSG) in RCC and lung cancer.

  7. Optimal Surface Marker Locations for Tumor Motion Estimation in Lung Cancer Radiotherapy

    CERN Document Server

    Dong, Bin; Jia, Xun; Jiang, Steve B

    2012-01-01

    Using fiducial markers on patient's body surface to predict the tumor location is a widely used approach in lung cancer radiotherapy. The purpose of this work is to propose an algorithm that automatically identifies a sparse set of locations on the patient's surface with the optimal prediction power for the tumor motion. The sparse selection of markers on the external surface and the assumed linear relationship between the marker motion and the internal tumor motion are represented by a prediction matrix. Such a matrix is determined by solving an optimization problem, where the objective function contains a sparsity term that penalizes the number of markers chosen on the patient's surface. The performance of our algorithm has been tested on realistic clinical data of four lung cancer patients. Thoracic 4DCT scans with 10 phases are used for the study. On a reference phase, a grid of points are casted on the patient's surface (except for patient's back) and propagated to other phases via deformable image regis...

  8. Sublingual vaccination induces mucosal and systemic adaptive immunity for protection against lung tumor challenge.

    Directory of Open Access Journals (Sweden)

    Shailbala Singh

    Full Text Available Sublingual route offers a safer and more practical approach for delivering vaccines relative to other systemic and mucosal immunization strategies. Here we present evidence demonstrating protection against ovalbumin expressing B16 (B16-OVA metastatic melanoma lung tumor formation by sublingual vaccination with the model tumor antigen OVA plus synthetic glycolipid alpha-galactosylceramide (aGalCer for harnessing the adjuvant potential of natural killer T (NKT cells, which effectively bridge innate and adaptive arms of the immune system. The protective efficacy of immunization with OVA plus aGalCer was antigen-specific as immunized mice challenged with parental B16 tumors lacking OVA expression were not protected. Multiple sublingual immunizations in the presence, but not in the absence of aGalCer, resulted in repeated activation of NKT cells in the draining lymph nodes, spleens, and lungs of immunized animals concurrent with progressively increasing OVA-specific CD8+ T cell responses as well as serum IgG and vaginal IgA levels. Furthermore, sublingual administration of the antigen only in the presence of the aGalCer adjuvant effectively boosted the OVA-specific immune responses. These results support potential clinical utility of sublingual route of vaccination with aGalCer-for prevention of pulmonary metastases.

  9. Sublingual vaccination induces mucosal and systemic adaptive immunity for protection against lung tumor challenge.

    Science.gov (United States)

    Singh, Shailbala; Yang, Guojun; Schluns, Kimberly S; Anthony, Scott M; Sastry, K Jagannadha

    2014-01-01

    Sublingual route offers a safer and more practical approach for delivering vaccines relative to other systemic and mucosal immunization strategies. Here we present evidence demonstrating protection against ovalbumin expressing B16 (B16-OVA) metastatic melanoma lung tumor formation by sublingual vaccination with the model tumor antigen OVA plus synthetic glycolipid alpha-galactosylceramide (aGalCer) for harnessing the adjuvant potential of natural killer T (NKT) cells, which effectively bridge innate and adaptive arms of the immune system. The protective efficacy of immunization with OVA plus aGalCer was antigen-specific as immunized mice challenged with parental B16 tumors lacking OVA expression were not protected. Multiple sublingual immunizations in the presence, but not in the absence of aGalCer, resulted in repeated activation of NKT cells in the draining lymph nodes, spleens, and lungs of immunized animals concurrent with progressively increasing OVA-specific CD8+ T cell responses as well as serum IgG and vaginal IgA levels. Furthermore, sublingual administration of the antigen only in the presence of the aGalCer adjuvant effectively boosted the OVA-specific immune responses. These results support potential clinical utility of sublingual route of vaccination with aGalCer-for prevention of pulmonary metastases.

  10. Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages.

    Directory of Open Access Journals (Sweden)

    Kosuke Watari

    Full Text Available Tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF-C through its receptor (VEGFR-3 and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL-1α, with similarly augmented expression of IL-1α and IL-1β by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages. These tumor-associated macrophages were mainly of the M2 type. Administration of a macrophage-targeting drug suppressed the production of these potent angiogenic and lymphangiogenic factors, resulting in decreased tumor growth, angiogenesis, lymphangiogenesis, and lymph node metastasis. In Matrigel plug assays, the highly metastatic cells formed tumors that were extensively infiltrated by M2-type macrophages and exhibited enhanced angiogenesis and lymphangiogenesis. All of these responses were suppressed by the IL-1 receptor (IL-1R antagonist anakinra. Thus, the IL-1α-driven inflammatory activation of angiogenesis and lymphangiogenesis seems to provide a highly metastatic tumor microenvironment favorable for lymph node metastasis through cross-talk with macrophages. Accordingly, the IL-1R/M2-type macrophage axis may be a good therapeutic target for patients with this form of lung cancer.

  11. Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages.

    Science.gov (United States)

    Watari, Kosuke; Shibata, Tomohiro; Kawahara, Akihiko; Sata, Ken-ichi; Nabeshima, Hiroshi; Shinoda, Ai; Abe, Hideyuki; Azuma, Koichi; Murakami, Yuichi; Izumi, Hiroto; Takahashi, Takashi; Kage, Masayoshi; Kuwano, Michihiko; Ono, Mayumi

    2014-01-01

    Tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF)-C through its receptor (VEGFR-3) and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL)-1α, with similarly augmented expression of IL-1α and IL-1β by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages. These tumor-associated macrophages were mainly of the M2 type. Administration of a macrophage-targeting drug suppressed the production of these potent angiogenic and lymphangiogenic factors, resulting in decreased tumor growth, angiogenesis, lymphangiogenesis, and lymph node metastasis. In Matrigel plug assays, the highly metastatic cells formed tumors that were extensively infiltrated by M2-type macrophages and exhibited enhanced angiogenesis and lymphangiogenesis. All of these responses were suppressed by the IL-1 receptor (IL-1R) antagonist anakinra. Thus, the IL-1α-driven inflammatory activation of angiogenesis and lymphangiogenesis seems to provide a highly metastatic tumor microenvironment favorable for lymph node metastasis through cross-talk with macrophages. Accordingly, the IL-1R/M2-type macrophage axis may be a good therapeutic target for patients with this form of lung cancer.

  12. Identification of a small, naked virus in tumor-like aggregates in cell lines derived from a green turtle, Chelonia mydas, with fibropapillomas

    Science.gov (United States)

    Lu, Y.; Aguirre, A.A.; Work, T.M.; Balazs, G.H.; Nerurkar, V.R.; Yanagihara, R.

    2000-01-01

    Serial cultivation of cell lines derived from lung, testis, periorbital and tumor tissues of a green turtle (Chelonia mydas) with fibropapillomas resulted in the in vitro formation of tumor-like cell aggregates, ranging in size from 0.5 to 2.0 mm in diameter. Successful induction of tumor-like aggregates was achieved in a cell line derived from lung tissue of healthy green turtles, following inoculation with cell-free media from these tumor-bearing cell lines, suggesting the presence of a transmissible agent. Thin-section electron microscopy of the cell aggregates revealed massive collagen deposits and intranuclear naked viral particles, measuring 50??5 nm in diameter. These findings, together with the morphological similarity between these tumor-like cell aggregates and the naturally occurring tumor, suggest a possible association between this novel virus and the disease. Further characterization of this small naked virus will clarify its role in etiology of green turtle fibropapilloma, a life-threatening disease of this endangered marine species. Copyright (C) 2000 Elsevier Science B.V.

  13. Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases.

    Science.gov (United States)

    Lamora, Audrey; Mullard, Mathilde; Amiaud, Jérôme; Brion, Régis; Heymann, Dominique; Redini, Françoise; Verrecchia, Franck

    2015-06-10

    Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because we recently demonstrated that TGF-β/Smad cascade plays a crucial role in osteosarcoma metastatic progression, we investigated the effect of halofuginone, identified as an inhibitor of the TGF-β/Smad3 cascade, on osteosarcoma progression. A preclinical model of osteosarcoma was used to evaluate the impact of halofuginone on tumor growth, tumor microenvironment and metastasis development. In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that halofuginone decreases cell viability mainly by its ability to induce caspase-3 dependent cell apoptosis. Moreover, halofuginone inhibits the TGF-β/Smad3 cascade and the response of TGF-β key targets involved in the metastases dissemination process such as MMP-2. In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis. Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment. Using halofuginone may be a promising therapeutic strategy against tumor progression of osteosarcoma specifically against lung metastases dissemination.

  14. Swarm rat chondrosarcoma cells as an in vivo model: lung colonization and effects of tissue environment on tumor growth.

    Science.gov (United States)

    Morcuende, Jose A; Stevens, Jeff W; Scheetz, Todd E; de Fatima Bonaldoc, Maria; Casavant, Thomas L; Otero, Jesse E; Soares, Marcelo B

    2012-01-01

    Swarm rat chondrosarcoma cells have been used extensively for biochemical studies of extra-cellular matrix metabolism in cartilage. However, these cells also possess tumor-like behavior in vivo and are useful in investigation of chondrosarcoma biology. the current study was designed to develop a metastatic model using swarm rat chondrosarcoma cells, and to assess the effect of tissue-environment on tumor behavior in vivo. Tumors were implanted subcutaneously or into bone, and animals were assessed radiographically and microscopically for tumor growth and metastasis. The subcutaneous tumor grew to an average mass of 35 g, while tumor implanted into bone grew 75 mg. Transplantation of the cells into the bone led to extensive bone remodeling with invasion of the medullary cavity and destruction of the bone cortex. Light microscopy demonstrated no significant differences in the number of mitoses, cellular atypia or extracellular matrix staining between the two sites of tumor implantation. Interestingly, lung colonization was observed in none of the animals in the subcutaneous tumor injection group, while tumors colonized the lungs in 95% of the rats with tumor injected into bone. Analysis of cDNA libraries from subcutaneous and bone-transplanted tumors demonstrated a complex and diverse array of expressed transcripts, and there were significant differences in gene expression between tumors at different sites. The results of this study suggest swarm rat chondrosarcoma is a model that resembles human chondrosarcoma mimicking its ability to infiltrate and remodel local bone and to colonize the lungs. Furthermore, the interaction between host-tissue and tumor cells plays a major role in the tumor behavior in this model. Identifying these interactions will lead to further understanding of chondrosarcoma and contribute to therapeutic targets in the future.

  15. Tumor Angiogenesis Correlated with bFGF and FGFR-1 in Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    ZHOUTao; PANTiecheng

    2005-01-01

    Objective: To study the relationship between angiogenesis and the expression of bFGF and FGFR-1 in lung cancer. Methods: The specimens of 56 patients with lung cancer treated with surgery were collected. Anti-Von Willebrand factor antibody was used to measure microvascular density (MVD) by means of SABC immunohistochemical technique, and antibody to basic fibroblast growth factor (bFGF)and its receptor (FGFR-1) to detect the expression of these three proteins in the tumor tissues. The survival time was compared between low MVD and high MVD groups by the Kaplan-Meier method. Results: (1)The expression of MVD showed no significant difference in some clinical characteristics, including sex,age, T stage, M stage and pathologic type, but significant difference in N stage (P<0.01) and clinical stage (P<0.05). (2) Survival analysis showed that high MVD group was associated with a risk of death (P<0.01). (3) The expression of bFGF and FGFR-1 were both related to lymphatic metastasis and clinical staging (P<0.05). (4) Significant difference was seen between low MVD and high MVD groups in the bFGF expression in lung cancer (P<0.01), whereas no correlation in FGFR-1. (5) High co-expression of bFGF and FGFR-1 was consistent in tumor cells. Conclusion: (1) MVD is a good prognostic factor for patients of lung cancer, and the same as bFGF. (2) The angiogenesis may be induced after bFGF binding to FGFR-1.

  16. Crosstalk between Tumor Cells and Macrophages in Stroma Renders Tumor Cells as the Primary Source of MCP-1/CCL2 in Lewis Lung Carcinoma.

    Science.gov (United States)

    Yoshimura, Teizo; Liu, Mingyong; Chen, Xin; Li, Liangzhu; Wang, Ji Ming

    2015-01-01

    The chemokine MCP-1/CCL2 is produced by a variety of tumors and plays an important role in cancer progression. We and others previously demonstrated that the primary source of MCP-1 in several mouse tumors, including 4T1 breast cancer, M5076 sarcoma, and B16 melanoma, was stromal cells. In the present study, we identified that tumor cells were the primary source of MCP-1 in Lewis lung carcinoma (LLC), because MCP-1 mRNA was highly expressed in tumors grown in both wild type (WT) and MCP-1(-/-) mice with elevated serum MCP-1 levels. Since LLC cells isolated from tumors expressed low levels of MCP-1 in vitro, it appeared that the tumor-stromal cell interaction in a tumor microenvironment increased MCP-1 expression in LLC cells. In fact, co-culture of LLC cells with normal mouse peritoneal macrophages or normal lung cells containing macrophages increased MCP-1 expression by LLC cells. Macrophages from TNFα(-/-) mice failed to activate LLC cells and anti-TNFα neutralizing antibody abolished the effect of WT macrophages on LLC cells. When LLC cells were transplanted into TNFα(-/-) mice, the levels of MCP-1 mRNA in tumors and serum MCP-1 levels were markedly lower as compared to WT mice, and importantly, tumors grew more slowly. Taken together, our results indicate that TNFα released by tumor cell-activated macrophages is critical for increased MCP-1 production by tumors cells. Thus, disruption of tumor-stromal cell interaction may inhibit tumor progression by reducing the production of tumor-promoting proinflammatory mediators, such as MCP-1.

  17. Crosstalk between Tumor Cells and Macrophages in Stroma Renders Tumor Cells as the Primary Source of MCP-1/CCL2 in Lewis Lung Carcinoma

    Directory of Open Access Journals (Sweden)

    Teizo eYoshimura

    2015-06-01

    Full Text Available The chemokine MCP-1/CCL2 is produced by a variety of tumors and plays an important role in cancer progression. We and others previously demonstrated that the primary source of MCP-1 in several mouse tumors, including 4T1 breast cancer, M5076 sarcoma and B16 melanoma, was stromal cells. In the present study, we identified that tumor cells were the primary source of MCP-1 in Lewis lung carcinoma (LLC, because MCP-1 mRNA was highly expressed in tumors grown in both WT and MCP-1-/- mice with elevated serum MCP-1 levels. Since LLC cells isolated from tumors expressed low levels of MCP-1 in vitro, it appeared that the tumor-stromal cell interaction in a tumor microenvironment increased MCP-1 expression in LLC cells. In fact, co-culture of LLC cells with normal mouse peritoneal macrophages or normal lung cells containing macrophages increased MCP-1 expression by LLC cells. Macrophages from TNFα-/- mice failed to activate LLC cells and anti-TNFα neutralizing antibody abolished the effect of WT macrophages on LLC cells. When LLC cells were transplanted into TNFα-/- mice, the levels of MCP-1 mRNA in tumors and serum MCP-1 levels were markedly lower as compared to WT mice, and importantly tumors grew more slowly. Taken together, our results indicate that TNFα released by tumor cell-activated macrophages is critical for increased MCP-1 production by tumors cells. Thus, disruption of tumor-stromal cell interaction may inhibit tumor progression by reducing the production of tumor-promoting proinflammatory mediators, such as MCP-1.

  18. Stereotactic body radiotherapy for stage I lung cancer and small lung metastasis: evaluation of an immobilization system for suppression of respiratory tumor movement and preliminary results

    Directory of Open Access Journals (Sweden)

    Ayakawa Shiho

    2009-05-01

    Full Text Available Abstract Background In stereotactic body radiotherapy (SBRT for lung tumors, reducing tumor movement is necessary. In this study, we evaluated changes in tumor movement and percutaneous oxygen saturation (SpO2 levels, and preliminary clinical results of SBRT using the BodyFIX immobilization system. Methods Between 2004 and 2006, 53 consecutive patients were treated for 55 lesions; 42 were stage I non-small cell lung cancer (NSCLC, 10 were metastatic lung cancers, and 3 were local recurrences of NSCLC. Tumor movement was measured with fluoroscopy under breath holding, free breathing on a couch, and free breathing in the BodyFIX system. SpO2 levels were measured with a finger pulseoximeter under each condition. The delivered dose was 44, 48 or 52 Gy, depending on tumor diameter, in 4 fractions over 10 or 11 days. Results By using the BodyFIX system, respiratory tumor movements were significantly reduced compared with the free-breathing condition in both craniocaudal and lateral directions, although the amplitude of reduction in the craniocaudal direction was 3 mm or more in only 27% of the patients. The average SpO2 did not decrease by using the system. At 3 years, the local control rate was 80% for all lesions. Overall survival was 76%, cause-specific survival was 92%, and local progression-free survival was 76% at 3 years in primary NSCLC patients. Grade 2 radiation pneumonitis developed in 7 patients. Conclusion Respiratory tumor movement was modestly suppressed by the BodyFIX system, while the SpO2 level did not decrease. It was considered a simple and effective method for SBRT of lung tumors. Preliminary results were encouraging.

  19. Validation of the Lung Subtyping Panel in Multiple Fresh-Frozen and Formalin-Fixed, Paraffin-Embedded Lung Tumor Gene Expression Data Sets.

    Science.gov (United States)

    Faruki, Hawazin; Mayhew, Gregory M; Fan, Cheng; Wilkerson, Matthew D; Parker, Scott; Kam-Morgan, Lauren; Eisenberg, Marcia; Horten, Bruce; Hayes, D Neil; Perou, Charles M; Lai-Goldman, Myla

    2016-06-01

    Context .- A histologic classification of lung cancer subtypes is essential in guiding therapeutic management. Objective .- To complement morphology-based classification of lung tumors, a previously developed lung subtyping panel (LSP) of 57 genes was tested using multiple public fresh-frozen gene-expression data sets and a prospectively collected set of formalin-fixed, paraffin-embedded lung tumor samples. Design .- The LSP gene-expression signature was evaluated in multiple lung cancer gene-expression data sets totaling 2177 patients collected from 4 platforms: Illumina RNAseq (San Diego, California), Agilent (Santa Clara, California) and Affymetrix (Santa Clara) microarrays, and quantitative reverse transcription-polymerase chain reaction. Gene centroids were calculated for each of 3 genomic-defined subtypes: adenocarcinoma, squamous cell carcinoma, and neuroendocrine, the latter of which encompassed both small cell carcinoma and carcinoid. Classification by LSP into 3 subtypes was evaluated in both fresh-frozen and formalin-fixed, paraffin-embedded tumor samples, and agreement with the original morphology-based diagnosis was determined. Results .- The LSP-based classifications demonstrated overall agreement with the original clinical diagnosis ranging from 78% (251 of 322) to 91% (492 of 538 and 869 of 951) in the fresh-frozen public data sets and 84% (65 of 77) in the formalin-fixed, paraffin-embedded data set. The LSP performance was independent of tissue-preservation method and gene-expression platform. Secondary, blinded pathology review of formalin-fixed, paraffin-embedded samples demonstrated concordance of 82% (63 of 77) with the original morphology diagnosis. Conclusions .- The LSP gene-expression signature is a reproducible and objective method for classifying lung tumors and demonstrates good concordance with morphology-based classification across multiple data sets. The LSP panel can supplement morphologic assessment of lung cancers, particularly

  20. SU-E-J-190: Characterization of Radiation Induced CT Number Changes in Tumor and Normal Lung During Radiation Therapy for Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yang, C; Liu, F; Tai, A; Gore, E; Johnstone, C; Li, X [Medical College of Wisconsin Milwaukee WI (United States)

    2014-06-01

    Purpose: To measure CT number (CTN) changes in tumor and normal lung as a function of radiation therapy (RT) dose during the course of RT delivery for lung cancer using daily IGRT CT images and single respiration phase CT images. Methods: 4D CT acquired during planning simulation and daily 3D CT acquired during daily IGRT for 10 lung cancer cases randomly selected in terms of age, caner type and stage, were analyzed using an in-house developed software tool. All patients were treated in 2 Gy fractions to primary tumors and involved nodal regions. Regions enclosed by a series of isodose surfaces in normal lung were delineated. The obtained contours along with target contours (GTVs) were populated to each singlephase planning CT and daily CT. CTN in term of Hounsfield Unit (HU) of each voxel in these delineated regions were collectively analyzed using histogram, mean, mode and linear correlation. Results: Respiration induced normal lung CTN change, as analyzed from single-phase planning CTs, ranged from 9 to 23 (±2) HU for the patients studied. Normal lung CTN change was as large as 50 (±12) HU over the entire treatment course, was dose and patient dependent and was measurable with dose changes as low as 1.5 Gy. For patients with obvious tumor volume regression, CTN within the GTV drops monotonically as much as 10 (±1) HU during the early fractions with a total dose of 20 Gy delivered. The GTV and CTN reductions are significantly correlated with correlation coefficient >0.95. Conclusion: Significant RT dose induced CTN changes in lung tissue and tumor region can be observed during even the early phase of RT delivery, and may potentially be used for early prediction of radiation response. Single respiration phase CT images have dramatically reduced statistical noise in ROIs, making daily dose response evaluation possible.

  1. Volume change determination of metastatic lung tumors in CT images using 3-D template matching

    Science.gov (United States)

    Ambrosini, Robert D.; Wang, Peng; O'Dell, Walter G.

    2009-02-01

    The ability of a clinician to properly detect changes in the size of lung nodules over time is a vital element to both the diagnosis of malignant growths and the monitoring of the response of cancerous lesions to therapy. We have developed a novel metastasis sizing algorithm based on 3-D template matching with spherical tumor appearance models that were created to match the expected geometry of the tumors of interest while accounting for potential spatial offsets of nodules in the slice thickness direction. The spherical template that best-fits the overall volume of each lung metastasis was determined through the optimization of the 3-D normalized cross-correlation coefficients (NCCC) calculated between the templates and the nodules. A total of 17 different lung metastases were extracted manually from real patient CT datasets and reconstructed in 3-D using spherical harmonics equations to generate simulated nodules for testing our algorithm. Each metastasis 3-D shape was then subjected to 10%, 25%, 50%, 75% and 90% scaling of its volume to allow for 5 possible volume change combinations relative to the original size per each reconstructed nodule and inserted back into CT datasets with appropriate blurring and noise addition. When plotted against the true volume change, the nodule volume changes calculated by our algorithm for these 85 data points exhibited a high degree of accuracy (slope = 0.9817, R2 = 0.9957). Our results demonstrate that the 3-D template matching method can be an effective, fast, and accurate tool for automated sizing of metastatic tumors.

  2. Cooperation of tyrosine kinase receptor TrkB and epidermal growth factor receptor signaling enhances migration and dispersal of lung tumor cells.

    Directory of Open Access Journals (Sweden)

    Rudolf Götz

    Full Text Available TrkB mediates the effects of brain-derived neurotrophic factor (BDNF in neuronal and nonnneuronal cells. Based on recent reports that TrkB can also be transactivated through epidermal growth-factor receptor (EGFR signaling and thus regulates migration of early neurons, we investigated the role of TrkB in migration of lung tumor cells. Early metastasis remains a major challenge in the clinical management of non-small cell lung cancer (NSCLC. TrkB receptor signaling is associated with metastasis and poor patient prognosis in NSCLC. Expression of this receptor in A549 cells and in another adenocarcinoma cell line, NCI-H441, promoted enhanced migratory capacity in wound healing assays in the presence of the TrkB ligand BDNF. Furthermore, TrkB expression in A549 cells potentiated the stimulatory effect of EGF in wound healing and in Boyden chamber migration experiments. Consistent with a potential loss of cell polarity upon TrkB expression, cell dispersal and de-clustering was induced in A549 cells independently of exogeneous BDNF. Morphological transformation involved extensive cytoskeletal changes, reduced E-cadherin expression and suppression of E-cadherin expression on the cell surface in TrkB expressing tumor cells. This function depended on MEK and Akt kinase activity but was independent of Src. These data indicate that TrkB expression in lung adenoma cells is an early step in tumor cell dissemination, and thus could represent a target for therapy development.

  3. A Novel Minimally Invasive Technique to Create a Rabbit VX2 Lung Tumor Model for Nano-Sized Image Contrast and Interventional Studies

    OpenAIRE

    Takashi Anayama; Takahiro Nakajima; Michael Dunne; Jinzi Zheng; Christine Allen; Brandon Driscoll; Douglass Vines; Shaf Keshavjee; David Jaffray; Kazuhiro Yasufuku

    2013-01-01

    BACKGROUND: The rabbit VX2 lung cancer model is a large animal model useful for preclinical lung cancer imaging and interventional studies. However, previously reported models had issues in terms of invasiveness of tumor inoculation, control of tumor aggressiveness and incidence of complications. PURPOSE: We aimed to develop a minimally invasive rabbit VX2 lung cancer model suitable for imaging and transbronchial interventional studies. METHODS: New Zealand white rabbits and VX2 tumors were u...

  4. In Vivo Tagging of Lung Epithelial Cells To Define the Early Steps of Tumor Cell Dissemination

    Science.gov (United States)

    2015-12-01

    determine the tumor cell of origin [KrasG12D L/-/ /Sftpc- creER or KrasG12D L/-/ / p53 L/L /Sftpc-creER], or the contribution of alveolar type II cells in...cancer have advanced disease at the time of presentation, a finding that may be consistent with early spread. Even when lung cancer is diagnosed and...identify early stage patients at high risk of recurrence or metastatic disease as well as to develop more effective therapies for NSCLC. 7 The studies

  5. Frameless high dose rate stereotactic lung radiotherapy: intrafraction tumor position and delivery time.

    Science.gov (United States)

    Peguret, Nicolas; Dahele, Max; Cuijpers, Johan P; Slotman, Ben J; Verbakel, Wilko F A R

    2013-06-01

    Intrafraction change in tumor position (Δ) was evaluated for stereotactic lung radiotherapy delivered with flattening filter free volumetric modulated arc therapy. In 140 fractions from 32 patients mean Δ (±SD) was -0.7±1.4 mm (vertical), -0.7±1.3 mm (longitudinal) and +0.2±1.2 mm (lateral) with mean vector 2.1±1.2 mm. Mean delivery time was 4.4±3.4 min (mean beam-on 1.9±0.4 min). Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. Pigment epithelium-derived factor mediates impaired lung vascular development in neonatal hyperoxia.

    Science.gov (United States)

    Chetty, Anne; Bennett, Michelle; Dang, Linh; Nakamura, Daisy; Cao, Gong-Jie; Mujahid, Sana; Volpe, MaryAnn; Herman, Ira; Becerra, S Patricia; Nielsen, Heber C

    2015-03-01

    Bronchopulmonary dysplasia is a chronic lung disease of preterm infants characterized by arrested microvascularization and alveolarization. Studies show the importance of proangiogenic factors for alveolarization, but the importance of antiangiogenic factors is unknown. We proposed that hyperoxia increases the potent angiostatin, pigment epithelium-derived factor (PEDF), in neonatal lungs, inhibiting alveolarization and microvascularization. Wild-type (WT) and PEDF(-/-) mice were exposed to room air (RA) or 0.9 fraction of inspired oxygen from Postnatal Day 5 to 13. PEDF protein was increased in hyperoxic lungs compared with RA-exposed lungs (P epithelium. Hyperoxia reduced alveolarization in WT mice (P lung microvascularization by vascular endothelial growth factor and PEDF was studied in vitro using MFLM-91U cells, a fetal mouse lung endothelial cell line. Vascular endothelial growth factor stimulation of proliferation, migration, and capillary tube formation was inhibited by PEDF. MFLM-91U cells exposed to conditioned medium (CM) from E17 fetal mouse lung type II (T2) cells cultured in 0.9 fraction of inspired oxygen formed fewer capillary tubes than CM from T2 cells cultured in RA (hyperoxia CM, 51 ± 10% of RA CM, P < 0.05), an effect abolished by PEDF antibody. We conclude that PEDF mediates reduced vasculogenesis and alveolarization in neonatal hyperoxia. Bronchopulmonary dysplasia likely results from an altered balance between pro- and antiangiogenic factors.

  7. Genetic instability of cell lines derived from a single human small cell carcinoma of the lung

    DEFF Research Database (Denmark)

    Engelholm, S A; Vindeløv, L L; Spang-Thomsen, M

    1985-01-01

    with different DNA content appeared. By cloning, permanent cell lines were established from the new subpopulations, whereas the original population stopped growing. The cloned cell lines were characterized by morphology, chromosomes analysis, electron microscopy and plating efficiency; the stability of the DNA......Specimens from a human small cell carcinoma of the lung were established as a cell line in vitro. Flow cytometric DNA analysis demonstrated only one tumor cell population in the parent tumor as well as in the early passages in vitro. After six passages in vitro, two new subpopulations...

  8. A Quantitative Volumetric Micro-Computed Tomography Method to Analyze Lung Tumors in Genetically Engineered Mouse Models

    Directory of Open Access Journals (Sweden)

    Brian B. Haines

    2009-01-01

    Full Text Available Two genetically engineered, conditional mouse models of lung tumor formation, K-rasLSL-G12D and K-rasLSL-G12D/p53LSL-R270H, are commonly used to model human lung cancer. Developed by Tyler Jacks and colleagues, these models have been invaluable to study in vivo lung cancer initiation and progression in a genetically and physiologically relevant context. However, heterogeneity, multiplicity and complexity of tumor formation in these models make it challenging to monitor tumor growth in vivo and have limited the application of these models in oncology drug discovery. Here, we describe a novel analytical method to quantitatively measure total lung tumor burden in live animals using micro-computed tomography imaging. Applying this methodology, we studied the kinetics of tumor development and response to targeted therapy in vivo in K-ras and K-ras/p53 mice. Consistent with previous reports, lung tumors in both models developed in a time- and dose (Cre recombinase-dependent manner. Furthermore, the compound K-rasLSL-G12D/p53LSL-R270H mice developed tumors faster and more robustly than mice harboring a single K-rasLSL-G12D oncogene, as expected. Erlotinib, a small molecule inhibitor of the epidermal growth factor receptor, significantly inhibited tumor growth in K-rasLSL-G12D/p53LSL-R270H mice. These results demonstrate that this novel imaging technique can be used to monitor both tumor progression and response to treatment and therefore supports a broader application of these genetically engineered mouse models in oncology drug discovery and development.

  9. STUDY ON THE ANTI-TUMOR EFFICACY INDUCED BY HEAT SHOCK PROTEIN 70-PEPTIDE COMPLEXES DERIVED FROM TUMOR CELLS

    Institute of Scientific and Technical Information of China (English)

    傅庆国; 张玮; 孟凡东; 郭仁宣; 姚振宇

    2002-01-01

    Objective. To study the efficacy and explore the mechanism of the anti-tumor immunity elicited by heat shock protein 70-peptide complexes (HSP70-PC) derived from tumor cells. Methods. Cells culture, flow cytometric analysis, affinity chromatography for protein purification, SDS-PAGE, Western-blotting and animal experiment were used. Results. HSP70-PC immunization rendered protective effect to both naive and tumorl-bearing mice. All of the naive mice obtained complete resistance to Hcaf cell attack; 40% of the tumor-bearing mice survived for over 90 days, whereas the mice of control group died within 2 weeks (P<0.01). CD8+ subset of T lymphocytes in the peripheral blood of immunized mice increased by 12% . Conclusion. HSP70-PC induces anti-tumor immunity via activation of cytotoxic T lymphocytes (CTLs), and it possesses strong tumor vaccine effect. Our research adds more evidence to support the clinical use of HSP70-PC to fight human cancers.

  10. Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model

    Directory of Open Access Journals (Sweden)

    Chen X-C

    2008-10-01

    Full Text Available Abstract Background Bone marrow-derived stromal cells (BMSCs are important for development, tissue cell replenishment, and wound healing in physiological and pathological conditions. BMSCs were found to preferably reach sites undergoing the process of cell proliferation, such as wound and tumor, suggesting that BMSCs may be used as a vehicle for gene therapy of tumor. Methods Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1. The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models. Results BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors. Conclusion We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.

  11. Lung and skeleton malignant tumor induction due to high let emitters

    Energy Technology Data Exchange (ETDEWEB)

    Buldakov, L.A.; Lyubchansky, E.R.; Kalmikova, Z.I.; Buhtoyarova, Z.M. [Institute of biophysics, Moscow (Russian Federation)] [and others

    1992-06-01

    Experimental studies show that malignant tumor induction is of primary importance in regard to the biological action of transuranium elements on the animal body. Clarification of quantitative relationship between these parameters for low-level radiation is aproblem to be solved by health physics. This report aims at analysis of the dose-response relationship following rat exposure to PU-239, Am-241, and NP-237 over a wide range of doses, and also at comparison between risk fact obtained experimentally and tose recommended by the ICRP. The biological effect of transuranium elements was investigated regarding malignant tumor incidence in rat bone for all the pathways of intake covered and in the lung for intakes of radionuclides into the respiratory system.

  12. Clinical evaluation for radiotherapy of metastatic brain tumors in lung cancer. Prognostic analyses relevant to QOL

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    Myojin, Miyako; Nishio, Masamichi; Mizoguchi, Fumiki; Kawashima, Kazuyuki; Mita, Noriko [Sapporo National Hospital (Japan); Fujita, Akihisa

    1998-01-01

    From 1986 through 1992, 144 patients with metastatic brain tumors of lung cancer were treated with X-ray irradiation to whole brain or a comparatively wide field of the brain. To identify the subset of patients indicated for boost therapy like a stereotactic radiotherapy, we have analyzed the treatment results concerning both survival and performance status (PS). Median survival time of the patients in good PS (0-2) was 6.7 months, which was significantly better than 2.3 months in poor PS (3-4). Complete tumor-resectability, age, steroid therapy and condition within two months after the beginning of brain irradiation, seemed to be important prognostic indicators correlated with PS by both univariate and multivariates analyses. (author)

  13. A study on thallium-201 SPECT in brain metastases of lung cancer. With special reference to tumor size and tumor to normal brain thallium uptake ratio

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    Togawa, Takashi; Yui, Nobuharu; Kinoshita, Fujimi; Yanagisawa, Masamichi; Namba, Hiroki [Chiba Cancer Center (Japan). Hospital

    1995-03-01

    Thallium-201 brain SPECT was performed on 20 patients with brain metastases of lung cancer using a three-head rotating gamma camera and the effect of tumor size on tumor detectability and tumor to normal brain thallium uptake ratio (T/N ratio) was studied. Among 71 metastatic lesions, only 9 (22.5%) of 40 lesions of 13 mm diameter or below and 31 (100%) of 31 lesions of 14 mm diameter or above could be detected in this study. There was significant correlation between T/N ratio and tumor size (r=0.75, p<0.001). The greater the metastatic lesion, the higher the T/N ratio. Even among the tumors in a single patient with multiple brain metastases, there was a significant linear correlation between tumor size and T/N ratio (r=0.96, p<0.01). In this patient, T/N ratio varied by the tumor size and these differences in T/N ratios were thought to be based on the partial volume effect. However, T/N{center_dot}d which was a parameter corrected by tumor diameter (d) showed a constant value regardless of tumor size. The present results showed that T/N ratio, which was usually believed to quantitate the malignancy grade of brain tumor, was affected by tumor size and that more accurate parameter could be obtained by the correction of T/N ratio by tumor size. (author).

  14. Experimental rat lung tumor model with intrabronchial tumor cell implantation Modelo experimental de tumor de pulmão em rato por via intrabrônquica

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    Antero Gomes Neto

    2008-02-01

    Full Text Available PURPOSE: The objective of this study was to develop a rat lung tumor model for anticancer drug testing. METHODS: Sixty-two female Wistar rats weighing 208 ± 20 g were anesthetized intraperitoneally with 2.5% tribromoethanol (1 ml/100 g live weight, tracheotomized and intubated with an ultrafine catheter for inoculation with Walker's tumor cells. In the first step of the experiment, a technique was established for intrabronchial implantation of 10(5 to 5×10(5 tumor cells, and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from high-resolution computed tomography (HRCT with findings from necropsia and determining time of survival. RESULTS: The tumor take rate was 94.7% for implants with 4×10(5 tumor cells, HRCT and necropsia findings matched closely (r=0.953; pOBJETIVO: O objetivo foi desenvolver um modelo de tumor de pulmão em rato que permita o teste de fármacos no tratamento deste câncer. MÉTODOS: Sessenta e dois ratos Wistar fêmeas, peso médio de 208±20 g, foram anestesiados com tribromo-etanol 2,5% IP (1ml/100g de rato, traqueostomizados e intubados com cateter ultrafino para injetar células do tumor de Walker. Na 1ª etapa, estabeleceu-se a técnica do implante de células tumorais por via intrabrônquica e o índice de pega tumoral, usando-se de 10(5 a 5×10(5 células. Na 2ª, avaliou-se o volume tumoral e a correlação dos achados obtidos na tomografia computadorizada de alta resolução (TCAR de tórax com os da necropsia e verificou-se a sobrevida. RESULTADOS: O índice de pega foi de 94,7, com o implante de 4×10(5 células do tumor; as medidas do tumor feitas na TCAR e comparadas com as da necropsia foram semelhantes (r=0, 953, p<0,0001; a sobrevida mediana foi de 11 dias; e a mortalidade cirúrgica de 4,8 %. CONCLUSÃO: O modelo mostrou-se viável, com alto índice de pega, mortalidade cirúrgica desprezível, de execução simples e f

  15. Integration between in vivo dosimetry and image guided radiotherapy for lung tumors.

    Science.gov (United States)

    Piermattei, Angelo; Cilla, Savino; Grimaldi, Luca; Sabatino, Domenico; Fidanzio, Andrea; Greco, Francesca; Mameli, Alessandra; Balducci, Mario; Mattiucci, Gian Carlo; Frascino, Vincenzo; Stimato, Gerardina; Gaudino, Diego; Ramella, Sara; Trodella, Lucio; D'Onofrio, Guido; Zini, Giampaolo; Macchia, Gabriella; Digesu', Cinzia; Morganti, Alessio G; Clemente, Stefania; Cozzolino, Mariella; Pedicini, Piernicola; Fusco, Vincenzo

    2009-06-01

    The article reports a feasibility study about the potentiality of an in vivo dosimetry method for the adaptive radiotherapy of the lung tumors treated by 3D conformal radiotherapy techniques (3D CRTs). At the moment image guided radiotherapy (IGRT) has been used for this aim, but it requires taking many periodic radiological images during the treatment that increase workload and patient dose. In vivo dosimetry reported here can reduce the above efforts, alerting the medical staff for the commissioning of new radiological images for an eventual adaptive plan. The in vivo dosimetry method applied on 20 patients makes use of the transit signal St on the beam central axis measured by a small ion chamber positioned on an electronic portal imaging device (EPID) or by the EPID itself. The reconstructed in vivo dosimetry at the isocenter point Diso requires a convolution between the transit signal St and a dose reconstruction factor C that essentially depends on (i) tissue inhomogeneities along the beam central axis and (ii) the in-patient isocenter depth. The C factors, one for every gantry angle, are obtained by processing the patient's computed tomography scan. The method has been recently applied in some Italian centers to check the radiotherapy of pelvis, breast, head, and thorax treatments. In this work the dose reconstruction was carried out in five centers to check the Diso in the lung tumor during the 3D CRT, and the results have been used to detect the interfraction tumor anatomy variations that can require new CT imaging and an adaptive plan. In particular, in three centers a small ion chamber was positioned below the patient and used for the St measurement. In two centers, the St signal was obtained directly by 25 central pixels of an a-Si EPID, equipped with commercial software that enabled its use as a stable detector. A tolerance action level of +/- 6% for every checked beam was assumed. This means that when a difference greater than 6% between the predicted

  16. Human tumor-derived genomic DNA transduced into a recipient cell induces tumor-specific immune responses ex vivo

    OpenAIRE

    2002-01-01

    This article describes a DNA-based vaccination strategy evaluated ex vivo with human cells. The vaccine was prepared by transferring tumor-derived genomic DNA to PCI-13 cells, a highly immunogenic tumor cell line (“recipient cell”), which had been genetically modified to secrete IL-2 (PCI-13/IL-2). PCI-13 cells expressed class I MHC determinants (HLA-A2) shared with the tumor from which the DNA was obtained as well as allogeneic determinants. DNA from a gp100+ melanoma ce...

  17. Pathology, classification, and staging of lung tumors; Pathologie, Klassifikation und Stadieneinteilung boesartiger Lungentumoren

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    Mueller, K.M.; Wiethege, T. [Institut fuer Pathologie an den Berufsgenossenschaftlichen Kliniken Bergmannsheil der Ruhr-Universitaet Bochum (Germany)

    2004-05-01

    The histopathogical, immunohistochemical, and genetic characterization of specimens of, mostly advanced, lung tumors that show variable phenotypes in biopsies of just 1-2 mm does not allow conclusions regarding causal factors (e.g., smoking, radon, asbestos etc.) or further progress of the disease. Therapeutical approach and the still unfavorable prognosis remain essentially, as in the last thirty years, to be characterized by TNM and performance status of the individual patient and, to a lesser extent, by the main histological type of tumor. In recent years, our knowledge of the quite variable biology of tumors has been significantly increased by the use of immunohistochemical methods and molecular biology. These methods facilitated an improved qualitative and quantitative characterization of heterogeneously differentiated lung tumors (e.g., neuroendocrine/blastomatoid portions etc.). The detection of genetic alterations of tumor suppressor genes and oncogenes is, at the moment, only of scientific interest. The heterogeneity of tumors is emphasized by results obtained by molecular genetic techniques. A connection between the detected genetic anomalies and histomorphological growth patterns can not be seen. At the present time, the validity of individual findings for a correlation between operability, tumor progress, chemotherapy and prognosis is not sufficiently elucidated by investigations nor secured. (orig.) [German] Die histopathologische, immunhistochemische und genetische Charakterisierung nur 1-2 mm grosser Biopsien von in der Regel bereits weit fortgeschrittenen boesartigen Lungentumoren mit variablem Phaenotyp erlauben weder Rueckschluesse auf Kausalfaktoren (z. B. Rauchen, Radon, Asbest), noch lassen sich diese Befunde im individuellen Fall als prognostische Marker nutzen. Entscheidend fuer Therapie und Prognose des einzelnen Patienten sind heute nach wie vor ganz wesentlich der TNM-Status, der Performance-Status und bedingt der fuehrende

  18. Novel role for tumor-induced expansion of myeloid-derived cells in cancer cachexia.

    Science.gov (United States)

    Cuenca, Alex G; Cuenca, Angela L; Winfield, Robert D; Joiner, Dallas N; Gentile, Lori; Delano, Matthew J; Kelly-Scumpia, Kindra M; Scumpia, Philip O; Matheny, Michael K; Scarpace, Philip J; Vila, Lizette; Efron, Philip A; LaFace, Drake M; Moldawer, Lyle L

    2014-06-15

    Cancer progression is associated with inflammation, increased metabolic demand, infection, cachexia, and eventually death. Myeloid-derived suppressor cells (MDSCs) commonly expand during cancer and are associated with adaptive immune suppression and inflammatory metabolite production. We propose that cancer-induced cachexia is driven at least in part by the expansion of MDSCs. MDSC expansion in 4T1 mammary carcinoma-bearing hosts is associated with induction of a hepatic acute-phase protein response and altered host energy and fat metabolism, and eventually reduced survival to polymicrobial sepsis and endotoxemia. Similar results are also seen in mice bearing a Lewis lung carcinoma and a C26 colon adenocarcinoma. However, a similar cachexia response is not seen with equivalent growth of the 66C4 subclone of 4T1, in which MDSC expansion does not occur. Importantly, reducing MDSC numbers in 4T1-bearing animals can ameliorate some of these late responses and reduce susceptibility to inflammation-induced organ injury and death. In addition, administering MDSCs from both tumor- and nontumor-bearing mice can produce an acute-phase response. Thus, we propose a previously undescribed mechanism for the development of cancer cachexia, whereby progressive MDSC expansion contributes to changes in host protein and energy metabolism and reduced resistance to infection.

  19. Expression of prostate-specific membrane antigen in lung cancer cells and tumor neovasculature endothelial cells and its clinical significance.

    Directory of Open Access Journals (Sweden)

    Hai-long Wang

    Full Text Available Prostate-specific membrane antigen (PSMA has been found in tumor neovasculature endothelial cells (NECs of non-prostate cancers and may become the most promising target for anti-tumor therapy. To study the value of PSMA as a potential new target for lung cancer treatment, PSMA expression in non-small cell lung cancer (NSCLC and small cell lung cancer (SCLC tissues and its relationship with clinicopathology were investigated in the current study.Immunohistochemistry was used to detect PSMA expression in a total of 150 lung specimens of patients with lung cancer. The data were analyzed using univariate and multivariate statistical analyses.The percentages of NSCLC patients who had PSMA (+ tumor cells and PSMA (+ NECs were 54.02% and 85.06%, respectively. The percentage of patients younger than 60 years old who had PSMA (+ tumor cells was 69.05%, which was significantly greater than the percentage of patients aged 60 years or older (40.00%, p<0.05. A significant difference was observed in the percentage of NSCLC patients with PMSA (+ NECs and stage I or II cancer (92.98% and those patients with stage III or IV cancer (76.77%. In the SCLC tissues, NEC PSMA expression (70.00% did not differ significantly from NSCLC. SCLC tumor cells and normal lung tissues cells were all negative. There was no significant correlation between the presence of PSMA (+ NECs in SCLC patients and the observed clinicopathological parameters.PSMA is expressed not only in NECs of NSCLC and SCLC but also in tumor cells of most NSCLC patients. The presence of PSMA (+ tumor cells and PSMA (+ NECs in NSCLC was negatively correlated with age and the clinicopathological stage of the patients, respectively.

  20. Stimulation of neoplastic mouse lung cell proliferation by alveolar macrophage-derived, insulin-like growth factor-1 can be blocked by inhibiting MEK and PI3K activation

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    Malkinson Alvin M

    2011-06-01

    Full Text Available Abstract Background Worldwide, lung cancer kills more people than breast, colon and prostate cancer combined. Alterations in macrophage number and function during lung tumorigenesis suggest that these immune effector cells stimulate lung cancer growth. Evidence from cancer models in other tissues suggests that cancer cells actively recruit growth factor-producing macrophages through a reciprocal signaling pathway. While the levels of lung macrophages increase during tumor progression in mouse models of lung cancer, and high pulmonary macrophage content correlates with a poor prognosis in human non-small cell lung cancer, the specific role of alveolar macrophages in lung tumorigenesis is not clear. Methods After culturing either an immortalized lung macrophage cell line or primary murine alveolar macrophages from naïve and lung-tumor bearing mice with primary tumor isolates and immortalized cell lines, the effects on epithelial proliferation and cellular kinase activation were determined. Insulin-like growth factor-1 (IGF-1 was quantified by ELISA, and macrophage conditioned media IGF-1 levels manipulated by IL-4 treatment, immuno-depletion and siRNA transfection. Results Primary macrophages from both naïve and lung-tumor bearing mice stimulated epithelial cell proliferation. The lungs of tumor-bearing mice contained 3.5-times more IGF-1 than naïve littermates, and media conditioned by freshly isolated tumor-educated macrophages contained more IGF-1 than media conditioned by naïve macrophages; IL-4 stimulated IGF-1 production by both macrophage subsets. The ability of macrophage conditioned media to stimulate neoplastic proliferation correlated with media IGF-1 levels, and recombinant IGF-1 alone was sufficient to induce epithelial proliferation in all cell lines evaluated. Macrophage-conditioned media and IGF-1 stimulated lung tumor cell growth in an additive manner, while EGF had no effect. Macrophage-derived factors increased p-Erk1/2, p

  1. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    Science.gov (United States)

    Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-09-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity culture system as a platform for studying tumor vascularization.

  2. Wnt pathway activation predicts increased risk of tumor recurrence in patients with stage I nonsmall cell lung cancer.

    Science.gov (United States)

    Shapiro, Mark; Akiri, Gal; Chin, Cynthia; Wisnivesky, Juan P; Beasley, Mary B; Weiser, Todd S; Swanson, Scott J; Aaronson, Stuart A

    2013-03-01

    To determine the incidence of Wnt pathway activation in patients with stage I NSCLC and its influence on lung cancer recurrence. Despite resection, the 5-year recurrence with localized stage I nonsmall cell lung cancer (NSCLC) is 18.4%-24%. Aberrant Wnt signaling activation plays an important role in a wide variety of tumor types. However, there is not much known about the role the Wnt pathway plays in patients with stage I lung cancer. Tumor and normal lung tissues from 55 patients following resection for stage I NSCLC were subjected to glutathione S-transferase (GST) E-cadherin pulldown and immunoblot analysis to assess levels of uncomplexed β-catenin, a reliable measure of Wnt signaling activation. The β-catenin gene was also screened for oncogenic mutations in tumors with activated Wnt signaling. Cancer recurrence rates were correlated in a blinded manner in patients with Wnt pathway-positive and -negative tumors. Tumors in 20 patients (36.4%) scored as Wnt positive, with only 1 exhibiting a β-catenin oncogenic mutation. Patients with Wnt-positive tumors experienced a significantly higher rate of overall cancer recurrence than those with Wnt-negative tumors (30.0% vs. 5.7%, P = 0.02), with 25.0% exhibiting distal tumor recurrence compared with 2.9% in the Wnt-negative group (P = 0.02). Wnt pathway activation occurred in a substantial fraction of Stage I NSCLCs, which was rarely due to mutations. Moreover, Wnt pathway activation was associated with a significantly higher rate of tumor recurrence. These findings suggest that Wnt pathway activation reflects a more aggressive tumor phenotype and identifies patients who may benefit from more aggressive therapy in addition to resection.

  3. Feasibility Study of Automated Framework for Estimating Lung Tumor Locations for Target-Based Patient Positioning in Stereotactic Body Radiotherapy

    Directory of Open Access Journals (Sweden)

    Satoshi Yoshidome

    2015-01-01

    Full Text Available Objective. To investigate the feasibility of an automated framework for estimating the lung tumor locations for tumor-based patient positioning with megavolt-cone-beam computed tomography (MV-CBCT during stereotactic body radiotherapy (SBRT. Methods. A lung screening phantom and ten lung cancer cases with solid lung tumors, who were treated with SBRT, were employed to this study. The locations of tumors in MV-CBCT images were estimated using a tumor-template matching technique between a tumor template and the MV-CBCT. Tumor templates were produced by cropping the gross tumor volume (GTV regions, which were enhanced by a Sobel filter or a blob structure enhancement (BSE filter. Reference tumor locations (grand truth were determined based on a consensus between a radiation oncologist and a medical physicist. Results. According to the results of the phantom study, the average Euclidean distances of the location errors in the original, Sobel-filtered, and BSE-filtered images were 2.0 ± 4.1 mm, 12.8 ± 9.4 mm, and 0.4 ± 0.5 mm, respectively. For clinical cases, these were 3.4 ± 7.1 mm, 7.2 ± 11.6 mm, and 1.6 ± 1.2 mm, respectively. Conclusion. The feasibility study suggests that our proposed framework based on the BSE filter may be a useful tool for tumor-based patient positioning in SBRT.

  4. Tumor-derived death receptor 6 modulates dendritic cell development.

    Science.gov (United States)

    DeRosa, David C; Ryan, Paul J; Okragly, Angela; Witcher, Derrick R; Benschop, Robert J

    2008-06-01

    Studies in murine models of cancer as well as in cancer patients have demonstrated that the immune response to cancer is often compromised. This paradigm is viewed as one of the major mechanisms of tumor escape. Many therapies focus on employing the professional antigen presenting dendritic cells (DC) as a strategy to overcome immune inhibition in cancer patients. Death receptor 6 (DR6) is an orphan member of the tumor necrosis factor receptor superfamily (TNFRSF21). It is overexpressed on many tumor cells and DR6(-/-) mice display altered immunity. We investigated whether DR6 plays a role in tumorigenesis by negatively affecting the generation of anti-tumor activity. We show that DR6 is uniquely cleaved from the cell surface of tumor cell lines by the membrane-associated matrix metalloproteinase (MMP)-14, which is often overexpressed on tumor cells and is associated with malignancy. We also demonstrate that >50% of monocytes differentiating into DC die when the extracellular domain of DR6 is present. In addition, DR6 affects the cell surface phenotype of the resulting immature DC and changes their cytokine production upon stimulation with LPS/IFN-gamma. The effects of DR6 are mostly amended when these immature DC are matured with IL-1beta/TNF-alpha, as measured by cell surface phenotype and their ability to present antigen. These results implicate MMP-14 and DR6 as a mechanism tumor cells can employ to actively escape detection by the immune system by affecting the generation of antigen presenting cells.

  5. Bone marrow-derived cells are recruited by the melanoma tumor with endothelial cells contributing to tumor vasculature.

    Science.gov (United States)

    Bonfim-Silva, R; Souza, L E B; Melo, F U F; Oliveira, V C; Magalhães, D A R; Oliveira, H F; Covas, D T; Fontes, A M

    2017-01-01

    Tumor expansion is dependent on neovascularization, a process that requires sustained new vessel formation. Although the critical role of angiogenesis by endothelial sprouting in this process, controversy still prevails on whether angiogenesis involving bone marrow-derived endothelial cells, does contribute to this process. This study aims to evaluate the recruitment of bone marrow-derived cells by the melanoma tumor, including endothelial cells, and if they contribute to angiogenesis. A chimeric mouse model of GFP bone marrow was used to induce melanoma tumors derived from murine B16-F10 cell line. These tumors were evaluated for the presence of myeloid cells (CD11b), T lymphocytes (CD3, CD4 and CD8) and endothelial cells (VEGFR2 and CD31) derived from bone marrow. Mice transplanted with GFP+ cells showed significant bone marrow chimerism (90.9 ± 0.87 %) when compared to the GFP transgenic mice (90.66 ± 2.1 %, p = 0.83) demonstrating successful engraftment of donor bone marrow stem/progenitor cells. Analysis of the murine melanoma tumor showed the presence of donor cells in the tumors (3.5 ± 1.7 %) and interestingly, these cells represent endothelial cells (CD31+ cells; 11.5 ± 6.85 %) and myeloid cells (CD11b+ cells; 80 ± 21 %), but also tumor-infiltrating lymphocytes (CD8+ T cells, 13.31 ± 0.2 %; CD4+ T-cells, 2.1 ± 1.2 %). Examination of the tumor endothelium by confocal microscopy suggests the presence of donor CD31+/GFP+ cells in the wall of some blood vessels. This study demonstrates that bone marrow-derived cells are recruited by the murine melanoma tumor, with myeloid cells and CD4 and CD8 T lymphocytes migrating as antitumor immune response, and endothelial cells participating of the tumor blood vessels formation.

  6. SU-E-J-23: An Accurate Algorithm to Match Imperfectly Matched Images for Lung Tumor Detection Without Markers

    Energy Technology Data Exchange (ETDEWEB)

    Rozario, T; Bereg, S [University of Texas at Dallas, Richardson, TX (United States); Chiu, T; Liu, H; Kearney, V; Jiang, L; Mao, W [UT Southwestern Medical Center, Dallas, TX (United States)

    2014-06-01

    Purpose: In order to locate lung tumors on projection images without internal markers, digitally reconstructed radiograph (DRR) is created and compared with projection images. Since lung tumors always move and their locations change on projection images while they are static on DRRs, a special DRR (background DRR) is generated based on modified anatomy from which lung tumors are removed. In addition, global discrepancies exist between DRRs and projections due to their different image originations, scattering, and noises. This adversely affects comparison accuracy. A simple but efficient comparison algorithm is reported. Methods: This method divides global images into a matrix of small tiles and similarities will be evaluated by calculating normalized cross correlation (NCC) between corresponding tiles on projections and DRRs. The tile configuration (tile locations) will be automatically optimized to keep the tumor within a single tile which has bad matching with the corresponding DRR tile. A pixel based linear transformation will be determined by linear interpolations of tile transformation results obtained during tile matching. The DRR will be transformed to the projection image level and subtracted from it. The resulting subtracted image now contains only the tumor. A DRR of the tumor is registered to the subtracted image to locate the tumor. Results: This method has been successfully applied to kV fluoro images (about 1000 images) acquired on a Vero (Brainlab) for dynamic tumor tracking on phantom studies. Radiation opaque markers are implanted and used as ground truth for tumor positions. Although, other organs and bony structures introduce strong signals superimposed on tumors at some angles, this method accurately locates tumors on every projection over 12 gantry angles. The maximum error is less than 2.6 mm while the total average error is 1.0 mm. Conclusion: This algorithm is capable of detecting tumor without markers despite strong background signals.

  7. The influence of the pituitary tumor transforming gene-1 (PTTG-1 on survival of patients with small cell lung cancer and non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Geddert Helene

    2006-01-01

    Full Text Available Abstract Background PTTG-1 (pituitary tumor transforming gene is a novel oncogene that is overexpressed in tumors, such as pituitary adenoma, breast and gastrointestinal cancers as well as in leukemia. In this study, we examined the role of PTTG-1 expression in lung cancer with regard to histological subtype, the correlation of PTTG-1 to clinical parameters and relation on patients' survival. Methods Expression of PTTG-1 was examined immunohistochemically on formalin-fixed, paraffin-embedded tissue sections of 136 patients with small cell lung cancer (SCLC and 91 patients with non-small cell lung cancer (NSCLC, retrospectively. The intensity of PTTG-1 expression as well as the proportion of PTTG-1 positive cells within a tumor was used for univariate and multivariate analysis. Results PTTG-1 expression was observed in 64% of SCLC tumors and in 97.8% of NSCLC tumors. In patients with SCLC, negative or low PTTG-1 expression was associated with a shorter mean survival time compared with patients with strong PTTG-1 expression (265 ± 18 days vs. 379 ± 66 days; p = 0.0291. Using the Cox regression model for multivariate analysis, PTTG-1 expression was a significant predictor for survival next to performance status, tumor stage, LDH and hemoglobin. In contrast, in patients with NSCLC an inverse correlation between survival and PTTG-1 expression was seen. Strong PTTG-1 expression was associated with a shorter mean survival of 306 ± 58 days compared with 463 ± 55 days for those patients with no or low PTTG-1 intensities (p = 0.0386. Further, PTTG-1 expression was associated with a more aggressive NSCLC phenotype with an advanced pathological stage, extensive lymph node metastases, distant metastases and increased LDH level. Multivariate analysis using Cox regression confirmed the prognostic relevance of PTTG-1 expression next to performance status and tumor stage in patients with NSCLC. Conclusion Lung cancers belong to the group of tumors expressing

  8. Overexpression of JAM-A in non-small cell lung cancer correlates with tumor progression.

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    Min Zhang

    Full Text Available The objective of the current study was to determine the clinical significance of junctional adhesion molecule A (JAM-A in patients with non-small cell lung cancer (NSCLC and the biological function of JAM-A in NSCLC cell lines. We showed that JAM-A is predominantly expressed in cell membranes and high expression of JAM-A occurred in 37% of lung tumor specimens compared to corresponding normal tissues. High expression of JAM-A was significantly correlated with TNM stage (P = 0.021, lymph node metastasis (P = 0.007, and decreased overall survival (P = 0.02, In addition, we observed that silencing JAM-A by small interfering RNA inhibited tumor cell proliferation and induced cell cycle arrest at the G1/S boundary. Western blotting analysis revealed that knockdown of JAM-A decreased the protein levels of cyclin D1, CDK4, 6, and P-Rb. Thus, JAM-A plays an important role in NSCLC progression.

  9. GLUT1: A novel tool reflecting proliferative activity of lung neuroendocrine tumors?

    Science.gov (United States)

    Benzerdjeb, Nazim; Berna, Pascal; Sevestre, Henri

    2017-01-01

    Lung neuroendocrine tumors (LNT) represents approximately 20% of all lung cancers. The classification of LNT relies upon morphology. Recently, in the World Health Organization (WHO) classification, Ki-67 rate has been proposed for classification. It is, however, known that Ki-67 count has a poor interlaboratory reproducibly. For that reason, our team has looked for a new biomarker. GLUT1 protein a facilitative glucose transporter protein which has ubiquitous expression in mammalian. GLUT1 is overexpressed in many human cancers. But, no study has evaluated the GLUT1 staining as an aid diagnosis in LNT. Our team have assessed the GLUT1 immunohistochemical staining in 36 LNT and to assess its diagnostic value. GLUT1 staining was higher in neuroendocrine carcinoma than in carcinoid tumor. A positive predictive value in a priori and posteriori testing for diagnosis of LNT is demonstrated. GLUT1 staining could aid in the diagnosis and should be validated in a large prospective cohort. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

  10. Hybrid liposomes inhibit tumor growth and lung metastasis of murine osteosarcoma cells.

    Science.gov (United States)

    Kitajima, Hideki; Komizu, Yuji; Ichihara, Hideaki; Goto, Koichi; Ueoka, Ryuichi

    2013-06-01

    Antitumor effects of hybrid liposomes (HL) composed of l-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene(23) dodecyl ether (C₁₂(EO)₂₃) on the metastatic growth of murine osteosarcoma (LM8) cells were investigated in vitro and in vivo. Remarkable inhibitory effects of HL-23 on the growth of LM8 cells were obtained through the induction of apoptotic cell death in vitro. It was also indicated that HL-23 should dramatically suppress the invasion of LM8 cells and the formation of filopodia on the cell surface in vitro. Furthermore, significantly high therapeutic effects were observed in the homograft mouse models of LM8 cells with lung metastasis after the treatment with HL-23 in vivo. That is, the histological analysis demonstrated that the primary tumor growth of LM8 cells implanted subcutaneously into the mice was inhibited along with the induction of apoptosis. In addition, it was found that HL-23 significantly decreased the lung metastasis of LM8 cells in the mouse models through the inhibition of primary tumor invasion. These results suggest that HL-23 could be a novel agent for the chemotherapy of osteosarcoma.

  11. Overexpression of JAM-A in non-small cell lung cancer correlates with tumor progression.

    Science.gov (United States)

    Zhang, Min; Luo, Wenting; Huang, Bo; Liu, Zihui; Sun, Limei; Zhang, Qingfu; Qiu, Xueshan; Xu, Ke; Wang, Enhua

    2013-01-01

    The objective of the current study was to determine the clinical significance of junctional adhesion molecule A (JAM-A) in patients with non-small cell lung cancer (NSCLC) and the biological function of JAM-A in NSCLC cell lines. We showed that JAM-A is predominantly expressed in cell membranes and high expression of JAM-A occurred in 37% of lung tumor specimens compared to corresponding normal tissues. High expression of JAM-A was significantly correlated with TNM stage (P = 0.021), lymph node metastasis (P = 0.007), and decreased overall survival (P = 0.02), In addition, we observed that silencing JAM-A by small interfering RNA inhibited tumor cell proliferation and induced cell cycle arrest at the G1/S boundary. Western blotting analysis revealed that knockdown of JAM-A decreased the protein levels of cyclin D1, CDK4, 6, and P-Rb. Thus, JAM-A plays an important role in NSCLC progression.

  12. A Gaussian mixture model for definition of lung tumor volumes in positron emission tomography.

    Science.gov (United States)

    Aristophanous, Michalis; Penney, Bill C; Martel, Mary K; Pelizzari, Charles A

    2007-11-01

    The increased interest in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in radiation treatment planning in the past five years necessitated the independent and accurate segmentation of gross tumor volume (GTV) from FDG-PET scans. In some studies the radiation oncologist contours the GTV based on a computed tomography scan, while incorporating pertinent data from the PET images. Alternatively, a simple threshold, typically 40% of the maximum intensity, has been employed to differentiate tumor from normal tissue, while other researchers have developed algorithms to aid the PET based GTV definition. None of these methods, however, results in reliable PET tumor segmentation that can be used for more sophisticated treatment plans. For this reason, we developed a Gaussian mixture model (GMM) based segmentation technique on selected PET tumor regions from non-small cell lung cancer patients. The purpose of this study was to investigate the feasibility of using a GMM-based tumor volume definition in a robust, reliable and reproducible way. A GMM relies on the idea that any distribution, in our case a distribution of image intensities, can be expressed as a mixture of Gaussian densities representing different classes. According to our implementation, each class belongs to one of three regions in the image; the background (B), the uncertain (U) and the target (T), and from these regions we can obtain the tumor volume. User interaction in the implementation is required, but is limited to the initialization of the model parameters and the selection of an "analysis region" to which the modeling is restricted. The segmentation was developed on three and tested on another four clinical cases to ensure robustness against differences observed in the clinic. It also compared favorably with thresholding at 40% of the maximum intensity and a threshold determination function based on tumor to background image intensities proposed in a recent paper. The parts of the

  13. Dendritic-tumor fusion cells derived heat shock protein70-peptide complex has enhanced immunogenicity.

    Science.gov (United States)

    Zhang, Yunfei; Zhang, Yong; Chen, Jun; Liu, Yunyan; Luo, Wen

    2015-01-01

    Tumor-derived heat shock protein70-peptide complexes (HSP70.PC-Tu) have shown great promise in tumor immunotherapy due to numerous advantages. However, large-scale phase III clinical trials showed that the limited immunogenicity remained to be enhanced. In previous research, we demonstrated that heat shock protein 70-peptide complexes (HSP70.PC-Fc) derived from dendritic cell (DC)-tumor fusions exhibit enhanced immunogenicity compared with HSP70.PCs from tumor cells. However, the DCs used in our previous research were obtained from healthy donors and not from the patient population. In order to promote the clinical application of these complexes, HSP70.PC-Fc was prepared from patient-derived DC fused directly with patient-derived tumor cells in the current study. Our results showed that compared with HSP70.PC-Tu, HSP70.PC-Fc elicited much more powerful immune responses against the tumor from which the HSP70 was derived, including enhanced T cell activation, and CTL responses that were shown to be antigen specific and HLA restricted. Our results further indicated that the enhanced immunogenicity is related to the activation of CD4+ T cells and increased association with other heat shock proteins, such as HSP90. Therefore, the current study confirms the enhanced immunogenicity of HSP70.PC derived from DC-tumor fusions and may provide direct evidence promoting their future clinical use.

  14. Tumor Antigen-Derived Peptides Delivery for Cancer Immunotherapy.

    Science.gov (United States)

    Wenxue, Ma

    2014-02-05

    Tumor antigenic peptides therapeutics is a promising field for cancer immunotherapy. Benefits include the ease and rapid synthesis of antigenic peptides and capacity for modifications. In the past years, many peptide-based cancer vaccines have been tested in clinical trials with a limited success because of the difficulties associated with peptide stability and delivery approaches, consequently, resulting in inefficient antigen presentation and low response rates in patients with cancer. The development of suitable and efficient vaccine carrier systems still remains a major challenge. This article aims to describe a new delivery approach for tumor antigenic peptides and rationales of dendritic cells (DCs)-based vaccination. In order to elicit enhanced immune responses, poly(DL-lactide-co-glycolide) (PLGA), which has been approved by the US Food and Drug Administration (FDA) for the use of drug delivery, diagnostics and other applications of clinical and basic science research were employed for the formulation of making nanoparticles (NPs) while delivering tumor antigenic peptides.

  15. A novel method for sample preparation of fresh lung cancer tissue for proteomics analysis by tumor cell enrichment and removal of blood contaminants

    OpenAIRE

    Orre Lotta; Bergman Per; Elmberger Göran; Pernemalm Maria; De Petris Luigi; Lewensohn Rolf; Lehtiö Janne

    2010-01-01

    Abstract Background In-depth proteomics analyses of tumors are frequently biased by the presence of blood components and stromal contamination, which leads to large experimental variation and decreases the proteome coverage. We have established a reproducible method to prepare freshly collected lung tumors for proteomics analysis, aiming at tumor cell enrichment and reduction of plasma protein contamination. We obtained enriched tumor-cell suspensions (ETS) from six lung cancer cases (two ade...

  16. The potential of positron emission tomography for intratreatment dynamic lung tumor tracking: A phantom study

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Jaewon [Department of Electrical Engineering, Stanford University, Stanford, California 94305 and Department of Radiation Oncology, Stanford University, Stanford, California 94305 (United States); Yamamoto, Tokihiro [Department of Radiation Oncology, University of California Davis, Sacramento, California 95817 (United States); Mazin, Samuel R. [RefleXion Medical, Inc., Burlingame, California 94010 (United States); Graves, Edward E. [Department of Radiation Oncology, Stanford University, Stanford, California 94305 (United States); Keall, Paul J., E-mail: paul.keall@sydney.edu.au [Radiation Physics Laboratory, University of Sydney, Sydney, NSW 2006 (Australia)

    2014-02-15

    Purpose: This study aims to evaluate the potential and feasibility of positron emission tomography for dynamic lung tumor tracking during radiation treatment. The authors propose a center of mass (CoM) tumor tracking algorithm using gated-PET images combined with a respiratory monitor and investigate the geometric accuracy of the proposed algorithm. Methods: The proposed PET dynamic lung tumor tracking algorithm estimated the target position information through the CoM of the segmented target volume on gated PET images reconstructed from accumulated coincidence events. The information was continuously updated throughout a scan based on the assumption that real-time processing was supported (actual processing time at each frame ≈10 s). External respiratory motion and list-mode PET data were acquired from a phantom programmed to move with measured respiratory traces (external respiratory motion and internal target motion) from human subjects, for which the ground truth target position was known as a function of time. The phantom was cylindrical with six hollow sphere targets (10, 13, 17, 22, 28, and 37 mm in diameter). The measured respiratory traces consisted of two sets: (1) 1D-measured motion from ten healthy volunteers and (2) 3D-measured motion from four lung cancer patients. The authors evaluated the geometric accuracy of the proposed algorithm by quantifying estimation errors (Euclidean distance) between the actual motion of targets (1D-motion and 3D-motion traces) and CoM trajectories estimated by the proposed algorithm as a function of time. Results: The time-averaged error of 1D-motion traces over all trajectories of all targets was 1.6 mm. The error trajectories decreased with time as coincidence events were accumulated. The overall error trajectory of 1D-motion traces converged to within 2 mm in approximately 90 s. As expected, more accurate results were obtained for larger targets. For example, for the 37 mm target, the average error over all 1D

  17. The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells

    Science.gov (United States)

    Malanga, Donatella; De Marco, Carmela; Guerriero, Ilaria; Colelli, Fabiana; Rinaldo, Nicola; Scrima, Marianna; Mirante, Teresa; De Vitis, Claudia; Zoppoli, Pietro; Ceccarelli, Michele; Riccardi, Miriam; Ravo, Maria; Weisz, Alessandro; Federico, Antonella; Franco, Renato; Rocco, Gaetano; Mancini, Rita; Rizzuto, Antonia; Gulletta, Elio; Ciliberto, Gennaro; Viglietto, Giuseppe

    2015-01-01

    Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation (n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC. PMID:26486080

  18. The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells.

    Science.gov (United States)

    Malanga, Donatella; De Marco, Carmela; Guerriero, Ilaria; Colelli, Fabiana; Rinaldo, Nicola; Scrima, Marianna; Mirante, Teresa; De Vitis, Claudia; Zoppoli, Pietro; Ceccarelli, Michele; Riccardi, Miriam; Ravo, Maria; Weisz, Alessandro; Federico, Antonella; Franco, Renato; Rocco, Gaetano; Mancini, Rita; Rizzuto, Antonia; Gulletta, Elio; Ciliberto, Gennaro; Viglietto, Giuseppe

    2015-12-15

    Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation (n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC.

  19. Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers.

    Science.gov (United States)

    Guo, Wei; Lu, Jianjun; Dai, Meng; Wu, Taihua; Yu, Zhenlong; Wang, Jingshu; Chen, Wangbing; Shi, Dingbo; Yu, Wendan; Xiao, Yao; Yi, Canhui; Tang, Zhipeng; Xu, Tingting; Xiao, Xiangsheng; Yuan, Yuhui; Liu, Quentin; Du, Guangwei; Deng, Wuguo

    2014-10-15

    Upregulated expression and activation of human telomerase reverse transcriptase (hTERT) is a hallmarker of lung tumorigenesis. However, the mechanism underlying the aberrant hTERT activity in lung cancer cells remains poorly understood. In this study, we found the transcriptional co-activator CBP as a new hTERT promoter-binding protein that regulated hTERT expression and tumor growth in lung adenocarcinoma cells using a biotin-streptavidin-bead pulldown technique. Chromatin immunoprecipitation assay verified the immortalized cell and tumor cell-specific binding of CBP on hTERT promoter. Overexpression of exogenous CBP upregulated the expression of the hTERT promoter-driven luciferase and endogenous hTERT protein in lung cancer cells. Conversely, inhibition of CBP by CBP-specific siRNA or its chemical inhibitor repressed the expression of hTERT promoter-driven luciferase and endogenous hTERT protein as well as telomerase activity. Moreover, inhibition of CBP expression or activity also significantly reduced the proliferation of lung cancer cells in vitro and tumor growth in an xenograft mouse model in vivo. Immunohistochemical analysis of tissue microarrays of lung cancers revealed a positive correlation between CBP and hTERT. Importantly, the patients with high CBP and hTERT expression had a significantly shorter overall survival. Furthermore, CBP was found to interact with and acetylate transactivator Sp1 in lung cancer cells. Inhibition of CBP by CBP-specific siRNA or its chemical inhibitor significantly inhibited Sp1 acetylation and its binding to the hTERT promoter. Collectively, our results indicate that CBP contributes to the upregulation of hTERT expression and tumor growth, and overexpression of CBP predicts poor prognosis in human lung cancers.

  20. A block matching-based registration algorithm for localization of locally advanced lung tumors

    Science.gov (United States)

    Robertson, Scott P.; Weiss, Elisabeth; Hugo, Geoffrey D.

    2014-01-01

    Purpose: To implement and evaluate a block matching-based registration (BMR) algorithm for locally advanced lung tumor localization during image-guided radiotherapy. Methods: Small (1 cm3), nonoverlapping image subvolumes (“blocks”) were automatically identified on the planning image to cover the tumor surface using a measure of the local intensity gradient. Blocks were independently and automatically registered to the on-treatment image using a rigid transform. To improve speed and robustness, registrations were performed iteratively from coarse to fine image resolution. At each resolution, all block displacements having a near-maximum similarity score were stored. From this list, a single displacement vector for each block was iteratively selected which maximized the consistency of displacement vectors across immediately neighboring blocks. These selected displacements were regularized using a median filter before proceeding to registrations at finer image resolutions. After evaluating all image resolutions, the global rigid transform of the on-treatment image was computed using a Procrustes analysis, providing the couch shift for patient setup correction. This algorithm was evaluated for 18 locally advanced lung cancer patients, each with 4–7 weekly on-treatment computed tomography scans having physician-delineated gross tumor volumes. Volume overlap (VO) and border displacement errors (BDE) were calculated relative to the nominal physician-identified targets to establish residual error after registration. Results: Implementation of multiresolution registration improved block matching accuracy by 39% compared to registration using only the full resolution images. By also considering multiple potential displacements per block, initial errors were reduced by 65%. Using the final implementation of the BMR algorithm, VO was significantly improved from 77% ± 21% (range: 0%–100%) in the initial bony alignment to 91% ± 8% (range: 56%–100%; p < 0.001). Left

  1. Oncocytic carcinoid of lung: an ultrastructural analysis.

    Science.gov (United States)

    Scharifker, D; Marchevsky, A

    1981-02-01

    A 52-year-old man with a typical carcinoid tumor of the lung in which the tumor cells displayed marked oncocytic metaplasia is presented. The clinicopathologic and ultrastructural differences with so-called oncocytic of the lung are discussed. The potential of Kulchitsky cell derivatives to undergo oncocytic metaplasma is documented ultrastructurally.

  2. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

    Directory of Open Access Journals (Sweden)

    Lucia Regales

    Full Text Available BACKGROUND: The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR(L858R+T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR(T790M-expressing animals develop tumors with longer latency than EGFR(L858R+T790M-bearing mice and in the absence of additional kinase domain mutations. CONCLUSIONS/SIGNIFICANCE: These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFR(T790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations.

  3. Measurement of ventilation- and perfusion-mediated cooling during laser ablation in ex vivo human lung tumors.

    Science.gov (United States)

    Vietze, Andrea; Koch, Franziska; Laskowski, Ulrich; Linder, Albert; Hosten, Norbert

    2011-11-01

    Perfusion-mediated tissue cooling has often been described in the literature for thermal ablation therapies of liver tumors. The objective of this study was to investigate the cooling effects of both perfusion and ventilation during laser ablation of lung malignancies. An ex vivo lung model was used to maintain near physiological conditions for the specimens. Fourteen human lung lobes containing only primary lung tumors (non-small cell lung cancer) were used. Laser ablation was carried out using a Nd:YAG laser with a wavelength of 1064 nm and laser fibers with 30 mm diffusing tips. Continuous invasive temperature measurement in 10 mm distance from the laser fiber was performed. Laser power was increased at 2 W increments starting at 10 W up to a maximum power of 12-20 W until a temperature plateau around 60 °C was reached at one sensor. Ventilation and perfusion were discontinued for 6 min each to assess their effects on temperature development. The experiments lead to 25 usable temperature profiles. A significant temperature increase was observed for both discontinued ventilation and perfusion. In 6 min without perfusion, the temperature rose about 5.5 °C (mean value, Pcooling are significant influencing factors on temperature development during thermal ablation. They should be taken into account during the planning and preparation of minimally invasive lung tumor treatment in order to achieve complete ablation. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. Imaging of lung metastasis tumor mouse model using [{sup 18}F]FDG small animal PET and CT

    Energy Technology Data Exchange (ETDEWEB)

    Kim, June Youp; Woo, Sang Keun; Lee, Tae Sup [Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul (Korea, Republic of)] (and others)

    2007-02-15

    The purpose of this study is to image metastaic lung melanoma model with optimal pre-conditions for animal handling by using [{sup 18}F]FDG small animal PET and clinical CT. The pre-conditions for lung region tumor imaging were 16-22 h fasting and warming temperature at 30 .deg. C. Small animal PET image was obtained at 60 min postinjection of 7.4 MBq [{sup 18}F]FDG and compared pattern of [{sup 18}F]FDG uptake and glucose standard uptake value (SUVG) of lung region between Ketamine/Xylazine (Ke/Xy) and Isoflurane (Iso) anesthetized group in normal mice. Metastasis tumor mouse model to lung was established by intravenous injection of B16-F10 cells in C57BL/6 mice. In lung metastasis tumor model, [{sup 18}F]FDG image was obtained and fused with anatomical clinical CT image. Average blood glucose concentration in normal mice were 128.0 {+-} 22.87 and 86.0 {+-} 21.65 mg/dL in Ke/Xy group and Iso group, respectively. Ke/Xy group showed 1.5 fold higher blood glucose concentration than Iso group. Lung to Background ratio (L/B) in SUVG image was 8.6 {+-} 0.48 and 12.1 {+-}0.63 in Ke/Xy group and Iso group, respectively. In tumor detection in lung region, [{sup 18}F]FDG image of Iso group was better than that of Ke/Xy group, because of high L/B ratio. Metastatic tumor location in [{sup 18}F]FDG small animal PET image was confirmed by fusion image using clinical CT. Tumor imaging in small animal lung region with [{sup 18}F]FDG small animal PET should be considered pre-conditions which fasting, warming and an anesthesia during [{sup 18}F]FDG uptake. Fused imaging with small animal PET and CT image could be useful for the detection of metastatic tumor in lung region.

  5. Clinicopathological and Prognostic Significance of a Panel of Tumor Biomarkers 
in Lung Adenocarcinoma: a Tissue Microarray Study

    Directory of Open Access Journals (Sweden)

    Xin YANG

    2014-03-01

    Full Text Available Background and objective Lung adenocarcinoma is one of the most common histological subtypes of lung cancer. The incidence of this disease was continuously increased. This study aims to detect the expressions of Napsin A, TTF-1, ERCC1, RRM1, EGFR, HER2, ERα, ERβ, PR, and Bcl-2 in lung adenocarcinoma and to explore their correlations with clinicopathological characteristics and prognosis. Methods A total of 227 lung adenocarcinoma specimens were constructed in tissue microarrays. The expressions of the 10 tumor biomarkers were analyzed by immunohistochemistry on paraffin-embedded sections. Results Among the 10 markers, Napsin A was gender-related (P=0.049. Napsin A, PR, and EGFR were significantly associated with smoking. TTF-1 and ERCC1 were closely associated with tumor size. Napsin A, TTF-1, ERα, and PR were remarkably associated with tumor differentiation. TTF-1, Bcl-2, and ERCC1 were closely associated with tumor stage (P0.05. Univariate analysis results showed that Napsin A, TTF-1, and ERCC1 were significantly associated with overall survival. TTF-1 was remarkably associated with disease-free survival (P0.05. Multivariate analysis results showed that pathological staging was significantly associated with overall survival and disease-free survival (P0.05. Conclusion Napsin A, TTF-1, and ERCC1 are the markers indicating good prognosis of lung adenocarcinoma.

  6. Periodic loss of reactivity of a myeloma tumor with cytotoxic thymus-derived lymphocytes.

    Science.gov (United States)

    Russell, J H; Hale, A H; Ginns, L C; Eisen, H N

    1978-01-01

    During each transplantation passage of a line of mouse myeloma tumor MOPC-315 through syngeneic (BALB/c) hosts, the tumor cells lose reactivity with cytotoxic thymus-derived lymphocytes directed against products of the BALB/c major histocompatibility complex (H-2d) and regain reactivity on transfer to fresh hosts. In contrast to this cyclical change, the tumor cells remain uniformly reactive with anti-H-2d alloantisera throughout the transplantation cycle. PMID:75547

  7. Truncation of the Catalytic Domain of the Cylindromatosis Tumor Suppressor Impairs Lung Maturation

    Directory of Open Access Journals (Sweden)

    Eirini Trompouki

    2009-05-01

    Full Text Available Cyld encodes a 956-amino acid deubiquitinating enzyme (CYLD, which is a negative regulator of nuclear factor κB and mitogen-activated protein kinase pathways. Mutations that truncate and inactivate the carboxyl-terminal deubiquitinating domain of CYLD underlie the development of skin appendage tumors in humans, whereas down-regulation of Cyld expression has been associated with the development of various types of human malignancies including lung cancer. To establish an animal model of human CYLD inactivation and characterize the biological role of CYLD in vivo, we generated mice carrying a homozygous deletion of Cyld exon 9 (CyldΔ9/Δ9 mice using a conditional approach. Deletion of exon 9 would cause a carboxyl-terminal truncation of CYLD and inactivation of its deubiquitinating activity. In accordance with previous studies, fibroblasts from CyldΔ9/Δ9 embryos had hyperactive nuclear factor κB and c-Jun kinase pathways compared with control fibroblasts. CyldΔ9/Δ9 newborn mice were smaller than wild-type littermates with a short and kinky tail and nomajor developmental defects. However, CyldΔ9/Δ9 mice died shortly after birth from apparent respiratory dysfunction. Histological examination of E18.5 CyldΔ9/Δ9 lungs demonstrated an immature phenotype characterized by hyperplasic mesenchyme but apparently normal epithelial, smooth muscle. and endothelial structures. Our study identifies an important role of CYLD in lung maturation, which may underlie the development of many cases of lung cancer.

  8. Donor lung derived myeloid and plasmacytoid dendritic cells differentially regulate T cell proliferation and cytokine production

    Directory of Open Access Journals (Sweden)

    Benson Heather L

    2012-03-01

    Full Text Available Abstract Background Direct allorecognition, i.e., donor lung-derived dendritic cells (DCs stimulating recipient-derived T lymphocytes, is believed to be the key mechanism of lung allograft rejection. Myeloid (cDCs and plasmacytoid (pDCs are believed to have differential effects on T cell activation. However, the roles of each DC type on T cell activation and rejection pathology post lung transplantation are unknown. Methods Using transgenic mice and antibody depletion techniques, either or both cell types were depleted in lungs of donor BALB/c mice (H-2d prior to transplanting into C57BL/6 mice (H-2b, followed by an assessment of rejection pathology, and pDC or cDC-induced proliferation and cytokine production in C57BL/6-derived mediastinal lymph node T cells (CD3+. Results Depleting either DC type had modest effect on rejection pathology and T cell proliferation. In contrast, T cells from mice that received grafts depleted of both DCs did not proliferate and this was associated with significantly reduced acute rejection scores compared to all other groups. cDCs were potent inducers of IFNγ, whereas both cDCs and pDCs induced IL-10. Both cell types had variable effects on IL-17A production. Conclusion Collectively, the data show that direct allorecognition by donor lung pDCs and cDCs have differential effects on T cell proliferation and cytokine production. Depletion of both donor lung cDC and pDC could prevent the severity of acute rejection episodes.

  9. Cationic lipid guided short-hairpin RNA interference of annexin A2 attenuates tumor growth and metastasis in a mouse lung cancer stem cell model.

    Science.gov (United States)

    Andey, Terrick; Marepally, Srujan; Patel, Apurva; Jackson, Tanise; Sarkar, Shubhashish; O'Connell, Malaney; Reddy, Rakesh C; Chellappan, Srikumar; Singh, Pomila; Singh, Mandip

    2014-06-28

    The role of side populations (SP) or cancer stem-like cells (CSC) in promoting the resistance phenotype presents a viable anticancer target. Human-derived H1650 SP cells over-express annexin A2 (AnxA2) and SOX2, and are resistant to conventional cytotoxic chemotherapeutics. AnxA2 and SOX2 bind to proto-oncogenes, c-Myc and c-Src, and AnxA2 forms a functional heterotetramer with S100A10 to promote tumor motility. However, the combined role of AnxA2, S100A10 and SOX2 in promoting the resistant phenotype of SP cells has not been investigated. In the current studies, we examined for the first time a possible role of AnxA2 in regulating SA100A10 and SOX2 in promoting a resistant phenotype of lung tumors derived from H1650 SP cells. The resistance of H1650 SP cells to chemotherapy compared to H1650 MP cells was investigated by cell viability studies. A short hairpin RNA targeting AnxA2 (shAnxA2) was formulated in a liposomal (cationic ligand-guided, CLG) carrier and characterized for size, charge and entrapment and loading efficiencies; CLG carrier uptake by H1650 SP cells was demonstrated by fluorescence microscopy, and knockdown of AnxA2 confirmed by qRT-PCR and Western blot. Targeting of xenograft and orthotopic lung tumors was demonstrated with fluorescent (DiR) CLG carriers in mice. The therapeutic efficacy of CLG-AnxA2, compared to that of placebo, was investigated after 2 weeks of treatment in terms of tumor weights and tumor burden in vivo. Compared to mixed population cells, H1650 SP cells showed exponential resistance to docetaxel (15-fold), cisplatin (13-fold), 5-fluorouracil (31-fold), camptothecin (7-fold), and gemcitabine (16-fold). CLG carriers were nanoparticulate (199nm) with a slight positive charge (21.82mV); CLG-shAnx2 was of similar size (217nm) with decreased charge (12.11mV), and entrapment and loading efficiencies of 97% and 6.13% respectively. Fluorescence microscopy showed high uptake of CLG-shAnxA2 in H1650 SP cells after 2h resulting in a 6

  10. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism

    Science.gov (United States)

    Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate tha...

  11. Different expression of EZH2, BMI1 and Ki67 in low and high grade neuroendocrine tumors of the lung

    DEFF Research Database (Denmark)

    Bondgaard, Anna-Louise Reinert Ørsum; Poulsen, Thomas Tuxen; Poulsen, Hans Skovgaard

    2012-01-01

    Enhancer of Zeste Homolog 2 (EZH2) and B lymphoma Mo-MLV Insertion region 1 polycomb ring finger (BMI1) are involved in malignant transformation of many human carcinomas. Still, in neuroendocrine tumors of the lung (NELT) their expression pattern is largely unknown. This study evaluated their exp......Enhancer of Zeste Homolog 2 (EZH2) and B lymphoma Mo-MLV Insertion region 1 polycomb ring finger (BMI1) are involved in malignant transformation of many human carcinomas. Still, in neuroendocrine tumors of the lung (NELT) their expression pattern is largely unknown. This study evaluated...

  12. Long-term disease control of a non-operable neuroendocrine tumor of the lung with lanreotide: a case study.

    Science.gov (United States)

    Van Fraeyenhove, F; De Droogh, E; Meireson, N; Galdermans, D; Goor, C; Van Acker, F; Mattelaer, C; De Ruyter, V; Schrijvers, D

    2012-09-01

    Bronchopulmonary neuroendocrine tumors (NETs) are malignant tumors that represent approximately 20% of all lung cancers. The therapeutic option for advanced or metastatic bronchopulmonary NETs is mainly palliation of symptoms; options need to be individualized and, therefore, rely on the knowledge of multidisciplinary teams. Somatostatin analogs have been widely used in NETs for control of hormonal syndromes and are currently under evaluation for their antiproliferative activity. Here, we present a case of NET of the lung, for which we achieved long-term disease control with a treatment comprising the somatostatin analog lanreotide Autogel(®) in a patient with limited therapeutic options due to considerable comorbidity, while preserving his quality of life.

  13. Intravascular placement of metallic coils as lung tumor markers for CyberKnife stereotactic radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Karaman, Kutlay; Dokdok, A. Murat; Karadeniz, Okatay; Ceylan, Cemile; Engin, Kayihan [Anadolu Medical Center, Kocaeli (Turkey)

    2015-06-15

    To present our experience with placing endovascular coils in pulmonary arteries used as a fiducial marker for CyberKnife therapy and to describe the technical details and complications of the procedure. Between June 2005 and September 2013, 163 patients with primary or secondary lung malignancies, referred for fiducial placement for stereotactic radiosurgery, were retrospectively reviewed. Fourteen patients (9 men, 5 women; mean age, 70 years) with a history of pneumonectomy (n = 3), lobectomy (n = 3) or with severe cardiopulmonary co-morbidity (n = 8) underwent coil (fiducial marker) placement. Pushable or detachable platinum micro coils (n = 49) 2-3 mm in size were inserted through coaxial microcatheters into a small distal pulmonary artery in the vicinity of the tumor under biplane angiography/fluoroscopy guidance. Forty nine coils with a median number of 3 coils per tumor were placed with a mean tumor-coil distance of 2.7 cm. Forty three (87.7%) of 49 coils were successfully used as fiducial markers. Two coils could not be used due to a larger tumor-coil distance (> 50 mm). Four coils were in an acceptable position but their non-coiling shape precluded tumor tracking for CyberKnife treatment. No major complications needing further medication other than nominal therapy, hospitalization more than one night or permanent adverse sequale were observed. Endovascular placement of coil as a fiducial marker is safe and feasible during CyberKnife therapy, and might be an option for the patients in which percutaneous transthoracic fiducial placement might be risky.

  14. Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor.

    Science.gov (United States)

    Farma, Jeffrey M; Puhlmann, Markus; Soriano, Perry A; Cox, Derrick; Paciotti, Giulio F; Tamarkin, Lawrence; Alexander, H Richard

    2007-06-01

    Tumor necrosis factor (TNF) causes regression of advanced cancers when used in isolation perfusion with melphalan; evidence suggests these effects are mediated via selective yet uncharacterized actions on tumor neovasculature. A novel derivative, colloidal gold bound TNF (cAu-TNF) has been shown to have similar antitumor effects as native TNF with less systemic toxicity in mice. These studies were done to determine their effects on tumor neovasculature, using in vivo video microscopy. Female C57BL/6 mice bearing 20 mm(2) MC38 or LLC tumors that are TNF sensitive and resistant tumors, respectively, had dorsal skinfold chambers implanted. The rate of interstitial accumulation of Texas red fluorescently labeled albumin in tumor and normal vasculature was measured after intravenous TNF, cAu-TNF or PBS. Changes in interstitial fluorescent intensity over time were quantified as a reflection of alterations in vascular permeability. MC38 bearing mice treated with TNF or cAu-TNF demonstrated a rapid, selective and significant increase in tracer accumulation in areas of neovasculature compared to those of normal vasculature. Experiments in LLC tumor bearing mice showed similar results. Monoclonal antibody against tissue factor partially abrogated the effects of TNF on MC38 neovasculature. These data provide direct evidence that TNF and cAu-TNF selectively and rapidly alter permeability in tumor neovasculature; a phenomenon that may be exploited to enhance selective delivery of chemotherapeutics to tumor.

  15. Tumor Expression of the Carcinoembryonic Antigen Correlates with High Mitotic Activity and Cell Pleomorphism Index in Lung Carcinoma

    Directory of Open Access Journals (Sweden)

    Rancés Blanco

    2013-01-01

    Full Text Available At present, some research efforts are focusing on the evaluation of a variety of tumor associated antigens (TAAs for a better understanding of tumor biology and genetics of lung tumors. For this reason, we evaluated the tissue expression of carcinoembryonic antigen (CEA and ior C2 (a cell surface O-linked glycoprotein carbohydrate chain TAA in lung carcinomas, as well as its correlation with a variety of clinicopathological features. The tissue expression of CEA was evidenced in 22/43 (51.16% lung carcinomas and it was correlated with mitotic activity, cell pleomorphism indexes, and age of patients. The expression of ior C2 was observed in 15/43 (34.88% tumors but no correlation with the clinicopathological features mentioned above was obtained. No correlation between both CEA and ior C2 antigens expression and the overall survival (OS of non-small-cell lung cancer patients was also observed. However, CEA-negative patients displayed higher OS rates as compared with positive ones (69.74 versus 58.26 months. Our results seem to be in agreement with the role of CEA expression in tumor cell proliferation, inhibition of cell polarizations and tissue architecture distortion. The significance of ior C2 antigen in these malignancies and it potential use in diagnosis, prognosis, and/or immunotherapy must be reevaluated.

  16. Application of a spring-dashpot system to clinical lung tumor motion data

    CERN Document Server

    Ackerley, E J; Wilson, P L; Berbeco, R I; Meyer, J

    2012-01-01

    A spring-dashpot system based on the Voigt model was developed to model the correlation between abdominal respiratory motion and tumor motion during lung radiotherapy. The model was applied to clinical data comprising 52 treatment beams from 10 patients, treated on the Mitsubishi Real-Time Radiation Therapy system, Sapporo, Japan. In Stage 1, model parameters were optimized for individual patients and beams to determine reference values and to investigate how well the model can describe the data. In Stage 2, for each patient the optimal parameters determined for a single beam were applied to data from other beams to investigate whether a beam-specific set of model parameters is sufficient to model tumor motion over a course of treatment. In Stage 1 the baseline root mean square (RMS) residual error for all individually-optimized beam data was 0.90 plus or minus 0.40 mm. In Stage 2, patient-specific model parameters based on a single beam were found to model the tumor position closely, even for irregular beam ...

  17. Marker-free lung tumor trajectory estimation from a cone beam CT sinogram

    Science.gov (United States)

    Hugo, Geoffrey D.; Liang, Jian; Yan, Di

    2010-05-01

    An algorithm was developed to estimate the 3D lung tumor position using the projection data forming a cone beam CT sinogram and a template registration method. A pre-existing respiration-correlated CT image was used to generate templates of the target, which were then registered to the individual cone beam CT projections, and estimates of the target position were made for each projection. The registration search region was constrained based on knowledge of the mean tumor position during the cone beam CT scan acquisition. Several template registration algorithms were compared, including correlation coefficient and robust methods such as block correlation, robust correlation coefficient and robust gradient correlation. Robust registration metrics were found to be less sensitive to occlusions such as overlying tissue and the treatment couch. The mean accuracy of the position estimation was 1.4 mm in phantom with a robust registration algorithm. In two research subjects with peripheral tumors, the mean position and mean target excursion were estimated to within 2.0 mm compared to the results obtained with a '4D' registration of 4D image volumes.

  18. Bone marrow-derived dendritic cells pulsed with tumor lysates induce anti-tumor immunity against gastric cancer ex vivo

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    AIM: To investigate whether bone marrow-derived denritic cells pulsed with tumor lysates induce immunity against gastric cancer ex vivo. METHODS: c-kit+ hematopoietic progenitor cells were magnetically isolated with a MiniMACS separator from BALB/c mice bone marrow cells. These cells were cultured with cytokines GM-CSF, IL-4, and TNFα to induce their maturation. They were analysed by morphological observation, phenotype analysis, and mixed lymphocyte reaction (MLR). Bone marrow-derived DCs (BM-DCs) were pulsed with tumor cell lysate obtained by rapid freezing and thawing at a 1:3 DC:tumor cell ratio. Finally, cytotoxic T lymphocyte (CTL) activity and interferon gamma (IFNy) secretion was evaluated ex vivo.RESULTS: c-kit+ hematopoietic progenitor cells from mice bone marrow cells cultured with cytokines for 8 d showed the character of typical mature DCs. Norphologically, observed by light microscope, these cells were large with oval or irregularly shaped nuclei and with many small dendrites. Phenotypically, FACS analysis showed that they expressed.high levels of Ia, DEC-205, CD11b, CD80 and CD86 antigen, moderate levels of CD40, and negative for F4/80. Functionally, these ceils gained the capacity to stimulate allogeneic T cells in MLR assay. However, immature DCs cultured with cytokines for 5 d did not have typical DCs phenotypic markers and could not stimulate allogeneic T cells. Ex vivo primed T cells with SGC-7901 tumor cell lysate-pulsed (TP) DCs were able to induce effective CTL activity against SGC-7901 tumor cells (E:T = 100:1, 69.55% ± 6.05% specific lysis), but not B16 tumor cells, and produced higher levels of IFNγ, when stimulated with SGC-7901 tumor cells but not when stimulated with B16 tumor cells (1575.31 ± 60.25 pg/mL in SGC-7901 group vs 164.11 ± 18.52 pg/mL in B16 group, P < 0.01).CONCLUSION: BM-derived DCs pulsed with tumor lysates can induce anti-tumor immunity specific to gastric cancer ex vivo.

  19. Immunophenotypic features of metastatic lymph node tumors to predict recurrence in N2 lung squamous cell carcinoma

    Science.gov (United States)

    Matsuwaki, Rie; Ishii, Genichiro; Zenke, Yoshitaka; Neri, Shinya; Aokage, Keiju; Hishida, Tomoyuki; Yoshida, Junji; Fujii, Satoshi; Kondo, Haruhiko; Goya, Tomoyuki; Nagai, Kanji; Ochiai, Atsushi

    2014-01-01

    Patients with mediastinal lymph node metastasis (N2) in squamous cell carcinoma (SqCC) of the lung have poor prognosis after surgical resection of the primary tumor. The aim of this study was to clarify predictive factors of the recurrence of pathological lung SqCC with N2 focusing on the biological characteristics of both cancer cells and cancer-associated fibroblasts (CAFs) in primary and metastatic lymph node tumors. We selected 64 patients with pathological primary lung N2 SqCC who underwent surgical complete resection and investigated the expressions of four epithelial–mesenchymal transition-related markers (caveolin, clusterin, E-cadherin, ZEB2), three cancer stem cell-related markers (ALDH-1, CD44 variant6, podoplanin) of cancer cells, and four markers of CAFs (caveolin, CD90, clusterin, podoplanin) in both primary and matched metastatic lymph node tumors in the N2 area. In the primary tumors, the expressions of all the examined molecules were not related to recurrence. However, in the metastatic lymph node tumors, high clusterin and ZEB2 expressions in the cancer cells and high podoplanin expression in the CAFs were significantly correlated with recurrence (P = 0.03, 0.04, and 0.007, respectively). In a multivariate analysis, only podoplanin expression in the CAFs in metastatic lymph node tumors was identified as a significantly independent predictive factor of recurrence (P = 0.03). Our study indicated that the immunophenotypes of both cancer cells and CAFs in metastatic lymph node tumors, but not primary tumors, provide useful information for predicting the recurrence of pathological N2 lung SqCC. PMID:24814677

  20. Fibroblasts weaken the anti-tumor effect of gefitinib on co-cultured non-small cell lung cancer cells

    Institute of Scientific and Technical Information of China (English)

    Yong Xiao; Wang Peiqin; Jiang Tao; Yu Wenchen; Shang Yan; Han Yiping; Zhang Pingping

    2014-01-01

    Background Non-small cell lung cancer (NSCLC) is the most common lung malignancy worldwide.The metastatic potential of NSCLC cells has been shown to be associated with the tumor microenvironment,which consists of tumor cells,stroma,blood vessels,immune infiltrates and the extracellular matrix.Fibroblasts can produce numerous extraceilular matrix molecules and growth factors.Gefitinib has been evaluated as a first-line treatment in selected patients,and it has shown favorable efficacy especially in NSCLC,but it is not effective for everyone.Methods In this study,we examined the antitumor activity of gefitinib on lung fibroblasts co-cultured of lung cancer cells.A series of co-culture experiments that employed cell counting kit-8 (CCK8),transwells,real-time polymerase chain reaction (RT-PCR) and Western blotting with HFL-1 fibroblasts and A549 human lung carcinoma cells were performed to learn more about tumor cell proliferation,migration and invasion; and to determine any change of epithelial mesenchymal transition (EMT)-associated tumor markers vimentin,matrix metallopro-teinase 2 (MMP2) and chemotaxis cytokines receptor 4 (CXCR4) mRNA levels.Results A549 cell proliferation in the presence of HFL-1 cells was not significantly increased compared with A549 cells alone,but A549 cell spheroid body formation was increased after co-culture,and treatment with gefitinib increased further.Our study also revealed that fibroblasts attenuated the lung cancer cell inhibition ratio of migration and invasion after gefitinib treatment in vitro.To further study this mechanism,RT-PCR analysis showed that vimentin,MMP2 and CXCR4 mRNA levels were more highly expressed in the lung cancer cells after co-culture,but did not obviously decrease compared with the control cells following gefitinib treatment.This suggests the mechanism by which fibroblasts attenuate gefitinib-induced expression of EMT-associated tumor markers.Finally,our results demonstrated that co-culture with A549 lung

  1. Aberrant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas

    Science.gov (United States)

    Luo, Susan Y.; Sit, Ko-Yung; Sihoe, Alan D.L.; Suen, Wai-Sing; Au, Wing-Kuk; Tang, Ximing; Ma, Edmond S.K.; Chan, Wai-Kong; Wistuba, Ignacio I.; Minna, John D.; Tsao, George S.W.; Lam, David C.L.

    2015-01-01

    Background Large tumor suppressor 2 (LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer. The aim of this study is to explore the association of aberrant LATS2 expression with EGFR mutation and survival in lung adenocarcinoma (AD), and the effects of LATS2 silencing in both lung AD cell lines. Methods LATS2 mRNA and protein expression in resected lung AD were correlated with demographic characteristics, EGFR mutation and survival. LATS2-specific siRNA was transfected into four EGFR wild-type (WT) and three EGFR mutant AD cell lines and the changes in LATS2 expression and relevant signaling molecules before and after LATS2 knockdown were assayed. Results Fifty resected lung AD were included (M:F = 23:27, smokers:non-smokers = 19:31, EGFR mutant:wild-type = 21:29) with LATS2 mRNA levels showed no significant difference between gender, age, smoking and pathological stages while LATS2 immunohistochemical staining on an independent set of 79 lung AD showed similar trend. LATS2 mRNA level was found to be a significant independent predictor for survival status (disease-free survival RR = 0.217; p = 0.003; Overall survival RR = 0.238; p = 0.036). siRNA-mediated suppression of LATS2 expression resulted in augmentation of ERK phosphorylation in EGFR wild-type AD cell lines with high basal LATS2 expression, discriminatory modulation of Akt signaling between EGFR wild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baseline p53 levels. Conclusions LATS2 expression level is predictive of survival in patients with resected lung AD. LATS2 may modulate and contribute to tumor growth via different signaling pathways in EGFR mutant and wild-type tumors. PMID:24976335

  2. INDUCTION OF DNA ADDUCTS, TUMORS, AND KI-RAS ONCOGENE MUTATIONS IN STRAIN A/J MOUSE LUNG BY IP. ADMINISTRATION OF DIBENZ[A,H]ANTHRACENE

    Science.gov (United States)

    Induction of DNA adducts, tumors, and Ki-ras oncogene mutations in strain AlJ mouse lung by ip. administration of dibenz[a,h]anthracene Previous studies of polycyclic aromatic hydrocarbon (P AH) induced lung tumors in the strain NJ mouse model system have demonstrated qua...

  3. [Using 3.0 T MR to dynamically observe ablated lung tumors after percutaneous cryotherapy therapy].

    Science.gov (United States)

    Li, J; Qu, J R; Zhang, H K; Xiao, J C; Jiang, L N; Zhao, Y; Li, H L

    2016-09-20

    Objective: To initially explore MRI features and its changing trends including of lung tumors after Argon-Helium cryoablation therapy, and enhance the recognition of MR findings of lung tumors postcryoablation. Methods: Twenty-three cases of patients with twenty six nodules of pulmonary malignance who received Argon-Helium cryoablation therapy in Henan Cancer Hospital from July 2014 to January 2016 were enrolled.All patients underwent unenhanced and dynamic contrast-enhanced MRI scans at pre-and 1-day, 1-week, 1-, 3-, 6-, 12-month postcryoablation. Two radiologists independently reviewed MRI images, signal intensity in the ablated zone on T1WI and T2WI were assessed by a 5-point scale.The changing trends of size and signal intensity with time were showed by time-maximum diameter and time-score curve.Time-signal intensity curves based on dynamic enhanced sequence were also performed. Results: Typical MRI findings includes: heterogeneous signal intensity on both T1WI and T2WI at 1-day postcryoablation(26/26, 100%). Hyper-intense on T1WI(22/26, 84.6%) and T2WI(17/26, 65.4%) with a hypo-intense rim at 1-week postcryoablation.Decreasing signal intensity on T1WI(17/26, 65.4%) and increasing signal intensity on T2WI(22/26, 84.6%) at 1-month.Signal intensity declined to the level of muscle on both T1WI(18/26, 69.2%) and T2WI(19/26, 73.1%) at 3-month, nineteen ablated zone turned into patchy shape(19/26, 73.1%). The maximum diameter was largest at 1-day and gradually shrunk with time. The mean score value toped at 1-week and gradually decreased. A straight line type without definite enhancement was found from 1-day to 1-month postcryoablation, an inflow curve with a mild delayed enhancement was seen from 3- to 12- month. Totally 4 recurrence (4/26, 15.4%) all occurred at 3-month and were lack of a complete hypo-intense rim at 1-week postcryoablation. Conclusion: MRI findings of lung tumors postcryoablation are characteristic, a complete hypo-intense rim at 1-week is helpful

  4. Paraneoplastic Galactorrhea in Childhood T-ALL: An Evaluation of Tumor-derived Prolactin.

    Science.gov (United States)

    Grimes, Allison; Mirkheshti, Nooshin; Chatterjee, Bandana; Tomlinson, Gail; Assanasen, Chatchawin

    2017-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) comprises 15% of childhood leukemia. Although multiagent pulse chemotherapy has improved event-free survival in recent decades, the lack of reliable prognosticators and high rate of relapse remain a challenge. Described is a novel discovery of tumor-derived hyperprolactinemia in childhood T-ALL through a case associated with paraneoplastic galactorrhea. Prolactin production by tumor cells, although a rare phenomenon, is previously demonstrated in several adult cancers and 2 pediatric malignancies with unknown implications. This is the first report demonstrating tumor-derived prolactin in pediatric T-ALL and offers potential as a disease marker and therapeutic drug target.

  5. MicroRNA-2 suppresses Lewis lung cancer cells proliferation, invasion, and migration in tumor-bearing mice.

    Science.gov (United States)

    Wang, Xu; Wang, Ping-fan; Yuan, Wu-ying

    2014-12-01

    We sought to find the biological effects of MicroRNA-2 in suppressing Lewis lung cancer cells proliferation, invasion, and migration in tumor-bearing mice. MicroRNA-2 was transfected into Lewis lung cancer cells of tumor-bearing mice by gene transient transfection technique and these Lewis-microRNA-2 cells were taken as MicroRNA transfection group. At the same time, Lewis cells were taken as control group and Lewis-EGFP cells as empty plasmid group. The growth curves of cells in the three groups were drawn by manual counting method, while the invasiveness of cells in the three groups was compared by transmembrane cell invasion assay. The three kinds of cells were seeded into BALB/Nude SPF level nude mice to detect the formation of tumors and the number of metastases by Xenograft experiments. The result showed that the MicroRNA transfection group has the lowest vitality of cells proliferation, fewest cells passed through matrigel matrix protein layer, and lowest cells invasive rate. Mice with Lewis-microRNA-2 cells apparently had a longer time of tumor formation. The average tumor mass and the number of metastases were significantly lower than the other two groups. MicroRNA-2 significantly inhibited Lewis lung cancer cell proliferation, invasion and migration in tumor-bearing mice, which may be associated with the regulation of target genes PLK1 and TGF-β.

  6. Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram

    Science.gov (United States)

    Duan, Xiaopin; Xiao, Jisheng; Yin, Qi; Zhang, Zhiwen; Yu, Haijun; Mao, Shirui; Li, Yaping

    2014-03-01

    Metastasis, the main cause of cancer related deaths, remains the greatest challenge in cancer treatment. Disulfiram (DSF), which has multi-targeted anti-tumor activity, was encapsulated into redox-sensitive shell crosslinked micelles to achieve intracellular targeted delivery and finally inhibit tumor growth and metastasis. The crosslinked micelles demonstrated good stability in circulation and specifically released DSF under a reductive environment that mimicked the intracellular conditions of tumor cells. As a result, the DSF-loaded redox-sensitive shell crosslinked micelles (DCMs) dramatically inhibited cell proliferation, induced cell apoptosis and suppressed cell invasion, as well as impairing tube formation of HMEC-1 cells. In addition, the DCMs could accumulate in tumor tissue and stay there for a long time, thereby causing significant inhibition of 4T1 tumor growth and marked prevention in lung metastasis of 4T1 tumors. These results suggested that DCMs could be a promising delivery system in inhibiting the growth and metastasis of breast cancer.

  7. Respiratory Failure due to Possible Donor-Derived Sporothrix schenckii Infection in a Lung Transplant Recipient.

    Science.gov (United States)

    Bahr, Nathan C; Janssen, Katherine; Billings, Joanne; Loor, Gabriel; Green, Jaime S

    2015-01-01

    Background. De novo and donor-derived invasive fungal infections (IFIs) contribute to morbidity and mortality in solid organ transplant (SOT) recipients. Reporting of donor-derived IFIs (DDIFIs) to the Organ Procurement Transplant Network has been mandated since 2005. Prior to that time no systematic monitoring of DDIFIs occurred in the United States. Case Presentation. We report a case of primary graft dysfunction in a 49-year-old male lung transplant recipient with diffuse patchy bilateral infiltrates likely related to pulmonary Sporothrix schenckii infection. The organism was isolated from a bronchoalveolar lavage on the second day after transplantation. Clinical and radiographic responses occurred after initiation of amphotericin B lipid formulation. Conclusion. We believe that this was likely a donor-derived infection given the early timing of the Sporothrix isolation after transplant in a bilateral single lung transplant recipient. This is the first case report of sporotrichosis in a lung transplant recipient. Our patient responded well to amphotericin induction therapy followed by maintenance therapy with itraconazole. The implications of donor-derived fungal infections and Sporothrix in transplant recipients are reviewed. Early recognition and management of these fungi are essential in improving outcomes.

  8. Respiratory Failure due to Possible Donor-Derived Sporothrix schenckii Infection in a Lung Transplant Recipient

    Directory of Open Access Journals (Sweden)

    Nathan C. Bahr

    2015-01-01

    Full Text Available Background. De novo and donor-derived invasive fungal infections (IFIs contribute to morbidity and mortality in solid organ transplant (SOT recipients. Reporting of donor-derived IFIs (DDIFIs to the Organ Procurement Transplant Network has been mandated since 2005. Prior to that time no systematic monitoring of DDIFIs occurred in the United States. Case Presentation. We report a case of primary graft dysfunction in a 49-year-old male lung transplant recipient with diffuse patchy bilateral infiltrates likely related to pulmonary Sporothrix schenckii infection. The organism was isolated from a bronchoalveolar lavage on the second day after transplantation. Clinical and radiographic responses occurred after initiation of amphotericin B lipid formulation. Conclusion. We believe that this was likely a donor-derived infection given the early timing of the Sporothrix isolation after transplant in a bilateral single lung transplant recipient. This is the first case report of sporotrichosis in a lung transplant recipient. Our patient responded well to amphotericin induction therapy followed by maintenance therapy with itraconazole. The implications of donor-derived fungal infections and Sporothrix in transplant recipients are reviewed. Early recognition and management of these fungi are essential in improving outcomes.

  9. Differential effects of drugs targeting cancer stem cell (CSC and non-CSC populations on lung primary tumors and metastasis.

    Directory of Open Access Journals (Sweden)

    Leyre Larzabal

    Full Text Available Cancer stem cells (CSCs are thought to be responsible for tumor initiation and recurrence after chemotherapy. Targeting CSCs and non-CSCs with specific compounds may be an effective approach to reduce lung cancer growth and metastasis. The aim of this study was to investigate the effect of salinomycin, a selective inhibitor of CSCs, with or without combination with paclitaxel, in a metastatic model. To evaluate the effect of these drugs in metastasis and tumor microenvironment we took advantage of the immunocompetent and highly metastatic LLC mouse model. Aldefluor assays were used to analyze the ALDH+/- populations in murine LLC and human H460 and H1299 lung cancer cells. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the H460 and H1299 cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules (p<0.05, whereas salinomycin had no effect on primary tumors but reduced lung metastasis (p<0.05. Combination of both drugs did not improve the effect of single therapies. ALDH1A1, SOX2, CXCR4 and SDF-1 mRNA levels were higher in metastatic lesions than in primary tumors, and were significantly elevated in both locations by paclitaxel treatment. On the contrary, such levels were reduced (or in some cases did not change when mice were administered with salinomycin. The number of F4/80+ and CD11b+ cells was also reduced upon administration of both drugs, but particularly in metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. In contrast, paclitaxel (although reducing primary tumor growth promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster

  10. Down-regulation of cytoplasmic PLZF correlates with high tumor grade and tumor aggression in non-small cell lung carcinoma.

    Science.gov (United States)

    Xiao, Guang-Qian; Li, Faqian; Findeis-Hosey, Jennifer; Hyrien, Ollivier; Unger, Pamela D; Xiao, Lu; Dunne, Richard; Kim, Eric S; Yang, Qi; McMahon, Loralee; Burstein, David E

    2015-11-01

    There are currently no effective prognostic biomarkers for lung cancer. Promyelocytic leukemia zinc finger (PLZF), a transcriptional repressor, has a role in cell cycle progression and tumorigenicity in various cancers. The expression and value of PLZF in lung carcinoma, particularly in the subclass of non-small cell lung carcinoma (NSCLC), has not been studied. Our aim was to study the immunohistochemical expression of PLZF in lung adenocarcinoma and squamous cell carcinoma and correlate the alteration of PLZF expression with tumor differentiation, lymph node metastasis, tumor stage, and overall survival. A total of 296 NSCLCs being mounted on tissue microarray (181 adenocarcinomas and 91 squamous cell carcinomas) were investigated. Moderate to strong expression of PLZF was found in the cytoplasm of all the nonneoplastic respiratory epithelium and most (89.9%) well-differentiated adenocarcinoma. The proportions of moderately differentiated, poorly differentiated adenocarcinoma, and paired lymph node adenocarcinoma metastases that demonstrated negative or only weak PLZF reactivity were 75.6%, 97.2%, and 89.9%, respectively. The expression of PLZF in squamous cell carcinoma was mostly weak or absent and significantly lower than that in adenocarcinoma of the same grade (P carcinoma and adenocarcinoma (P < .0001). Down-regulation of PLZF also correlated with higher tumor stage and shorter overall survival (P < .05). These results support a prognostic value for loss of cytoplasmic PLZF expression in the stratification of NSCLC and a possible role of cytoplasmic shift and down-regulation of PLZF in the pathogenesis of NSCLC.

  11. A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy.

    Science.gov (United States)

    Gurpinar, Evrim; Grizzle, William E; Shacka, John J; Mader, Burton J; Li, Nan; Piazza, Nicholas A; Russo, Suzanne; Keeton, Adam B; Piazza, Gary A

    2013-05-01

    Nonsteroidal anti-inflammatory drugs such as sulindac sulfide have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from COX inhibition limit their use in cancer therapy. We recently described a N,N-dimethylethyl amine derivative of sulindac sulfide, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth-inhibitory activity. Here, we studied the basis for the growth-inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2 to 5 μmol/L compared with 44 to 52 μmol/L for sulindac sulfide. SSA also suppressed DNA synthesis and caused a G0-G1 cell-cycle arrest. SSA-induced cell death was associated with characteristics of autophagy, but significant caspase activation or PARP cleavage was not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, whereas pan-caspase inhibitor ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA inhibits lung tumor cell growth by a mechanism involving autophagy induction through the suppression of Akt/mTOR signaling. This unique mechanism of action, along with its increased potency and lack of COX inhibition, supports the development of SSA or related analogs for the prevention and/or treatment of lung cancer.

  12. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient.

    Directory of Open Access Journals (Sweden)

    Ninette Amariglio

    2009-02-01

    Full Text Available BACKGROUND: Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells. METHODS AND FINDINGS: A boy with ataxia telangiectasia (AT was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors. CONCLUSIONS: This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

  13. Multiple Tumor Types May Originate from Bone Marrow-Derived Cells

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    Chunfang Liu

    2006-09-01

    Full Text Available It was believed that tumors originated from the transformation of their tissue-specific stem cells. However, bone marrow-derived cells (BMDCs, which possess an unexpected degree of plasticity and often reside in other tissues, might also represent a potential source of malignancy. To study whether BMDCs play a role in the source of other tumors, BMDCs from mice were treated with 3-methycholanthrene until malignant transformation was achieved. Here we show that transformed BMDCs could form many tumor types, including epithelial tumors, neural tumors, muscular tumors, tumors of fibroblasts, blood vessel endothelial tumors, and tumors of poor differentiation in vivo. Moreover, a single transformed BMDC has the ability to self-renew, differentiate spontaneously into various types of tumor cells in vitro, express markers associated with multipotency, and form teratoma in vivo. These data suggest that multipotent cancer stem cells seemed to originate from transformed BMDCs. Conclusively, these findings reveal that BMDCs might be a source of many tumor types, even teratoma. In addition, multipotent cancer stem cells might originate from malignant transformed BMDCs.

  14. Therapeutic efficacy of tumor-derived heat shock protein 70 immunotherapy combining interleukin-2 on tumor-bearing mice

    Institute of Scientific and Technical Information of China (English)

    傅庆国; 孟凡东; 沈晓东; 郭仁宣

    2003-01-01

    Objective To investigate the therapeutic efficacy of compound immunotherapy of tumor-derived heat shock protein 70 (HSP70) and interleukin-2 (IL-2) on tumor-bearing mice, and to provide reference for translating this strategy to human cancer. Methods Cell culture, techniques for protein extraction and purification, SDS-PAGE, Wes tern blot and capillary electrophoresis for HSP70 detection and purity analysis, and animal experiments were used. Mice were treated with HSP70 5 or 10 μg and IL-2 50 kU, 100 kU or 2 kU (maintaining dosage) at pre viously designated intervals. Results Both the mono-administration of either HSP70 or IL-2 and the compound immunoth erapy of HSP70 and IL-2 obviously inhibited the growth of the implanted tumor and prolonged the life span of the mice to different extents. However, long periods of tumor-free suvival (over 90 days) were demonstrated only in HSP70 10 μg group, HSP70 10 μg-IL-2 50 kU group, and HSP70 10 μg-IL-2 100 kU group (4 0%, 40%, 60% respectively). On the other hand, none of the mice in the rest gr oups achieved long-term survival. Statistical significance was apparent in com parison with the groups without long period survival (P<0.025-0.05). Conclusion Our research revealed that tumor-derived HSP70 immunotherapy was much more effective than IL-2 alone. And in compound immunotherapy, HSP70 was the main factor in delaying or eradicating the tumors. The proper combination of HSP70 and IL-2 (10 μg HSP70 and 100 kU IL-2 in this experimental mouse model) clea rly enhanced the immunotherapy efficacy which indicated that the specific immuno therapy as a main part of tumor immunotherapy assisted by cytokine immunotherapy would be a promising strategy in cancer treatment.

  15. Solitary Lung Tumors and Their Spontaneous Metastasis in Athymic Nude Mice Orthotopically Implanted with Human Non-Small Cell Lung Cancer

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    Takeshi Yamaura

    2000-07-01

    Full Text Available We examined the tumorigenic and metastatic potentials of three human non-small cell lung cancer (NSCLC cell lines. PC-14, A549 or Lu-99 cell lines suspended in Matrigel-containing phosphate-buffered saline were orthotopically implanted into the lungs of nude mice. The formation of a solitary tumor nodule in the lung was observed after the implantation of all cell lines. Intrapulmonary implantation of PC-14 or Lu-99 cells resulted in spontaneous distant metastases. In contrast, A549 cells caused multiple intrapulmonary metastases to the right and left lobes of the lung without producing visible lymphatic metastasis. We also investigated the expression of matrix metal loproteinases (MMPs, urokinase-type plasminogen activator (u-PA, u-PA receptor (u-PAR and c-MET in these cell lines in vitro and in vivo. Reverse transcription polymerase chain reaction (RT-PCR analysis showed that the expression of MMP-2 and membrane-type 1 MMP (MT1-MMP was elevated in PC-14 as compared with the other two cell lines. In contrast, stronger expression of c-METwas observed in A549 than in PC-14 or Lu-99. These results indicate that differential patterns of metastasis of lung cancer might be associated with differential expression of metastasis-associated molecules. Our orthotopic implantation models display clinical features resembling those of NSCLC, may provide a useful basis for lung cancer research.

  16. Effect of Retinoic acid on Platelet-derived Growth Factor and Lung Development in Newborn Rats

    Institute of Scientific and Technical Information of China (English)

    陈红兵; 常立文; 刘汉楚; 容志惠; 祝华平; 张谦慎; 李文斌

    2004-01-01

    Summary: The influence of platelet-derived growth factor (PDGF) on lung development in newborn rats and the effect of retinoic acid (RA) on PDGF in lung development were investigated. Newborn Sprague-Dawley (SD) rats were randomly assigned to two groups: control group and RA group.The rats in RA group was intraperitoneally injected with all trans-retinoic acid (500 μg/kg every day) for consecutive 3 days after birth, while those in the control group were not subjected to intervention, Immunohistochemical assay was performed to locate the expression of PDGF. mRNA levels of PDGF were measured by reverse transcription polymerase chain reaction (RT-PCR) at age of 1, 3, 5, 7, 10, 14, 21 days. The method of radial alveolar counts (RAC) was used to measure the amount of the alveoli of the lungs. It was found that with increasing days, levels of PDGF-A and PDGF-B changed to verying degrees. RA could elevate significantly the expression levels of PDGF A mRNA and protein (P<0.01), but not affect the expression levels of PDGF-B mRNA and pro tein markedly (P>0.05). It is suggested that PDGF might play an important role in lung development. RA can stimulate lung development through increasing the expression levels of PDGF-A mRNA and protein.

  17. An approach of selecting appropriate markers from the primary tumor to enable detection of circulating tumor cells in patients with non-small cell lung cancer.

    Science.gov (United States)

    Warawdekar, Ujjwala M; Sirajuddin, Mohamed M; Pramesh, Conjeevaram S; Mistry, Rajesh C

    2015-01-01

    Circulating tumor cells (CTCs) are rare and difficult to isolate, and require selecting minimal but appropriate markers. The aim of this study was to identify markers in the primary non small cell lung cancer (NSCLC) tissue to guide isolation of CTCs from the peripheral blood of patients with lung cancer. The expression of CK-19, EGFR and MUC-1 was evaluated by RT-PCR in the NSCLC tumor and paired adjacent normal tissues from 27 patients. The normal cytology, and the neoplastic and fibrotic pathology of the tissue were analyzed by histochemistry. The expression of the markers was analyzed in relation to the stage and grade of disease. Expression analysis showed that 42% of the tumors were positive for CK-19, whereas 85% for both EGFR and MUC-1. Ninety two percent of the tumors expressed any one marker. All (100%) adjacent normal tissues were CK-19 negative, 52% EGFR negative and 44% MUC-1 negative. CK-19 expression was specific to the tumor tissue but it was expressed by only 42% of them, manifesting a need for at least three markers to guide the detection of CTCs isolated from the peripheral blood of NSCLC patients. Histopathology demonstrated that 58% were adenocarcinomas, 35% squamous cell carcinomas and 7% had mixed pathology. This data serves as a prelude and emphasizes the importance of selecting markers expressed in the primary tumor tissue to facilitate and enable enumeration of CTCs.

  18. Bone marrow-derived mesenchymal stem cells protect rats from endotoxin-induced acute lung injury

    Institute of Scientific and Technical Information of China (English)

    LIANG Zhi-xin; SUN Ji-ping; WANG Ping; TIAN Qing; YANG Zhen; CHEN Liang-an

    2011-01-01

    Background Acute lung injury (ALI) is a serious and common condition for which there are currently no specific strategies for treatment.Recent studies have suggested that bone marrow-derived multipotent mesenchymal stem cells (MSCs) may have therapeutic applications in multiple clinical disorders.We explored the biological effects of MSCs during endotoxin-induced ALl and the mechanisms involved.Methods MSCs were isolated from male rat bone marrow and the ALl model was induced by intravenous endotoxin injection.Female rats were sacrificed at 6 hours,24 hours,4 days,1 week and 3 weeks post-injection of MSCs or saline and the lung tissue,bronchoalveolar lavage fluid,and serum were harvested for analysis.We further evaluated the survival of the rats and examined the effects of endotoxin-induced injury on the interaction between alveolar macrophages (AMs) and MSCs in ex vivo.Results There was a significant decrease in numbers of neutrophils in bronchoalveolar lavage fluid (P <0.05),and myeloperoxidase activity in the lung (P<0.01),and of TNF-α and IL-1β in serum (P <0.05) in the MSC treated rats at 4 days.Furthermore,MSC treated rats exhibited improved survival,lower lung injury score,higher concentration of IL-10 in the serum and a reduced hydroxyproline content,but these differences were not statistically significant.Moreover,co-cultures of MSCs and AMs had significantly reduced levels of TNF-α,IL-1β and macrophage inflammatory protein (MIP)-1α and significantly increased levels of IL-10 (P<0.05) in the culture supernatants.Conclusions Treatment with intravenous injection of bone marrow-derived MSCs have beneficial effects on endotoxin-induced ALl in rats.The beneficial effect might be achieved through the engraftment of differentiated MSCs in the lungs and appears derive more from their capacity to secrete soluble factors that modulate immune responses.

  19. Two different types of carcinoid tumors of the lung: immunohistochemical and ultrastructural investigation and their histogenetic consideration.

    Science.gov (United States)

    Min, Kyung-Whan

    2013-02-01

    Carcinoid tumors have been an interesting clinical and pathological entity for pathologists because of their unique histopathologic pattern of "Zellballen" (cell ball) and the hormones they produce demonstrable by histochemical and biochemical methods, including immunohistochemistry, and the presence of cytoplasmic dense-core particles demonstrable by electron microscopy. Since carcinoid tumors were established as an entity more than a century ago by Oberndorfer, who was credited with coining the term "carcinoid," meaning carcinoma-like tumors, tumors presenting with similar characteristics have been reported in most of parenchymal organs, including lungs. Carcinoid tumors in the lungs usually occur as bronchocentric tumors and present with typical histopathologic characteristics of carcinoid tumors, but they may present with significant variation in their cellular compositions, in contrast to the midgut carcinoid tumors. In the latter, tumor cells are quite similar to enterochromaffin granule containing crypt cells, which are regarded as their progenitor cells. Currently, a similar histogenetic explanation is applied to all carcinoid tumors occurring elsewhere. The bronchus is one of the most common anatomic sites in which the carcinoid tumors occur. However, bronchial carcinoid tumors differ from the midgut counterparts in microscopic appearance, showing more variability in cellular shape and composition from the classical form of midgut carcinoid tumors. In the lungs, neuroendocrine cells (NEC) are normally found in two different ways. Firstly, they are found as randomly scattered single cells (Kultchitsky cells) similar to enteric counterparts, and, secondly, they are found in aggregates known as "neuroepithelial bodies" (NEB) usually found in the branching point of bronchi. Interestingly, they keep a close anatomic relationship with parasympathetic nerve structures and even form synapses. NEB are usually found in the early stage of fetal development and are

  20. SU-E-J-236: Audiovisual Biofeedback Improves Breath-Hold Lung Tumor Position Reproducibility Measured with 4D MRI

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    Lee, D; Pollock, S; Keall, P [Radiation Physics Laboratory, Sydney Medical School, The University of Sydney, NSW (Australia); Greer, P [School of Mathematical and Physical Sciences, The University of Newcastle, Newcastle, NSW (Australia); Department of Radiation Oncology, Calvary Mater Newcastle, Newcastle, NSW (Australia); Lapuz, C; Ludbrook, J [Department of Radiation Oncology, Calvary Mater Newcastle, Newcastle, NSW (Australia); Kim, T [Radiation Physics Laboratory, Sydney Medical School, The University of Sydney, NSW (Australia); Department of Radiation Oncology, University of Virginia Health System, Charlottesville, VA (United States)

    2015-06-15

    Purpose: Audiovisual biofeedback breath-hold (AVBH) was employed to reproduce tumor position on inhale and exhale breath-holds for 4D tumor information. We hypothesize that lung tumor position will be more consistent using AVBH compared with conventional breath-hold (CBH). Methods: Lung tumor positions were determined for seven lung cancer patients (age: 25 – 74) during to two separate 3T MRI sessions. A breathhold training session was performed prior to the MRI sessions to allow patients to become comfortable with AVBH and their exhale and inhale target positions. CBH and AVBH 4D image datasets were obtained in the first MRI session (pre-treatment) and the second MRI session (midtreatment) within six weeks of the first session. Audio-instruction (MRI: Siemens Skyra) in CBH and verbal-instruction (radiographer) in AVBH were used. A radiation oncologist contoured the lung tumor using Eclipse (Varian Medical Systems); tumor position was quantified as the centroid of the contoured tumor after rigid registration based on vertebral anatomy across two MRI sessions. CBH and AVBH were compared in terms of the reproducibility assessed via (1) the difference between the two exhale positions for the two sessions and the two inhale positions for the sessions. (2) The difference in amplitude (exhale to inhale) between the two sessions. Results: Compared to CBH, AVBH improved the reproducibility of two exhale (or inhale) lung tumor positions relative to each other by 33%, from 6.4±5.3 mm to 4.3±3.0 mm (p=0.005). Compared to CBH, AVBH improved the reproducibility of exhale and inhale amplitude by 66%, from 5.6±5.9 mm to 1.9±1.4 mm (p=0.005). Conclusions: This study demonstrated that audiovisual biofeedback can be utilized for improving the reproducibility of breath-hold lung tumor position. These results are advantageous towards achieving more accurate emerging radiation treatment planning methods, in addition to imaging and treatment modalities utilizing breath

  1. Anti-VEGF-A affects the angiogenic properties of tumor-derived microparticles.

    Science.gov (United States)

    Munster, Michal; Fremder, Ella; Miller, Valeria; Ben-Tsedek, Neta; Davidi, Shiri; Scherer, Stefan J; Shaked, Yuval

    2014-01-01

    Tumor derived microparticles (TMPs) have recently been shown to contribute to tumor re-growth partially by inducing the mobilization and tumor homing of specific bone marrow derived pro-angiogenic cells (BMDCs). Since antiangiogenic drugs block proangiogenic BMDC mobilization and tumor homing, we asked whether TMPs from cells exposed to an antiangiogenic drug may affect BMDC activity and trafficking. Here we show that the level of VEGF-A is reduced in TMPs from EMT/6 breast carcinoma cells exposed to the anti-VEGF-A antibody, B20. Consequently, these TMPs exhibit reduced angiogenic potential as evaluated by a Matrigel plug and Boyden chamber assays. Consistently, BMDC mobilization, tumor angiogenesis, microvessel density and BMDC-colonization in growing tumors are reduced in mice inoculated with TMPs from B20-exposed cells as compared to mice inoculated with control TMPs. Collectively, our results suggest that the neutralization of VEGF-A in cultured tumor cells can block TMP-induced BMDC mobilization and colonization of tumors and hence provide another mechanism of action by which antiangiogenic drugs act to inhibit tumor growth and angiogenesis.

  2. Anti-VEGF-A affects the angiogenic properties of tumor-derived microparticles.

    Directory of Open Access Journals (Sweden)

    Michal Munster

    Full Text Available Tumor derived microparticles (TMPs have recently been shown to contribute to tumor re-growth partially by inducing the mobilization and tumor homing of specific bone marrow derived pro-angiogenic cells (BMDCs. Since antiangiogenic drugs block proangiogenic BMDC mobilization and tumor homing, we asked whether TMPs from cells exposed to an antiangiogenic drug may affect BMDC activity and trafficking. Here we show that the level of VEGF-A is reduced in TMPs from EMT/6 breast carcinoma cells exposed to the anti-VEGF-A antibody, B20. Consequently, these TMPs exhibit reduced angiogenic potential as evaluated by a Matrigel plug and Boyden chamber assays. Consistently, BMDC mobilization, tumor angiogenesis, microvessel density and BMDC-colonization in growing tumors are reduced in mice inoculated with TMPs from B20-exposed cells as compared to mice inoculated with control TMPs. Collectively, our results suggest that the neutralization of VEGF-A in cultured tumor cells can block TMP-induced BMDC mobilization and colonization of tumors and hence provide another mechanism of action by which antiangiogenic drugs act to inhibit tumor growth and angiogenesis.

  3. Tumor-derived exosomes in cancer progression and treatment failure

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    Yu, Shaorong; Cao, Haixia; Shen,Bo; Feng, Jifeng

    2015-01-01

    Exosomes have diameter within the range of 30-100nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materi...

  4. Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications.

    Science.gov (United States)

    Ishiguro, Tatsuya; Ohata, Hirokazu; Sato, Ai; Yamawaki, Kaoru; Enomoto, Takayuki; Okamoto, Koji

    2017-03-01

    Recently, many types of in vitro 3-D culture systems have been developed to recapitulate the in vivo growth conditions of cancer. The cancer 3-D culture methods aim to preserve the biological characteristics of original tumors better than conventional 2-D monolayer cultures, and include tumor-derived organoids, tumor-derived spheroids, organotypic multicellular spheroids, and multicellular tumor spheroids. The 3-D culture methods differ in terms of cancer cell sources, protocols for cell handling, and the required time intervals. Tumor-derived spheroids are unique because they are purposed for the enrichment of cancer stem cells (CSCs) or cells with stem cell-related characteristics. These spheroids are grown as floating spheres and have been used as surrogate systems to evaluate the CSC-related characteristics of solid tumors in vitro. Because eradication of CSCs is likely to be of clinical importance due to their association with the malignant nature of cancer cells, such as tumorigenicity or chemoresistance, the investigation of tumor-derived spheroids may provide invaluable clues to fight against cancer. Spheroid cultures have been established from cancers including glioma, breast, colon, ovary, and prostate cancers, and their biological and biochemical characteristics have been investigated by many research groups. In addition to the investigation of CSCs, tumor-derived spheroids may prove to be instrumental for a high-throughput screening platform or for the cultivation of CSC-related tumor cells found in the circulation or body fluids. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  5. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer.

    Science.gov (United States)

    Sharma, Sherven; Yang, Seok-Chul; Zhu, Li; Reckamp, Karen; Gardner, Brian; Baratelli, Felicita; Huang, Min; Batra, Raj K; Dubinett, Steven M

    2005-06-15

    Cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 underlie an immunosuppressive network that is important in the pathogenesis of non-small cell lung cancer. CD4+ CD25+ T regulatory (Treg) cells play an important role in maintenance of immunologic self-tolerance. CD4+ CD25+ Treg cell activities increase in lung cancer and appear to play a role in suppressing antitumor immune responses. Definition of the pathways controlling Treg cell activities will enhance our understanding of limitation of the host antitumor immune responses. Tumor-derived COX-2/PGE2 induced expression of the Treg cell-specific transcription factor, Foxp3, and increased Treg cell activity. Assessment of E-prostanoid (EP) receptor requirements revealed that PGE2-mediated induction of Treg cell Foxp3 gene expression was significantly reduced in the absence of the EP4 receptor and ablated in the absence of the EP2 receptor expression. In vivo, COX-2 inhibition reduced Treg cell frequency and activity, attenuated Foxp3 expression in tumor-infiltrating lymphocytes, and decreased tumor burden. Transfer of Treg cells or administration of PGE2 to mice receiving COX-2 inhibitors reversed these effects. We conclude that inhibition of COX-2/PGE2 suppresses Treg cell activity and enhances antitumor responses.

  6. Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation.

    Science.gov (United States)

    Hu, Yue; Xiong, Liu-Lin; Zhang, Piao; Wang, Ting-Hua

    2017-01-01

    Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway.

  7. Cancer-Associated Fibroblasts from lung tumors maintain their immuno-suppressive abilities after high-dose irradiation

    Directory of Open Access Journals (Sweden)

    Laia eGorchs

    2015-05-01

    Full Text Available Accumulating evidence supports the notion that high-dose (>5 Gy radiotherapy (RT regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study we have investigated the effects of high-dose irradiation (HD-RT on the immunomodulating functions of cancer-associated fibroblasts (CAFs. Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays and T-cell cytokine production. Additionally, CAF-secreted immuno-regulatory factors were studied by multiplex protein arrays, ELISAs and by LC-MS/MS proteomics. In all functional assays we observed a powerful immuno-suppressive effect exerted by CAF-conditioned medium on activated T-cells (p>0,001, and this effect was sustained after a single radiation dose of 18 Gy. Relevant immuno-suppressive molecules such as prostaglandin E2, interleukin-6 and -10, or transforming growth factor-β were found in CAF conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immuno-suppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.

  8. Newly synthesized podophyllotoxin derivative, LJ12, induces apoptosis and mitotic catastrophe in non-small cell lung cancer cells in vitro.

    Science.gov (United States)

    Hui, Ling; Sang, Chunyan; Wang, Donghong; Wang, Xiaohui; Wang, Meiliang; Jia, Qinghua; Ma, Mingren; Chen, Shiwu

    2016-01-01

    Deoxypodophyllotoxin (DPT), an active compound isolated from a number of herbs and used in traditional medicine, has been reported to exhibit promising anti‑tumor activity. A newly synthesized derivative, N-(1-oxyl‑4'-demethyl-4-deoxyp odophyllic)-L‑methine-4'-piperazine carbamate (LJ12) may have improved antitumor activity and fewer side effects. The present study assessed the effect of LJ12 on cell viability, apoptosis, cell cycle distribution and mitotic catastrophe in A549 human lung cancer cells in vitro. The molecular mechanisms underlying the antitumor activity of LJ12 were also examined. The results demonstrated that LJ12 reduced A549 cell viability in a time‑ and dose‑dependent manner, with a lower half maximal inhibitory concentration of ~0.1 µM, compared with another known DPT derivative, etoposide (10 µM). Flow cytometric analysis showed that LJ12 induced tumor cell arrest at the G2/M phase of the cell cycle. The present study also observed an expected concomitant decrease in the numbers of cells cells in the G0/G1 and S phases. LJ12 was found to upregulate the protein expression levels of Cdc2 and Cyclin B1. Furthermore, LJ12 induced tumor cell apoptosis and the protein expression of B cell lymphoma‑2‑associated X protein, caspase‑3 and p53. The present study also observed the formation of giant, multinucleated cells, indicating that LJ12 induced mitotic catastrophe in the tumor cells. These results indicated that LJ12 has anti‑non‑small cell lung cancer activity in vitro. Further investigations aim to develop LJ12 as a therapeutic agent for the treatment of lung cancer.

  9. Rapid Diagnosis of Lung Tumors, a Feasability Study Using Maldi-Tof Mass Spectrometry.

    Directory of Open Access Journals (Sweden)

    Geoffrey Brioude

    Full Text Available Despite recent advances in imaging and core or endoscopic biopsies, a percentage of patients have a major lung resection without diagnosis. We aimed to assess the feasibility of a rapid tissue preparation/analysis to discriminate cancerous from non-cancerous lung tissue.Fresh sample preparations were analyzed with the Microflex LTTM MALDI-TOF analyzer. Each main reference spectra (MSP was consecutively included in a database. After definitive pathological diagnosis, each MSP was labeled as either cancerous or non-cancerous (normal, inflammatory, infectious nodules. A strategy was constructed based on the number of concordant responses of a mass spectrometry scoring algorithm. A 3-step evaluation included an internal and blind validation of a preliminary database (n = 182 reference spectra from the 100 first patients, followed by validation on a whole cohort database (n = 300 reference spectra from 159 patients. Diagnostic performance indicators were calculated.127 cancerous and 173 non-cancerous samples (144 peripheral biopsies and 29 inflammatory or infectious lesions were processed within 30 minutes after biopsy sampling. At the most discriminatory level, the samples were correctly classified with a sensitivity, specificity and global accuracy of 92.1%, 97.1% and 95%, respectively.The feasibility of rapid MALDI-TOF analysis, coupled with a very simple lung preparation procedure, appears promising and should be tested in several surgical settings where rapid on-site evaluation of abnormal tissue is required. In the operating room, it appears promising in case of tumors with an uncertain preoperative diagnosis and should be tested as a complementary approach to frozen-biopsy analysis.

  10. Deriving cell lines from zebrafish embryos and tumors.

    Science.gov (United States)

    Choorapoikayil, Suma; Overvoorde, John; den Hertog, Jeroen

    2013-09-01

    Over the last two decades the zebrafish has emerged as a powerful model organism in science. The experimental accessibility, the broad range of zebrafish mutants, and the highly conserved genetic and biochemical pathways between zebrafish and mammals lifted zebrafish to become one of the most attractive vertebrate models to study gene function and to model human diseases. Zebrafish cell lines are highly attractive to investigate cell biology and zebrafish cell lines complement the experimental tools that are available already. We established a straightforward method to culture cells from a single zebrafish embryo or a single tumor. Here we describe the generation of fibroblast-like cell lines from wild-type and ptenb(-/-) embryos and an endothelial-like cell line from a tumor of an adult ptena(+/-)ptenb(-/-) zebrafish. This protocol can easily be adapted to establish stable cell lines from any mutant or transgenic zebrafish line and the average time to obtain a pro-stable cell line is 3-5 months.

  11. Stereotactic ablative radiotherapy (SABR) for central lung tumors: Plan quality and long-term clinical outcomes.

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    Tekatli, Hilâl; Senan, Suresh; Dahele, Max; Slotman, Ben J; Verbakel, Wilko F A R

    2015-10-01

    Central lung SABR is less established due to toxicity concerns. We describe plan quality and clinical outcomes for patients treated with VMAT SABR using 8×7.5Gy. We studied 80 consecutive patients with primary NSCLC and PTV ⩽2cm from the proximal bronchial tree (PBT), treated between 2008 and 2013. Dosimetric data were compared with institutional guidelines and study protocols, and long-term clinical outcomes were analyzed. PTV V95% was 60Gy in 96% of patients. Dmax was ⩾60Gy in 40% of patients for PBT, 26.3% for aorta, 55% for heart, and 1.3% for trachea. Esophageal maximum Dmax was 58Gy. Mean lung V5Gy/V20Gy was 21/8%. 54 patients (68%) exceeded RTOG0813 Dmax for ⩾1 organ-at-risk (OAR), with 27 exceeding PBT Dmax. 5 of 78 patients (6.4%) with adequate follow-up information had grade 3 toxicity. Grade 4 toxicity was not observed. Treatment-related death was considered possible (n=3) or likely (n=3) in 6 patients (7.5%). With median follow-up of 47months, 3-year survival was 53%, compared with 57% for 252 peripheral tumors treated with 3/5-fractions SABR in the same period (p=0.369). Although a substantial proportion of central SABR patients received ⩾60Gy to OARs, the 3-year survival was no different from peripheral SABR. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Neuroendocrine tumors of the lung: major radiologic findings in a series of 22 histopathologically confirmed cases

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    Santos, Marcel Koenigkam, E-mail: marcelk46@yahoo.com.br [Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (HCFMRP-USP), SP (Brazil); Department of Diagnostic and Interventional Radiology, Heidelberg University (Germany); Barreto, Andre Rodrigues Facanha [Clinica Radius, Clinica Sao Carlos Imagem and Santa Casa de Misericordia de Fortaleza, Fortaleza, CE (Brazil); Chagas Neto, Francisco Abaete [Program of Health Sciences Applied to the Locomotor System - Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FMRP-USP), Ribeirao Preto, SP (Brazil); Muglia, Valdair Francisco; Elias Junior, Jorge [Division of Radiology, Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FMRPUSP), Ribeirao Preto, SP (Brazil)

    2012-07-15

    Objective: To describe key imaging findings in a series of cases of primary neuroendocrine tumors of the lung (NTLs), with emphasis on computed tomography changes. Materials And Methods: Imaging studies of 22 patients (12 men, mean age 60 years) with histopathologically confirmed diagnosis, evaluated in the author's institution during the last five years were retrospectively reviewed by two radiologists, with findings being consensually described focusing on changes observed at computed tomography. Results: The authors have described five typical carcinoids, three atypical carcinoids, three large-cell neuroendocrine carcinomas (LCNCs), and 11 small-cell lung cancers (SCLCs). Only one typical carcinoid presented the characteristic appearance of central endobronchial nodule with distal pulmonary atelectasis, while the others were pulmonary nodules or masses. The atypical carcinoids corresponded to peripheral heterogeneous masses. One out of the three LCNCs was a peripheral homogeneous mass, while the others were ill-defined and heterogeneous. The 11 SCLCs corresponded to central, infiltrating and heterogeneous masses with secondary pleuropulmonary changes. Calcifications were absent both in LGNCs and SCLCs. Metastases were found initially and also at follow-up of all the cases of LCNCs and SCLCs. Conclusion: Although some imaging features may be similar, radiologic findings considered together with clinical information may play a relevant role in the differentiation of histological types of NTLs. (author)

  13. Lung metastasis fails in MMTV-PyMT oncomice lacking S100A4 due to a T-cell deficiency in primary tumors

    DEFF Research Database (Denmark)

    Grum-Schwensen, Birgitte; Klingelhöfer, Jörg; Grigorian, Mariam

    2010-01-01

    Interactions between tumor and stroma cells are essential for the progression of cancer from its initial growth at a primary site to its metastasis to distant organs. The metastasis-stimulating protein S100A4 exerts its function as a stroma cell-derived factor. Genetic depletion of S100A4...... significantly reduced the metastatic burden in lungs of PyMT-induced mammary tumors. In S100A4(+/+) PyMT mice, massive leukocyte infiltration at the site of the growing tumor at the stage of malignant transition was associated with increased concentration of extracellular S100A4 in the tumor microenvironment....... In contrast, in S100A4(-/-) PyMT tumors, a significant suppression of T-cell infiltration was documented at the transition period. In vitro, the S100A4 protein mediated the attraction of T cells. Moreover, S100A4(+/+), but not S100A4(-/-), fibroblasts stimulated the invasion of T lymphocytes into fibroblast...

  14. Effects of sulfur dioxide derivatives on expression of oncogenes and tumor suppressor genes in human bronchial epithelial cells.

    Science.gov (United States)

    Qin, Guohua; Meng, Ziqiang

    2009-04-01

    Sulfur dioxide (SO(2)) is a major air pollutant suspected to act as a promoter or co-carcinogen. The present study was designed to investigate whether SO(2) derivatives (bisulfite and sulfite) had effects on the expression of several proto-oncogenes and tumor suppressor genes in cultured human bronchial epithelial (BEP2D) cells. The mRNA and protein levels were measured by real-time RT-PCR and western blotting, respectively, following exposure to differing SO(2)-derivative concentrations and exposure times. SO(2) derivatives caused mRNA and protein over-expression of c-fos, c-jun, and c-myc at all tested doses (0.001-2mM). Over-expression of H-ras and p53 were observed in cells receiving the highest concentration (0.1-2mM), as well as the under-expression of p16 and Rb. The over-expression of c-fos and c-jun was observed after 24h recovery. The expression of c-myc and H-ras decreased to base line levels while the p53 expression decreased compared with control after 24h recovery. The mRNA and protein expression of p16 and Rb remained at initial levels after 24h recovery. The data support the hypothesis that SO(2) derivatives could cause the activation of proto-oncogenes and inactivation of tumor suppressor genes and SO(2) derivatives may play a role in the pathogenesis of SO(2)-associated lung cancer.

  15. VGLL4 functions as a new tumor suppressor in lung cancer by negatively regulating the YAP-TEAD transcriptional complex.

    Science.gov (United States)

    Zhang, Wenjing; Gao, Yijun; Li, Peixue; Shi, Zhubing; Guo, Tong; Li, Fei; Han, Xiangkun; Feng, Yan; Zheng, Chao; Wang, Zuoyun; Li, Fuming; Chen, Haiquan; Zhou, Zhaocai; Zhang, Lei; Ji, Hongbin

    2014-03-01

    Lung cancer is one of the most devastating diseases worldwide with high incidence and mortality. Hippo (Hpo) pathway is a conserved regulator of organ size in both Drosophila and mammals. Emerging evidence has suggested the significance of Hpo pathway in cancer development. In this study, we identify VGLL4 as a novel tumor suppressor in lung carcinogenesis through negatively regulating the formation of YAP-TEAD complex, the core component of Hpo pathway. Our data show that VGLL4 is frequently observed to be lowly expressed in both mouse and human lung cancer specimens. Ectopic expression of VGLL4 significantly suppresses the growth of lung cancer cells in vitro. More importantly, VGLL4 significantly inhibits lung cancer progression in de novo mouse model. We further find that VGLL4 inhibits the activity of the YAP-TEAD transcriptional complex. Our data show that VGLL4 directly competes with YAP in binding to TEADs and executes its growth-inhibitory function through two TDU domains. Collectively, our study demonstrates that VGLL4 is a novel tumor suppressor for lung cancer through negatively regulating the YAP-TEAD complex formation and thus the Hpo pathway.

  16. SU-E-J-182: Reproducibility of Tumor Motion Probability Distribution Function in Stereotactic Body Radiation Therapy of Lung Using Real-Time Tumor-Tracking Radiotherapy System

    Energy Technology Data Exchange (ETDEWEB)

    Shiinoki, T; Hanazawa, H; Park, S; Takahashi, T; Shibuya, K [Yamaguchi University, Ube, Yamaguchi (Japan); Kawamura, S; Uehara, T; Yuasa, Y; Koike, M [Yamaguchi University Hospital, Ube, Yamaguchi (Japan)

    2015-06-15

    Purpose: We aim to achieve new four-dimensional radiotherapy (4DRT) using the next generation real-time tumor-tracking (RTRT) system and flattening-filter-free techniques. To achieve new 4DRT, it is necessary to understand the respiratory motion of tumor. The purposes of this study were: 1.To develop the respiratory motion analysis tool using log files. 2.To evaluate the reproducibility of tumor motion probability distribution function (PDF) during stereotactic body RT (SBRT) of lung tumor. Methods: Seven patients having fiducial markers closely implanted to the lung tumor were enrolled in this study. The positions of fiducial markers were measured using the RTRT system (Mitsubishi Electronics Co., JP) and recorded as two types of log files during the course of SBRT. For each patients, tumor motion range and tumor motion PDFs in left-right (LR), anterior-posterior (AP) and superior-inferior (SI) directions were calculated using log files of all beams per fraction (PDFn). Fractional PDF reproducibility (Rn) was calculated as Kullback-Leibler (KL) divergence between PDF1 and PDFn of tumor motion. The mean of Rn (Rm) was calculated for each patient and correlated to the patient’s mean tumor motion range (Am). The change of Rm during the course of SBRT was also evluated. These analyses were performed using in-house developed software. Results: The Rm were 0.19 (0.07–0.30), 0.14 (0.07–0.32) and 0.16 (0.09–0.28) in LR, AP and SI directions, respectively. The Am were 5.11 mm (2.58–9.99 mm), 7.81 mm (2.87–15.57 mm) and 11.26 mm (3.80–21.27 mm) in LR, AP and SI directions, respectively. The PDF reproducibility decreased as the tumor motion range increased in AP and SI direction. That decreased slightly through the course of RT in SI direction. Conclusion: We developed the respiratory motion analysis tool for 4DRT using log files and quantified the range and reproducibility of respiratory motion for lung tumors.

  17. Dendritic Cell-Derived Exosomes Stimulate Stronger CD8+ CTL Responses and Antitumor Immunity than Tumor Cell-Derived Exosomes

    Institute of Scientific and Technical Information of China (English)

    Siguo Hao; Ou Bai; Jinying Yuan; Mabood Qureshi; Jim Xiang

    2006-01-01

    Exosomes (EXO) derived from dendritic cells (DC) and tumor cells have been used to stimulate antitumor immune responses in animal models and in clinical trials. However, there has been no side-by-side comparison of the stimulatory efficiency of the antitumor immune responses induced by these two commonly used EXO vaccines. In this study, we selected to study the phenotype characteristics of EXO derived from a transfected EG7 tumor cells expressing ovalbumin (OVA) and OVA-pulsed DC by flow cytometry. We compared the stimulatory effect in induction of OVA-specific immune responses between these two types of EXO. We found that OVA protein-pulsed DCovA-derived EXO (EXODC) can more efficiently stimulate naive OVA-specific CD8+ T cell proliferation and differentiation into cytotoxic T lymphocytes in vivo, and induce more efficient antitumor immunity than EG7 tumor cell-derived EXO (EXOEG7). In addition, we elucidated the important role of the host DC in EXO vaccines that the stimulatory effect of EXO is delivered to T cell responses by the host DC. Therefore, DC-derived EXO may represent a more effective EXO-based vaccine in induction of antitumor immunity.

  18. A Catalog of Genes Homozygously Deleted in Human Lung Cancer and the Candidacy of PTPRD as a Tumor Suppressor Gene

    Science.gov (United States)

    Kohno, Takashi; Otsuka, Ayaka; Girard, Luc; Sato, Masanori; Iwakawa, Reika; Ogiwara, Hideaki; Sanchez-Cespedes, Montse; Minna, John D.; Yokota, Jun

    2010-01-01

    A total of 176 genes homozygously deleted in human lung cancer were identified by DNA array-based whole genome scanning of 52 lung cancer cell lines and subsequent genomic PCR in 74 cell lines, including the 52 cell lines scanned. One or more exons of these genes were homozygously deleted in one (1%) to 20 (27%) cell lines. These genes included known tumor suppressor genes, e.g., CDKN2A/p16, RB1, and SMAD4, and candidate tumor suppressor genes whose hemizygous or homozygous deletions were reported in several types of human cancers, such as FHIT, KEAP1, and LRP1B/LRP-DIP. CDKN2A/p16 and p14ARF located in 9p21 were most frequently deleted (20/74, 27%). The PTPRD gene was most frequently deleted (8/74, 11%) among genes mapping to regions other than 9p21. Somatic mutations, including a nonsense mutation, of the PTPRD gene were detected in 8/74 (11%) of cell lines and 4/95 (4%) of surgical specimens of lung cancer. Reduced PTPRD expression was observed in the majority (>80%) of cell lines and surgical specimens of lung cancer. Therefore, PTPRD is a candidate tumor suppressor gene in lung cancer. Microarray-based expression profiling of 19 lung cancer cell lines also indicated that some of the 176 genes, such as KANK and ADAMTS1, are preferentially inactivated by epigenetic alterations. Genetic/epigenetic as well as functional studies of these 176 genes will increase our understanding of molecular mechanisms behind lung carcinogenesis. PMID:20073072

  19. A Bayesian approach for three-dimensional markerless tumor tracking using kV imaging during lung radiotherapy

    Science.gov (United States)

    Shieh, Chun-Chien; Caillet, Vincent; Dunbar, Michelle; Keall, Paul J.; Booth, Jeremy T.; Hardcastle, Nicholas; Haddad, Carol; Eade, Thomas; Feain, Ilana

    2017-04-01

    The ability to monitor tumor motion without implanted markers can potentially enable broad access to more accurate and precise lung radiotherapy. A major challenge is that kilovoltage (kV) imaging based methods are rarely able to continuously track the tumor due to the inferior tumor visibility on 2D kV images. Another challenge is the estimation of 3D tumor position based on only 2D imaging information. The aim of this work is to address both challenges by proposing a Bayesian approach for markerless tumor tracking for the first time. The proposed approach adopts the framework of the extended Kalman filter, which combines a prediction and measurement steps to make the optimal tumor position update. For each imaging frame, the tumor position is first predicted by a respiratory-correlated model. The 2D tumor position on the kV image is then measured by template matching. Finally, the prediction and 2D measurement are combined based on the 3D distribution of tumor positions in the past 10 s and the estimated uncertainty of template matching. To investigate the clinical feasibility of the proposed method, a total of 13 lung cancer patient datasets were used for retrospective validation, including 11 cone-beam CT scan pairs and two stereotactic ablative body radiotherapy cases. The ground truths for tumor motion were generated from the the 3D trajectories of implanted markers or beacons. The mean, standard deviation, and 95th percentile of the 3D tracking error were found to range from 1.6-2.9 mm, 0.6-1.5 mm, and 2.6-5.8 mm, respectively. Markerless tumor tracking always resulted in smaller errors compared to the standard of care. The improvement was the most pronounced in the superior-inferior (SI) direction, with up to 9.5 mm reduction in the 95th-percentile SI error for patients with  >10 mm 5th-to-95th percentile SI tumor motion. The percentage of errors with 3D magnitude  <5 mm was 96.5% for markerless tumor tracking and 84.1% for the

  20. Tumor Associated Fibroblasts Promote PD-L1 Expression in Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Haiyang HE

    2017-05-01

    Full Text Available Background and objective Tumor-associated fibroblasts (TAF is an important part of TME, which inhibits the function of immune cells. CD8+ T cells play a significant role in tumor immunity. T-cell membrane possesses a distinct type of molecule with a negative regulatory function. Upon interaction with its corresponding ligand [programmed death factor ligand 1 (PD-L1], programmed death factor 1 (PD-1 is activated and thus inhibits the kinase activity of T cells. This study aims to explore the possible effects of TAF on PD-L1 expression in lung cancer cells. Methods Lung cancer cell lines H1975 and H520 were co-cultured with (experiment or without TAF (control via Transwell assay for through 48 hours under the same culture condition. H1975 and H520 cells were counted using a microscope. The protein and mRNA expression levels of PD-L1 were detected by FCM assay and PCR analysis, respectively. Results The numbers of lung cancer cells in 100 μm2 for H1975 and H520 cells are (46±21 and (38±10 in the experiment group, respectively, and (16±5 and (12±5 in the control group, respectively (P<0.05. The expression levels of the PD-L1 protein in H1975 and H520 cells are (20.93%±3.54% and (19.26%±3.04% in the experiment group, respectively, and (12.58%±2.52% and (11.60%±2.65% in the control group, respectively (P<0.05. The mRNA expression levels in H1975 and H520 cells are (16.45±1.25 and (15.38±2.02 pg/mL in the experiment group, respectively, and (7.78±1.27 and (7.20±1.58 pg/mL (P<0.05 in the control group, respectively (P<0.05. Conclusion TAF promotes the growth and increases the expression of PD-L1 in H1975 and H520 cells.

  1. Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma.

    Science.gov (United States)

    Togashi, Yosuke; Masago, Katsuhiro; Kubo, Takeshi; Fujimoto, Daichi; Sakamori, Yuichi; Nagai, Hiroki; Kim, Young Hak; Togashi, Kaori; Mishima, Michiaki

    2012-12-01

    Mutation of the epidermal growth factor receptor gene (EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4 %). EGFR mutation was found to be significantly related to women (P = 0.0070), never-smokers (P area (P area (P = 0.0001), and tumor size >30 mm (P = 0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular-poor area (80.4 %), 19 of 36 never-smokers with vascular-poor area (52.8 %), 19 of 37 current or former-smokers without vascular-poor area (51.4 %), and 16 of 54 current or former-smokers with vascular-poor area (29.6 %). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency.

  2. Role of Cyclooxygenase-2 on Intermittent Hypoxia-Induced Lung Tumor Malignancy in a Mouse Model of Sleep Apnea

    Science.gov (United States)

    Campillo, Noelia; Torres, Marta; Vilaseca, Antoni; Nonaka, Paula Naomi; Gozal, David; Roca-Ferrer, Jordi; Picado, César; Montserrat, Josep Maria; Farré, Ramon; Navajas, Daniel; Almendros, Isaac

    2017-01-01

    An adverse role for obstructive sleep apnea (OSA) in cancer epidemiology and outcomes has recently emerged from clinical and animal studies. In animals, intermittent hypoxia (IH) mimicking OSA promotes tumor malignancy both directly and via host immune alterations. We hypothesized that IH could potentiate cancer aggressiveness through activation of the cyclooxygenase-2 (COX-2) pathway and the concomitant increases in prostaglandin E2 (PGE2). The contribution of the COX-2 in IH-induced enhanced tumor malignancy was assessed using celecoxib as a COX-2 specific inhibitor in a murine model of OSA bearing Lewis lung carcinoma (LLC1) tumors. Exposures to IH accelerated tumor progression with a tumor associated macrophages (TAMs) shift towards a pro-tumoral M2 phenotype. Treatment with celecoxib prevented IH-induced adverse tumor outcomes by inhibiting IH-induced M2 polarization of TAMs. Furthermore, TAMs isolated from IH-exposed mice treated with celecoxib reduced the proliferation of LLC1 naïve cells, while the opposite occurred with placebo-treated IH-exposed mice. Finally, in vitro IH exposures of murine macrophages and LLC1 cells showed that both cell types increased PGE2 release in response to IH. These results suggest a crucial role for the COX-2 signaling pathway in the IH-exacerbated malignant processes, and designate macrophages and lung adenocarcinoma cells, as potential sources of PGE2. PMID:28300223

  3. Therapeutic effects of autologous tumor-derived nanovesicles on melanoma growth and metastasis.

    Directory of Open Access Journals (Sweden)

    Eun-Young Lee

    Full Text Available Cancer vaccines with optimal tumor-associated antigens show promise for anti-tumor immunotherapy. Recently, nano-sized vesicles, such as exosomes derived from tumors, were suggested as potential antigen candidates, although the total yield of exosomes is not sufficient for clinical applications. In the present study, we developed a new vaccine strategy based on nano-sized vesicles derived from primary autologous tumors. Through homogenization and sonication of tumor tissues, we achieved high yields of vesicle-bound antigens. These nanovesicles were enriched with antigenic membrane targets but lacked nuclear autoantigens. Furthermore, these nanovesicles together with adjuvant activated dendritic cells in vitro, and induced effective anti-tumor immune responses in both primary and metastatic melanoma mouse models. Therefore, autologous tumor-derived nanovesicles may represent a novel source of antigens with high-level immunogenicity for use in acellular vaccines without compromising safety. Our strategy is cost-effective and can be applied to patient-specific cancer therapeutic vaccination.

  4. Patient-derived xenografts from non-small cell lung cancer brain metastases are valuable translational platforms for the development of personalized targeted therapy.

    Science.gov (United States)

    Lee, Hye Won; Lee, Jung-Il; Lee, Se Jeong; Cho, Hyun Jung; Song, Hye Jin; Jeong, Da Eun; Seo, Yun Jee; Shin, Sang; Joung, Je-Gun; Kwon, Yong-Jun; Choi, Yoon-La; Park, Woong-Yang; Lee, Hyun Moo; Seol, Ho Jun; Shim, Young Mog; Joo, Kyeung Min; Nam, Do-Hyun

    2015-03-01

    The increasing prevalence of distant metastases from non-small cell lung cancer (NSCLC) indicates an urgent need for novel therapeutic modalities. Brain metastasis is particularly common in NSCLC, with severe adverse effects on clinical prognosis. Although the molecular heterogeneity of NSCLC and availability of various targeted agents suggest personalized therapeutic approaches for such brain metastases, further development of appropriate preclinical models is needed to validate the strategies. We established patient-derived xenografts (PDX) using NSCLC brain metastasis surgical samples and elucidated their possible preclinical and clinical implications for personalized treatment. NSCLC brain metastases (n = 34) showed a significantly higher successful PDX establishment rate than primary specimens (n = 64; 74% vs. 23%). PDXs derived from NSCLC brain metastases recapitulated the pathologic, genetic, and functional properties of corresponding parental tumors. Furthermore, tumor spheres established in vitro from the xenografts under serum-free conditions maintained their in vivo brain metastatic potential. Differential phenotypic and molecular responses to 20 targeted agents could subsequently be screened in vitro using these NSCLC PDXs derived from brain metastases. Although PDX establishment from primary NSCLCs was significantly influenced by histologic subtype, clinical aggressiveness, and genetic alteration status, the brain metastases exhibited consistently adequate in vivo tumor take rate and in vitro tumor sphere formation capacity, regardless of clinical and molecular conditions. Therefore, PDXs from NSCLC brain metastases may better represent the heterogeneous advanced NSCLC population and could be utilized as preclinical models to meet unmet clinical needs such as drug screening for personalized treatments. ©2014 American Association for Cancer Research.

  5. Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart.

    Science.gov (United States)

    Erin, Nuray; Boyer, Philip J; Bonneau, Robert H; Clawson, Gary A; Welch, Danny R

    2004-01-01

    Capsaicin specifically activates or destroys small diameter nociceptive sensory neurons that contain the capsaicin receptor, also called vanilloid receptor 1. Neurons sensitive to capsaicin mediate inflammatory pain and are important targets for management of chronic pain. These neurons also regulate local tissue homeostasis, inflammation, healing and development, especially under conditions of psychological stress. Stress contributes to increased cancer recurrence and metastasis through as yet undefined mechanisms. Likewise, activity of capsaicin-sensitive neurons is altered by pathological conditions that may lead to metastatic growth (e.g. stress). Therefore, we examined effects of a treatment that induces sensory nerve denervation on breast cancer metastases. Systemic denervation of sensory neurons caused by treatment with 125 mg/kg capsaicin resulted in significantly more lung and cardiac metastases in adult mice injected orthotopically with syngeneic 4T1 mammary carcinoma cells than was observed in vehicle-treated controls. Heart metastases, normally very rare, occurred as pericardial nodules, intra-myocardial nodules, or combined pericardial-myocardial lesions. Since the rate of primary tumor growth was unaffected, effects on metastases appear to be host tissue-specific. Although preliminary, these observations provide one possible explanation for resistance of cardiac tissue to tumor involvement and highlight contributions of host tissue, including sensory neurons, in the efficiency of cancer metastasis.

  6. Methylation of the estrogen receptor CpG island distinguishes spontaneous and plutonium-induced tumors from nitrosamine-induced lung tumors

    Energy Technology Data Exchange (ETDEWEB)

    Belinsky, S.A.; Baylin, S.B.; Issa, J.J. [Johns Hopkins Univ., Baltimore, MD (United States)

    1995-12-01

    CpG islands located in the promoter region of genes constitute one mechanism for regulating transcription. These islands are normally free of methylation, regardless of the expression state of the gene. Hypermethylation of CpG islands, the addition of a methyl group to the internal cytosine within CpG dinucleotides, can cause silencing of a gene. Hypermethylation has been detected as an early event at specific chromosome loci during the development of colon cancer and represents one mechanism used by neoplatic cells to inactivate tumor suppressor genes. Recent studies have demonstrated this mechanism in inactivation of the VHL tumor suppressor gene in 19% of sporadic renal tumors and the p16 {sup INK4a} tumor suppressor gene in 30% of non-small cell lung cancers. A recent report indicates that the estrogen receptor gene could also be inactivated through methylation. In addition, estrogen receptor CpG island methylation arises as a direct function of age in normal colonic mucosa and is present in virtually all colonic tumors. In cultured colon cancer cells, methylation-associated loss of expression of the estrogen receptor gene results in deregulated growth, suggesting a role for the estrogen receptor in colon cancer development. These results provide further evidence that gene silencing through methylation could be a predominant epigenetic mechanism underlying the development of many different types of cancer. The purpose of the current investigation was to determine whether estrogen receptor CpG island methylation is involved in the development of lung cancer. The frequency for methylation of the estrogen receptor CpG island in rodent lung tumors is summarized.

  7. Mechanistic Basis for Inflammation and Tumor Promotion in Lungs of BHT-Treated Mice: Electrophilic Metabolites Alkylate and Inactivate Antioxidant Enzymes

    Science.gov (United States)

    Meier, Brent W.; Gomez, Jose D.; Kirichenko, Oleg V.; Thompson, John A.

    2008-01-01

    An established model for mechanistic analysis of lung carcinogenesis involves administration of 3-methylcholanthrene to mice followed by several weekly injections of the tumor promoter 2,6-di-tert-butyl-4-methylphenol (BHT). BHT is metabolized to quinone methides (QMs) responsible for promoting tumor formation. QMs are strongly electrophilic and readily form adducts with proteins. The goal of the present study was to identify adducted proteins in the lungs of mice injected with BHT and to assess the potential impact of these modifications on tumorigenesis. Cytosolic proteins from treated mouse lungs were separated by two-dimensional electrophoresis, adducts detected by immunoblotting, and proteins identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Eight adducts were detected in the lungs of most, or all, of 6 experimental groups of BALB mice. Of these adducts, several were structural proteins but others, namely peroxiredoxin 6 (Prx6), Cu,Zn-superoxide dismutase (SOD1), carbonyl reductase, and selenium-binding protein 1, have direct or indirect antioxidant functions. When the 9000 g supernatant fraction of mouse lung was treated with BHT-QM (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone), substantial lipid peroxidation and increases in hydrogen peroxide and superoxide formation were observed. Studies with human Prx6 and bovine SOD1 demonstrated inhibition of enzyme activity concomitant with adduct formation. LC-MS/MS analysis of digests of adducted Prx6 demonstrated adduction of both Cys 91 and Cys 47; the latter residue is essential for peroxidatic activity. Analysis of QM-treated bovine SOD1 by matrix-assisted laser desorption ionization-time of flight MS demonstrated predominance of a mono-adduct at His 78. This study provides evidence that indicates Prx6, SOD1 and possibly other antioxidant enzymes in mouse lung are inhibited by BHT-derived QMs leading to enhanced levels of reactive oxygen species and inflammation, and providing a

  8. The Role of Microvesicles Derived from Mesenchymal Stem Cells in Lung Diseases

    Directory of Open Access Journals (Sweden)

    Jie Chen

    2015-01-01

    Full Text Available Microvesicles (MVs are membrane vesicles that are released by many types of cells and have recently been considered important mediators of cell-to-cell communication. MVs serve as a vehicle to transfer proteins and messenger RNA and microRNA (miRNA to distant cells, which alters the gene expression, proliferation, and differentiation of the recipient cells. Several studies have demonstrated that mesenchymal stem cells (MSCs have the capacity to reverse acute and chronic lung injury in different experimental models through paracrine mechanisms. This paracrine action may be partially accounted for by MVs that are derived from MSCs. MSC-derived MVs may confer a stem cell-like phenotype to injured cells with the consequent activation of self-regenerative programmers. In this review, we summarize the characteristics and biological activities of MSC-derived MVs, and we describe their potential in novel therapeutic approaches in regenerative medicine to repair damaged tissues. Additionally, we provide an overview of studies that have assessed the role of MSC-derived MVs in lung diseases, including the mechanisms that may account for their therapeutic potential. Finally, we discuss the clinical use of MSC-derived MVs with several suggestions for enhancing their therapeutic efficiency.

  9. Anesthesia condition for {sup 18}F-FDG imaging of lung metastasis tumors using small animal PET

    Energy Technology Data Exchange (ETDEWEB)

    Woo, Sang-Keun; Lee, Tae Sup; Kim, Kyeong Min; Kim, June-Youp; Jung, Jae Ho; Kang, Joo Hyun [Division of Nuclear Medicine and RI Application, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706 (Korea, Republic of); Cheon, Gi Jeong [Division of Nuclear Medicine and RI Application, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706 (Korea, Republic of); Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706 (Korea, Republic of)], E-mail: larry@kcch.re.kr; Choi, Chang Woon; Lim, Sang Moo [Division of Nuclear Medicine and RI Application, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706 (Korea, Republic of); Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences (KIRAMS), Nowon-Gu, Seoul 139-706 (Korea, Republic of)

    2008-01-15

    Small animal positron emission tomography (PET) with {sup 18}F-FDG has been increasingly used for tumor imaging in the murine model. The aim of this study was to establish the anesthesia condition for imaging of lung metastasis tumor using small animal {sup 18}F-FDG PET. Methods: To determine the impact of anesthesia on {sup 18}F-FDG distribution in normal mice, five groups were studied under the following conditions: no anesthesia, ketamine and xylazine (Ke/Xy), 0.5% isoflurane (Iso 0.5), 1% isoflurane (Iso 1) and 2% isoflurane (Iso 2). The ex vivo counting, standard uptake value (SUV) image and glucose SUV of {sup 18}F-FDG in various tissues were evaluated. The {sup 18}F-FDG images in the lung metastasis tumor model were obtained under no anesthesia, Ke/Xy and Iso 0.5, and registered with CT image to clarify the tumor region. Results: Blood glucose concentration and muscle uptake of {sup 18}F-FDG in the Ke/Xy group markedly increased more than in the other groups. The Iso 2 group increased {sup 18}F-FDG uptake in heart compared with the other groups. The Iso 0.5 anesthesized group showed the lowest {sup 18}F-FDG uptake in heart and chest wall. The small size of lung metastasis tumor (2 mm) was clearly visualized by {sup 18}F-FDG image with the Iso 0.5 anesthesia. Conclusion: Small animal {sup 18}F-FDG PET imaging with Iso 0.5 anesthesia was appropriate for the detection of lung metastasis tumor. To acquire {sup 18}F-FDG PET images with small animal PET, the type and level of anesthetic should be carefully considered to be suitable for the visualization of target tissue in the experimental model.

  10. Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549

    Institute of Scientific and Technical Information of China (English)

    Bin YE; Yan XIE; Zheng-hong QIN; Jun-chao WU; Rong HAN; Jing-kang HE

    2011-01-01

    Aim:To assess the cytotoxic effect of crotoxin (CrTX),a potent neurotoxin extracted from the venom of the pit viper Crotalus durissus terrificus,in human lung adenocarcinoma A549 cells and investigated the underlying mechanisms.Methods:A549 cells were treated with gradient concentrations of CrTX,and the cell cycle and apoptosis were analyzed using a flow cytometric assay.The changes of cellular effectors p53,caspase-3 and cleaved caspase-3,total P38MAPK and pP38MAPK were investigated using Western blot assays.A549 xenograft model was used to examine the inhibition of CrTX on tumor growth in vivo.Results:Treatment of A549 cells with CrTX (25-200 μg/mL) for 48 h significantly inhibited the cell growth in a dose-dependent manner (IC50=78 μg/mL).Treatment with CrTX (25 iJg/mL) for 24 h caused G1 arrest and induced cell apoptosis.CrTX (25 μg/mL) significantly increased the expression of wt p53,cleaved caspase-3 and phospho-P38MAPK.Pretreatment with the specific P38MAPK inhibitor SB203580 (5 μmol/L) significantly reduced CrTX-induced apoptosis and cleaved caspase-3 level,but G1 arrest remained unchanged and highly expressed p53 sustained.Intraperitoneal injection of CrTX (10 μg/kg,twice a week for 4 weeks) significantly inhibited A549 tumor xenograft growth,and decreased MVD and VEGF levels.Conclusion:CrTX produced significant anti-tumor effects by inducing cell apoptosis probably due to activation of P38MAPK and caspase-3,and by cell cycle arrest mediated by increased wt p53 expression.In addition,CrTX displayed anti-angiogenic effects in vivo.

  11. Tumorer

    DEFF Research Database (Denmark)

    Prause, J.U.; Heegaard, S.

    2005-01-01

    oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer......oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer...

  12. Treatment of Experimental Brain Tumors with Trombospondin-1 Derived Peptides: an In Vivo Imaging Study

    Directory of Open Access Journals (Sweden)

    A. Bogdanov, Jr.

    1999-11-01

    Full Text Available Antiangiogenic and antiproliferative effects of synthetic D-reverse peptides derived from the type 1 repeats of thrombospondin (TSP1 [1,2] were studied in rodent C6 glioma and 9L gliosarcomas. To directly measure tumor size and vascular parameters, we employed in vivo magnetic resonance (MR imaging and corroborated results by traditional morphometric tissue analysis. Rats bearing either C6 or 9L tumors were treated with TSP1-derived peptide (D-reverse amKRFKQDGGWSHWSPWSSac, n=13 or a control peptide (D-reverse am KRAKQAGGASHASPASSac, n=12 at 10 mg/kg, administered either intravenously or through subcutaneous miniosmotic pumps starting 10 days after tumor implantation. Eleven days later, the effect of peptide treatment was evaluated. TSP1 peptide-treated 9L tumors (50.7±44.2 mm3, n=7 and C6 tumors (41.3±34.2 mm3, n=6 were significantly smaller than tumors treated with control peptide (9L: 215.7±67.8 mm3, n=6; C6:184.2±105.2 mm3, n=6. In contrast, the in vivo vascular volume fraction, the mean vascular area (determined by microscopy, and the microvascular density of tumors were not significantly different in any of the experimental groups. In cell culture, TSP1, and the amKRFKQDGGWSHWSPWSSac peptide showed antiproliferative effects against C6 with an IC of 45 nM for TSP1. These results indicate that TSP1derived peptides retard brain tumor growth presumably as a result of slower de novo blood vessel formation and synergistic direct antiproliferative effects on tumor cells. We also show that in vivo MR imaging can be used to assess treatment efficacy of novel antiangiogenic drugs non-invasively, which has obvious implications for clinical trials.

  13. Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model.

    Directory of Open Access Journals (Sweden)

    Chenjie Yang

    Full Text Available Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs.

  14. Delivery of platinum(IV) drug to subcutaneous tumor and lung metastasis using bradykinin-potentiating peptide-decorated chitosan nanoparticles.

    Science.gov (United States)

    Wang, Xin; Yang, Chenchen; Zhang, Yajun; Zhen, Xu; Wu, Wei; Jiang, Xiqun

    2014-08-01

    Selectively activating tumor vessels to increase drug delivery and reduce interstitial fluid pressure of tumors is actively pursued. Here we developed a vasoactive peptide-decorated chitosan nanoparticles for enhancing drug accumulation and penetration in subcutaneous tumor and lung metastasis. The vasoactive peptide used here is bradykinin-potentiating peptide (BPP) containing 9 amino acid residues and the drug is bioreductively sensitive platinum(IV) compound which becomes cisplatin in intracellular reductive environments. Both peptide and drug are covalently linked with chitosan nanoparticles with a diameter of 120 nm. We demonstrate that BPP-decorated chitosan nanoparticles increase the tumorous vascular permeability and reduce the interstitial fluid pressure of tumor simultaneously, both of which improve the penetration of nanoparticles in tumor tissues. The in vivo biodistribution and tumor inhibition examinations demonstrate that the BPP-decorated nanoparticle formulation has more superior efficacy in enhancing drug accumulation in tumor, restraining tumor growth and prolonging the lifetime of tumor-bearing mice than free drug and non-decorated nanoparticle formulation. Meanwhile, the drug accumulation in the lung with metastasis reaches 17% and 20% injected dose per gram of lung for the chitosan nanoparticles without and with BPP decoration, respectively, which is 10-fold larger than that of free cisplatin. The examination of lung metastasis inhibition further indicates that BPP-decorated chitosan nanoparticle formulations can more effectively inhibit lung metastasis.

  15. Radio-photothermal therapy mediated by a single compartment nanoplatform depletes tumor initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor model

    Science.gov (United States)

    Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun

    2015-11-01

    Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [64Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs are suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in the subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for the suppression of tumor metastasis through localized RT/PTT therapy.Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress

  16. Identification of an HLA-A*0201 restricted Bcl2-derived epitope expressed on tumors

    DEFF Research Database (Denmark)

    Wang, Mingjun; Johansen, Britta; Nissen, Mogens H

    2006-01-01

    A large number of human tumor-associated antigen-derived peptides have been identified that are recognized by CTLs in a MHC-I restricted fashion. The apoptosis inhibitory protein Bcl2 is overexpressed in many human cancers as part of their neoplastic phenotype. Since inhibition or loss of Bcl2...... expression might impair tumor growth and survival, this protein may serve as a rational target for vaccine-induced CTL responses. By Western blot technique, we screened a panel of established human tumor cell lines for proteins involved in the apoptotic process. Two of eight tumor cell lines, a B lymphoma...... (Loukes) and a colon carcinoma (CCL220) cell line showed increased Bcl2 protein expression whereas the majority of tumor cell lines expressed proapoptotic proteins. Neither fibroblasts nor peripheral blood mononuclear cells showed Bcl2 expression. An HLA-A*0201 restricted CTL epitope was deduced in silica...

  17. Noninvasive Evaluation of Microscopic Tumor Extensions Using Standardized Uptake Value and Metabolic Tumor Volume in Non-Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Meng Xue; Sun Xindong [Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan (China); Mu Dianbin [Department of Pathology, Shandong Cancer Hospital and Institute, Shandong University, Jinan (China); Xing Ligang [Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan (China); Ma Li [Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong University, Jinan (China); Zhang Baijiang [Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Shandong University, Jinan (China); Zhao Shuqiang; Yang Guoren [Department of Nuclear Medicine, Shandong Cancer Hospital and Institute, Shandong University, Jinan (China); Kong Fengming [Department of Radiation Oncology, University of Michigan, Ann Arbor, MI (United States); Yu Jinming, E-mail: yujinmingsd@yahoo.com.cn [Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan (China)

    2012-02-01

    Purpose: To prospectively evaluate whether maximal microscopic extensions (MEmax) correlate with maximal standardized uptake value (SUVmax) and metabolic tumor volume (MTV) at 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) images in non-small-cell lung cancer (NSCLC). Methods and Materials: Thirty-nine patients with Stage I-IIIA NSCLC underwent surgery after FDG-PET/CT scanning. SUVmax and MTV were calculated on the PET/CT images. The maximum linear distance from the tumor margin to the farthest extent of the tumor in every dimension was measured at the tumor section. The correlations among MEmax, SUVmax, MTV and other clinical pathologic parameters were analyzed. Results: MEmax for all patients had a significant correlation with SUVmax (r = 0.777, p = 0.008) and MTV (r = 0.724, p < 0.001). When expressed in terms of the probability of covering ME with respect to a given margin, we suggested that margins of 1.93 mm, 3.90 mm, and 9.60 mm for SUVmax {<=}5, 5-10, and >10 added to the gross tumor volume would be adequate to cover 95% of ME. Conclusions: This study demonstrated that tumors with high SUVmax and MTV have more MEmax and would therefore require more margin expansion from gross tumor volume to clinical target volume. FDG-PET/CT, especially for SUVmax, is promising and effective and merits additional study in noninvasive delimiting of the clinical target volume margin for NSCLC.

  18. Expression of tumor necrosis factor-alpha-mediated genes predicts recurrence-free survival in lung cancer.

    Science.gov (United States)

    Wang, Baohua; Song, Ning; Yu, Tong; Zhou, Lianya; Zhang, Helin; Duan, Lin; He, Wenshu; Zhu, Yihua; Bai, Yunfei; Zhu, Miao

    2014-01-01

    In this study, we conducted a meta-analysis on high-throughput gene expression data to identify TNF-α-mediated genes implicated in lung cancer. We first investigated the gene expression profiles of two independent TNF-α/TNFR KO murine models. The EGF receptor signaling pathway was the top pathway associated with genes mediated by TNF-α. After matching the TNF-α-mediated mouse genes to their human orthologs, we compared the expression patterns of the TNF-α-mediated genes in normal and tumor lung tissues obtained from humans. Based on the TNF-α-mediated genes that were dysregulated in lung tumors, we developed a prognostic gene signature that effectively predicted recurrence-free survival in lung cancer in two validation cohorts. Resampling tests suggested that the prognostic power of the gene signature was not by chance, and multivariate analysis suggested that this gene signature was independent of the traditional clinical factors and enhanced the identification of lung cancer patients at greater risk for recurrence.

  19. Expression of tumor necrosis factor-alpha-mediated genes predicts recurrence-free survival in lung cancer.

    Directory of Open Access Journals (Sweden)

    Baohua Wang

    Full Text Available In this study, we conducted a meta-analysis on high-throughput gene expression data to identify TNF-α-mediated genes implicated in lung cancer. We first investigated the gene expression profiles of two independent TNF-α/TNFR KO murine models. The EGF receptor signaling pathway was the top pathway associated with genes mediated by TNF-α. After matching the TNF-α-mediated mouse genes to their human orthologs, we compared the expression patterns of the TNF-α-mediated genes in normal and tumor lung tissues obtained from humans. Based on the TNF-α-mediated genes that were dysregulated in lung tumors, we developed a prognostic gene signature that effectively predicted recurrence-free survival in lung cancer in two validation cohorts. Resampling tests suggested that the prognostic power of the gene signature was not by chance, and multivariate analysis suggested that this gene signature was independent of the traditional clinical factors and enhanced the identification of lung cancer patients at greater risk for recurrence.

  20. Optimizing production of asperolide A, a potential anti-tumor tetranorditerpenoid originally produced by the algal-derived endophytic fungus Aspergillus wentii EN-48

    Science.gov (United States)

    Xu, Rui; Li, Xiaoming; Xu, Gangming; Wang, Bingui

    2016-07-01

    The marine algal-derived endophytic fungus Aspergillus wentii EN-48 produces the potential anti-tumor agent asperolide A, a tetranorlabdane diterpenoid active against lung cancer. However, the fermentation yield of asperolide A was very low and only produced in static cultures. Static fermentation conditions of A. wentii EN-48 were optimized employing response surface methodology to enhance the production of asperolide A. The optimized conditions resulted in a 13.9-fold yield enhancement, which matched the predicted value, and the optimized conditions were successfully used in scale-up fermentation for the production of asperolide A. Exogenous addition of plant hormones (especially 10 μmol/L methyl jasmonate) stimulated asperolide A production. To our knowledge, this is first optimized production of an asperolide by a marine-derived fungus. The optimization is Effective and valuable to supply material for further anti-tumor mechanism studies and preclinical evaluation of asperolide A and other norditerpenoids.