Radio-photothermal therapy mediated by a single compartment nanoplatform depletes tumor initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor model

NASA Astrophysics Data System (ADS)

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

[Malignant nonepithelial tumors of the lung].

PubMed

Trakhtenberg, A Kh; Biriukov, Iu V; Frank, G A; Kunitsyn, A G; Grigor'eva, S P; Aĭtakov, Z N; Korenev, S V; Efimova, O Iu; Vial'tsev, N V

1990-01-01

The main peculiarities of the clinical course of lung sarcoma were determined from representative material of 134 patients. The main features differentiating malignant nonepithelial tumors from carcinoma of the lung are: younger age (average age 45.5 years), predominantly peripheral clinico-anatomical form (82.8%), and prevalent hematogenic metastasis. Five-year survival in the whole group of patients after surgical treatment was 54%. The size and histological form of the tumor are the main factors of prognosis. The degree of differentiation acquires prognostic significance in tumors measuring more than 3 cm in diameter.

K-ras p21 expression and activity in lung and lung tumors.

PubMed

Ramakrishna, G; Sithanandam, G; Cheng, R Y; Fornwald, L W; Smith, G T; Diwan, B A; Anderson, L M

2000-12-01

Although K-ras is mutated in many human and mouse lung adenocarcinomas, the function of K-ras p21 in lung is not known. We sought evidence for the prevalent hypothesis that K-ras p21 activates raf, which in turn passes the signal through the extracellular signal regulated kinases (Erks) to stimulate cell division, and that this pathway is upregulated when K-ras is mutated. Results from both mouse lung tumors and immortalized cultured E10 and C10 lung type II cells failed to substantiate this hypothesis. Lung tumors did not have more total K-ras p21 or K-ras p21 GTP than normal lung tissue, nor were high levels of these proteins found in tumors with mutant K-ras. Activated K-ras p21-GTP levels did not correlate with proliferating cell nuclear antigen. Special features of tumors with mutant K-ras included small size of carcinomas compared with carcinomas lacking this mutation, and correlation of proliferating cell nuclear antigen with raf-1. In nontransformed type II cells in culture, both total and activated K-ras p21 increased markedly at confluence but not after serum stimulation, whereas both Erk1/2 and the protein kinase Akt were rapidly activated by the serum treatment. Reverse transcriptase-polymerase chain reaction (RT-PCR) assays of K-ras mRNA indicated an increase in confluent and especially in postconfluent cells. Together the findings indicate that normal K-ras p21 activity is associated with growth arrest of lung type II cells, and that the exact contribution of mutated K-ras p21 to tumor development remains to be discovered.

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy.

PubMed

Guckenberger, Matthias; Klement, Rainer J; Allgäuer, Michael; Andratschke, Nicolaus; Blanck, Oliver; Boda-Heggemann, Judit; Dieckmann, Karin; Duma, Marciana; Ernst, Iris; Ganswindt, Ute; Hass, Peter; Henkenberens, Christoph; Holy, Richard; Imhoff, Detlef; Kahl, Henning K; Krempien, Robert; Lohaus, Fabian; Nestle, Ursula; Nevinny-Stickel, Meinhard; Petersen, Cordula; Semrau, Sabine; Streblow, Jan; Wendt, Thomas G; Wittig, Andrea; Flentje, Michael; Sterzing, Florian

2016-03-01

To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis

PubMed Central

Lau, Allison N; Curtis, Stephen J; Fillmore, Christine M; Rowbotham, Samuel P; Mohseni, Morvarid; Wagner, Darcy E; Beede, Alexander M; Montoro, Daniel T; Sinkevicius, Kerstin W; Walton, Zandra E; Barrios, Juliana; Weiss, Daniel J; Camargo, Fernando D; Wong, Kwok-Kin; Kim, Carla F

2014-01-01

Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24-dependent and Yap/Taz-dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease. PMID:24497554

Tumor heterogeneity in small cell lung cancer defined and investigated in pre-clinical mouse models

PubMed Central

Shue, Yan Ting; Lim, Jing Shan

2018-01-01

Small cell lung carcinoma (SCLC) is a fast-growing, highly metastatic form of lung cancer. A major difference between SCLC and other forms of lung cancer is that SCLC tumors often respond well to chemotherapy initially; unfortunately, resistant tumors rapidly recur. In addition, despite a large number of clinical trials with a variety of therapeutic agents, little progress has been achieved in the past three decades in improving the survival of SCLC patients. These clinical observations indicate that SCLC tumors have a high degree of plasticity and rapid adaptability to changes in growth conditions. Here we consider recent evidence pointing to several levels of heterogeneity in SCLC that may explain the ability of these tumors to adjust to different microenvironment and therapeutics. In particular, we review new data pointing to the existence of several subpopulations of tumor cells that interact with each other to promote tumor growth. We also discuss how SCLC tumors that look similar at the histopathological level may actually represent distinct subtypes of tumors and how these differences impact the response to specific therapeutic agents. A better understanding of genetic and cellular heterogeneity will guide the development of personalized approaches to help SCLC patients. PMID:29535910

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

PubMed Central

Wei, Fang; Wong, David T.; Su, Wu-Chou

2015-01-01

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. PMID:26448936

Lung tumor induction in strain A mice with benzotrichloride.

PubMed

Stoner, G D; You, M; Morgan, M A; Superczynski, M J

1986-11-01

Benzotrichloride (BTC) is used in the synthesis of benzoyl chloride and benzoyl peroxide. Epidemiological data suggest that BTC is a human lung carcinogen. In the present study, BTC was evaluated for its ability to induce lung adenomas in strain A/J mice. Four groups of 15 male and 15 female A/J mice were injected i.p. with either tricaprylin or BTC in tricaprylin three times a week for 8 weeks. BTC groups received doses totaling 1440 mg/kg, 719 mg/kg or 287 mg/kg. The mean number of lung tumors per mouse was 127 87 +/- 5.81, 43 +/- 2.44, and 17.73 +/- 1.09 in the groups treated with either 1440 mg/kg, 719 mg/kg, or 287 mg/kg, respectively. Tricaprylin-vehicle controls had a mean number of 0.46 +/- 0.15 lung tumors per mouse. Therefore, BTC produced a significant (P less than 0.001) and dose-related increase in the lung tumor response when compared to tricaprylin controls and is a potent carcinogen in the strain A mouse lung tumor bioassay.

Pulmonary emphysema and tumor microenvironment in primary lung cancer.

PubMed

Murakami, Junichi; Ueda, Kazuhiro; Sano, Fumiho; Hayashi, Masataro; Nishimoto, Arata; Hamano, Kimikazu

2016-02-01

To clarify the relationship between the presence of pulmonary emphysema and tumor microenvironment and their significance for the clinicopathologic aggressiveness of non-small cell lung cancer. The subjects included 48 patients with completely resected and pathologically confirmed stage I non-small cell lung cancer. Quantitative computed tomography was used to diagnose pulmonary emphysema, and immunohistochemical staining was performed to evaluate the matrix metalloproteinase (MMP) expression status in the intratumoral stromal cells as well as the microvessel density (MVD). Positive MMP-9 staining in the intratumoral stromal cells was confirmed in 17 (35%) of the 48 tumors. These 17 tumors were associated with a high MVD, frequent lymphovascular invasion, a high proliferative activity, and high postoperative recurrence rate (all, P < 0.05). The majority of the tumors (13 of 17) arose in patients with pulmonary emphysema (P = 0.02). Lung cancers arising from pulmonary emphysema were also associated with a high MVD, proliferative activity, and postoperative recurrence rate (all, P < 0.05). The MMP-9 expression in intratumoral stromal cells is associated with the clinicopathologic aggressiveness of lung cancer and is predominantly identified in tumors arising in emphysematous lungs. Further studies regarding the biological links between the intratumoral and extratumoral microenvironment will help to explain why lung cancers originating in emphysematous lung tissues are associated with a poor prognosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Fluoroscopic tumor tracking for image-guided lung cancer radiotherapy

NASA Astrophysics Data System (ADS)

Lin, Tong; Cerviño, Laura I.; Tang, Xiaoli; Vasconcelos, Nuno; Jiang, Steve B.

2009-02-01

Accurate lung tumor tracking in real time is a keystone to image-guided radiotherapy of lung cancers. Existing lung tumor tracking approaches can be roughly grouped into three categories: (1) deriving tumor position from external surrogates; (2) tracking implanted fiducial markers fluoroscopically or electromagnetically; (3) fluoroscopically tracking lung tumor without implanted fiducial markers. The first approach suffers from insufficient accuracy, while the second may not be widely accepted due to the risk of pneumothorax. Previous studies in fluoroscopic markerless tracking are mainly based on template matching methods, which may fail when the tumor boundary is unclear in fluoroscopic images. In this paper we propose a novel markerless tumor tracking algorithm, which employs the correlation between the tumor position and surrogate anatomic features in the image. The positions of the surrogate features are not directly tracked; instead, we use principal component analysis of regions of interest containing them to obtain parametric representations of their motion patterns. Then, the tumor position can be predicted from the parametric representations of surrogates through regression. Four regression methods were tested in this study: linear and two-degree polynomial regression, artificial neural network (ANN) and support vector machine (SVM). The experimental results based on fluoroscopic sequences of ten lung cancer patients demonstrate a mean tracking error of 2.1 pixels and a maximum error at a 95% confidence level of 4.6 pixels (pixel size is about 0.5 mm) for the proposed tracking algorithm.

Diesel exhaust particle promotes tumor lung metastasis via the induction of BLT1-mediated neutrophilic lung inflammation.

PubMed

Li, Wenjing; Liu, Ting; Xiong, Yingluo; Lv, Jiaoyan; Cui, Xinyi; He, Rui

2018-06-05

BLT1, the primary functional receptor of Leukotriene B4 (LTB4), is involved in tissue inflammation by mediating leukocyte recruitment, and recently LTB4-dependent inflammation was reported to promote lung tumor growth. Exposure to diesel exhaust particle (DEP), the major component of particulate matter 2.5 (PM 2.5 ), can elicit lung inflammation, which may increase the risk of lung cancer. However, it remains unknown about the critical factors mediating DEP-induced lung inflammation and the subsequent effect on tumor metastasis. In this study, we found that DEP exposure led to acute lung inflammation, characterized by abundant infiltration of neutrophils and elevated lung levels in LTB4, as well as several pro-inflammatory cytokines and chemokines, including IL-1β, IL-6, TNF-α, CXCL1/2. Furthermore, DEP exposure promoted lung metastasis of 3LL and 4T1 cells. BLT1 blockade by its specific antagonist U75302 significantly inhibited neutrophilic lung inflammation following DEP exposure. Importantly, BLT1 blockade before the onset of inflammation significantly reduced DEP-enhanced lung metastasis, which was associated with greatly decreased infiltrating neutrophils in lungs. Interestingly, BLT1 blockade after the occurrence of lung metastases had no effect on the magnitude of lung metastasis, suggesting that inhibition of BLT1-mediated lung inflammation was insufficient to suppress established metastatic tumor. Administration of BLT2 inhibitor LY255283 fails to inhibit DEP-induced lung inflammation and tumor metastasis. Collectively, our results demonstrate that DEP exposure causes BLT1-mediated lung neutrophilic inflammation, which is critical for tumor lung metastasis, and suggest that interruption of the LTB4-BLT1 axis could be useful for preventing PM 2.5 -induced inflammation and subsequent susceptible to lung metastasis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Local control of metastatic lung tumors treated with SBRT of 48 Gy in four fractions: in comparison with primary lung cancer.

PubMed

Hamamoto, Yasushi; Kataoka, Masaaki; Yamashita, Motohiro; Shinkai, Tetsu; Kubo, Yoshiro; Sugawara, Yoshifumi; Inoue, Takeshi; Sakai, Shinya; Aono, Shoji; Takahashi, Tadaaki; Semba, Takatoshi; Uwatsu, Kotaro

2010-02-01

The optimal dose of stereotactic body radiotherapy (SBRT) for metastatic lung tumors has not been clarified. Local control rates of metastatic lung tumors treated with SBRT of 48 Gy in four fractions, which is one of the common dose schedules for Stage I primary lung cancer in Japan, were examined. Between 2006 and 2008, 12 metastatic lung tumors (colorectal cancer, 7; others, 5) in 10 patients and 56 lesions of Stage I primary lung cancer (T1, 43; T2, 13) in 52 patients were treated with SBRT of 48 Gy in four fractions at the isocenter. Two-year overall survival rates were 86% for patients with metastatic lung tumors and 96% for patients with Stage I primary lung cancer (P = 0.4773). One- and 2-year local control rates were 48% and 25% for metastatic lung tumors, and 91% and 88% for Stage I primary lung cancer, respectively (P < 0.0001). The local control rates after SBRT of 48 Gy in four fractions were significantly worse in metastatic lung tumors compared with Stage I primary lung cancer. In SBRT, metastatic lung tumors should be clearly differentiated from primary lung cancer and should be given higher doses.

Lung Tumors Treated With Percutaneous Radiofrequency Ablation: Computed Tomography Imaging Follow-Up

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palussiere, Jean, E-mail: palussiere@bergonie.org; Marcet, Benjamin; Descat, Edouard

2011-10-15

Purpose: To describe the morphologic evolution of lung tumors treated with radiofrequency ablation (RFA) by way of computed tomography (CT) images and to investigate patterns of incomplete RFA at the site of ablation. Materials and Methods: One hundred eighty-nine patients with 350 lung tumors treated with RFA underwent CT imaging at 2, 4, 6, and 12 months. CT findings were interpreted separately by two reviewers with consensus. Five different radiologic patterns were predefined: fibrosis, cavitation, nodule, atelectasis, and disappearance. The appearance of the treated area was evaluated at each follow-up CT using the predefined patterns. Results: At 1 year aftermore » treatment, the most common evolutions were fibrosis (50.5%) or nodules (44.8%). Differences were noted depending on the initial size of the tumor, with fibrosis occurring more frequently for tumors <2 cm (58.6% vs. 22.9%, P = 1 Multiplication-Sign 10{sup -5}). Cavitation and atelectasis were less frequent patterns (2.4% and 1.4%, respectively, at 1 year). Tumor location (intraparenchymatous, with pleural contact <50% or >50%) was not significantly correlated with follow-up image pattern. Local tumor progressions were observed with each type of evolution. At 1 year, 12 local recurrences were noted: 2 cavitations, which represented 40% of the cavitations noted at 1 year; 2 fibroses (1.9%); 7 nodules (7.4%); and 1 atelectasis (33.3%). Conclusion: After RFA of lung tumors, follow-up CT scans show that the shape of the treatment zone can evolve in five different patterns. None of these patterns, however, can confirm the absence of further local tumor progression at subsequent follow-up.« less

Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation.

PubMed

Amirkhosravi, M; Francis, J L

1995-01-01

Tumor cells interact with the hemostatic system in various ways and may thus influence malignant growth and spread. MC28 fibrosarcoma cells possess a potent procoagulant activity (PCA) and form lung tumors following intravenous injection. The aim of this work was to study the relationship between PCA, intravascular coagulation and lung seeding in the MC28 model. MC28 cells were injected into control, warfarinized and heparinized hooded Lister rats. Coagulation changes were monitored by thromboelastography (TEG) and Sonoclot analysis (SA), lung fibrin formation by light and electron microscopy, tumor seeding by macroscopic counting and tumor cell and platelet deposition in the lungs by radiolabelling. PCA was measured by chromogenic assay. MC28 PCA was characterized as a tissue factor-factor VIIa complex that probably arose during cell culture or disaggregation of solid tumors. Injection of tumor cells caused marked coagulopathy and was rapidly (within 30 min) followed by fibrin deposition in the lungs and accumulation of radiolabelled platelets. Heparin and warfarin significantly reduced lung seeding (p < 0.001) and reduced retention of radiolabelled tumor cells in the pulmonary circulation (p < 0.01). Inhibition of cellular PCA by prior treatment with concanavalin A markedly reduced intravascular coagulation and lung seeding. We conclude that MC28 cells cause intravascular coagulation as a direct result of their procoagulant activity. The data suggest that tumor cells form complexes with platelets and fibrin which are retained in the lungs long enough for extravasation and seeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

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

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leung, F.L.; Park, J.F.; Dagle, G.E.

1993-06-01

In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 ofmore » 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.« less

Lung tumor segmentation in PET images using graph cuts.

PubMed

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. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Percutaneous radiofrequency ablation of lung tumors in a large animal model.

PubMed

Ahrar, Kamran; Price, Roger E; Wallace, Michael J; Madoff, David C; Gupta, Sanjay; Morello, Frank A; Wright, Kenneth C

2003-08-01

Percutaneous radiofrequency ablation (RFA) is accepted therapy for liver tumors in the appropriate clinical setting, but its use in lung neoplasms remains investigational. We undertook this study to evaluate the feasibility and immediate effectiveness of RFA for treatment of both solitary pulmonary nodules and clusters of lung tumors in a large animal model. Percutaneous RFA of 14 lung tumors in five dogs was performed under CT guidance. Animals were euthanatized 8-48 hours after the procedure. The lungs and adjacent structures were harvested for gross and histopathologic evaluation. Five solitary pulmonary nodules (range, 17-26 mm) and three clusters of three nodules each (range, 7-17 mm per nodule) were treated with RFA. All ablations were technically successful. Perilesional ground-glass opacity and small asymptomatic pneumothoraces (n = 4) were visualized during the RFA sessions. One dog developed a large pneumothorax treated with tube thoracostomy but was euthanatized 8 hours post-RFA for persistent pneumothorax and continued breathing difficulty. Follow-up CT 48 hours post-RFA revealed opacification of the whole lung segment. Gross and histopathologic evaluation showed complete thermal coagulation necrosis of all treated lesions without evidence of any viable tumor. The region of thermal coagulation necrosis typically extended to the lung surface. Small regions of pulmonary hemorrhage and congestion often surrounded the areas of coagulation necrosis. RFA can be used to treat both solitary pulmonary nodules and clusters of tumor nodules in the canine lung tumor model. This model may be useful for development of specific RFA protocols for human lung tumors.

Percutaneous Radiofrequency Ablation of Lung Tumors in Contact with the Aorta: Dangerous and Difficult but Efficient: A Report of Two Cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thanos, Loukas, E-mail: loutharad@yahoo.co; Mylona, Sofia; Giannoulakos, Nikolaos

Percutaneous imaging-guided tumor ablation is a widely accepted method for the treatment of primary and secondary lung tumors. Although it is generally feasible and effective for local tumor control, some conditions may affect its feasibility and effectiveness. Herein the authors report their experience with two patients with lung malignancies contiguous to the aorta who were successfully treated with radiofrequency ablation, even though it initially appeared highly risky due to the possible fatal complications.

Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression.

PubMed

Nuciforo, Paolo Giovanni; Luise, Chiara; Capra, Maria; Pelosi, Giuseppe; d'Adda di Fagagna, Fabrizio

2007-10-01

Tumor initiation and progression provide a multitude of occasions for the generation of DNA damage and the consequent activation of the DNA damage response (DDR) pathway. DDR signaling involves the engagement of key factors such as ATM, CHK2, 53BP1 and the phosphorylation of histone H2AX (gamma-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and gamma-H2AX were engaged in cancer but the extent of their activation was strongly affected by the organ and cell type involved, whereas 53BP1 loss was the most consistent feature among the tumor studied. Unexpectedly, we also observed activated DDR markers in morphologically normal tissues, also in association with inflammation. Analysis of the dynamic engagement of DDR along the different stages of lung tumorigenesis showed that 53BP1 loss occurs early at the transition from normal to dysplastic change whereas the activated forms of ATM and CHK2, but not gamma-H2AX, initially accumulate in pre-invasive lesions and are then lost during tumor progression. In individual lung tumors, the activation of ATM, CHK2 and the presence of 53BP1 were consistently correlated, whereas gamma-H2AX did not correlate with activated ATM. Finally, the study of associations between critical clinicopathological parameters and activated DDR factors highlighted a statistically meaningful correlation between reduced local tumor extension and the phosphorylation of ATM, CHK2 and the presence of 53BP1, whereas no significant correlations with parameters such as survival or relapse of early-stage lung carcinomas were found.

Radiation-induced lung fibrosis in a tumor-bearing mouse model is associated with enhanced Type-2 immunity.

PubMed

Chen, Jing; Wang, Yacheng; Mei, Zijie; Zhang, Shimin; Yang, Jie; Li, Xin; Yao, Ye; Xie, Conghua

2016-03-01

Lung fibrosis may be associated with Type-2 polarized inflammation. Herein, we aim to investigate whether radiation can initiate a Type-2 immune response and contribute to the progression of pulmonary fibrosis in tumor-bearing animals. We developed a tumor-bearing mouse model with Lewis lung cancer to receive either radiation therapy alone or radiation combined with Th1 immunomodulator unmethylated cytosine-phosphorothioate-guanine containing oligodeoxynucleotide (CpG-ODN). The Type-2 immune phenotype in tumors and the histological grade of lung fibrosis were evaluated in mice sacrificed three weeks after irradiation. Mouse lung tissues were analyzed for hydroxyproline and the expression of Type-1/Type-2 key transcription factors (T-bet/GATA-3). The concentration of Type-1/Type-2 cytokines in serum was measured by cytometric bead array. Lung fibrosis was observed to be more serious in tumor-bearing mice than in normal mice post-irradiation. The fibrosis score in irradiated tumor-bearing mice on Day 21 was 4.33 ± 0.82, which was higher than that of normal mice (2.00 ± 0.63; P < 0.05). Hydroxyproline and GATA-3 expression were increased in the lung tissues of tumor-bearing mice following irradiation. CpG-ODN attenuated fibrosis by markedly decreasing GATA-3 expression. Serum IL-13 and IL-5 were elevated, whereas INF-γ and IL-12 expression were decreased in irradiated tumor-bearing mice. These changes were reversed after CpG-ODN treatment. Thus, Type-2 immunity in tumors appeared to affect the outcome of radiation damage and might be of interest for future studies on developing approaches in which Type-1-related immunotherapy and radiotherapy are used in combination. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

[New TNM classification of lung tumors].

PubMed

Wittekind, C

2014-11-01

The TNM classification of lung tumors has undergone many changes in the seventh edition published in 2010. These changes reflect current data and are based on the findings of the International Association for the Study of Lung Cancer (IASLC) from 81,495 patients and concern definitions of the T and M categories as well as stage grouping. They include a better description of regional lymph nodes of the lungs based on uniformly accepted definitions by the IASLC. The changes can lead to problems in the use of the definitions and will be discussed.

Lung Metastases in Neuroblastoma at Initial Diagnosis: A Report from the International Neuroblastoma Risk Group (INRG) Project

PubMed Central

DuBois, Steven G.; London, Wendy B.; Zhang, Yang; Matthay, Katherine K.; Monclair, Tom; Ambros, Peter F.; Cohn, Susan L.; Pearson, Andrew; Diller, Lisa

2009-01-01

Background Neuroblastoma is the most common extracranial pediatric solid cancer. Lung metastasis is rarely detected in children with newly diagnosed neuroblastoma. We aimed to describe the incidence, clinical characteristics, and outcome of patients with lung metastasis at initial diagnosis using a large international database. Procedure The subset of patients from the International Neuroblastoma Risk Group database with INSS stage 4 neuroblastoma and known data regarding lung metastasis at diagnosis was selected for analysis. Clinical and biological characteristics were compared between patients with and without lung metastasis. Survival for patients with and without lung metastasis was estimated by Kaplan-Meier methods. Cox proportional hazards methods were used to determine the independent prognostic value of lung metastasis at diagnosis. Results Of the 2,808 patients with INSS stage 4 neuroblastoma diagnosed between 1990 and 2002, 100 patients (3.6%) were reported to have lung metastasis at diagnosis. Lung metastasis was more common among patients with MYCN amplified tumors, adrenal primary tumors, or elevated lactate dehydrogenase (LDH) levels (p < 0.02 in each case). Five-year overall survival ± standard error for patients with lung metastasis was 34.5% ± 6.8% compared to 44.7% ± 1.3% for patients without lung metastasis (p=0.0002). However, in multivariable analysis, the presence of lung metastasis was not independently predictive of outcome. Conclusions Lung metastasis at initial diagnosis of neuroblastoma is associated with MYCN amplification and elevated LDH levels. Although lung metastasis at diagnosis was not independently predictive of outcome in this analysis, it remains a useful prognostic marker of unfavorable outcome. PMID:18649370

Icotinib as initial treatment in lung adenocarcinoma patients with brain metastases.

PubMed

Xu, Jian-Ping; Liu, Xiao-Yan; Yang, Sheng; Zhang, Chang-Gong; Wang, Lin; Shi, Yuan-Kai

2016-07-01

To evaluate the antitumor activity and toxicity of icotinib as initial treatment in lung adenocarcinoma patients with brain metastases. Twenty-one patients with histologically or pathologically documented brain metastatic lung cancer were administered icotinib as initial treatment from 2011 to 2015 at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences. Chemotherapy response was assessed by Response Evaluation Criteria in Solid Tumors and toxicity was evaluated according to National Cancer Institute-Common Toxicity Criteria. Icotinib was administered three times per day at a dose of 125mg. The median overall and progression-free survival rates were 15.2 (1.2-31.5 months, 95% confidence interval [CI] 6.6-23.7 months) and 8.9 months (0.6-30.5 months, 95% CI 3.4-14.3 months), respectively. The overall response and disease control rates were 61.9% and 90.5%, respectively. Icotinib was well tolerated, and no grade 3/4 adverse events were observed. The most common grade 1/2 adverse events included acneiform eruptions (38.1%), diarrhea (19.0%), and stomatitis (9.5%). Icotinib is effective and well tolerated as initial treatment in lung adenocarcinoma patients with brain metastases.

Tumor Acquisition for Biomarker Research in Lung Cancer

PubMed Central

Stevenson, Marvaretta; Christensen, Jared; Shoemaker, Debra; Foster, Traci; Barry, William T.; Tong, Betty C.; Wahidi, Momen; Shofer, Scott; Datto, Michael; Ginsburg, Geoffrey; Crawford, Jeffrey; D’Amico, Thomas; Ready, Neal

2015-01-01

The biopsy collection data from two lung cancer trials that required fresh tumor samples be obtained for microarray analysis were reviewed. In the trial for advanced disease, microarray data were obtained on 50 patient samples, giving an overall success rate of 60.2%. The majority of the specimens were obtained through CT-guided lung biopsies (N=30). In the trial for early-stage patients, 28 tissue specimens were collected from excess tumor after surgical resection with a success rate of 85.7%. This tissue procurement program documents the feasibility in obtaining fresh tumor specimens prospectively that could be used for molecular testing. PMID:24810245

Efficacy of a cancer vaccine against ALK-rearranged lung tumors

PubMed Central

Voena, Claudia; Di Giacomo, Filomena; Longo, Dario Livio; Castella, Barbara; Merlo, Maria Elena Boggio; Ambrogio, Chiara; Wang, Qi; Minero, Valerio Giacomo; Poggio, Teresa; Martinengo, Cinzia; D'Amico, Lucia; Panizza, Elena; Mologni, Luca; Cavallo, Federica; Altruda, Fiorella; Butaney, Mohit; Capelletti, Marzia; Inghirami, Giorgio; Jänne, Pasi A.; Chiarle, Roberto

2015-01-01

Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKIs), but is successful for only a limited amount of time; most cases relapse due to the development of drug resistance. Here we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti-PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC. PMID:26419961

[Lung metastases: tumor reduction as an oncologic concept].

PubMed

Dienemann, H; Hoffmann, H; Trainer, C; Muley, T

1998-01-01

The principle of surgery for lung metastases is the removal of all lesions in the lung that are either visible or detectable by palpation. This may be combined with complete dissection of all ipsilateral lymph nodes. Therefore, "tumor reduction" rather than "complete" or "radical resection" may be an adequate description of this surgical approach. Since the dissemination of--macroscopically not detectable--tumor cells represents the major mannerism of every metastatic disease, any local therapy appears to be a discrepancy. However, in most cases the rationale of surgery for lung metastases is the lack of effective systemic therapy and the low morbidity of surgery, along with up to 60% 5-year survival rates.

Feasibility of carbon-ion radiotherapy for re-irradiation of locoregionally recurrent, metastatic, or secondary lung tumors.

PubMed

Hayashi, Kazuhiko; Yamamoto, Naoyoshi; Karube, Masataka; Nakajima, Mio; Tsuji, Hiroshi; Ogawa, Kazuhiko; Kamada, Tadashi

2018-05-01

Intrathoracic recurrence after carbon-ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer-related deaths. However, treatment options are limited. Herein, we report on the toxicity and efficacy of re-irradiation with carbon-ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon-ion radiotherapy who were treated with re-irradiation with carbon-ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy-three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon-ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re-irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 18 months. In terms of grade ≥3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2-year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re-irradiation with carbon-ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re-irradiation with carbon-ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

SU-G-JeP1-06: Correlation of Lung Tumor Motion with Tumor Location Using Electromagnetic Tracking

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muccigrosso, D; Maughan, N; Parikh, P

Purpose: It is well known that lung tumors move with respiration. However, most measurements of lung tumor motion have studied long treatment times with intermittent imaging; those populations may not necessarily represent conventional LINAC patients. We summarized the correlation between tumor motion and location in a multi-institutional trial with electromagnetic tracking, and identified the patient cohort that would most benefit from respiratory gating. Methods: Continuous electromagnetic transponder data (Varian Medical, Seattle, WA) of lung tumor motion was collected from 14 patients (214 total fractions) across 3 institutions during external beam radiation therapy in a prospective clinical trial (NCT01396551). External interventionmore » from the clinician, such as couch shifts, instructed breath-holds, and acquisition pauses, were manually removed from the 10 Hz tracking data according to recorded notes. The average three-dimensional displacement from the breathing cycle’s end-expiratory to end-inhalation phases (peak-to-peak distance) of the transponders’ isocenter was calculated for each patient’s treatment. A weighted average of each isocenter was used to assess the effects of location on motion. A total of 14 patients were included in this analysis, grouped by their transponders’ location in the lung: upper, medial, and lower. Results: 8 patients had transponders in the upper lung, and 3 patients each in the medial lobe and lower lung. The weighted average ± standard deviation of all peak-to-peak distances for each group was: 1.04 ± 0.39 cm in the lower lung, 0.56 ± 0.14 cm in the medial lung, and 0.30 ± 0.06 cm in the upper lung. Conclusion: Tumors in the lower lung are most susceptible to excessive motion and daily variation, and would benefit most from continuous motion tracking and gating. Those in the medial lobe might be at moderate risk. The upper lobes have limited motion. These results can guide different motion management

Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients.

PubMed

Ben-Avi, Ronny; Farhi, Ronit; Ben-Nun, Alon; Gorodner, Marina; Greenberg, Eyal; Markel, Gal; Schachter, Jacob; Itzhaki, Orit; Besser, Michal J

2018-05-29

Adoptive cell therapy (ACT) of tumor infiltration lymphocytes (TIL) yields promising clinical results in metastatic melanoma patients, who failed standard treatments. Due to the fact that metastatic lung cancer has proven to be susceptible to immunotherapy and possesses a high mutation burden, which makes it responsive to T cell attack, we explored the feasibility of TIL ACT in non-small cell lung cancer (NSCLC) patients. Multiple TIL cultures were isolated from tumor specimens of five NSCLC patients undergoing thoracic surgery. We were able to successfully establish TIL cultures by various methods from all patients within an average of 14 days. Fifteen lung TIL cultures were further expanded to treatment levels under good manufacturing practice conditions and functionally and phenotypically characterized. Lung TIL expanded equally well as 103 melanoma TIL obtained from melanoma patients previously treated at our center, and had a similar phenotype regarding PD1, CD28, and 4-1BB expressions, but contained a higher percent of CD4 T cells. Lung carcinoma cell lines were established from three patients of which two possessed TIL cultures with specific in vitro anti-tumor reactivity. Here, we report the successful pre-clinical production of TIL for immunotherapy in the lung cancer setting, which may provide a new treatment modality for patients with metastatic NSCLC. The initiation of a clinical trial is planned for the near future.

Gastroesphageal Variceal Hemorrhage Induced by Metastatic Liver Tumor of Lung Cancer

PubMed Central

Honda, Takayuki; Kobayashi, Hiroaki; Saiki, Masafumi; Sogami, Yusuke; Miyashita, Yoshihiro; Inase, Naohiko

2012-01-01

Gastroesophageal variceal hemorrhage is a lethal complication of portal hypertension. Liver cirrhosis is often the principal cause of the portal hypertensive state. Malignant tumors coexist with portal hypertension in some cases. Non-small-cell lung cancer (NSCLC) is likely to become metastatic. Liver is a frequent site of cancer metastasis, but diffuse hepatic sinusoidal metastasis is uncommon as a metastatic form of NSCLC. This report describes a patient with gastroesophageal variceal hemorrhage owing to a metastatic liver tumor of NSCLC. The patient, a male smoker with stage IV NSCLC, was free of any hepatitis viral infection and had no alcohol addiction. Liver dysfunction and liver disease had never been pointed out in his medical history. His tumor harbored an L858R epidermal growth factor receptor mutation. Gefitinib was initiated but had to be ceased because of interstitial lung disease. Sequential steroid therapy was effective and bevacizumab-containing chemotherapy was commenced. Both chemotherapy regimens produced favorable effects against the metastatic liver tumor, eliciting atrophic change regardless of the chemotherapy-free interval. One day the patient was admitted to our hospital because of black stool and hypotension. Upper gastrointestinal endoscopy revealed a beaded appearance of the gastroesophageal varix with bloody gastric contents. The portal hypertension might have been caused by changes in portal vein hemodynamics induced by the conformational changes underlying the favorable response of the liver tumor to molecular targeted chemotherapy and notable regression. PMID:23275780

Unusual cardiac paraganglioma mimicking an atypical carcinoid tumor of the lung

PubMed Central

Evans, Mark; Wang, Beverly; Delrosario, J. Lawrence; Cheng, Timmy; Milliken, Jeffrey

2018-01-01

We present a case of unusual cardiac paraganglioma (PG) initially misdiagnosed as atypical carcinoid tumor of the lung and discuss key clinical and pathologic characteristics that guide surgical management of these rare chromaffin cell tumors. A 64-year-old female with persistent cough and back pain was found to have a 4 cm × 3 cm mass abutting multiple cardiopulmonary structures. A biopsy was performed at an outside institution and pathology reported “atypical neuroendocrine carcinoma, consistent with carcinoid”. The patient was transferred to our institution and pericardial resection with right pneumonectomy was performed to excise the tumor. Histology of the mass was that of PG with multiple ethanol embolizations. Immunohistochemical examination revealed that type I (chief) cells were positive for neuroendocrine markers (chromogranin A and synaptophysin), while type II (sustentacular) cells were positive for S100. There was no evidence of atypical carcinoid tumor in the lung. PG is an entity of chromaffin cell tumors that often affects the adrenal glands and carotid body. PG rarely occurs in the thoracic region, accounting for just 1–2% of all PG. Proper diagnosis of cardiac PG is challenging owing to its rare prevalence, subtle symptoms of presentation, and the neuroendocrine histopathological features it shares with atypical carcinoids. These tumors are typically benign and are best treated by surgical resection. Our report examines the approach to appropriate diagnosis of cardiac PG vs. atypical carcinoid, preoperative management, and surgical treatment by describing successful resection through thoracotomy without the use of cardiopulmonary bypass. PMID:29600100

Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors.

PubMed

Voena, Claudia; Menotti, Matteo; Mastini, Cristina; Di Giacomo, Filomena; Longo, Dario Livio; Castella, Barbara; Merlo, Maria Elena Boggio; Ambrogio, Chiara; Wang, Qi; Minero, Valerio Giacomo; Poggio, Teresa; Martinengo, Cinzia; D'Amico, Lucia; Panizza, Elena; Mologni, Luca; Cavallo, Federica; Altruda, Fiorella; Butaney, Mohit; Capelletti, Marzia; Inghirami, Giorgio; Jänne, Pasi A; Chiarle, Roberto

2015-12-01

Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKI), but the treatment is successful for only a limited amount of time; most patients experience a relapse due to the development of drug resistance. Here, we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti-PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC. ©2015 American Association for Cancer Research.

Reproducibility of lung tumor position and reduction of lung mass within the planning target volume using active breathing control (ABC).

PubMed

Cheung, Patrick C F; Sixel, Katharina E; Tirona, Romeo; Ung, Yee C

2003-12-01

The active breathing control (ABC) device allows for temporary immobilization of respiratory motion by implementing a breath hold at a predefined relative lung volume and air flow direction. The purpose of this study was to quantitatively evaluate the ability of the ABC device to immobilize peripheral lung tumors at a reproducible position, increase total lung volume, and thereby reduce lung mass within the planning target volume (PTV). Ten patients with peripheral non-small-cell lung cancer tumors undergoing radiotherapy had CT scans of their thorax with and without ABC inspiration breath hold during the first 5 days of treatment. Total lung volumes were determined from the CT data sets. Each peripheral lung tumor was contoured by one physician on all CT scans to generate gross tumor volumes (GTVs). The lung density and mass contained within a 1.5-cm PTV margin around each peripheral tumor was calculated using CT numbers. Using the center of the GTV from the Day 1 ABC scan as the reference, the displacement of subsequent GTV centers on Days 2 to 5 for each patient with ABC applied was calculated in three dimensions. With the use of ABC inspiration breath hold, total lung volumes increased by an average of 42%. This resulted in an average decrease in lung mass of 18% within a standard 1.5-cm PTV margin around the GTV. The average (+/- standard deviation) displacement of GTV centers with ABC breath hold applied was 0.3 mm (+/- 1.8 mm), 1.2 mm (+/- 2.3 mm), and 1.1 mm (+/- 3.5 mm) in the lateral direction, anterior-posterior direction, and superior-inferior direction, respectively. Results from this study indicate that there remains some inter-breath hold variability in peripheral lung tumor position with the use of ABC inspiration breath hold, which prevents significant PTV margin reduction. However, lung volumes can significantly increase, thereby decreasing the mass of lung within a standard PTV.

[A case of lung abscess during chemotherapy for testicular tumor].

PubMed

Hayashi, Yujiro; Miyago, Naoki; Takeda, Ken; Yamaguchi, Yuichiro; Nakayama, Masashi; Arai, Yasuyuki; Kakimoto, Ken-ichi; Nishimura, Kazuo

2014-05-01

32-year-old man was seen in a clinic because of prolonged cough and slight-fever. Chest X-ray showed multiple pulmonary nodules, and multiple lung and mediastinal lymph node metastases from right testicular tumor was suspected by positron emission tomography/CT (PET/CT) scan. He was diagnosed with right testicular germ cell tumor (embryonal carcinoma + seminoma, pT2N1M1b), and classified into the intermediate risk group according to International Germ Cell Cancer Collaborative Group. He underwent 4 cycles of chemotherapy with bleomycin, etoposide and cisplatin (BEP therapy). During BEP therapy, sputum with foul odor appeared and chest CT scan revealed lung abscess with a necrotic lesion of metastatic tumor. The lung abscess was treated successfully with antibiotics.

Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters.

PubMed

Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

2015-11-21

Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation.

[Giant-cell tumor of the patella with lung metastases: a case report].

PubMed

Bahri, I; Ben Yahia, N; Boudawara, T; Makni, S; Fakhfakh, B; Kechaou, S; Keskes, H; Jlidi, R

2003-06-01

Giant-cell tumors are an infrequent clinical, radiological, and pathological entity observed in 5% of primary bone tumors. They generally occur at the epiphysis of long bones, particularly in the knee area but patellar localization seems very rare. Despite their perfectly benign histological aspect, giant-cell tumors may be aggressive, leading to local recurrence or even distant metastasis to the lung. We report a case of benign giant-cell tumor of the patella with lung metastasis observed in a 23-year-old woman. The aggressive radiological image was suggestive of chondrosarcoma. Histologically the differential diagnosis with chondroblastoma was difficult. The tumor and lung metastasis were treated by surgical resection. Four years later there has been no recurrence. We present the anatomic and clinical aspects of giant-cell tumor of the bone together with the diagnostic approach and the clinical course.

Soluble tumor necrosis factor receptor-1 in preterm infants with chronic lung disease.

PubMed

Sato, Miho; Mori, Masaaki; Nishimaki, Shigeru; An, Hiromi; Naruto, Takuya; Sugai, Toshiyuki; Shima, Yoshio; Seki, Kazuo; Yokota, Shumpei

2010-04-01

It is clear that inflammation plays an important role in developing chronic lung disease in preterm infants. The purpose of the present study is to investigate changes of serum soluble tumor necrosis factor receptor-1 levels over time in infants with chronic lung disease. The serum levels of soluble tumor necrosis factor receptor-1 were measured after delivery, and at 7, 14, 21 and 28 days of age in 10 infants with chronic lung disease and in 18 infants without chronic lung disease. The serum level of soluble tumor necrosis factor receptor-1 was significantly higher in infants with chronic lung disease than in infants without chronic lung disease after delivery. The differences between these two groups remained up to 28 days of age. Prenatal inflammation with persistence into postnatal inflammation may be involved in the onset of chronic lung disease.

Sensitivity of Tumor Motion Simulation Accuracy to Lung Biomechanical Modeling Approaches and Parameters

PubMed Central

Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu

2015-01-01

Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the Neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation. PMID:26531324

Live attenuated measles virus vaccine induces apoptosis and promotes tumor regression in lung cancer.

PubMed

Zhao, Danhua; Chen, Ping; Yang, Huiqiang; Wu, Yonglin; Zeng, Xianwu; Zhao, Yu; Wen, Yanjun; Zhao, Xia; Liu, Xiaolin; Wei, Yuquan; Li, Yuhua

2013-01-01

Although the treatment of lung carcinoma has improved, at least 65% of patients with this tumor succumb to progressive disease. Measles virus oncolytic therapy has been reported to be effective in reducing tumor burden in immunocompetent or nude mice; however, its potential to reduce tumor burden in lung carcinoma remains to be determined. Herein, we report the potent antitumor effects of a live attenuated measles vaccine virus Hu-191 strain (MV) against lung carcinoma. Immunocompetent C57BL/6 mice bearing Lewis lung carcinoma (LLC) cells were treated with MV (1x104 to 1x106 CCID50/ml) once every other day for 10 days. Our results showed that treatment with MV effectively suppressed tumor growth and significantly prolonged the survival time of tumor-bearing animals. Histological examination revealed that the antitumor effects of MV therapy may result from increased induction of apoptosis, tumor necrosis and elevated lymphocyte infiltration. Our data suggest that MV, one of the widely used vaccines in China, has the ability to inhibit the growth of mouse lung carcinoma and may prove useful in the further exploration of the application of this approach in the treatment of human advanced lung cancer.

K-ras mutations in benzotrichloride-induced lung tumors of A/J mice.

PubMed

You, M; Wang, Y; Nash, B; Stoner, G D

1993-06-01

Benzotrichloride (BTC) is used extensively as a chemical intermediate in the synthesis of benzoyl chloride and benzoyl peroxide. Epidemiological data suggest that BTC is a human lung carcinogen. BTC is also a carcinogen in the A/J mouse lung tumor bioassay. Activated K-ras protooncogenes were detected in BTC-induced lung tumors from A/J mice. The polymerase chain reaction was used to amplify specific DNA segments likely to contain activating mutations, and the amplified DNAs were sequenced to identify the mutation. The activating mutation present in the K-ras gene from all BTC-induced lung tumors (24/24) was a GC-->AT transition in codon 12. Thus, BTC may exert its carcinogenic action by activation of the K-ras protooncogene through a genotoxic mechanism.

The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis.

PubMed

Huang, Yu-Ting; Lan, Qiang; Lorusso, Girieca; Duffey, Nathalie; Rüegg, Curzio

2017-02-07

Matricellular proteins play multiple roles in primary tumor growth, local invasion and tumor angiogenesis. However, their contribution to metastasis and the putative mechanisms involved are less well characterized. In ER-negative human breast cancer, elevated expression levels of the matricellular protein Cysteine-rich angiogenic inducer 61 (CYR61) are associated with more aggressive progression. Here, we investigated the role of CYR61 in breast cancer lung metastasis using the triple negative human breast cancer cell lines MDA-MB-231 and SUM159. Silencing of CYR61 significantly decreased lung metastasis from tumors orthotopically implanted in pre-irradiated or naive mammary tissue and upon tail vein injection. Constitutive CYR61 silencing impaired cancer cell extravasation to the lung during the first 24 hours after tail vein injection. In contrast, CYR61 inducible silencing starting 24 hours after cancer cell injection had no impact on lung metastasis formation. In vitro experiments revealed that CYR61 silencing decreased cancer cell transendothelial migration and motility, reduced CYR61 levels present at the cell surface and sensitized cancer cells to anoikis. Furthermore, we demonstrate that CYR61-dependent cell survival under non-adhesive conditions relied, at least partially, on β1 integrin ligation and AMPKα signaling while it was independent of AKT, FAK and ERK1/2 activation. Our data provide the first evidence that CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and protecting from anoikis during initial seeding to the lung. The uncovered CYR61-β1 integrin-AMPKα axis may serve as a potential therapeutic target to prevent breast cancer metastasis to the lung.

Evaluation of diagnostic value of four tumor markers in bronchoalveolar lavage fluid of peripheral lung cancer.

PubMed

Li, Jian; Chen, Ping; Mao, Chao-Ming; Tang, Xing-Ping; Zhu, Li-Rong

2014-06-01

The diagnostic role of carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC) antigen, Cyfra 21-1 and neuron-specific enolase (NSE) in the bronchoalveolar lavage fluid (BALF) for lung cancer is still controversial. The aim of this study was to evaluate the diagnostic value of these four tumor markers in BALF for peripheral lung cancer. We measured and compared the levels of CEA, SCC, Cyfra21-1 and NSE in BALF in 42 patients with peripheral lung cancer and 22 patients with benign lung disease. In the patients with peripheral lung cancer, the BAL was separately performed in the bronchus of the tumor-bearing lung and in the corresponding bronchus of the opposite healthy lung. The levels of CEA, SCC, Cyfra21-1 and NSE were significantly elevated in BALF from the tumor-bearing lung compared with the opposite healthy lung in the lung cancer patients (P < 0.001) or the benign lung disease patients (P < 0.005). The diagnostic sensitivities of Cyfra21-1 (86 and 76%), with a specificity of 91%, were the highest among the four tumor markers for the tumor-bearing lung versus the opposite healthy lung and benign lung disease. The combination of Cyfra21-1 and CEA increased the sensitivity to 93 and 86 percent, respectively. The assay of these tumor markers in BALF may be used as a diagnostic tool to complement a cytological examination in the diagnosis of peripheral lung cancer. © 2013 Wiley Publishing Asia Pty Ltd.

Primary mesenchymal or mixed-cell-origin lung tumors in four dogs.

PubMed

Watson, A D; Young, K M; Dubielzig, R R; Biller, D S

1993-03-15

Primary lung tumors of mesenchymal or mixed cell origin were diagnosed in 4 dogs with clinical and radiographic abnormalities indicating an intrathoracic mass. Each dog had 1 large intrapulmonary lesion, and 1 dog also had nodules scattered throughout all lung lobes. Two dogs were euthanatized; 1 had a biphasic pulmonary blastoma; and the other had a pulmonary chondroblastic osteosarcoma with intrapulmonary metastases. The masses in the other 2 dogs were hamartomas (lipomatous in 1, microcystic in the other), which were resected. Both dogs survived more than 1 year after surgery. Primary lung tumors are uncommon in dogs and are generally malignant (adenocarcinomas or carcinomas). Tumors of connective tissue or mixed cell origin are rare, but the outcome is potentially good after surgical removal.

The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets.

PubMed

Wood, Steven L; Pernemalm, Maria; Crosbie, Philip A; Whetton, Anthony D

2014-05-01

Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and currently has an overall five-year survival rate of only 15%. Patients presenting with advanced stage NSCLC die within 18-months of diagnosis. Metastatic spread accounts for >70% of these deaths. Thus elucidation of the mechanistic basis of NSCLC-metastasis has potential to impact on patient quality of life and survival. Research on NSCLC metastasis has recently expanded to include non-cancer cell components of tumors-the stromal cellular compartment and extra-cellular matrix components comprising the tumor-microenvironment. Metastasis (from initial primary tumor growth through angiogenesis, intravasation, survival in the bloodstream, extravasation and metastatic growth) is an inefficient process and few released cancer cells complete the entire process. Micro-environmental interactions assist each of these steps and discovery of the mechanisms by which tumor cells co-operate with the micro-environment are uncovering key molecules providing either biomarkers or potential drug targets. The major sites of NSCLC metastasis are brain, bone, adrenal gland and the liver. The mechanistic basis of this tissue-tropism is beginning to be elucidated offering the potential to target stromal components of these tissues thus targeting therapy to the tissues affected. This review covers the principal steps involved in tumor metastasis. The role of cell-cell interactions, ECM remodeling and autocrine/paracrine signaling interactions between tumor cells and the surrounding stroma is discussed. The mechanistic basis of lung cancer metastasis to specific organs is also described. The signaling mechanisms outlined have potential to act as future drug targets minimizing lung cancer metastatic spread and morbidity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Surgical treatment of lung metastases in patients with embryonal pediatric solid tumors: an update.

PubMed

Fuchs, Joerg; Seitz, Guido; Handgretinger, Rupert; Schäfer, Juergen; Warmann, Steven W

2012-02-01

Distant metastases regularly occur in children with solid tumors. The most affected organ is the lung. Nearly in all extracranial pediatric solid tumors, the presence of lung metastases is associated with an adverse prognosis for the children. Therefore, the correct treatment of lung metastases is essential and influences the outcome. Despite different national and international trials for pediatric tumor entities, specific surgical aspects or guidelines for lung metastases are usually not addressed thoroughly in these protocols. The aim of this article is to present the diagnostic challenges and principles of surgical treatment by focusing on the influence of surgery on the outcome of children. Special points of interest are discussed that emphasize sarcomas, nephroblastomas, hepatoblastomas, and other tumors. Surgery of lung metastases is safe, has a positive impact on the patients' prognosis, and should be aggressive depending on the tumor entity. An interdisciplinary approach, including pediatric oncology and radiology, is mandatory in any case. Copyright © 2012 Elsevier Inc. All rights reserved.

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

PubMed

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

2015-06-21

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).

Identification of an Unfavorable Immune Signature in Advanced Lung Tumors from Nrf2-Deficient Mice.

PubMed

Zhang, Di; Rennhack, Jonathan; Andrechek, Eran R; Rockwell, Cheryl E; Liby, Karen T

2018-04-16

Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in normal cells inhibits carcinogenesis, whereas constitutive activation of Nrf2 in cancer cells promotes tumor growth and chemoresistance. However, the effects of Nrf2 activation in immune cells during lung carcinogenesis are poorly defined and could either promote or inhibit cancer growth. Our studies were designed to evaluate tumor burden and identify immune cell populations in the lungs of Nrf2 knockout (KO) versus wild-type (WT) mice challenged with vinyl carbamate. Nrf2 KO mice developed lung tumors earlier than the WT mice and exhibited more and larger tumors over time, even at late stages. T cell populations were lower in the lungs of Nrf2 KO mice, whereas tumor-promoting macrophages and myeloid-derived suppressor cells were elevated in the lungs and spleen, respectively, of Nrf2 KO mice relative to WT mice. Moreover, 34 immune response genes were significantly upregulated in tumors from Nrf2 KO mice, especially a series of cytokines (Cxcl1, Csf1, Ccl9, Cxcl12, etc.) and major histocompatibility complex antigens that promote tumor growth. Our studies discovered a novel immune signature, characterized by the infiltration of tumor-promoting immune cells, elevated cytokines, and increased expression of immune response genes in the lungs and tumors of Nrf2 KO mice. A complementary profile was also found in lung cancer patients, supporting the clinical significance of our findings. Overall, our results confirmed a protective role for Nrf2 in late-stage carcinogenesis and, unexpectedly, suggest that activation of Nrf2 in immune cells may be advantageous for preventing or treating lung cancer. Antioxid. Redox Signal. 00, 000-000.

MOLECULAR AND CYTOGENETIC ANALYSIS OF LUNG TUMOR CELL LINES

EPA Science Inventory

We have measured the levels of amplification of oncogenes and tumor marker genes or other genes of interest in nine human lung tumor cell lines in comparison to normal human bronchial epithelial cells or normal blood lymphocytes to test the hypothesis that aberrant amplification ...

Feasibility of Pathology-Correlated Lung Imaging for Accurate Target Definition of Lung Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stroom, Joep; Blaauwgeers, Hans; Baardwijk, Angela van

2007-09-01

Purpose: To accurately define the gross tumor volume (GTV) and clinical target volume (GTV plus microscopic disease spread) for radiotherapy, the pretreatment imaging findings should be correlated with the histopathologic findings. In this pilot study, we investigated the feasibility of pathology-correlated imaging for lung tumors, taking into account lung deformations after surgery. Methods and Materials: High-resolution multislice computed tomography (CT) and positron emission tomography (PET) scans were obtained for 5 patients who had non-small-cell lung cancer (NSCLC) before lobectomy. At the pathologic examination, the involved lung lobes were inflated with formalin, sectioned in parallel slices, and photographed, and microscopic sectionsmore » were obtained. The GTVs were delineated for CT and autocontoured at the 42% PET level, and both were compared with the histopathologic volumes. The CT data were subsequently reformatted in the direction of the macroscopic sections, and the corresponding fiducial points in both images were compared. Hence, the lung deformations were determined to correct the distances of microscopic spread. Results: In 4 of 5 patients, the GTV{sub CT} was, on average, 4 cm{sup 3} ({approx}53%) too large. In contrast, for 1 patient (with lymphangitis carcinomatosa), the GTV{sub CT} was 16 cm{sup 3} ({approx}40%) too small. The GTV{sub PET} was too small for the same patient. Regarding deformations, the volume of the well-inflated lung lobes on pathologic examination was still, on average, only 50% of the lobe volume on CT. Consequently, the observed average maximal distance of microscopic spread (5 mm) might, in vivo, be as large as 9 mm. Conclusions: Our results have shown that pathology-correlated lung imaging is feasible and can be used to improve target definition. Ignoring deformations of the lung might result in underestimation of the microscopic spread.« less

CT-guided automated detection of lung tumors on PET images

NASA Astrophysics Data System (ADS)

Cui, Yunfeng; Zhao, Binsheng; Akhurst, Timothy J.; Yan, Jiayong; Schwartz, Lawrence H.

2008-03-01

The calculation of standardized uptake values (SUVs) in tumors on serial [ 18F]2-fluoro-2-deoxy-D-glucose ( 18F-FDG) positron emission tomography (PET) images is often used for the assessment of therapy response. We present a computerized method that automatically detects lung tumors on 18F-FDG PET/Computed Tomography (CT) images using both anatomic and metabolic information. First, on CT images, relevant organs, including lung, bone, liver and spleen, are automatically identified and segmented based on their locations and intensity distributions. Hot spots (SUV >= 1.5) on 18F-FDG PET images are then labeled using the connected component analysis. The resultant "hot objects" (geometrically connected hot spots in three dimensions) that fall into, reside at the edges or are in the vicinity of the lungs are considered as tumor candidates. To determine true lesions, further analyses are conducted, including reduction of tumor candidates by the masking out of hot objects within CT-determined normal organs, and analysis of candidate tumors' locations, intensity distributions and shapes on both CT and PET. The method was applied to 18F-FDG-PET/CT scans from 9 patients, on which 31 target lesions had been identified by a nuclear medicine radiologist during a Phase II lung cancer clinical trial. Out of 31 target lesions, 30 (97%) were detected by the computer method. However, sensitivity and specificity were not estimated because not all lesions had been marked up in the clinical trial. The method effectively excluded the hot spots caused by mediastinum, liver, spleen, skeletal muscle and bone metastasis.

The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.

PubMed

Detterbeck, Frank C; Bolejack, Vanessa; Arenberg, Douglas A; Crowley, John; Donington, Jessica S; Franklin, Wilbur A; Girard, Nicolas; Marom, Edith M; Mazzone, Peter J; Nicholson, Andrew G; Rusch, Valerie W; Tanoue, Lynn T; Travis, William D; Asamura, Hisao; Rami-Porta, Ramón

2016-05-01

Separate tumor nodules with the same histologic appearance occur in the lungs in a small proportion of patients with primary lung cancer. This article addresses how such tumors can be classified to inform the eighth edition of the anatomic classification of lung cancer. Separate tumor nodules should be distinguished from second primary lung cancer, multifocal ground glass/lepidic tumors, and pneumonic-type lung cancer, which are addressed in separate analyses. Survival of patients with separate tumor nodules in the International Association for the Study of Lung Cancer database were analyzed. This was compared with a systematic literature review. Survival of clinically staged patients decreased according to the location of the separate tumor nodule relative to the index tumor (same lobe > same side > other side) in N0 and N-any cohorts (all M0 except possible other-side nodules). However, there was also a decrease in the proportion of patients resected; among only surgically resected or among nonresected patients no survival differences were noted. There were no survival differences between patients with same-lobe nodules and those with other T3 tumors, between patients with same-side nodules and those with T4 tumors, and patients with other-side nodules and those with other M1a tumors. The data correlated with those identified in a literature review. Tumors with same-lobe separate tumor nodules (with the same histologic appearance) are recommended to be classified as T3, same-side nodules as T4, and other-side nodules as M1a. Thus, there is no recommended change between the seventh and eighth edition of the TNM classification of lung cancer. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Clinical significance of tumor cavitation in surgically resected early-stage primary lung cancer.

PubMed

Tomizawa, Kenji; Shimizu, Shigeki; Ohara, Shuta; Fujino, Toshio; Nishino, Masaya; Sesumi, Yuichi; Kobayashi, Yoshihisa; Sato, Katsuaki; Chiba, Masato; Shimoji, Masaki; Suda, Kenichi; Takemoto, Toshiki; Mitsudomi, Tetsuya

2017-10-01

The prognostic impact of tumor cavitation is unclear in patients with early-stage primary lung cancer. The aim of the present study was to examine the clinicopathological features and prognoses of patients with pathological stage I-IIA (p-stage I-IIA) primary lung cancers harboring tumor cavitation. This study was conducted according to the eighth edition of the TNM classification for lung cancer. We examined 602 patients with p-stage I-IIA primary lung cancer out of 890 patients who underwent pulmonary resection from January 2007 through March 2014 and searched for the presence of tumor cavitation, which is defined as the presence of air space within the primary tumor. A total of 59 out of the 602 patients had tumor cavitation (10%). Compared with patients without tumor cavitation, those with tumor cavitation had a significantly higher frequency of the following characteristics: high serum carcinoembryonic antigen (CEA) level (≥5ng/ml, p=0.027), interstitial pneumonia (p=0.0001), high SUVmax value on FDG-PET scan (≥4.2, p=0.023), tumors located in the lower lobe (p=0.024), large tumor size (>3cm, p=0.002), vascular invasion (66% vs 17%, p<0.0001) and non-adenocarcinoma histology (p=0.025). The overall survival period of patients with tumor cavitation was significantly shorter than that of patients without tumor cavitation (log-rank test: p<0.0001, 5-year OS rate: 56% vs 81%). Tumor cavitation was found to be an independent and significant factor associated with poor prognosis in the multivariate analysis (hazard ratio: 1.76, 95% confidence interval: 1.02-3.10, p=0.042). Tumor cavitation is an independent factor for poor prognosis in patients with resected p-stage I-IIA primary lung cancer. Based on our analyses, patients with tumor cavitation should be regarded as a separate cohort that requires more intensive follow-up. Copyright © 2017 Elsevier B.V. All rights reserved.

Autophagy Sustains Mitochondrial Glutamine Metabolism and Growth of BRAFV600E–Driven Lung Tumors

PubMed Central

Strohecker, Anne M.; Guo, Jessie Yanxiang; Karsli-Uzunbas, Gizem; Price, Sandy M.; Chen, Guanghua Jim; Mathew, Robin; McMahon, Martin; White, Eileen

2013-01-01

Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse model of BRAFV600E-induced lung cancer in the presence or absence of the tumor suppressor TRP53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7 and Nrf2 had no additive effect suggesting that both genes modulate tumorigenesis by regulating oxidative stress, revealing a potential mechanism of autophagy-mediated tumor suppression. At later stages of tumorigenesis, Atg7 deficiency resulted in an accumulation of defective mitochondria, proliferative defects, reduced tumor burden, conversion of adenomas and adenocarcinomas to oncocytomas, and increased mouse lifespan. Autophagy-defective tumor-derived cell lines were impaired in their ability to respire, survive starvation and were glutamine-dependent, suggesting that autophagy-supplied substrates from protein degradation sustains BRAFV600E-tumor growth and metabolism. PMID:23965987

The role of multimodal treatment in patients with advanced lung neuroendocrine tumors

PubMed Central

Ungaro, Antonio; Spada, Francesca; Cella, Chiara Alessandra; Pisa, Eleonora; Barberis, Massimo; Grana, Chiara; Zerini, Dario; Bertani, Emilio; Ribero, Dario; Funicelli, Luigi; Bonomo, Guido; Ravizza, Davide; Guarize, Juliana; De Marinis, Filippo; Petrella, Francesco; Del Signore, Ester; Pelosi, Giuseppe; Spaggiari, Lorenzo

2017-01-01

Lung neuroendocrine tumors (NETs) comprise typical (TC) and atypical carcinoids (AC). They represent the well differentiated (WD) or low/intermediate grade forms of lung neuroendocrine neoplasms (NENs). Unlike the lung poorly differentiated NENs, that are usually treated with chemotherapy, lung NETs can be managed with several different therapies, making a multidisciplinary interaction a key point. We critically discussed the multimodal clinical management of patients with advanced lung NETs. Provided that no therapeutic algorithm has been validate so far, each clinical case should be discussed within a NEN-dedicated multidisciplinary team. Among the systemic therapies available for metastatic lung NETs everolimus is the only approved drug, on the basis of the results of the phase III RADIANT-4 trial. Another phase III trial, the SPINET, is ongoing comparing lanreotide with placebo. Peptide receptor radionuclide therapy and chemotherapy were not studied within phase III trials for lung NETs, and they have been reported to be active within retrospective or phase II prospective studies. Temozolomide and oxaliplatin are two interesting chemotherapeutic agents in lung NETs. While some European Institutions were certificated as Centers of Excellence for gastroenteropancreatic NENs by the European Neuroendocrine Tumor Society (ENETS), an equivalent ENETS certification for lung NENs does not exist yet. Ideally a lung NEN-dedicated multidisciplinary tumor board should include NEN-dedicated medical oncologists, thoracic medical oncologist, thoracic surgeons, pathologists, interventional radiologists, endocrinologists, radiotherapists, interventional pneumologists, nuclear physician. PMID:29201453

Impact of Audio-Coaching on the Position of Lung Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haasbeek, Cornelis J.A.; Spoelstra, Femke; Lagerwaard, Frank J.

2008-07-15

Purpose: Respiration-induced organ motion is a major source of positional, or geometric, uncertainty in thoracic radiotherapy. Interventions to mitigate the impact of motion include audio-coached respiration-gated radiotherapy (RGRT). To assess the impact of coaching on average tumor position during gating, we analyzed four-dimensional computed tomography (4DCT) scans performed both with and without audio-coaching. Methods and Materials: Our RGRT protocol requires that an audio-coached 4DCT scan is performed when the initial free-breathing 4DCT indicates a potential benefit with gating. We retrospectively analyzed 22 such paired scans in patients with well-circumscribed tumors. Changes in lung volume and position of internal target volumesmore » (ITV) generated in three consecutive respiratory phases at both end-inspiration and end-expiration were analyzed. Results: Audio-coaching increased end-inspiration lung volumes by a mean of 10.2% (range, -13% to +43%) when compared with free breathing (p = 0.001). The mean three-dimensional displacement of the center of ITV was 3.6 mm (SD, 2.5; range, 0.3-9.6mm), mainly caused by displacement in the craniocaudal direction. Displacement of ITV caused by coaching was more than 5 mm in 5 patients, all of whom were in the subgroup of 9 patients showing total tumor motion of 10 mm or more during both coached and uncoached breathing. Comparable ITV displacements were observed at end-expiration phases of the 4DCT. Conclusions: Differences in ITV position exceeding 5 mm between coached and uncoached 4DCT scans were detected in up to 56% of mobile tumors. Both end-inspiration and end-expiration RGRT were susceptible to displacements. This indicates that the method of audio-coaching should remain unchanged throughout the course of treatment.« less

Assessment of interpatient heterogeneity in tumor radiosensitivity for nonsmall cell lung cancer using tumor-volume variation data.

PubMed

Chvetsov, Alexei V; Yartsev, Slav; Schwartz, Jeffrey L; Mayr, Nina

2014-06-01

In our previous work, the authors showed that a distribution of cell surviving fractions S2 in a heterogeneous group of patients could be derived from tumor-volume variation curves during radiotherapy for head and neck cancer. In this research study, the authors show that this algorithm can be applied to other tumors, specifically in nonsmall cell lung cancer. This new application includes larger patient volumes and includes comparison of data sets obtained at independent institutions. Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancer with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage computed tomography. Statistical distributions of cell surviving fractions S2 and clearance half-lives of lethally damaged cells T(1/2) have been reconstructed in each patient group by using a version of the two-level cell population model of tumor response and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Nonsmall cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractions S2 for nonsmall cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S2 reconstructed from tumor volume variation agree with the PDF measured in vitro. The data obtained in this work, when taken together with the data obtained

Nitrilase 1 modulates lung tumor progression in vitro and in vivo

PubMed Central

Wang, Yong Antican; Sun, Yunguang; Le Blanc, Justin M.; Solomides, Charalambos; Zhan, Tingting; Lu, Bo

2016-01-01

Uncovering novel growth modulators for non-small cell lung cancer (NSCLC) may lead to new therapies for these patients. Previous studies suggest Nit1 suppresses chemically induced carcinogenesis of the foregut in a mouse model. In this study we aimed to determine the role of Nit1 in a transgenic mouse lung cancer model driven by a G12D Kras mutation. Nit1 knockout mice (Nit1−/−) were crossed with KrasG12D/+ mice to investigate whether a G12D Kras mutation and Nit1 inactivation interact to promote or inhibit the development of NSCLC. We found that lung tumorigenesis was suppressed in the Nit1-null background (Nit1−/−:KrasG12D/+). Micro-CT scans and gross tumor measurements demonstrated a 5-fold reduction in total tumor volumes compared to Nit1+/+KrasG12D/+ (p<0.01). Furthermore, we found that Nit1 is highly expressed in human lung cancer tissues and cell lines and use of siRNA against Nit1 decreased overall cell survival of lung cancer cells in culture. In addition, cisplatin response was enhanced in human lung cancer cells when Nit1 was knocked down and Nit1−/−:KrasG12D/+ tumors showed increased sensitivity to cisplatin in vivo. Together, our data indicate that Nit1 may play a supportive role in the modulation of lung tumorigenesis and represent a novel target for NSCLCs treatment. PMID:26967383

Bioenergetics of lung tumors: alteration of mitochondrial biogenesis and respiratory capacity.

PubMed

Bellance, N; Benard, G; Furt, F; Begueret, H; Smolková, K; Passerieux, E; Delage, J P; Baste, J M; Moreau, P; Rossignol, R

2009-12-01

Little is known on the metabolic profile of lung tumors and the reminiscence of embryonic features. Herein, we determined the bioenergetic profiles of human fibroblasts taken from lung epidermoid carcinoma (HLF-a) and fetal lung (MRC5). We also analysed human lung tumors and their surrounding healthy tissue from four patients with adenocarcinoma. On these different models, we measured functional parameters (cell growth rates in oxidative and glycolytic media, respiration, ATP synthesis and PDH activity) as well as compositional features (expression level of various energy proteins and upstream transcription factors). The results demonstrate that both the lung fetal and cancer cell lines produced their ATP predominantly by glycolysis, while oxidative phosphorylation was only capable of poor ATP delivery. This was explained by a decreased mitochondrial biogenesis caused by a lowered expression of PGC1alpha (as shown by RT-PCR and Western blot) and mtTFA. Consequently, the relative expression of glycolytic versus OXPHOS markers was high in these cells. Moreover, the re-activation of mitochondrial biogenesis with resveratrol induced cell death specifically in cancer cells. A consistent reduction of mitochondrial biogenesis and the subsequent alteration of respiratory capacity was also observed in lung tumors, associated with a lower expression level of bcl2. Our data give a better characterization of lung cancer cells' metabolic alterations which are essential for growth and survival. They designate mitochondrial biogenesis as a possible target for anti-cancer therapy.

Thoracic multidisciplinary tumor board routinely impacts therapeutic plans in patients with lung and esophageal cancer: a prospective cohort study.

PubMed

Schmidt, Henner M; Roberts, John M; Bodnar, Artur M; Kunz, Sonia; Kirtland, Steven H; Koehler, Richard P; Hubka, Michal; Low, Donald E

2015-05-01

National and subspecialty guidelines for lung and esophageal cancers recommend treatment decisions to be made in a multidisciplinary tumor board (MTB). This study prospectively analyzes the actual impact of presentation at the thoracic tumor board on decision making in thoracic cancer cases. During the electronic submission process for presentation at MTB managing physicians documented their current treatment plan. The initial treatment plan was compared with the MTB final recommendation. Patient demographics, physician's proposed treatment plan, MTB recommendation, and documentation of application of MTB recommendations were prospectively recorded in an Institutional Review Board approved database. Between June 2010 and December 2012, 185 patients with esophageal and 294 patients with lung cancer were presented at the MTB. One hundred sixty-six patients were presented on more than 1 occasion, resulting in 724 assessments of 479 patients. In 48 esophageal cancer patients (26%) and 118 lung cancer patients (40%) MTB recommendations differed from the initial treatment plan. Overall, a differing MTB recommendation from the primary treatment plan occurred in 330 of 724 case presentations (46%). The MTB recommendations changed treatment plans in 40% and staging and assessment plans in 60% of patients. Follow-up in a cohort of 249 patients confirmed that MTB recommendations were followed in 97% of cases. This study validates the impact of the thoracic MTB. Recommendations will differ from the managing providers' initial plan in 26% to 40% of cases. However, MTB recommendations can be successfully initiated in the majority of patients. Complex thoracic cancer patients will benefit from multidisciplinary review and should ideally be presented at tumor board. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Blockade of Tumor-Expressed PD-1 promotes lung cancer growth

PubMed Central

Du, Shisuo; McCall, Neal; Park, Kyewon; Guan, Qing; Fontina, Paolo; Ertel, Adam; Zhan, Tingting; Dicker, Adam P.; Lu, Bo

2018-01-01

ABSTRACT Anti-PD-1 immunotherapy is the standard of care for treating many patients with non-small cell lung cancer (NSCLC), yet mechanisms of treatment failure are emerging. We present a case of NSCLC, who rapidly progressed during a trial (NCT02318771) combining palliative radiotherapy and pembrolizumab. Planned tumor biopsy demonstrated PD-1 expression by NSCLC cells. We validated this observation by detecting PD-1 transcript in lung cancer cells and by co-localizing PD-1 and lung cancer-specific markers in resected lung cancer tissues. We further investigated the biological role of cancer-intrinsic PD-1 in a mouse lung cancer cell line, M109. Knockout or antibody blockade of PD-1 enhanced M109 viability in-vitro, while PD-1 overexpression and exposure to recombinant PD-L1 diminished viability. PD-1 blockade accelerated growth of M109-xenograft tumors with increased proliferation and decreased apoptosis in immune-deficient mice. This represents a first-time report of NSCLC-intrinsic PD-1 expression and a potential mechanism by which PD-1 blockade may promote cancer growth. PMID:29632720

Blockade of Tumor-Expressed PD-1 promotes lung cancer growth.

PubMed

Du, Shisuo; McCall, Neal; Park, Kyewon; Guan, Qing; Fontina, Paolo; Ertel, Adam; Zhan, Tingting; Dicker, Adam P; Lu, Bo

2018-01-01

Anti-PD-1 immunotherapy is the standard of care for treating many patients with non-small cell lung cancer (NSCLC), yet mechanisms of treatment failure are emerging. We present a case of NSCLC, who rapidly progressed during a trial (NCT02318771) combining palliative radiotherapy and pembrolizumab. Planned tumor biopsy demonstrated PD-1 expression by NSCLC cells. We validated this observation by detecting PD-1 transcript in lung cancer cells and by co-localizing PD-1 and lung cancer-specific markers in resected lung cancer tissues. We further investigated the biological role of cancer-intrinsic PD-1 in a mouse lung cancer cell line, M109. Knockout or antibody blockade of PD-1 enhanced M109 viability in-vitro, while PD-1 overexpression and exposure to recombinant PD-L1 diminished viability. PD-1 blockade accelerated growth of M109-xenograft tumors with increased proliferation and decreased apoptosis in immune-deficient mice. This represents a first-time report of NSCLC-intrinsic PD-1 expression and a potential mechanism by which PD-1 blockade may promote cancer growth.

[Computer aided diagnosis model for lung tumor based on ensemble convolutional neural network].

PubMed

Wang, Yuanyuan; Zhou, Tao; Lu, Huiling; Wu, Cuiying; Yang, Pengfei

2017-08-01

The convolutional neural network (CNN) could be used on computer-aided diagnosis of lung tumor with positron emission tomography (PET)/computed tomography (CT), which can provide accurate quantitative analysis to compensate for visual inertia and defects in gray-scale sensitivity, and help doctors diagnose accurately. Firstly, parameter migration method is used to build three CNNs (CT-CNN, PET-CNN, and PET/CT-CNN) for lung tumor recognition in CT, PET, and PET/CT image, respectively. Then, we aimed at CT-CNN to obtain the appropriate model parameters for CNN training through analysis the influence of model parameters such as epochs, batchsize and image scale on recognition rate and training time. Finally, three single CNNs are used to construct ensemble CNN, and then lung tumor PET/CT recognition was completed through relative majority vote method and the performance between ensemble CNN and single CNN was compared. The experiment results show that the ensemble CNN is better than single CNN on computer-aided diagnosis of lung tumor.

Establishment and quantitative imaging of a 3D lung organotypic model of mammary tumor outgrowth.

PubMed

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 sponge to serve as a scaffold and co-cultured with a green fluorescent protein-labeled polyoma virus middle T antigen (PyVT) mammary tumor cell line. Analysis of the co-culture system was performed using flow cytometry to determine the relative constitution of the co-cultures over time. This analysis determined that the cultures consisted of viable lung and breast cancer cells over a 5-day period. Confocal microscopy was then used to perform live cell imaging of the co-cultures over time. Our studies determined that host lung cells influence the ability of tumor cells to grow, as the presence of lung parenchyma positively affected the proliferation of the mammary tumor cells in culture. In summary, we have developed a novel in vitro model of breast tumor cells in a common metastatic site that can be used to study tumor/host interactions in an important microenvironment.

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

PubMed

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.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shieh, C; Huang, C; Keall, P

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 tomore » 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

β-catenin contributes to lung tumor development induced by EGFR mutations

PubMed Central

Nakayama, Sohei; Sng, Natasha; Carretero, Julian; Welner, Robert; Hayashi, Yuichiro; Yamamoto, Mihoko; Tan, Alistair J.; Yamaguchi, Norihiro; Yasuda, Hiroyuki; Li, Danan; Soejima, Kenzo; Soo, Ross A.; Costa, Daniel B.; Wong, Kwok-Kin; Kobayashi, Susumu S.

2014-01-01

The discovery of somatic mutations in epidermal growth factor receptor (EGFR) and development of EGFR tyrosine kinase inhibitors (TKIs) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here we show that β-catenin is essential for development of EGFR mutated lung cancers. β-catenin was upregulated and activated in EGFR mutated cells. Mutant EGFR preferentially bound to and tyrosine-phosphorylated β-catenin, leading to increase in β-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacological inhibition of β-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth and genetic deletion of the β-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that β-catenin plays an essential role in lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs. PMID:25164010

Clinical characteristics and outcome of pneumothorax after stereotactic body radiotherapy for lung tumors.

PubMed

Asai, Kaori; Nakamura, Katsumasa; Shioyama, Yoshiyuki; Sasaki, Tomonari; Matsuo, Yoshio; Ohga, Saiji; Yoshitake, Tadamasa; Terashima, Kotaro; Shinoto, Makoto; Matsumoto, Keiji; Hirata, Hidenari; Honda, Hiroshi

2015-12-01

We retrospectively investigated the clinical characteristics and outcome of pneumothorax after stereotactic body radiotherapy (SBRT) for lung tumors. Between April 2003 and July 2012, 473 patients with lung tumors were treated with SBRT. We identified 12 patients (2.5 %) with pneumothorax caused by SBRT, and evaluated the clinical features of pneumothorax. All of the tumors were primary lung cancers. The severity of radiation pneumonitis was grade 1 in 10 patients and grade 2 in two patients. Nine patients had emphysema. The planning target volume and pleura overlapped in 11 patients, and the tumors were attached to the pleura in 7 patients. Rib fractures were observed in three patients before or at the same time as the diagnosis of pneumothorax. The median time to onset of pneumothorax after SBRT was 18.5 months (4-84 months). The severity of pneumothorax was grade 1 in 11 patients and grade 3 in one patient. Although pneumothorax was a relatively rare late adverse effect after SBRT, some patients demonstrated pneumothorax after SBRT for peripheral lung tumors. Although most pneumothorax was generally tolerable and self-limiting, careful follow-up is needed.

Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression

PubMed Central

DuPage, Michel; Cheung, Ann; Mazumdar, Claire; Winslow, Monte M.; Bronson, Roderick; Schmidt, Leah M.; Crowley, Denise; Chen, Jianzhu; Jacks, Tyler

2010-01-01

SUMMARY Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here we describe a system to introduce exogenous antigens into genetically engineered mouse lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors. PMID:21251614

Assessment of interpatient heterogeneity in tumor radiosensitivity for nonsmall cell lung cancer using tumor-volume variation data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chvetsov, Alexei V., E-mail: chvetsov2@gmail.com; Schwartz, Jeffrey L.; Mayr, Nina

2014-06-15

Purpose: In our previous work, the authors showed that a distribution of cell surviving fractionsS{sub 2} in a heterogeneous group of patients could be derived from tumor-volume variation curves during radiotherapy for head and neck cancer. In this research study, the authors show that this algorithm can be applied to other tumors, specifically in nonsmall cell lung cancer. This new application includes larger patient volumes and includes comparison of data sets obtained at independent institutions. Methods: Our analysis was based on two data sets of tumor-volume variation curves for heterogeneous groups of 17 patients treated for nonsmall cell lung cancermore » with conventional dose fractionation. The data sets were obtained previously at two independent institutions by using megavoltage computed tomography. Statistical distributions of cell surviving fractionsS{sub 2} and clearance half-lives of lethally damaged cells T{sub 1/2} have been reconstructed in each patient group by using a version of the two-level cell population model of tumor response and a simulated annealing algorithm. The reconstructed statistical distributions of the cell surviving fractions have been compared to the distributions measured using predictive assays in vitro. Results: Nonsmall cell lung cancer presents certain difficulties for modeling surviving fractions using tumor-volume variation curves because of relatively large fractional hypoxic volume, low gradient of tumor-volume response, and possible uncertainties due to breathing motion. Despite these difficulties, cell surviving fractionsS{sub 2} for nonsmall cell lung cancer derived from tumor-volume variation measured at different institutions have similar probability density functions (PDFs) with mean values of 0.30 and 0.43 and standard deviations of 0.13 and 0.18, respectively. The PDFs for cell surviving fractions S{sub 2} reconstructed from tumor volume variation agree with the PDF measured in vitro. Conclusions: The data

Long-term outcome of gamma knife radiosurgery for metastatic brain tumors originating from lung cancer

PubMed Central

Bir, Shyamal C.; Ambekar, Sudheer; Bollam, Papireddy; Nanda, Anil

2014-01-01

Background: Gamma knife radiosurgery (GKRS) has emerged as an important treatment option for metastasis brain tumors (MBTs). However, the long-term outcome of GKRS on MBTs originating from lung carcinoma is not well understood. The treatment of MBTs derived from lung cancer with GKRS at our institution is reviewed. Methods: We performed a retrospective review (2000-2013) of 173 patients with MBTs from lung cancer who received GKRS. Out of 173 patients, 38 patients had recurrent tumors after microsurgical resection and whole brain radiotherapy (WBT). Results: GKRS in MBTs metastasized from lung carcinoma showed significant variations in tumor growth control (decreased in 79 [45.7%] patients, arrested growth in 54 [31.2%] patients, and increased tumor size in 40 [23.1%] patients). The median survival in the study population was 14 months. Overall survival after 3 years was 25%, whereas progression-free survival after 3 years was 45%. The predictive factors for improving survival in the patients with MBTs were recursive partitioning analysis (RPA) class I (P = 0.005), absence of hydrocephalus (P = 0.001), Karnofsky performance scale (KPS) >70 (P = 0.007), age ≤65 (P = 0.041), tumor size ≤3 cm (P = 0.023), controlled primary tumor (P = 0.049), and single number of MBTS (P = 0.044). Conclusion: Long-term follow-up revealed that GKRS offers a high rate of tumor control and good overall survival period in both new and recurrent patients with MBTs originating from lung carcinoma. Thus, GKRS is an effective treatment option for new patients with MBTs from lung cancer, as well as an adjuvant therapy in patients with recurrent MBTs derived from lung cancer. PMID:25289169

Desmoplastic small round cell tumor of the lung.

PubMed

Muramatsu, Takashi; Shimamura, Mie; Furuichi, Motohiko; Nishii, Tatsuhiko; Takeshita, Shinji; Shiono, Motomi

2010-12-01

We report a rare case of desmoplastic small round cell tumor, which arose from the left lung. A 25-year-old man was found to have an abnormal shadow during a routine physical examination and was admitted to our hospital. A thoracoscopic tumor biopsy was performed under general anesthesia. According to the histopathologic findings of permanent sections, the tumor was composed of sharply outlined nests, clusters, and trabeculae of small round to oval cells separated by a spindle-shaped desmoplastic stroma. A gene analysis revealed chimera genes of Ewing's sarcoma and Wilms' tumor by reverse transcription polymerase chain reaction. Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Six Degrees-of-Freedom Prostate and Lung Tumor Motion Measurements Using Kilovoltage Intrafraction Monitoring

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Chen-Yu; Tehrani, Joubin Nasehi; Ng, Jin Aun

2015-02-01

Purpose: Tumor positional uncertainty has been identified as a major issue that deteriorates the efficacy of radiation therapy. Tumor rotational movement, which is not well understood, can result in significant geometric and dosimetric inaccuracies. The objective of this study was to measure 6 degrees-of-freedom (6 DoF) prostate and lung tumor motion, focusing on the more novel rotation, using kilovoltage intrafraction monitoring (KIM). Methods and Materials: Continuous kilovoltage (kV) projections of tumors with gold fiducial markers were acquired during radiation therapy for 267 fractions from 10 prostate cancer patients and immediately before or after radiation therapy for 50 fractions from 3more » lung cancer patients. The 6 DoF motion measurements were determined from the individual 3-dimensional (3D) marker positions, after using methods to reject spurious and smooth noisy data, using an iterative closest point algorithm. Results: There were large variations in the magnitude of the tumor rotation among different fractions and patients. Various rotational patterns were observed. The average prostate rotation angles around the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) axes were 1.0 ± 5.0°, 0.6 ± 3.3°, and 0.3 ± 2.0°, respectively. For 35% of the time, the prostate rotated more than 5° about the LR axis, indicating the need for intrafractional adaptation during radiation delivery. For lung patients, the average LR, SI, and AP rotation angles were 0.8 ± 4.2°, −0.8 ± 4.5°, and 1.7 ± 3.1°, respectively. For about 30% of the time, the lung tumors rotated more than 5° around the SI axis. Respiration-induced rotation was detected in 2 of the 3 lung patients. Conclusions: The prostate and lung tumors were found to undergo rotations of more than 5° for about a third of the time. The lung tumor data represent the first 6 DoF tumor motion measured by kV images. The 6 DoF KIM method can enable rotational and

Estimation of lung tumor position from multiple anatomical features on 4D-CT using multiple regression analysis.

PubMed

Ono, Tomohiro; Nakamura, Mitsuhiro; Hirose, Yoshinori; Kitsuda, Kenji; Ono, Yuka; Ishigaki, Takashi; Hiraoka, Masahiro

2017-09-01

To estimate the lung tumor position from multiple anatomical features on four-dimensional computed tomography (4D-CT) data sets using single regression analysis (SRA) and multiple regression analysis (MRA) approach and evaluate an impact of the approach on internal target volume (ITV) for stereotactic body radiotherapy (SBRT) of the lung. Eleven consecutive lung cancer patients (12 cases) underwent 4D-CT scanning. The three-dimensional (3D) lung tumor motion exceeded 5 mm. The 3D tumor position and anatomical features, including lung volume, diaphragm, abdominal wall, and chest wall positions, were measured on 4D-CT images. The tumor position was estimated by SRA using each anatomical feature and MRA using all anatomical features. The difference between the actual and estimated tumor positions was defined as the root-mean-square error (RMSE). A standard partial regression coefficient for the MRA was evaluated. The 3D lung tumor position showed a high correlation with the lung volume (R = 0.92 ± 0.10). Additionally, ITVs derived from SRA and MRA approaches were compared with ITV derived from contouring gross tumor volumes on all 10 phases of the 4D-CT (conventional ITV). The RMSE of the SRA was within 3.7 mm in all directions. Also, the RMSE of the MRA was within 1.6 mm in all directions. The standard partial regression coefficient for the lung volume was the largest and had the most influence on the estimated tumor position. Compared with conventional ITV, average percentage decrease of ITV were 31.9% and 38.3% using SRA and MRA approaches, respectively. The estimation accuracy of lung tumor position was improved by the MRA approach, which provided smaller ITV than conventional ITV. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Profile of epigenetic mechanisms in lung tumors of patients with underlying chronic respiratory conditions.

PubMed

Mateu-Jimenez, Mercè; Curull, Víctor; Rodríguez-Fuster, Alberto; Aguiló, Rafael; Sánchez-Font, Albert; Pijuan, Lara; Gea, Joaquim; Barreiro, Esther

2018-01-01

Chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and epigenetic events underlie lung cancer (LC) development. The study objective was that lung tumor expression levels of specific microRNAs and their downstream biomarkers may be differentially regulated in patients with and without COPD. In lung specimens (tumor and non-tumor), microRNAs known to be involved in lung tumorigenesis (miR-21, miR-200b, miR-126, miR-451, miR-210, miR-let7c, miR-30a-30p, miR-155 and miR-let7a, qRT-PCR), DNA methylation, and downstream biomarkers were determined (qRT-PCR and immunoblotting) in 40 patients with LC (prospective study, subdivided into LC-COPD and LC, N  = 20/group). Expression of miR-21, miR-200b, miR-210, and miR-let7c and DNA methylation were greater in lung tumor specimens of LC-COPD than of LC patients. Expression of downstream markers PTEN , MARCKs , TPM-1 , PDCD4 , SPRY-2 , ETS-1 , ZEB-2 , FGFRL-1 , EFNA-3 , and k-RAS together with P53 were selectively downregulated in tumor samples of LC-COPD patients. In these patients, tumor expression of miR-126 and miR-451 and that of the biomarkers PTEN , MARCKs , FGFRL-1 , SNAIL-1 , P63 , and k-RAS were reduced. Biomarkers of mechanisms involved in tumor growth, angiogenesis, migration, and apoptosis were differentially expressed in tumors of patients with underlying respiratory disease. These findings shed light into the underlying biology of the reported greater risk to develop LC seen in patients with chronic respiratory conditions. The presence of an underlying respiratory disease should be identified in all patients with LC as the differential biological profile may help determine tumor progression and the therapeutic response. Additionally, epigenetic events offer a niche for pharmacological therapeutic targets.

Automated framework for estimation of lung tumor locations in kV-CBCT images for tumor-based patient positioning in stereotactic lung body radiotherapy

NASA Astrophysics Data System (ADS)

Yoshidome, Satoshi; Arimura, Hidetaka; Terashima, Koutarou; Hirakawa, Masakazu; Hirose, Taka-aki; Fukunaga, Junichi; Nakamura, Yasuhiko

2017-03-01

Recently, image-guided radiotherapy (IGRT) systems using kilovolt cone-beam computed tomography (kV-CBCT) images have become more common for highly accurate patient positioning in stereotactic lung body radiotherapy (SLBRT). However, current IGRT procedures are based on bone structures and subjective correction. Therefore, the aim of this study was to evaluate the proposed framework for automated estimation of lung tumor locations in kV-CBCT images for tumor-based patient positioning in SLBRT. Twenty clinical cases are considered, involving solid, pure ground-glass opacity (GGO), mixed GGO, solitary, and non-solitary tumor types. The proposed framework consists of four steps: (1) determination of a search region for tumor location detection in a kV-CBCT image; (2) extraction of a tumor template from a planning CT image; (3) preprocessing for tumor region enhancement (edge and tumor enhancement using a Sobel filter and a blob structure enhancement (BSE) filter, respectively); and (4) tumor location estimation based on a template-matching technique. The location errors in the original, edge-, and tumor-enhanced images were found to be 1.2 ± 0.7 mm, 4.2 ± 8.0 mm, and 2.7 ± 4.6 mm, respectively. The location errors in the original images of solid, pure GGO, mixed GGO, solitary, and non-solitary types of tumors were 1.2 ± 0.7 mm, 1.3 ± 0.9 mm, 0.4 ± 0.6 mm, 1.1 ± 0.8 mm and 1.0 ± 0.7 mm, respectively. These results suggest that the proposed framework is robust as regards automatic estimation of several types of tumor locations in kV-CBCT images for tumor-based patient positioning in SLBRT.

Four-dimensional multislice computed tomography for determination of respiratory lung tumor motion in conformal radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leter, Edward M.; Cademartiri, Filippo; Levendag, Peter C.

2005-07-01

Purpose: We used four-dimensional multislice spiral computed tomography (MSCT) to determine respiratory lung-tumor motion and compared this strategy to common clinical practice in conformal radiotherapy treatment-planning imaging. Methods and Materials: The entire lung volume of 10 consecutive patients with 14 lung metastases were scanned by a 16-slice MSCT. During the scans, patients were instructed to breathe through a spirometer that was connected to a laptop computer. For each patient, 10 stacks of 1.5-mm slices, equally distributed throughout the respiratory cycle, were reconstructed from the acquired MSCT data. The lung tumors were manually contoured in each data set. For each patient,more » the tumor-volume contours of all data sets were copied to 1 data set, which allowed determination of the volume that encompassed all 10 lung-tumor positions (i.e., the tumor-traversed volume [TTV]) during the respiratory cycle. The TTV was compared with the 10 tumor volumes contoured for each patient, to which an empiric respiratory-motion margin was added. The latter target volumes were designated internal-motion included tumor volume (IMITV). Results: The TTV measurements were significantly smaller than the reference IMITV measurements (5.2 {+-} 10.2 cm{sup 3} and 10.1 {+-} 13.7 cm{sup 3}, respectively). All 10 IMITVs for 2 of the 4 tumors in 1 subject completely encompassed the TTV. All 10 IMITVs for 3 tumors in 2 patients did not show overlap with up to 35% of the corresponding TTV. The 10 IMITVs for the remaining tumors either completely encompassed the corresponding TTV or did not show overlap with up to 26% of the corresponding TTV. Conclusions: We found that individualized determination of respiratory lung-tumor motion by four-dimensional respiratory-gated MSCT represents a better and simple strategy to incorporate periodic physiologic motion compared with a generalized approach. The former strategy can, therefore, improve common and state-of-the-art clinical

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

NASA Astrophysics Data System (ADS)

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.

A biomechanical approach for in vivo lung tumor motion prediction during external beam radiation therapy

NASA Astrophysics Data System (ADS)

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

2015-03-01

Lung Cancer is the leading cause of cancer death in both men and women. Among various treatment methods currently being used in the clinic, External Beam Radiation Therapy (EBRT) is used widely not only as the primary treatment method, but also in combination with chemotherapy and surgery. However, this method may lack desirable dosimetric accuracy because of respiration induced tumor motion. Recently, biomechanical modeling of the respiratory system has become a popular approach for tumor motion prediction and compensation. This approach requires reasonably accurate data pertaining to thoracic pressure variation, diaphragm position and biomechanical properties of the lung tissue in order to predict the lung tissue deformation and tumor motion. In this paper, we present preliminary results of an in vivo study obtained from a Finite Element Model (FEM) of the lung developed to predict tumor motion during respiration.

Pulmonary inflammation and tumor induction in lung tumor susceptible A/J and resistant C57BL/6J mice exposed to welding fume.

PubMed

Zeidler-Erdely, Patti C; Kashon, Michael L; Battelli, Lori A; Young, Shih-Houng; Erdely, Aaron; Roberts, Jenny R; Reynolds, Steven H; Antonini, James M

2008-09-08

Welding fume has been categorized as "possibly carcinogenic" to humans. Our objectives were to characterize the lung response to carcinogenic and non-carcinogenic metal-containing welding fumes and to determine if these fumes caused increased lung tumorigenicity in A/J mice, a lung tumor susceptible strain. We exposed male A/J and C57BL/6J, a lung tumor resistant strain, by pharyngeal aspiration four times (once every 3 days) to 85 mug of gas metal arc-mild steel (GMA-MS), GMA-stainless steel (SS), or manual metal arc-SS (MMA-SS) fume, or to 25.5 mug soluble hexavalent chromium (S-Cr). Shams were exposed to saline vehicle. Bronchoalveolar lavage (BAL) was done at 2, 7, and 28 days post-exposure. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 48 and 78 weeks post-exposure. BAL revealed notable strain-dependent differences with regards to the degree and resolution of the inflammatory response after exposure to the fumes. At 48 weeks, carcinogenic metal-containing GMA-SS fume caused the greatest increase in tumor multiplicity and incidence, but this was not different from sham. By 78 weeks, tumor incidence in the GMA-SS group versus sham approached significance (p = 0.057). A significant increase in perivascular/peribronchial lymphoid infiltrates for the GMA-SS group versus sham and an increased persistence of this fume in lung cells compared to the other welding fumes was found. The increased persistence of GMA-SS fume in combination with its metal composition may trigger a chronic, but mild, inflammatory state in the lung possibly enhancing tumorigenesis in this susceptible mouse strain.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mampuya, Wambaka Ange; Nakamura, Mitsuhiro; Matsuo, Yukinori

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 thosemore » 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

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

PubMed

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.

Bronchovascular versus bronchial sleeve resection for central lung tumors.

PubMed

Lausberg, Henning F; Graeter, Thomas P; Tscholl, Dietmar; Wendler, Olaf; Schäfers, Hans-Joachim

2005-04-01

Pneumonectomy has traditionally been the treatment of choice for central lung tumors. Bronchial sleeve resections are increasingly considered as a reasonable alternative. For tumor involvement of both central airways and pulmonary artery, bronchovascular sleeve resections are possible, but considered to be technically demanding and associated with a higher perioperative risk. In addition, their role as adequate oncologic treatment for lung cancer is unclear. We have compared the early and long-term results of bronchovascular sleeve resection with those of bronchial sleeve resection and pneumonectomy. We retrospectively analyzed all patients who underwent bronchial sleeve resection (group I, n = 104), bronchovascular sleeve resection (group II, n = 67), and pneumonectomy (group III, n = 63) for central lung cancer in our institution. The groups were comparable regarding demographics and tumor, node, and metastasis (TNM) stage. Early mortality was 1.9% in group I, 1.5% in group II, and 6.3% in group III (p = 0.19). The rate of bronchial complications was 0.96% in group I, 0% in group II, and 7.9% in group III (p = 0.006). Five-year survival was 46.1% in group I, 42.9% in group II, and 30.4% in group III (p = 0.16). Freedom from local recurrence of disease (5 years) was 83.8% in group I, 84.2% in group II, and 88.7% in group III (p = 0.56). Bronchovascular sleeve resections are as safe as bronchial sleeve resections for the treatment of central lung cancer. Both procedures have comparable early and long-term results, which are similar to those of pneumonectomy. It appears reasonable to apply bronchovascular sleeve resections more liberally.

Targeting Tumor Oct4 to Deplete Prostate Tumor and Metastasis Initiating Cells

DTIC Science & Technology

2016-10-01

Award Number: W81XWH-13-1-0461 TITLE: Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells PRINCIPAL INVESTIGATOR: Daotai...29 2016 4. TITLE AND SUBTILE Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells 5a. CONTRACT NUMBER 5b. GRANT NUMBER...the c-MYC oncogene. POU5F1B is a pseudogene of embryonic Oct4 (POU5F1). A recent study found that tumor Oct4 found in prostate cancer cells is due

Lung adenocarcinoma with intraoperatively diagnosed pleural seeding: Is main tumor resection beneficial for prognosis?

PubMed

Li, Chi; Kuo, Shuenn-Wen; Hsu, Hsao-Hsun; Lin, Mong-Wei; Chen, Jin-Shing

2018-03-01

To evaluate whether main tumor resection improves survival compared with pleural biopsy alone in patients with lung adenocarcinoma with intraoperatively diagnosed pleural seeding. Forty-three patients with lung adenocarcinoma with pleural seeding diagnosed unexpectedly during surgery performed between January 2006 and December 2014 were included in this retrospective study using a prospectively collected lung cancer database. Each surgeon decided whether to perform main tumor resection or pleural biopsy alone. Main tumor and visible pleural nodule resection was performed in 30 patients (tumor resection group). The remaining 13 patients underwent pleural nodule biopsy alone (open-close group). The clinical T stage was higher in the open-close group than in the tumor resection group (P = .02). The tumor resection group had longer operative times compared with the open-close group (mean, 141.8 vs 80.3 minutes). There were no other statistically significant differences in perioperative parameters. The surgical method was the sole statistically significant prognostic factor. Patients in the tumor resection group had better progression-free survival (3-year survival: 44.5% vs 0%; P = .009) and overall survival (3-year survival: 82.9% vs 38.5%; P = .013) than did the open-close group. There was no significant survival difference between sublobar resection and lobectomy for the main tumor resection. Our study demonstrated improved progression-free and overall survival after main tumor and visible pleural nodule resection in patients with lung adenocarcinoma with intraoperatively diagnosed pleural seeding. Further randomized trials are needed to define the role of main tumor resection in these patients. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis.

PubMed

Liu, Jian; Cho, Sung-Nam; Akkanti, Bindu; Jin, Nili; Mao, Jianqiang; Long, Weiwen; Chen, Tenghui; Zhang, Yiqun; Tang, Ximing; Wistub, Ignacio I; Creighton, Chad J; Kheradmand, Farrah; DeMayo, Francesco J

2015-03-03

Lung cancer remains the leading cause of cancer death. Genome sequencing of lung tumors from patients with squamous cell carcinoma has identified SMAD4 to be frequently mutated. Here, we use a mouse model to determine the molecular mechanisms by which Smad4 loss leads to lung cancer progression. Mice with ablation of Pten and Smad4 in airway epithelium develop metastatic adenosquamous tumors. Comparative transcriptomic and in vivo cistromic analyses determine that loss of PTEN and SMAD4 results in ELF3 and ErbB2 pathway activation due to decreased expression of ERRFI1, a negative regulator of ERBB2 in mouse and human cells. The combinatorial inhibition of ErbB2 and Akt signaling attenuate tumor progression and cell invasion, respectively. Expression profile analysis of human lung tumors substantiated the importance of the ErbB2/Akt/ELF3 signaling pathway as both a prognostic biomarker and a therapeutic drug target for treating lung cancer. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery.

PubMed

Rottmann, Joerg; Keall, Paul; Berbeco, Ross

2013-09-01

To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient. 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps. Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error <1.0 mm [root mean square (rms) error of 0.3 mm] was observed. The tracking rms accuracy on BEV images from a lung SBRT patient (≈20 mm tumor motion range) is 1.0 mm. The authors demonstrate for the first time real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time.

Metastatic Lung Lesions as a Preferred Resection Site for Immunotherapy With Tumor Infiltrating Lymphocytes.

PubMed

Ben-Avi, Ronny; Itzhaki, Orit; Simansky, David; Zippel, Dov; Markel, Gal; Ben Nun, Alon; Schachter, Jacob; Besser, Michal J

2016-06-01

Adoptive cell therapy with tumor infiltrating lymphocytes (TIL) yields 50% response rates in metastatic melanoma and shows promising clinical results in other solid tumors. Autologous TIL cultures are isolated from resected tumor tissue, expanded ex vivo to large numbers and reinfused to the preconditioned patient. In this prospective study, we validate the origin of the tumor biopsy and its effect on T-cell function and clinical response. One hundred forty-four patients underwent surgery and 79 patients were treated with TIL adoptive cell therapy. Cultures from lung tissue were compared with other origins. The success rate of establishing TIL culture from lung tissue was significantly higher compared with nonlung tissue (94% vs. 72%, respectively, P≤0.003). Lung-derived TIL cultures gave rise to higher cell numbers (P≤0.011) and exhibited increased in vitro antitumor reactivity. The average fold expansion for lung-derived TIL during a rapid expansion procedure was 1349±557 compared with 1061±473 for nonlung TIL (P≤0.038). Patients treated with TIL cultures of lung origin (compared with nonlung) had prolonged median overall survival (29 vs. 9.5 mo; P≤0.065). Given the remarkable advancement in minimally invasive thoracic surgery and the results of this study, we suggest efforts should be taken to resect lung metastasis rather than other sites to generate TIL cultures for clinical use.

Pulmonary inflammation and tumor induction in lung tumor susceptible A/J and resistant C57BL/6J mice exposed to welding fume

PubMed Central

Zeidler-Erdely, Patti C; Kashon, Michael L; Battelli, Lori A; Young, Shih-Houng; Erdely, Aaron; Roberts, Jenny R; Reynolds, Steven H; Antonini, James M

2008-01-01

Background Welding fume has been categorized as "possibly carcinogenic" to humans. Our objectives were to characterize the lung response to carcinogenic and non-carcinogenic metal-containing welding fumes and to determine if these fumes caused increased lung tumorigenicity in A/J mice, a lung tumor susceptible strain. We exposed male A/J and C57BL/6J, a lung tumor resistant strain, by pharyngeal aspiration four times (once every 3 days) to 85 μg of gas metal arc-mild steel (GMA-MS), GMA-stainless steel (SS), or manual metal arc-SS (MMA-SS) fume, or to 25.5 μg soluble hexavalent chromium (S-Cr). Shams were exposed to saline vehicle. Bronchoalveolar lavage (BAL) was done at 2, 7, and 28 days post-exposure. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 48 and 78 weeks post-exposure. Results BAL revealed notable strain-dependent differences with regards to the degree and resolution of the inflammatory response after exposure to the fumes. At 48 weeks, carcinogenic metal-containing GMA-SS fume caused the greatest increase in tumor multiplicity and incidence, but this was not different from sham. By 78 weeks, tumor incidence in the GMA-SS group versus sham approached significance (p = 0.057). A significant increase in perivascular/peribronchial lymphoid infiltrates for the GMA-SS group versus sham and an increased persistence of this fume in lung cells compared to the other welding fumes was found. Conclusion The increased persistence of GMA-SS fume in combination with its metal composition may trigger a chronic, but mild, inflammatory state in the lung possibly enhancing tumorigenesis in this susceptible mouse strain. PMID:18778475

Clinical Study of Orthogonal-View Phase-Matched Digital Tomosynthesis for Lung Tumor Localization.

PubMed

Zhang, You; Ren, Lei; Vergalasova, Irina; Yin, Fang-Fang

2017-01-01

Compared to cone-beam computed tomography, digital tomosynthesis imaging has the benefits of shorter scanning time, less imaging dose, and better mechanical clearance for tumor localization in radiation therapy. However, for lung tumors, the localization accuracy of the conventional digital tomosynthesis technique is affected by the lack of depth information and the existence of lung tumor motion. This study investigates the clinical feasibility of using an orthogonal-view phase-matched digital tomosynthesis technique to improve the accuracy of lung tumor localization. The proposed orthogonal-view phase-matched digital tomosynthesis technique benefits from 2 major features: (1) it acquires orthogonal-view projections to improve the depth information in reconstructed digital tomosynthesis images and (2) it applies respiratory phase-matching to incorporate patient motion information into the synthesized reference digital tomosynthesis sets, which helps to improve the localization accuracy of moving lung tumors. A retrospective study enrolling 14 patients was performed to evaluate the accuracy of the orthogonal-view phase-matched digital tomosynthesis technique. Phantom studies were also performed using an anthropomorphic phantom to investigate the feasibility of using intratreatment aggregated kV and beams' eye view cine MV projections for orthogonal-view phase-matched digital tomosynthesis imaging. The localization accuracy of the orthogonal-view phase-matched digital tomosynthesis technique was compared to that of the single-view digital tomosynthesis techniques and the digital tomosynthesis techniques without phase-matching. The orthogonal-view phase-matched digital tomosynthesis technique outperforms the other digital tomosynthesis techniques in tumor localization accuracy for both the patient study and the phantom study. For the patient study, the orthogonal-view phase-matched digital tomosynthesis technique localizes the tumor to an average (± standard

Circulating Cell Free Tumor DNA Detection as a Routine Tool for Lung Cancer Patient Management

PubMed Central

Vendrell, Julie A.; Mau-Them, Frédéric Tran; Béganton, Benoît; Godreuil, Sylvain; Coopman, Peter; Solassol, Jérôme

2017-01-01

Circulating tumoral DNA (ctDNA), commonly named “liquid biopsy”, has emerged as a new promising noninvasive tool to detect biomarker in several cancers including lung cancer. Applications involving molecular analysis of ctDNA in lung cancer have increased and encompass diagnosis, response to treatment, acquired resistance and prognosis prediction, while bypassing the problem of tumor heterogeneity. ctDNA may then help perform dynamic genetic surveillance in the era of precision medicine through indirect tumoral genomic information determination. The aims of this review were to examine the recent technical developments that allowed the detection of genetic alterations of ctDNA in lung cancer. Furthermore, we explored clinical applications in patients with lung cancer including treatment efficiency monitoring, acquired therapy resistance mechanisms and prognosis value. PMID:28146051

Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer

PubMed Central

Hillebrand, Larissa E.; Bengsch, Fee; Hochrein, Jochen; Hülsdünker, Jan; Bender, Julia; Follo, Marie; Busch, Hauke; Boerries, Melanie; Reinheckel, Thomas

2016-01-01

Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45−, showed a high tumorigenicity compared to non-CD24+CD90+CD45− cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24+CD90+CD45− TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24+CD90+CD45− cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24+CD90+CD45− cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas. PMID:27542270

Bronchoscopic drainage of a malignant lung abscess.

PubMed

Katsenos, Stamatis; Psathakis, Konstantinos; Chatzivasiloglou, Fotini; Antonogiannaki, Elvira-Markela; Psara, Anthoula; Tsintiris, Konstantinos

2015-04-01

Bronchoscopic drainage of a pyogenic lung abscess is an established therapeutic approach in selected patients in whom conventional antibiotic therapy fails. This intervention has also been undertaken in patients with abscess owing to underlying lung cancer and prior combined radiochemotherapy. However, this procedure has rarely been performed in cavitary lesions of advanced tumor origin before initiating any chemotherapy/radiotherapy scheme. Herein, we describe a case of a 68-year-old woman with lung adenocarcinoma stage IIIB, who underwent bronchoscopic drainage of necrotizing tumor lesion, thus improving her initial poor clinical condition and rendering other treatment modalities, such as radiotherapy, more effective and beneficial. Bronchoscopic drainage of a symptomatic cancerous lung abscess should be considered as an alternative and palliative treatment approach in patients with advanced inoperable non-small cell lung cancer.

Molecular profiling of single circulating tumor cells from lung cancer patients.

PubMed

Park, Seung-Min; Wong, Dawson J; Ooi, Chin Chun; Kurtz, David M; Vermesh, Ophir; Aalipour, Amin; Suh, Susie; Pian, Kelsey L; Chabon, Jacob J; Lee, Sang Hun; Jamali, Mehran; Say, Carmen; Carter, Justin N; Lee, Luke P; Kuschner, Ware G; Schwartz, Erich J; Shrager, Joseph B; Neal, Joel W; Wakelee, Heather A; Diehn, Maximilian; Nair, Viswam S; Wang, Shan X; Gambhir, Sanjiv S

2016-12-27

Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.

A hybrid approach for fusing 4D-MRI temporal information with 3D-CT for the study of lung and lung tumor motion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Y. X.; Van Reeth, E.; Poh, C. L., E-mail: clpoh@ntu.edu.sg

2015-08-15

Purpose: Accurate visualization of lung motion is important in many clinical applications, such as radiotherapy of lung cancer. Advancement in imaging modalities [e.g., computed tomography (CT) and MRI] has allowed dynamic imaging of lung and lung tumor motion. However, each imaging modality has its advantages and disadvantages. The study presented in this paper aims at generating synthetic 4D-CT dataset for lung cancer patients by combining both continuous three-dimensional (3D) motion captured by 4D-MRI and the high spatial resolution captured by CT using the authors’ proposed approach. Methods: A novel hybrid approach based on deformable image registration (DIR) and finite elementmore » method simulation was developed to fuse a static 3D-CT volume (acquired under breath-hold) and the 3D motion information extracted from 4D-MRI dataset, creating a synthetic 4D-CT dataset. Results: The study focuses on imaging of lung and lung tumor. Comparing the synthetic 4D-CT dataset with the acquired 4D-CT dataset of six lung cancer patients based on 420 landmarks, accurate results (average error <2 mm) were achieved using the authors’ proposed approach. Their hybrid approach achieved a 40% error reduction (based on landmarks assessment) over using only DIR techniques. Conclusions: The synthetic 4D-CT dataset generated has high spatial resolution, has excellent lung details, and is able to show movement of lung and lung tumor over multiple breathing cycles.« less

A hybrid approach for fusing 4D-MRI temporal information with 3D-CT for the study of lung and lung tumor motion.

PubMed

Yang, Y X; Teo, S-K; Van Reeth, E; Tan, C H; Tham, I W K; Poh, C L

2015-08-01

Accurate visualization of lung motion is important in many clinical applications, such as radiotherapy of lung cancer. Advancement in imaging modalities [e.g., computed tomography (CT) and MRI] has allowed dynamic imaging of lung and lung tumor motion. However, each imaging modality has its advantages and disadvantages. The study presented in this paper aims at generating synthetic 4D-CT dataset for lung cancer patients by combining both continuous three-dimensional (3D) motion captured by 4D-MRI and the high spatial resolution captured by CT using the authors' proposed approach. A novel hybrid approach based on deformable image registration (DIR) and finite element method simulation was developed to fuse a static 3D-CT volume (acquired under breath-hold) and the 3D motion information extracted from 4D-MRI dataset, creating a synthetic 4D-CT dataset. The study focuses on imaging of lung and lung tumor. Comparing the synthetic 4D-CT dataset with the acquired 4D-CT dataset of six lung cancer patients based on 420 landmarks, accurate results (average error <2 mm) were achieved using the authors' proposed approach. Their hybrid approach achieved a 40% error reduction (based on landmarks assessment) over using only DIR techniques. The synthetic 4D-CT dataset generated has high spatial resolution, has excellent lung details, and is able to show movement of lung and lung tumor over multiple breathing cycles.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vassiliev, O; Wang, H

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 themore » 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.« less

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

PubMed

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.

Electromagnetic Tracking Navigation to Guide Radiofrequency Ablation (RFA) of a Lung Tumor

PubMed Central

Amalou, Hayet; Wood, Bradford J.

2013-01-01

Radiofrequency ablation (RFA) may be an option for patients with lung tumors who have unresectable disease and are not suitable for available palliative modalities. RFA electrode positioning may take several attempts, necessitating multiple imaging acquisitions or continuous use of CT (Computed Tomography). Electromagnetic tracking utilizes miniature sensors integrated with RFA equipment to guide tools in real-time, while referencing to pre-procedure imaging. This technology was demonstrated successfully during a lung tumor ablation, and was more accurate at targeting the tumor, compared to traditional freehand needle insertion. It is possible, although speculative and anecdotal, that more accuracy could prevent unnecessary repositioning punctures and decrease radiation exposure. Electromagnetic tracking has theoretical potential to benefit minimally invasive interventions. PMID:23207535

Impacts of lung and tumor volumes on lung dosimetry for nonsmall cell lung cancer.

PubMed

Lei, Weijie; Jia, Jing; Cao, Ruifen; Song, Jing; Hu, Liqin

2017-09-01

The purpose of this study was to determine the impacts of lung and tumor volumes on normal lung dosimetry in three-dimensional conformal radiotherapy (3DCRT), step-and-shoot intensity-modulated radiotherapy (ssIMRT), and single full-arc volumetric-modulated arc therapy (VMAT) in treatment of nonsmall cell lung cancers (NSCLC). All plans were designed to deliver a total dose of 66 Gy in 33 fractions to PTV for the 32 NSCLC patients with various total (bilateral) lung volumes, planning target volumes (PTVs), and PTV locations. The ratio of the lung volume (total lung volume excluding the PTV volume) to the PTV volume (LTR) was evaluated to represent the impacts in three steps. (a) The least squares method was used to fit mean lung doses (MLDs) to PTVs or LTRs with power-law function in the population cohort (N = 32). (b) The population cohort was divided into three groups by LTRs based on first step and then by PTVs, respectively. The MLDs were compared among the three techniques in each LTR group (LG) and each PTV group (PG). (c) The power-law correlation was tested by using the adaptive radiation therapy (ART) planning data of individual patients in the individual cohort (N = 4). Different curves of power-law function with high R 2 values were observed between averaged LTRs and averaged MLDs for 3DCRT, ssIMRT, and VMAT, respectively. In the individual cohort, high R 2 values of fitting curves were also observed in individual patients in ART, although the trend was highly patient-specific. There was a more obvious correlation between LTR and MLD than that between PTV and MLD. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Real-time soft tissue motion estimation for lung tumors during radiotherapy delivery

PubMed Central

Rottmann, Joerg; Keall, Paul; Berbeco, Ross

2013-01-01

Purpose: To provide real-time lung tumor motion estimation during radiotherapy treatment delivery without the need for implanted fiducial markers or additional imaging dose to the patient. Methods: 2D radiographs from the therapy beam's-eye-view (BEV) perspective are captured at a frame rate of 12.8 Hz with a frame grabber allowing direct RAM access to the image buffer. An in-house developed real-time soft tissue localization algorithm is utilized to calculate soft tissue displacement from these images in real-time. The system is tested with a Varian TX linear accelerator and an AS-1000 amorphous silicon electronic portal imaging device operating at a resolution of 512 × 384 pixels. The accuracy of the motion estimation is verified with a dynamic motion phantom. Clinical accuracy was tested on lung SBRT images acquired at 2 fps. Results: Real-time lung tumor motion estimation from BEV images without fiducial markers is successfully demonstrated. For the phantom study, a mean tracking error <1.0 mm [root mean square (rms) error of 0.3 mm] was observed. The tracking rms accuracy on BEV images from a lung SBRT patient (≈20 mm tumor motion range) is 1.0 mm. Conclusions: The authors demonstrate for the first time real-time markerless lung tumor motion estimation from BEV images alone. The described system can operate at a frame rate of 12.8 Hz and does not require prior knowledge to establish traceable landmarks for tracking on the fly. The authors show that the geometric accuracy is similar to (or better than) previously published markerless algorithms not operating in real-time. PMID:24007146

NF-κB activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer

PubMed Central

Blakely, Collin M.; Pazarentzos, Evangelos; Olivas, Victor; Asthana, Saurabh; Yan, Jenny Jiacheng; Tan, Irena; Hrustanovic, Gorjan; Chan, Elton; Lin, Luping; Neel, Dana S.; Newton, William; Bobb, Kathryn; Fouts, Timothy; Meshulam, Jeffrey; Gubens, Matthew A.; Jablons, David M.; Johnson, Jeffrey R.; Bandyopadhyay, Sourav; Krogan, Nevan J.; Bivona, Trever G.

2015-01-01

Summary Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR-mutant lung adenocarcinoma we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses. PMID:25843712

GLI pathogenesis-related 1 functions as a tumor-suppressor in lung cancer.

PubMed

Sheng, Xiumei; Bowen, Nathan; Wang, Zhengxin

2016-03-18

GLI pathogenesis-related 1 (GLIPR1) was originally identified in glioblastomas and its expression was also found to be down-regulated in prostate cancer. Functional studies revealed both growth suppression and proapoptotic activities for GLIPR1 in multiple cancer cell lines. GLIPR1's role in lung cancer has not been investigated. Protein arginine methyltransferase 5 (PRMT5) is a protein arginine methyltransferase and forms a stoichiometric complex with the WD repeat domain 77 (WDR77) protein. Both PRMT5 and WDR77 are essential for growth of lung epithelial and cancer cells. But additional gene products that interact genetically or biochemichally with PRMT5 and WDR77 in the control of lung cancer cell growth are not characterized. DNA microarray and immunostaining were used to detect GLIPR1 expression during lung development and lung tumorigenesis. GLIPR1 expression was also analyzed in the TCGA lung cancer cohort. The consequence of GLIPR1 on growth of lung cancer cells in the tissue culture and lung tumor xenografts in the nude mice was observed. We found that GLIPR1 expression is negatively associated with PRMT5/WDR77. GLIPR1 is absent in growing epithelial cells at the early stages of mouse lung development and highly expressed in the adult lung. Expression of GLIPR1 was down-regulated during lung tumorigenesis and its expression suppressed growth of lung cancer cells in the tissue culture and lung tumor xenografts in mice. GLIPR1 regulates lung cancer growth through the V-Erb-B avian erythroblastic leukemia viral oncogene homolog 3 (ErbB3). This study reveals a novel pathway that PRMT5/WDR77 regulates GLIPR1 expression to control lung cancer cell growth and GLIPR1 as a potential therapeutic agent for lung cancer.

BJ-TSA-9, a novel human tumor-specific gene, has potential as a biomarker of lung cancer.

PubMed

Li, Yunyan; Dong, Xueyuan; Yin, Yanhui; Su, Yanrong; Xu, Qingwen; Zhang, Yuxia; Pang, Xuewen; Zhang, Yu; Chen, Weifeng

2005-12-01

Using bioinformatics, we have identified a novel tumor-specific gene BJ-TSA-9, which has been validated by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). BJ-TSA-9 mRNA was expressed in 52.5% (21 of 40) of human lung cancer tissues and was especially higher in lung adenocarcinoma (68.8%). To explore the potential application of BJ-TSA-9 for the detection of circulating cancer cells in lung cancer patients, nested RT-PCR was performed. The overall positive detection rate was 34.3% (24 of 70) in peripheral blood mononuclear cells (PBMCs) of patients with various types of lung cancers and was 53.6% (15 of 28) in PBMCs of lung adenocarcinoma patients. In combination with the detection of two known marker genes SCC and LUNX, the detection rate was increased to 81.4%. A follow-up study was performed in 37 patients after surgical removal of tumor mass. Among nine patients with persistent detection of two to three tumor marker transcripts in PBMCs, six patients had recurrence/metastasis. In contrast, 28 patients with transient detection of one tumor marker or without detection of any tumor marker were all in remission. Thus, BJ-TSA-9 may serve as a marker for lung cancer diagnosis and as a marker, in combination with two other tumor markers, for the prediction of the recurrence and prognosis of lung cancer patients.

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

PubMed

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

SU-E-J-269: Tracking of Tumor Regression for Stage III Lung Cancer Using CBCT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, K; Biswas, T; Podder, T

2015-06-15

Purpose: This study is to evaluate the tumor regression over the course of EBRT treatment and to determine the difference of tumor reduction for stage III lung squamous cell cancer (SCC) and adenocarcinoma using CBCT. Methods: Twenty three stage III lung cancer patients treated in our clinic who had daily cone beam CT (CBCT) were selected for this study (16 adenocarcinoma and 7 SCC cases). Patients received prescription dose in the range of 50Gy–71.4Gy (mean =60.3Gy, median =50Gy) at 1.8Gy or 2Gy per fraction. Treatments spanned over a minimum of five weeks. Initial mean volume of the gross tumor volumemore » (GTV) was 123cc (range = 14.7cc–353.3cc). For this study, we choose six sets of CBCTs at an interval of one week, starting from the first fraction of treatment. Daily CBCTs from treatment linac computer were transferred to MIM Software version 6.0. An experienced physician contoured the primary GTV on each slices of the CBCT for these patients. Results: A consistent regression of the GTVs was observed in all patients, except in one patient (adeno case) where GTV did not change. Weekly volumetric reduction was in the range of 11.2%–16.6%. Maximum reductions were noticed in the first two weeks of the treatment cycle; mean overall (for adeno+SCC) reductions were 16.6%, 14.2% in week-1 and week-2, respectively. Mean reduction over five weeks of treatment was 49.8% (range = 0.1%–75.5%). Higher reduction was observed in SCC patients as compare to adenocarcinoma cases (54.9% vs. 47.6%); however, the difference was not statistically significant (p-value > 0.05). Conclusion: Large regression of tumors over the course of EBRT for stage III lung cancer patients was observed. Both SCC and adenocarcinoma responded well; overall reduction for SCC cases was higher. A future study is warranted for determining the co-relation between tumor volume reduction and treatment outcome.« less

Lung tumor motion change during stereotactic body radiotherapy (SBRT): an evaluation using MRI

PubMed Central

Olivier, Kenneth R.; Li, Jonathan G.; Liu, Chihray; Newlin, Heather E.; Schmalfuss, Ilona; Kyogoku, Shinsuke; Dempsey, James F.

2014-01-01

The purpose of this study is to investigate changes in lung tumor internal target volume during stereotactic body radiotherapy treatment (SBRT) using magnetic resonance imaging (MRI). Ten lung cancer patients (13 tumors) undergoing SBRT (48 Gy over four consecutive days) were evaluated. Each patient underwent three lung MRI evaluations: before SBRT (MRI‐1), after fraction 3 of SBRT (MRI‐3), and three months after completion of SBRT (MRI‐3m). Each MRI consisted of T1‐weighted images in axial plane through the entire lung. A cone‐beam CT (CBCT) was taken before each fraction. On MRI and CBCT taken before fractions 1 and 3, gross tumor volume (GTV) was contoured and differences between the two volumes were compared. Median tumor size on CBCT before fractions 1 (CBCT‐1) and 3 (CBCT‐3) was 8.68 and 11.10 cm3, respectively. In 12 tumors, the GTV was larger on CBCT‐3 compared to CBCT‐1 (median enlargement, 1.56 cm3). Median tumor size on MRI‐1, MRI‐3, and MRI‐3m was 7.91, 11.60, and 3.33 cm3, respectively. In all patients, the GTV was larger on MRI‐3 compared to MRI‐1 (median enlargement, 1.54 cm3). In all patients, GTV was smaller on MRI‐3m compared to MRI‐1 (median shrinkage, 5.44 cm3). On CBCT and MRI, all patients showed enlargement of the GTV during the treatment week of SBRT, except for one patient who showed minimal shrinkage (0.86 cm3). Changes in tumor volume are unpredictable; therefore, motion and breathing must be taken into account during treatment planning, and image‐guided methods should be used, when treating with large fraction sizes. PACS number: 87.53.Ly PMID:24892328

Delivery of platinum(IV) drug to subcutaneous tumor and lung metastasis using bradykinin-potentiating peptide-decorated chitosan nanoparticles.

PubMed

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

Multi-phase simultaneous segmentation of tumor in lung 4D-CT data with context information.

PubMed

Shen, Zhengwen; Wang, Huafeng; Xi, Weiwen; Deng, Xiaogang; Chen, Jin; Zhang, Yu

2017-01-01

Lung 4D computed tomography (4D-CT) plays an important role in high-precision radiotherapy because it characterizes respiratory motion, which is crucial for accurate target definition. However, the manual segmentation of a lung tumor is a heavy workload for doctors because of the large number of lung 4D-CT data slices. Meanwhile, tumor segmentation is still a notoriously challenging problem in computer-aided diagnosis. In this paper, we propose a new method based on an improved graph cut algorithm with context information constraint to find a convenient and robust approach of lung 4D-CT tumor segmentation. We combine all phases of the lung 4D-CT into a global graph, and construct a global energy function accordingly. The sub-graph is first constructed for each phase. A context cost term is enforced to achieve segmentation results in every phase by adding a context constraint between neighboring phases. A global energy function is finally constructed by combining all cost terms. The optimization is achieved by solving a max-flow/min-cut problem, which leads to simultaneous and robust segmentation of the tumor in all the lung 4D-CT phases. The effectiveness of our approach is validated through experiments on 10 different lung 4D-CT cases. The comparison with the graph cut without context constraint, the level set method and the graph cut with star shape prior demonstrates that the proposed method obtains more accurate and robust segmentation results.

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

NASA Astrophysics Data System (ADS)

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.

Tumor heterogeneity and resistance to EGFR-targeted therapy in advanced nonsmall cell lung cancer: challenges and perspectives

PubMed Central

Cheng, Xinghua; Chen, Haiquan

2014-01-01

Lung cancer, mostly nonsmall cell lung cancer, continues to be the leading cause of cancer-related death worldwide. With the development of tyrosine kinase inhibitors that selectively target lung cancer-related epidermal growth factor receptor mutations, management of advanced nonsmall cell lung cancer has been greatly transformed. Improvements in progression-free survival and life quality of the patients were observed in numerous clinical studies. However, overall survival is not prolonged because of later-acquired drug resistance. Recent studies reveal a heterogeneous subclonal architecture of lung cancer, so it is speculated that the tumor may rapidly adapt to environmental changes via a Darwinian selection mechanism. In this review, we aim to provide an overview of both spatial and temporal tumor heterogeneity as potential mechanisms underlying epidermal growth factor receptor tyrosine kinase inhibitor resistance in nonsmall cell lung cancer and summarize the possible origins of tumor heterogeneity covering theories of cancer stem cells and clonal evolution, as well as genomic instability and epigenetic aberrations in lung cancer. Moreover, investigational measures that overcome heterogeneity-associated drug resistance and new assays to improve tumor assessment are also discussed. PMID:25285017

[Effect of Buzhong Yiqi decoction on PI3K and AKT in spleen, stomach and lung of nude mice with lung adenocarcinoma transplantation tumor].

PubMed

Liu, Ya-Li; Wang, Ying; Yi, Jia-Li; Jing, Huan; Liu, Chun-Ying

2014-05-01

To explore the effect of Buzhong Yiqi decoction on PI3K/AKT signaling pathway in spleen, stomach and lung of nude mice with lung adenocarcinoma transplantation tumor. Totally 60 nude mice were randomly divided into the blank control group, the tumor-bearing control group, the cisplatin group, the low-dose Buzhong Yiqi decoction group, the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group. After the corresponding interventions, efforts were made to measure the transplanted tumor volume and calculate the tumor inhibiting rate. The immunohistochemical method and real time PCR were used to detect the expression of PI3K and AKT level in nude mice spleen, stomach and lung. Buzhong Yiqi decoction of different concentrations combined with cisplatin could inhibit the growth of the transplanted tumor, with the strongest inhibitory effect in the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group. All of the expressions of PI3K and AKT protein and gene in the spleen, stomach and lung increased, with the most significant increase in the tumor-bearing group. Along with the increase of the concentration of cisplatin and Buzhong Yiqi decoction, the expressions of PI3K and AKT gradually reduced. Compared with the tumor-bearing control group, there were statistical differences in spleen and stomach tissues (P < 0.05). Compared with the cisplatin group, the middle-dose Buzhong Yiqi decoction group and the high-dose Buzhong Yiqi decoction group showed statistical differences (P < 0.05), but without statistical difference compared with the blank control group. Among nude mice with lung adenocarcinoma transplantation tumor, the PI3K and AKT protein and gene expressions in spleen, stomach and lung tissues increased, which might indicated the effect of cisplatin and Buzhong Yiqi decoction in reducing PI3K and AKT expressions and the relations between the reduction degree and the concentrations of Buzhong Yiqi

Comparison of tumor biology of two distinct cell sub-populations in lung cancer stem cells.

PubMed

Wang, Jianyu; Sun, Zhiwei; Liu, Yongli; Kong, Liangsheng; Zhou, Shixia; Tang, Junlin; Xing, Hongmei Rosie

2017-11-14

Characterization of the stem-like properties of cancer stem cells (CSCs) remain indirect and qualitative, especially the ability of CSCs to undergo asymmetric cell division for self renewal and differentiation, a unique property of cells of stem origin. It is partly due to the lack of stable cellular models of CSCs. In this study, we developed a new approach for CSC isolation and purification to derive a CSC-enriched cell line (LLC-SE). By conducting five consecutive rounds of single cell cloning using the LLC-SE cell line, we obtained two distinct sub-population of cells within the Lewis lung cancer CSCs that employed largely symmetric division for self-renewal (LLC-SD) or underwent asymmetric division for differentiation (LLC-ASD). LLC-SD and LLC-ASD cell lines could be stably passaged in culture and be distinguished by cell morphology, stem cell marker, spheroid formation and subcutaneous tumor initiation efficiency, as well as orthotopic lung tumor growth, progression and survival. The ability LLC-ASD cells to undergo asymmetric division was visualized and quantified by the asymmetric segregation of labeled BrdU and NUMB to one of the two daughter cells in anaphase cell division. The more stem-like LLC-SD cells exhibited higher capacity for tumorigenesis and progression and shorter survival. As few as 10 LLC-SD could initiate subcutaneous tumor growth when transplanted to the athymic mice. Collectively, these observations suggest that the SD-type of cells appear to be on the top of the hierarchical order of the CSCs. Furthermore, they have lead to generated cellular models of CSC self-renewal for future mechanistic investigations.

Diagnostic value of bronchoalveolar lavage fluid and serum tumor markers for lung cancer.

PubMed

Wang, Hongmin; Zhang, Xiaohong; Liu, Xinkui; Liu, Kangdong; Li, Yuexia; Xu, Haijiang

2016-01-01

To analyze the changes of bronchoalveolar lavage fluid (BALF) and serum tumor markers in lung cancer. Fifty patients with lung cancer (study group) and 50 cases with benign lung lesions (control group) were selected from May, 2010 to May, 2013. The observation group included squamous cell carcinoma subgroup (n = 25), adenocarcinoma subgroup (n = 19), and small cell undifferentiated carcinoma subgroup (n = 6). The carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and cytokeratin 19 fragment (CYFRA21-1) concentration were compared; and the comparisons among subgroups were also performed. Three kinds of tumor markers in BALF and serum of the observation group were higher than that of the control group. NSE concentration of small.cell lung cancer was the highest, CYFRA21.1 concentration was highest in the squamous cell carcinoma, and CEA concentration was highest in the adenocarcinoma group; the former increased more significantly. BALF and serum NSE, CEA, and CYFRA21.1 elevated in lung cancer, which had prompt value for pathology, especially significant for BALF.

Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors

PubMed Central

Akbay, Esra A; Koyama, Shohei; Carretero, Julian; Altabef, Abigail; Tchaicha, Jeremy H; Christensen, Camilla L; Mikse, Oliver R; Cherniack, Andrew D; Beauchamp, Ellen M; Pugh, Trevor J; Wilkerson, Matthew D; Fecci, Peter E; Butaney, Mohit; Reibel, Jacob B; Soucheray, Margaret; Cohoon, Travis J; Janne, Pasi A; Meyerson, Matthew; Hayes, D. Neil; Shapiro, Geoffrey I; Shimamura, Takeshi; Sholl, Lynette M; Rodig, Scott J; Freeman, Gordon J; Hammerman, Peter S; Dranoff, Glenn; Wong, Kwok-Kin

2013-01-01

The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition. PMID:24078774

BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer.

PubMed

Rodriguez-Nieto, Salvador; Sanchez-Cespedes, Montse

2009-04-01

Losses of heterozygosity (LOH) of the short arm of chromosome 19 are frequent in lung cancer, suggesting that one or more tumor suppressor genes are present in this region. The LKB1 gene, also called STK11, is somatically inactivated through point mutations and large deletions in lung tumors, demonstrating that LKB1 is a target of the LOH of this chromosomal arm. Data from several independent groups have provided information about the profiles of lung tumors with LKB1 inactivation and it is generally agreed that this alteration strongly predominates in non-small cell lung cancer, in particular adenocarcinomas, in smokers. The LKB1 protein has serine-threonine kinase activity and is involved in the regulation of the cell energetic checkpoint through the phosphorylation and activation of adenosine monophosphate-dependent kinase (AMPK). LKB1 is also involved in other processes such as cell polarization, probably through substrates other than AMPK. Interestingly, another gene on chromosome 19p, BRG1, encoding a component of the SWI/SNF chromatin-remodeling complex, has emerged as a tumor suppressor gene that is altered in lung tumors. Similar to LKB1, BRG1 is somatically inactivated by point mutations or large deletions in lung tumors featuring LOH of chromosome 19p. These observations suggest an important role for BRG1 in lung cancer and highlight the need to further our understanding of the function of Brahma/SWI2-related gene 1 (BRG1) in cancer. Finally, simultaneous mutations at LKB1 and BRG1 are common in lung cancer cells, which exemplifies how a single event, LOH of chromosome 19p in this instance, targets two different tumor suppressors.

Primary Tumor and MEF Cell Isolation to Study Lung Metastasis.

PubMed

Dong, Shengli; Maziveyi, Mazvita; Alahari, Suresh K

2015-05-20

In breast tumorigenesis, the metastatic stage of the disease poses the greatest threat to the affected individual. Normal breast cells with altered genotypes now possess the ability to invade and survive in other tissues. In this protocol, mouse mammary tumors are removed and primary cells are prepared from tumors. The cells isolated from this procedure are then available for gene profiling experiments. For successful metastasis, these cells must be able to intravasate, survive in circulation, extravasate to distant organs, and survive in that new organ system. The lungs are the typical target of breast cancer metastasis. A set of genes have been discovered that mediates the selectivity of metastasis to the lung. Here we describe a method of studying lung metastasis from a genetically engineered mouse model.. Furthermore, another protocol for analyzing mouse embryonic fibroblasts (MEFs) from the mouse embryo is included. MEF cells from the same animal type provide a clue of non-cancer cell gene expression. Together, these techniques are useful in studying mouse mammary tumorigenesis, its associated signaling mechanisms and pathways of the abnormalities in embryos.

Noninvasive Tissue Characterization of Lung Tumors Using Integrated Backscatter Intravascular Ultrasound: An Ex Vivo Comparative Study With Pathological Diagnosis.

PubMed

Ito, Fumitaka; Kawasaki, Masanori; Ohno, Yasushi; Toyoshi, Sayaka; Morishita, Megumi; Kaito, Daizo; Yanase, Komei; Funaguchi, Norihiko; Asano, Masahiro; Endo, Junki; Mori, Hidenori; Kobayashi, Kazuhiro; Nishigaki, Kazuhiko; Miyazaki, Tatsuhiko; Takemura, Genzou; Minatoguchi, Shinya

2016-05-01

Endobronchial ultrasonography (EBUS) facilitates a lung cancer diagnosis. However, qualitative tissue characterization of lung tumors is difficult using EBUS. Integrated backscatter (IBS) is an ultrasound technique that calculates the power of the ultrasound signal to characterize tissue components in coronary arteries. We hypothesized that qualitative diagnosis of lung tumors is possible using the IBS technique. The aim of the present study was to elucidate whether the IBS technique can be used in lung tissue diagnoses. Thirty-five consecutive patients who underwent surgery for lung cancer were prospectively enrolled. Surgical specimens of the lung and the tumor tissue were obtained, and the IBS values were measured within 48 h after surgery. Histologic images of lung and tumor tissues were compared with IBS values, and the relative interstitial area according to results of Masson's trichrome staining were determined by using an imaging processor. The IBS values in tumor tissue were significantly lower than those in normal lung tissue (-50.9 ± 2.6 dB and -47.6 ± 2.6 dB, respectively; P < .001). The IBS values of adenocarcinomas associated with a good 5-year survival rate were higher than those of non-adenocarcinomas (-48.1 ± 1.6 dB and -52.6 ± 1.4 dB; P < .001). There were significant correlations between the IBS values and the relative interstitial area or micro air area in tumor (r = 0.53 and r = 0.67; P < .01). After combining normal lung tissue and adenocarcinomas with a good prognosis, the sensitivity and specificity for establishing the presence of lung tumors were 84% and 85%. Qualitative diagnosis of lung tumors was possible, with a sensitivity of 84% and a specificity of 85%, using the ultrasound IBS technique. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Three-dimensional lung tumor segmentation from x-ray computed tomography using sparse field active models.

PubMed

Awad, Joseph; Owrangi, Amir; Villemaire, Lauren; O'Riordan, Elaine; Parraga, Grace; Fenster, Aaron

2012-02-01

Manual segmentation of lung tumors is observer dependent and time-consuming but an important component of radiology and radiation oncology workflow. The objective of this study was to generate an automated lung tumor measurement tool for segmentation of pulmonary metastatic tumors from x-ray computed tomography (CT) images to improve reproducibility and decrease the time required to segment tumor boundaries. The authors developed an automated lung tumor segmentation algorithm for volumetric image analysis of chest CT images using shape constrained Otsu multithresholding (SCOMT) and sparse field active surface (SFAS) algorithms. The observer was required to select the tumor center and the SCOMT algorithm subsequently created an initial surface that was deformed using level set SFAS to minimize the total energy consisting of mean separation, edge, partial volume, rolling, distribution, background, shape, volume, smoothness, and curvature energies. The proposed segmentation algorithm was compared to manual segmentation whereby 21 tumors were evaluated using one-dimensional (1D) response evaluation criteria in solid tumors (RECIST), two-dimensional (2D) World Health Organization (WHO), and 3D volume measurements. Linear regression goodness-of-fit measures (r(2) = 0.63, p < 0.0001; r(2) = 0.87, p < 0.0001; and r(2) = 0.96, p < 0.0001), and Pearson correlation coefficients (r = 0.79, p < 0.0001; r = 0.93, p < 0.0001; and r = 0.98, p < 0.0001) for 1D, 2D, and 3D measurements, respectively, showed significant correlations between manual and algorithm results. Intra-observer intraclass correlation coefficients (ICC) demonstrated high reproducibility for algorithm (0.989-0.995, 0.996-0.997, and 0.999-0.999) and manual measurements (0.975-0.993, 0.985-0.993, and 0.980-0.992) for 1D, 2D, and 3D measurements, respectively. The intra-observer coefficient of variation (CV%) was low for algorithm (3.09%-4.67%, 4.85%-5.84%, and 5

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

NASA Astrophysics Data System (ADS)

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.

Respiratory gating during stereotactic body radiotherapy for lung cancer reduces tumor position variability.

PubMed

Saito, Tetsuo; Matsuyama, Tomohiko; Toya, Ryo; Fukugawa, Yoshiyuki; Toyofuku, Takamasa; Semba, Akiko; Oya, Natsuo

2014-01-01

We evaluated the effects of respiratory gating on treatment accuracy in lung cancer patients undergoing lung stereotactic body radiotherapy by using electronic portal imaging device (EPID) images. Our study population consisted of 30 lung cancer patients treated with stereotactic body radiotherapy (48 Gy/4 fractions/4 to 9 days). Of these, 14 were treated with- (group A) and 16 without gating (group B); typically the patients whose tumors showed three-dimensional respiratory motion ≧5 mm were selected for gating. Tumor respiratory motion was estimated using four-dimensional computed tomography images acquired during treatment simulation. Tumor position variability during all treatment sessions was assessed by measuring the standard deviation (SD) and range of tumor displacement on EPID images. The two groups were compared for tumor respiratory motion and position variability using the Mann-Whitney U test. The median three-dimensional tumor motion during simulation was greater in group A than group B (9 mm, range 3-30 mm vs. 2 mm, range 0-4 mm; p<0.001). In groups A and B the median SD of the tumor position was 1.1 mm and 0.9 mm in the craniocaudal- (p = 0.24) and 0.7 mm and 0.6 mm in the mediolateral direction (p = 0.89), respectively. The median range of the tumor position was 4.0 mm and 3.0 mm in the craniocaudal- (p = 0.21) and 2.0 mm and 1.5 mm in the mediolateral direction (p = 0.20), respectively. Although patients treated with respiratory gating exhibited greater respiratory tumor motion during treatment simulation, tumor position variability in the EPID images was low and comparable to patients treated without gating. This demonstrates the benefit of respiratory gating.

Short-term inhalation of stainless steel welding fume causes sustained lung toxicity but no tumorigenesis in lung tumor susceptible A/J mice.

PubMed

Zeidler-Erdely, Patti C; Battelli, Lori A; Stone, Sam; Chen, Bean T; Frazer, David G; Young, Shih-Houng; Erdely, Aaron; Kashon, Michael L; Andrews, Ronnee; Antonini, James M

2011-02-01

Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at-risk population for development of lung cancer. Our objective was to expose, by inhalation, lung tumor susceptible (A/J) and resistant C57BL/6J (B6) mice to stainless steel (SS) welding fume containing carcinogenic metals and characterize the lung-inflammatory and tumorigenic response. Male mice were exposed to air or gas metal arc (GMA)-SS welding fume at 40 mg/m(3)×3 h/day for 6 and 10 days. At 1, 4, 7, 10, 14, and 28 days after 10 days of exposure, bronchoalveolar lavage (BAL) was done. Lung cytotoxicity, permeability, inflammatory cytokines, and cell differentials were analyzed. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 78 weeks after 6 and 10 days of exposure. Inhalation of GMA-SS fume caused an early, sustained macrophage and lymphocyte response followed by a gradual neutrophil influx and the magnitudes of these differed between the mouse strains. Monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNF-α) were increased in both strains while the B6 also had increased interleukin-6 (IL-6) protein. BAL measures of cytotoxicity and damage were similar between the strains and significantly increased at all time points. Histopathology and tumorigenesis were unremarkable at 78 weeks. In conclusion, GMA-SS welding fume induced a significant and sustained inflammatory response in both mouse strains with no recovery by 28 days. Under our exposure conditions, GMA-SS exposure resulted in no significant tumor development in A/J mice.

The anti-apoptotic BAG3 protein is expressed in lung carcinomas and regulates small cell lung carcinoma (SCLC) tumor growth.

PubMed

Chiappetta, Gennaro; Basile, Anna; Barbieri, Antonio; Falco, Antonia; Rosati, Alessandra; Festa, Michelina; Pasquinelli, Rosa; Califano, Daniela; Palma, Giuseppe; Costanzo, Raffaele; Barcaroli, Daniela; Capunzo, Mario; Franco, Renato; Rocco, Gaetano; Pascale, Maria; Turco, Maria Caterina; De Laurenzi, Vincenzo; Arra, Claudio

2014-08-30

BAG3, member the HSP70 co-chaperones family, has been shown to play a relevant role in the survival, growth and invasiveness of different tumor types. In this study, we investigate the expression of BAG3 in 66 specimens from different lung tumors and the role of this protein in small cell lung cancer (SCLC) tumor growth. Normal lung tissue did not express BAG3 while we detected the expression of BAG3 by immunohistochemistry in all the 13 squamous cell carcinomas, 13 adenocarcinomas and 4 large cell carcinomas. Furthermore, we detected BAG3 expression in 22 of the 36 SCLCs analyzed. The role on SCLC cell survival was determined by down-regulating BAG3 levels in two human SCLC cell lines, i.e. H69 and H446, in vitro and measuring cisplatin induced apoptosis. Indeed down-regulation of BAG3 determines increased cell death and sensitizes cells to cisplatin treatment. The effect of BAG3 down-regulation on tumor growth was also investigated in an in vivo xenograft model by treating mice with an adenovirus expressing a specific bag3 siRNA. Treatment with bag3 siRNA-Ad significantly reduced tumor growth and improved animal survival. In conclusion we show that a subset of SCLCs over express BAG3 that exerts an anti-apoptotic effect resulting in resistance to chemotherapy.

[(99)Tc(m)N-NOET dual-phase SPECT in differential diagnosis of benign and malignant lung tumors].

PubMed

Liu, Haiyan; Li, Sijin; Yang, Suyun; Wu, Zhifang

2014-01-01

To investigate the value of (99)Tc(m)N-NOET dual-phase SPECT in differential diagnosis of benign and malignant lung tumors. CT scan, early (20 to 30 min) and delayed (2 h) imaging of NOET SPECT were performed on 61 patients suspected of lung lesions before operation. The results were compared with the pathological findings. All cases were not treated with radiotherapy, chemotherapy or surgery before checks. Moreover, all patients had pathological diagnosis. To determine the value in differential diagnosis of tumors by analyzing the tumor uptake and excretion of (99)Tc(m)N-NOET, and the results were compared with that of CT. The value of early T/N ratio (ER) in the malignant (G1) and benign (G2) groups was 1.25 ± 0.15 and 1.09 ± 0.11 (P < 0.001), respectively, and delayed T/N ratio (DR) was 1.40 ± 0.17 and 1.18 ± 0.21 (P < 0.001). The retention index (RI) of groups G1 was (12.22 ± 6.38)% and group G2 was (8.3 ± 10.91)%, with a non-significant difference between them (P > 0.05). The ER, DR and RI of NOET SPECT in the malignant patients were not significantly correlated with TNM staging, pathological types, tumor diameter, cavity in the lung tumor mass, history of smoking, tumor size and patient gender (P > 0.05). The sensitivity of NOET dual-phase SPECT and CT in the differential diagnosis of benign and malignant lung tumors was 94.1% vs. 90.2%, specificity was 70.0% vs. 80.0% , positive predictive value (PPV) was 94.1% vs. 95.8%, negative predictive value (NPV) was 70.0% vs. 61.5 %, and accuracy was 90.2%. vs. 88.5% (P > 0.05 for all). (99)Tc(m)N- NOET dual-phase SPECT could be used in differential diagnosis of benign and malignant lung tumors, with no significant differences compared with the efficacy of CT imaging. The semiquantitative indexes (ER, DR and RI) of NOET SPECT can also be used in differential diagnosis of benign and malignant lung tumors, and are not significantly correlated with TNM staging, pathological types, tumor diameter, cavity of the

Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer

PubMed Central

Lim, Tony KH; Tan, Daniel Shao-Weng; Chua, Yong Wei; Ang, Mei Kim; Pang, Brendan; Lim, Chwee Teck; Takano, Angela; Lim, Alvin Soon-Tiong; Leong, Man Chun; Lim, Wan-Teck

2016-01-01

Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) is routinely evaluated by fluorescent in-situ hybridization (FISH) testing on biopsy tissues. Testing can be challenging however, when suitable tissue samples are unavailable. We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3–15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0–2 cells/1.88 mL of blood). The latter range was validated as the ‘false positive’ cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential CTC counts in an index case of lung cancer with no evaluable tumor tissue treated with crizotinib showed six, three and eleven ALK-positive CTCs per 1.88 mL blood at baseline, partial response and post-progression time points, respectively. Furthermore, ALK FISH rearrangement suggestive of gene copy number increase was observed in CTCs following progression. Recapitulation of ALK rearrangement patterns in the tumor on CTCs, suggested that CTCs might be used to complement tissue-based ALK testing in NSCLC to guide ALK-targeted therapy when suitable tissue biopsy samples are unavailable for testing. PMID:26993609

Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer.

PubMed

Tan, Chye Ling; Lim, Tse Hui; Lim, Tony Kh; Tan, Daniel Shao-Weng; Chua, Yong Wei; Ang, Mei Kim; Pang, Brendan; Lim, Chwee Teck; Takano, Angela; Lim, Alvin Soon-Tiong; Leong, Man Chun; Lim, Wan-Teck

2016-04-26

Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) is routinely evaluated by fluorescent in-situ hybridization (FISH) testing on biopsy tissues. Testing can be challenging however, when suitable tissue samples are unavailable. We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3-15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0-2 cells/1.88 mL of blood). The latter range was validated as the 'false positive' cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential CTC counts in an index case of lung cancer with no evaluable tumor tissue treated with crizotinib showed six, three and eleven ALK-positive CTCs per 1.88 mL blood at baseline, partial response and post-progression time points, respectively. Furthermore, ALK FISH rearrangement suggestive of gene copy number increase was observed in CTCs following progression. Recapitulation of ALK rearrangement patterns in the tumor on CTCs, suggested that CTCs might be used to complement tissue-based ALK testing in NSCLC to guide ALK-targeted therapy when suitable tissue biopsy samples are unavailable for testing.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Binkley, Michael S.; Shrager, Joseph B.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California

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 SABRmore » 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

STRAIN-SPECIFIC SENSITIVITY TO INDUCTION OF MURINE LUNG TUMORS FOLLOWING IN UTERO EXPOSURE TO 3-METHYLCHOLANTHRENE

EPA Science Inventory

We previously demonstrated that different strains of fetal mice were more sensitive to lung tumor induction by 3-methylcholanthrene (MC) than were adults. Offspring from either a D2 x B6D2F1 backcross or from parental Balb/c mice exhibited a similar high incidence of lung tumors ...

Trehalose Liposomes Suppress the Growth of Tumors on Human Lung Carcinoma-bearing Mice by Induction of Apoptosis In Vivo.

PubMed

Ichihara, Hideaki; Kuwabara, Keiji; Matsumoto, Yoko

2017-11-01

Previous evidence demonstrates that trehalose liposomes (DMTreC14) composed of L-α-dimyristoylphosphatidylcholine (DMPC) and α-D-glycopyranosyl-α-D-glucopyranoside monomyristate (TreC14) inhibit proliferation and invasion on lung carcinoma (A549 cells) in vitro. Here, we aimed to investigate suppressive effects of DMTreC14 on the growth of tumor on human lung carcinoma bearing mice. DMTreC14 composed of 30 mol% DMPC and 70 mol% TreC14 were prepared by the sonication method. Anti-tumor activities of DMTreC14 using the subcutaneous and orthotopic graft-bearing mice of A549 cells were investigated in vivo. The remarkable reduction of volume and weight in subcutaneous tumors on subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were obtained. Apoptotic-positive cells in the subcutaneous tumor slice of subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were observed using TUNEL staining. Lung weights on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 were markedly decreased compared to those of the control group. Remarkable decrease in dimensions of tumor area of lung on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 was obtained in histological analysis using the hematoxylin and eosin staining. Remarkably high anti-tumor activities of DMTreC14 for the subcutaneous and orthotopic graft-bearing mice of lung carcinoma accompanied with apoptosis were revealed for the first time in vivo. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Malignant tumors of the liver and lungs in an area with a PVC industry.

PubMed

Saric, M; Kulcar, Z; Zorica, M; Gelić, I

1976-10-01

The incidence of malignant tumors of the lung and bronchus and of cytologically confirmed primary malignant tumor of the liver was analyzed for a 4-yr period in a city with several factories, including a PVC industry. Prior to the study two cases of angio-sarcoma of the liver were diagnosed in workers employed in PVC production. The total incidence of analyzed tumors was only slightly higher than predicted. The tumors of the liver recorded did not show any dependence on place of work or residence. During the period of observation, malignant tumors of the bronchus (lung) were not recorded in the PVC industry. Their rate in the area in which the PVC industry is situated was approximately the same as that for the entire city area. The study does not indicate that the occurrence of malignant tumors other than angiosarcoma is associated with exposure to vinyl chloride.

Malignant tumors of the liver and lungs in an area with a PVC industry.

PubMed Central

Saric, M; Kulcar, Z; Zorica, M; Gelić, I

1976-01-01

The incidence of malignant tumors of the lung and bronchus and of cytologically confirmed primary malignant tumor of the liver was analyzed for a 4-yr period in a city with several factories, including a PVC industry. Prior to the study two cases of angio-sarcoma of the liver were diagnosed in workers employed in PVC production. The total incidence of analyzed tumors was only slightly higher than predicted. The tumors of the liver recorded did not show any dependence on place of work or residence. During the period of observation, malignant tumors of the bronchus (lung) were not recorded in the PVC industry. Their rate in the area in which the PVC industry is situated was approximately the same as that for the entire city area. The study does not indicate that the occurrence of malignant tumors other than angiosarcoma is associated with exposure to vinyl chloride. PMID:1026404

Follow-up segmentation of lung tumors in PET and CT data

NASA Astrophysics Data System (ADS)

Opfer, Roland; Kabus, Sven; Schneider, Torben; Carlsen, Ingwer C.; Renisch, Steffen; Sabczynski, Jörg

2009-02-01

Early response assessment of cancer therapy is a crucial component towards a more effective and patient individualized cancer therapy. Integrated PET/CT systems provide the opportunity to combine morphologic with functional information. We have developed algorithms which allow the user to track both tumor volume and standardized uptake value (SUV) measurements during the therapy from series of CT and PET images, respectively. To prepare for tumor volume estimation we have developed a new technique for a fast, flexible, and intuitive 3D definition of meshes. This initial surface is then automatically adapted by means of a model-based segmentation algorithm and propagated to each follow-up scan. If necessary, manual corrections can be added by the user. To determine SUV measurements a prioritized region growing algorithm is employed. For an improved workflow all algorithms are embedded in a PET/CT therapy monitoring software suite giving the clinician a unified and immediate access to all data sets. Whenever the user clicks on a tumor in a base-line scan, the courses of segmented tumor volumes and SUV measurements are automatically identified and displayed to the user as a graph plot. According to each course, the therapy progress can be classified as complete or partial response or as progressive or stable disease. We have tested our methods with series of PET/CT data from 9 lung cancer patients acquired at Princess Margaret Hospital in Toronto. Each patient underwent three PET/CT scans during a radiation therapy. Our results indicate that a combination of mean metabolic activity in the tumor with the PET-based tumor volume can lead to an earlier response detection than a purely volume based (CT diameter) or purely functional based (e.g. SUV max or SUV mean) response measures. The new software seems applicable for easy, faster, and reproducible quantification to routinely monitor tumor therapy.

New insights in non-small-cell lung cancer: circulating tumor cells and cell-free DNA

PubMed Central

Duréndez-Sáez, Elena; Azkárate, Aitor; Meri, Marina; Calabuig-Fariñas, Silvia; Aguilar-Gallardo, Cristóbal; Blasco, Ana

2017-01-01

Lung cancer is the second most frequent tumor and the leading cause of death by cancer in both men and women. Increasing knowledge about the cancer genome and tumor environment has led to a new setting in which morphological and molecular characterization is needed to treat patients in the most personalized way in order to achieve better outcomes. Since tumor products can be detected in body fluids, the liquid biopsy, particularly, peripheral blood, has emerged as a new source for lung cancer biomarker’s analysis. A variety of tumor components can be used for this purpose. Among them, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) should be especially considered. Different detection methods for both CTCs and ctDNA have been and are being developed to improve the sensitivity and specificity of these tests. This would lead to better characterization and would solve some clinical doubts at different disease evolution times, e.g., intratumoral or temporal heterogeneity, difficulty in the obtaining a tumor sample, etc., and would also avoid the side effects of very expensive and complicated tumor obtaining interventions. CTCs and ctDNA are useful in different lung cancer settings. Their value has been shown for the early diagnosis, prognosis, prediction of treatment efficacy, monitoring responses and early detection of lung cancer relapse. CTCs have still not been validated for use in clinical settings in non-small-cell lung cancer (NSCLC), while ctDNA has been approved by the Food and Drug Administration (FDA) and European Medical Association (EMA), and the main clinical guidelines used for detect different epidermal growth factor receptor (EGFR) mutations and the monitoring and treatment choice of mutated patients with tyrosine kinase inhibitors (TKIs). This review, describes how ctDNA seem to be winning the race against CTCs from the laboratory bench to clinical practice due to easier obtaining methods, manipulation and its implementation into

STRAIN-DEPENDENT SUSCEPTIBILITY TO TRANSPLACENTALLY-INDUCED MURINE LUNG TUMORS

EPA Science Inventory

STRAIN-DEPENDENT SUSCEPTIBILITY TO TRANSPLACENTALLY-INDUCED MURINE LUNG TUMORS
M S Miller, J E Moore, M Xu, G B Nelson, S T Dance, N D Kock, J A Ross Wake Forest University, Winston-Salem, NC and USEPA, Research Triangle Park, NC

Previously, our laboratory demonstrated...

In Vivo Evaluation of Lung Microwave Ablation in a Porcine Tumor Mimic Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Planche, Olivier, E-mail: oli.hrp@gmail.com; Teriitehau, Christophe; Boudabous, Sana

2013-02-15

To evaluate the microwave ablation of created tumor mimics in the lung of a large animal model (pigs), with examination of the ablative synergy of multiple antennas. Fifty-six tumor-mimic models of various sizes were created in 15 pigs by using barium-enriched minced collected thigh muscle injected into the lung of the same animal. Tumors were ablated under fluoroscopic guidance by single-antenna and multiple-antenna microwaves. Thirty-five tumor models were treated in 11 pigs with a single antenna at 75 W for 15 min, with 15 measuring 20 mm in diameter, 10 measuring 30 mm, and 10 measuring 40 mm. Mean circularitymore » of the single-antenna ablation zones measured 0.64 {+-} 0.12, with a diameter of 35.7 {+-} 8.7 mm along the axis of the antenna and 32.7 {+-} 12.8 mm perpendicular to the feeding point. Multiple-antenna delivery of 75 W for 15 min caused intraprocedural death of 2 animals; modified protocol to 60 W for 10 min resulted in an ablation zone with a diameter of 43.0 {+-} 7.7 along the axis of the antenna and 54.8 {+-} 8.5 mm perpendicular to the feeding point; circularity was 0.70 {+-} 0.10. A single microwave antenna can create ablation zones large enough to cover lung tumor mimic models of {<=}4 cm with no heat sink effect from vessels of {<=}6 mm. Synergic use of 3 antennas allows ablation of larger volumes than single-antenna or radiofrequency ablation, but great caution must be taken when 3 antennas are used simultaneously in the lung in clinical practice.« less

ALK ambiguous-positive non-small cell lung cancers are tumors challenged by diagnostic and therapeutic issues.

PubMed

Uguen, Arnaud; Andrieu-Key, Sophie; Vergne, Florence; Descourt, Renaud; Quéré, Gilles; Quintin-Roué, Isabelle; Key, Stéphane; Guéguen, Paul; Talagas, Matthieu; De Braekeleer, Marc; Marcorelles, Pascale

2016-09-01

Searching for ALK rearrangements using the approved fluorescent in situ hybridization (FISH) test and complementary immunohistochemistry (IHC) has become the rule to treat patients with advanced non‑small cell lung cancer (NSCLC) with anti‑ALK targeted therapy. The concordance between the two techniques is reported to be strong but imperfect. We report our experience with cases of ALK‑rearranged lung adenocarcinomas pointing out particularly ambiguous cases. FISH and IHC data on ALK but also c‑MET IHC as well as EGFR and KRAS mutation screening are considered, together with response to crizotinib treatment. We classified the 55 FISH ALK‑rearranged tumors into two groups according to the FISH and IHC results: a concordant FISH+IHC+ group (31 tumors) and an ambiguous group (24 tumors). These tumors were considered as 'ambiguous' ALK‑positive due to negative (21 tumors) or non‑contributive (3 tumors) IHC. In addition, the percentage of FISH-positive nuclei was between 15 and 20% in 17 tumors belonging to one or the other group (now called borderline tumors). We discuss the accuracy of the different tests with intent to determine whether ambiguous and borderline tumors are real positive ALK‑rearranged tumors. To conclude, ambiguous ALK‑positive lung cancers are challenging tumors with diagnosis and therapeutic issues that can justify parallel FISH, IHC and molecular screening strategy.

Diagnostic Value of Combining Tumor and Inflammatory Markers in Lung Cancer.

PubMed

Yoon, Ho Il; Kwon, Oh-Ran; Kang, Kyung Nam; Shin, Yong Sung; Shin, Ho Sang; Yeon, Eun Hee; Kwon, Keon Young; Hwang, Ilseon; Jeon, Yoon Kyung; Kim, Yongdai; Kim, Chul Woo

2016-09-01

Despite major advances in lung cancer treatment, early detection remains the most promising way of improving outcomes. To detect lung cancer in earlier stages, many serum biomarkers have been tested. Unfortunately, no single biomarker can reliably detect lung cancer. We combined a set of 2 tumor markers and 4 inflammatory or metabolic markers and tried to validate the diagnostic performance in lung cancer. We collected serum samples from 355 lung cancer patients and 590 control subjects and divided them into training and validation datasets. After measuring serum levels of 6 biomarkers (human epididymis secretory protein 4 [HE4], carcinoembryonic antigen [CEA], regulated on activation, normal T cell expressed and secreted [RANTES], apolipoprotein A2 [ApoA2], transthyretin [TTR], and secretory vascular cell adhesion molecule-1 [sVCAM-1]), we tested various sets of biomarkers for their diagnostic performance in lung cancer. In a training dataset, the area under the curve (AUC) values were 0.821 for HE4, 0.753 for CEA, 0.858 for RANTES, 0.867 for ApoA2, 0.830 for TTR, and 0.552 for sVCAM-1. A model using all 6 biomarkers and age yielded an AUC value of 0.986 and sensitivity of 93.2% (cutoff at specificity 94%). Applying this model to the validation dataset showed similar results. The AUC value of the model was 0.988, with sensitivity of 93.33% and specificity of 92.00% at the same cutoff point used in the validation dataset. Analyses by stages and histologic subtypes all yielded similar results. Combining multiple tumor and systemic inflammatory markers proved to be a valid strategy in the diagnosis of lung cancer.

Analysis of Lung Tumor Motion in a Large Sample: Patterns and Factors Influencing Precise Delineation of Internal Target Volume

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knybel, Lukas; VŠB-Technical University of Ostrava, Ostrava; Cvek, Jakub, E-mail: Jakub.cvek@fno.cz

Purpose/Objective: To evaluate lung tumor motion during respiration and to describe factors affecting the range and variability of motion in patients treated with stereotactic ablative radiation therapy. Methods and Materials: Log file analysis from online respiratory tumor tracking was performed in 145 patients. Geometric tumor location in the lungs, tumor volume and origin (primary or metastatic), sex, and tumor motion amplitudes in the superior-inferior (SI), latero-lateral (LL), and anterior-posterior (AP) directions were recorded. Tumor motion variability during treatment was described using intrafraction/interfraction amplitude variability and tumor motion baseline changes. Tumor movement dependent on the tumor volume, position and origin, andmore » sex were evaluated using statistical regression and correlation analysis. Results: After analysis of >500 hours of data, the highest rates of motion amplitudes, intrafraction/interfraction variation, and tumor baseline changes were in the SI direction (6.0 ± 2.2 mm, 2.2 ± 1.8 mm, 1.1 ± 0.9 mm, and −0.1 ± 2.6 mm). The mean motion amplitudes in the lower/upper geometric halves of the lungs were significantly different (P<.001). Motion amplitudes >15 mm were observed only in the lower geometric quarter of the lungs. Higher tumor motion amplitudes generated higher intrafraction variations (R=.86, P<.001). Interfraction variations and baseline changes >3 mm indicated tumors contacting mediastinal structures or parietal pleura. On univariate analysis, neither sex nor tumor origin (primary vs metastatic) was an independent predictive factor of different movement patterns. Metastatic lesions in women, but not men, showed significantly higher mean amplitudes (P=.03) and variability (primary, 2.7 mm; metastatic, 4.9 mm; P=.002) than primary tumors. Conclusion: Online tracking showed significant irregularities in lung tumor movement during respiration. Motion amplitude was significantly lower in

Multiple template-based fluoroscopic tracking of lung tumor mass without implanted fiducial markers

NASA Astrophysics Data System (ADS)

Cui, Ying; Dy, Jennifer G.; Sharp, Gregory C.; Alexander, Brian; Jiang, Steve B.

2007-10-01

Precise lung tumor localization in real time is particularly important for some motion management techniques, such as respiratory gating or beam tracking with a dynamic multi-leaf collimator, due to the reduced clinical tumor volume (CTV) to planning target volume (PTV) margin and/or the escalated dose. There might be large uncertainties in deriving tumor position from external respiratory surrogates. While tracking implanted fiducial markers has sufficient accuracy, this procedure may not be widely accepted due to the risk of pneumothorax. Previously, we have developed a technique to generate gating signals from fluoroscopic images without implanted fiducial markers using a template matching method (Berbeco et al 2005 Phys. Med. Biol. 50 4481-90, Cui et al 2007 Phys. Med. Biol. 52 741-55). In this paper, we present an extension of this method to multiple-template matching for directly tracking the lung tumor mass in fluoroscopy video. The basic idea is as follows: (i) during the patient setup session, a pair of orthogonal fluoroscopic image sequences are taken and processed off-line to generate a set of reference templates that correspond to different breathing phases and tumor positions; (ii) during treatment delivery, fluoroscopic images are continuously acquired and processed; (iii) the similarity between each reference template and the processed incoming image is calculated; (iv) the tumor position in the incoming image is then estimated by combining the tumor centroid coordinates in reference templates with proper weights based on the measured similarities. With different handling of image processing and similarity calculation, two such multiple-template tracking techniques have been developed: one based on motion-enhanced templates and Pearson's correlation score while the other based on eigen templates and mean-squared error. The developed techniques have been tested on six sequences of fluoroscopic images from six lung cancer patients against the reference

IL-12 Can Target Human Lung Adenocarcinoma Cells and Normal Bronchial Epithelial Cells Surrounding Tumor Lesions

PubMed Central

Airoldi, Irma; Di Carlo, Emma; Cocco, Claudia; Caci, Emanuela; Cilli, Michele; Sorrentino, Carlo; Sozzi, Gabriella; Ferrini, Silvano; Rosini, Sandra; Bertolini, Giulia; Truini, Mauro; Grossi, Francesco; Galietta, Luis Juan Vicente; Ribatti, Domenico; Pistoia, Vito

2009-01-01

Background Non small cell lung cancer (NSCLC) is a leading cause of cancer death. We have shown previously that IL-12rb2 KO mice develop spontaneously lung adenocarcinomas or bronchioalveolar carcinomas. Aim of the study was to investigate i) IL-12Rβ2 expression in human primary lung adenocarcinomas and in their counterparts, i.e. normal bronchial epithelial cells (NBEC), ii) the direct anti-tumor activity of IL-12 on lung adenocarcinoma cells in vitro and vivo, and the mechanisms involved, and iii) IL-12 activity on NBEC. Methodology/Principal Findings Stage I lung adenocarcinomas showed significantly (P = 0.012) higher frequency of IL-12Rβ2 expressing samples than stage II/III tumors. IL-12 treatment of IL-12R+ neoplastic cells isolated from primary adenocarcinoma (n = 6) inhibited angiogenesis in vitro through down-regulation of different pro-angiogenic genes (e.g. IL-6, VEGF-C, VEGF-D, and laminin-5), as assessed by chorioallantoic membrane (CAM) assay and PCR array. In order to perform in vivo studies, the Calu6 NSCLC cell line was transfected with the IL-12RB2 containing plasmid (Calu6/β2). Similar to that observed in primary tumors, IL-12 treatment of Calu6/β2+ cells inhibited angiogenesis in vitro. Tumors formed by Calu6/β2 cells in SCID/NOD mice, inoculated subcutaneously or orthotopically, were significantly smaller following IL-12 vs PBS treatment due to inhibition of angiogenesis, and of IL-6 and VEGF-C production. Explanted tumors were studied by histology, immuno-histochemistry and PCR array. NBEC cells were isolated and cultured from lung specimens of non neoplastic origin. NBEC expressed IL-12R and released constitutively tumor promoting cytokines (e.g. IL-6 and CCL2). Treatment of NBEC with IL-12 down-regulated production of these cytokines. Conclusions This study demonstrates that IL-12 inhibits directly the growth of human lung adenocarcinoma and targets the adjacent NBEC. These novel anti-tumor activities of IL-12 add to the well

Solitary lung metastasis from intracranial hemangiopericytoma 18 years after initial resection.

PubMed

Doxtader, Erika E; Mukhopadhyay, Sanjay; Prayson, Richard A

2015-07-01

We report a 29-year-old woman who presented with severe headache, nausea and vomiting. A lesion was found in the left petrous ridge and near-total resection was performed. Pathologic examination showed anaplastic hemangiopericytoma (World Health Organization Grade III). Hemangiopericytoma is an uncommon mesenchymal tumor that rarely occurs in an intracranial location. Prior studies have reported a surprisingly high rate of late recurrence and extracranial metastases from intracranial hemangiopericytomas, including metastases to the lungs. Resection was followed by external beam radiation. The tumor recurred intracranially 6 and 13 years later and was treated with gamma knife stereotactic radiosurgery. At year 14, she noticed a lump in her neck and underwent parotidectomy for a mucoepidermoid carcinoma. This new diagnosis prompted a staging chest CT scan which showed a 4mm right upper lobe lung nodule along with additional < 5 mm indeterminate nodules. Over the next 3 years, the nodule increased to 8mm. Wedge biopsy of the lung nodule showed metastatic hemangiopericytoma, histologically similar to the intracranial hemangiopericytoma. Both the primary and the lung metastasis were positive for CD34 and STAT-6. To the best of our knowledge, this is the longest reported interval between a resected intracranial hemangiopericytoma and a histologically confirmed solitary metastasis to the lung. Copyright © 2015 Elsevier Ltd. All rights reserved.

fDOT for in vivo follow-up of tumor development in mice lungs

NASA Astrophysics Data System (ADS)

Koenig, Anne; Hervé, Lionel; Da Silva, Anabela; Dinten, Jean-Marc; Boutet, Jérôme; Berger, Michel; Josserand, Véronique; Coll, Jean-Luc; Peltié, Philippe; Rizo, Philippe

2007-07-01

This paper presents in vivo experiments conducted on cancerous mice bearing mammary murine tumors. In order to reconstruct the fluorescence yield even in highly attenuating and heterogeneous regions like lungs, we developed a fDOT reconstruction method which at first corrects the light propagation model from optical heterogeneities by using the transmitted excitation light measurements. The same approach is also designed to enable working without immersing the mouse in adaptation liquid. The 3D fluorescence map is then reconstructed from the emitted signal of fluorescence and from the corrected propagation model by an ART (Algebraic Reconstruction Technique) algorithm. The system ability to reconstruct fluorescence distribution in presence of high attenuating objects has been validated on phantoms presenting a fluorescent absorbent inclusion. A study was conducted on mice to follow up lungs at different stages of tumor development. The mice were imaged after intravenous injection to the animal of a cancer specific fluorescent marker. A control experiment was conducted in parallel on healthy mice to ensure that the multiple injections of fluorophore did not induce parasite fluorescence distribution. These results validate our system performances for studying small animal lungs tumor evolution. Detection and localization of the fluorophore fixations expresses the tumor development.

Association of locally produced IL10 and TGFb1 with tumor size, histological type and presence of metastases in patients with lung carcinoma.

PubMed

Karlicic, Vukoica; Vukovic, Jelena; Stanojevic, Ivan; Sotirovic, Jelena; Peric, Aleksandar; Jovic, Milena; Cvijanovic, Vlado; Djukic, Mirjana; Banovic, Tatjana; Vojvodic, Danilo

2016-01-01

Advanced lung carcinoma is charasterized with fast disease progression. Interleukin (IL)10 and transforming growth factor (TGF)b1 are immunosuppressive mediators and their role in lung carcinoma pathogenesis and in the antitumor response has not yet been elucidated. The purpose of this study was to correlate IL10 and TGFb1 levels in the serum and lung tumor microcirculation with clinical stage, disease extent, histological features and TNM stage. The study included 41 lung cancer patients in clinical stage III and IV. Histological type was determined immunohistochemically, while tumor size, localization and dissemination were determined radiologically by multislice computerized tomography (MSCT). IL10 and TGFb1 levels were quantified with commercial flow cytometric test in serum and lung tumor microcirculation samples. Non small cell lung cancer (NSCLC) patients had significantly elevated TGFb1 while small cell lung cancer (SCLC) patients had significantly increased IL10 in tumor microcirculation. IL10 was significantly elevated in patients with the largest tumors, as well as in patients with III clinical stage and without metastases, both in the serum and tumor microcirculation. TGFb1 was significantly increased in serum and tumor microcirculation in patients with larger tumors. We found significant correlation between these two immunosuppressive cytokines, IL10 and TGFb1, in tumor microcirculation but not in patient serum samples. IL10 and TGFb1 in systemic and tumor microcirculation are significantly associated with particular histological type of lung cancer, tumor size and degree of disease extent.

Elderly male smokers with right lung tumors are viable candidates for KRAS mutation screening.

PubMed

Yang, Yang; Shi, Chun; Sun, Hui; Yin, Wei; Zhou, Xiao; Zhang, Lei; Jiang, Gening

2016-01-07

Genetic aberrations in tumor driver genes provide specific molecular targets for therapeutic intervention, which can greatly improve therapeutic outcomes. Here, we analyzed the mutational frequency of EGFR and KRAS gene, as well as EML4-ALK rearrangement, and summarized the clinicopathological characters of Chinese lung cancer patients. We detected the mutation spectrum of 1033 primary lung cancer patients. The analyzed clinicopathological parameters included gender, age at diagnosis, smoking status, pathological TNM stage, tumor morphology and location, visceral pleural invasion, and histological type. A total of 618 patients had mutations in EGFR or KRAS gene as well as rearrangement of EML4-ALK. Exon 19 deletions and L858R in the EGFR gene were the most frequent mutations. Left-side lung cancer was more common in female patients carrying the KRAS mutation. Rearrangement of EML4-ALK was more common in non-tobacco-using male patients, who also exhibited a higher likelihood of visceral pleura invasion. Elderly females who never smoked and possessed 1-20 mm stage I adenocarcinomas in the right side exhibited a higher frequency of EGFR mutations. Elderly male smokers with right lung tumors were viable candidates for KRAS mutation screening.

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

ClinicalTrials.gov

2013-01-15

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

Dosimetric impact of gold markers implanted closely to lung tumors: a Monte Carlo simulation.

PubMed

Shiinoki, Takehiro; Sawada, Akira; Ishihara, Yoshitomo; Miyabe, Yuki; Matsuo, Yukinori; Mizowaki, Takashi; Kokubo, Masaki; Hiraoka, Masahiro

2014-05-08

We are developing an innovative dynamic tumor tracking irradiation technique using gold markers implanted around a tumor as a surrogate signal, a real-time marker detection system, and a gimbaled X-ray head in the Vero4DRT. The gold markers implanted in a normal organ will produce uncertainty in the dose calculation during treatment planning because the photon mass attenuation coefficient of a gold marker is much larger than that of normal tissue. The purpose of this study was to simulate the dose variation near the gold markers in a lung irradiated by a photon beam using the Monte Carlo method. First, the single-beam and the opposing-beam geometries were simulated using both water and lung phantoms. Subsequently, the relative dose profiles were calculated using a stereotactic body radiotherapy (SBRT) treatment plan for a lung cancer patient having gold markers along the anterior-posterior (AP) and right-left (RL) directions. For the single beam, the dose at the gold marker-phantom interface laterally along the perpendicular to the beam axis increased by a factor of 1.35 in the water phantom and 1.58 in the lung phantom, respectively. Furthermore, the entrance dose at the interface along the beam axis increased by a factor of 1.63 in the water phantom and 1.91 in the lung phantom, while the exit dose increased by a factor of 1.00 in the water phantom and 1.12 in the lung phantom, respectively. On the other hand, both dose escalations and dose de-escalations were canceled by each beam for opposing portal beams with the same beam weight. For SBRT patient data, the dose at the gold marker edge located in the tumor increased by a factor of 1.30 in both AP and RL directions. In clinical cases, dose escalations were observed at the small area where the distance between a gold marker and the lung tumor was ≤ 5 mm, and it would be clinically negligible in multibeam treatments, although further investigation may be required.

Circulating tumor cells in lung cancer.

PubMed

Young, Rachel; Pailler, Emma; Billiot, Fanny; Drusch, Françoise; Barthelemy, Amélie; Oulhen, Marianne; Besse, Benjamin; Soria, Jean-Charles; Farace, Françoise; Vielh, Philippe

2012-01-01

Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a 'liquid biopsy' is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment. Copyright © 2012 S. Karger AG, Basel.

Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

PubMed Central

Turrell, Frances K.; Kerr, Emma M.; Gao, Meiling; Thorpe, Hannah; Doherty, Gary J.; Cridge, Jake; Shorthouse, David; Speed, Alyson; Samarajiwa, Shamith; Hall, Benjamin A.; Griffiths, Meryl; Martins, Carla P.

2017-01-01

Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear. Through transcriptional and functional analysis of murine KrasG12D-p53null, -p53R172H (conformational), and -p53R270H (contact) mutant lung tumors, we identified genotype-independent and genotype-dependent therapeutic sensitivities. Unexpectedly, we found that wild-type p53 exerts a dominant tumor-suppressive effect on mutant tumors, as all genotypes were similarly sensitive to its restoration in vivo. These data show that the potential of p53 targeted therapies is comparable across all p53-deficient genotypes and may explain the high incidence of p53 loss of heterozygosity in mutant tumors. In contrast, mutant p53 gain of function and their associated vulnerabilities can vary according to mutation type. Notably, we identified a p53R270H-specific sensitivity to simvastatin in lung tumors, and the transcriptional signature that underlies this sensitivity was also present in human lung tumors, indicating that this therapeutic approach may be clinically relevant. PMID:28790158

Diagnostic Value of Combining Tumor and Inflammatory Markers in Lung Cancer

PubMed Central

Yoon, Ho Il; Kwon, Oh-Ran; Kang, Kyung Nam; Shin, Yong Sung; Shin, Ho Sang; Yeon, Eun Hee; Kwon, Keon Young; Hwang, Ilseon; Jeon, Yoon Kyung; Kim, Yongdai; Kim, Chul Woo

2016-01-01

Background Despite major advances in lung cancer treatment, early detection remains the most promising way of improving outcomes. To detect lung cancer in earlier stages, many serum biomarkers have been tested. Unfortunately, no single biomarker can reliably detect lung cancer. We combined a set of 2 tumor markers and 4 inflammatory or metabolic markers and tried to validate the diagnostic performance in lung cancer. Methods We collected serum samples from 355 lung cancer patients and 590 control subjects and divided them into training and validation datasets. After measuring serum levels of 6 biomarkers (human epididymis secretory protein 4 [HE4], carcinoembryonic antigen [CEA], regulated on activation, normal T cell expressed and secreted [RANTES], apolipoprotein A2 [ApoA2], transthyretin [TTR], and secretory vascular cell adhesion molecule-1 [sVCAM-1]), we tested various sets of biomarkers for their diagnostic performance in lung cancer. Results In a training dataset, the area under the curve (AUC) values were 0.821 for HE4, 0.753 for CEA, 0.858 for RANTES, 0.867 for ApoA2, 0.830 for TTR, and 0.552 for sVCAM-1. A model using all 6 biomarkers and age yielded an AUC value of 0.986 and sensitivity of 93.2% (cutoff at specificity 94%). Applying this model to the validation dataset showed similar results. The AUC value of the model was 0.988, with sensitivity of 93.33% and specificity of 92.00% at the same cutoff point used in the validation dataset. Analyses by stages and histologic subtypes all yielded similar results. Conclusions Combining multiple tumor and systemic inflammatory markers proved to be a valid strategy in the diagnosis of lung cancer. PMID:27722145

Intraoperative Molecular Imaging of Lung Adenocarcinoma Can Identify Residual Tumor Cells at the Surgical Margins

PubMed Central

Keating, Jane J.; Okusanya, Olugbenga T.; De Jesus, Elizabeth; Judy, Ryan; Jiang, Jack; Deshpande, Charuhas; Nie, Shuming; Low, Philip; Singhal, Sunil

2017-01-01

Purpose During lung surgery, identification of surgical margins is challenging. We hypothesized that molecular imaging with a fluorescent probe to pulmonary adenocarcinomas could enhance residual tumor during resection. Procedures Mice with flank tumors received a contrast agent targeting folate receptor alpha. Optimal dose and time of injection was established. Margin detection was compared using traditional methods versus molecular imaging. A pilot study was then performed in 3 humans with lung adenocarcinoma. Results The peak tumor-to background ratio (TBR) of murine tumors was 3.9. Fluorescence peaked at 2 hours and was not improved beyond 0.1 mg/kg. Traditional inspection identified 30% of mice with positive margins. Molecular imaging identified an additional 50% of residual tumor deposits (P<0.05). The fluorescent probe visually enhanced all human tumors with a mean TBR of 3.5. Conclusions Molecular imaging is an important adjunct to traditional inspection to identify surgical margins after tumor resection. PMID:26228697

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

PubMed

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

2017-03-01

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

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

NASA Astrophysics Data System (ADS)

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.

Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis

PubMed Central

MASUNAGA, SHIN-ICHIRO; SAKURAI, YOSHINORI; TANO, KEIZO; TANAKA, HIROKI; SUZUKI, MINORU; KONDO, NATSUKO; NARABAYASHI, MASARU; WATANABE, TSUBASA; NAKAGAWA, YOSUKE; MARUHASHI, AKIRA; ONO, KOJI

2014-01-01

The aim of the present study was to evaluate the effect of bevacizumab on local tumor response and lung metastatic potential during boron neutron capture therapy (BNCT) and in particular, the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously administered bromodeoxyuridine (BrdU) to label all proliferating (P) tumor cells. The tumors were irradiated with thermal neutron beams following the administration of a 10B-carrier [L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)], with or without the administration of bevacizumab. This was further combined with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH, 40°C for 60 min). Immediately following the irradiation, cells from certain tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q cells and the total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days following irradiation, lung metastases were enumerated. Three days following bevacizumab administration, the sensitivity of the total tumor cell population following BPA-BNCT had increased more than that following BSH-BNCT. The combination with MTH, but not with nicotinamide, further enhanced total tumor cell population sensitivity. Regardless of the presence of a 10B-carrier, MTH enhanced the sensitivity of the Q cell population. Regardless of irradiation, the administration of bevacizumab, as well as nicotinamide treatment, demonstrated certain potential in reducing the number of lung metastases especially in BPA-BNCT compared with BSH-BNCT. Thus, the current study revealed that BNCT combined with bevacizumab has the potential to sensitize total tumor cells and cause a reduction in the number of lung metastases to a similar level as nicotinamide. PMID:24944637

Grating-Based Phase-Contrast Imaging of Tumor Angiogenesis in Lung Metastases

PubMed Central

Li, Xiangting; Wang, Yujie; Ding, Bei; Shi, Chen; Liu, Huanhuan; Tang, Rongbiao; Sun, Jianqi; Yan, Fuhua; Zhang, Huan

2015-01-01

Purpose To assess the feasibility of the grating-based phase-contrast imaging (GPI) technique for studying tumor angiogenesis in nude BALB/c mice, without contrast agents. Methods We established lung metastatic models of human gastric cancer by injecting the moderately differentiated SGC-7901 gastric cancer cell line into the tail vein of nude mice. Samples were embedded in a 10% formalin suspension and dried before imaging. Grating-based X-ray phase-contrast images were obtained at the BL13W beamline of the Shanghai Synchrotron Radiation Facility (SSRF) and compared with histological sections. Results Without contrast agents, grating-based X-ray phase-contrast imaging still differentiated angiogenesis within metastatic tumors with high spatial resolution. Vessels, down to tens of microns, showed gray values that were distinctive from those of the surrounding tumors, which made them easily identifiable. The vessels depicted in the imaging study were similar to those identified on histopathology, both in size and shape. Conclusions Our preliminary study demonstrates that grating-based X-ray phase-contrast imaging has the potential to depict angiogenesis in lung metastases. PMID:25811626

Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development.

PubMed

Zhou, Yan; Hu, Zhangguo; Cao, Shuhui; Yan, Bo; Qian, Jialin; Zhong, Hua

2017-08-01

Lung cancer is the most common malignancy in humans. An increased population of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion.

Metformin selectively affects human glioblastoma tumor-initiating cell viability

PubMed Central

Würth, Roberto; Pattarozzi, Alessandra; Gatti, Monica; Bajetto, Adirana; Corsaro, Alessandro; Parodi, Alessia; Sirito, Rodolfo; Massollo, Michela; Marini, Cecilia; Zona, Gianluigi; Fenoglio, Daniela; Sambuceti, Gianmario; Filaci, Gilberto; Daga, Antonio; Barbieri, Federica; Florio, Tullio

2013-01-01

Cancer stem cell theory postulates that a small population of tumor-initiating cells is responsible for the development, progression and recurrence of several malignancies, including glioblastoma. In this perspective, tumor-initiating cells represent the most relevant target to obtain effective cancer treatment. Metformin, a first-line drug for type II diabetes, was reported to possess anticancer properties affecting the survival of cancer stem cells in breast cancer models. We report that metformin treatment reduced the proliferation rate of tumor-initiating cell-enriched cultures isolated from four human glioblastomas. Metformin also impairs tumor-initiating cell spherogenesis, indicating a direct effect on self-renewal mechanisms. Interestingly, analyzing by FACS the antiproliferative effects of metformin on CD133-expressing subpopulation, a component of glioblastoma cancer stem cells, a higher reduction of proliferation was observed as compared with CD133-negative cells, suggesting a certain degree of cancer stem cell selectivity in its effects. In fact, glioblastoma cell differentiation strongly reduced sensitivity to metformin treatment. Metformin effects in tumor-initiating cell-enriched cultures were associated with a powerful inhibition of Akt-dependent cell survival pathway, while this pathway was not affected in differentiated cells. The specificity of metformin antiproliferative effects toward glioblastoma tumor-initiating cells was confirmed by the lack of significant inhibition of normal human stem cells (umbilical cord-derived mesenchymal stem cells) in vitro proliferation after metformin exposure. Altogether, these data clearly suggest that metformin exerts antiproliferative activity on glioblastoma cells, showing a higher specificity toward tumor-initiating cells, and that the inhibition of Akt pathway may represent a possible intracellular target of this effect. PMID:23255107

Cellular Biochemistry and Cytogenetics in a Rat Lung Tumor Model

DTIC Science & Technology

1984-10-01

lung tumor system the specific aims are: 1. To conduct studies of the effect of 3-methylchlanthrene (MCA) on DNA synthesis and cell proliferation in...alkylation of nucleic acids of the rat by N-methyl-N- nitrosourea , dimethylnitrosamine, dimethylsulfate, and methylmethanesulfonate. Biochem. J. 110:39-47

Capnocytophaga lung abscess in a patient with metastatic neuroendocrine tumor.

PubMed

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.

"A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies"

PubMed Central

2012-01-01

Background The study of breast cancer metastasis depends on the use of established breast cancer cell lines that do not accurately represent the heterogeneity and complexity of human breast tumors. A tumor model was developed using primary breast tumor-initiating cells isolated from patient core biopsies that would more accurately reflect human breast cancer metastasis. Methods Tumorspheres were isolated under serum-free culture conditions from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity in vivo. Tumors and metastatic lesions were analyzed by hematoxylin and eosin (H+E) staining and immunohistochemistry (IHC). Results Tumorspheres were successfully isolated from all patient core biopsies, independent of the estrogen receptor α (ERα)/progesterone receptor (PR)/Her2/neu status or tumor grade. Each tumorsphere was estimated to contain 50-100 cells. Transplantation of 50 tumorspheres (1-5 × 103 cells) in combination with Matrigel into the mammary fat pad of NUDE mice resulted in small, palpable tumors that were sustained up to 12 months post-injection. Tumors were serially transplanted three times by re-isolation of tumorspheres from the tumors and injection into the mammary fat pad of NUDE mice. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Visible macrometastases were detected in the lung, liver and kidneys by 6 months post-injection. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear β catenin and fibronectin but were negative for ERα and vimentin. In lung and liver metastases, variable redistribution of E-cadherin and β catenin to the membrane of tumor cells was observed. ERα was re-expressed in lung metastatic cells in two of five samples. Conclusions

Density overwrites of internal tumor volumes in intensity modulated proton therapy plans for mobile lung tumors

NASA Astrophysics Data System (ADS)

Botas, Pablo; Grassberger, Clemens; Sharp, Gregory; Paganetti, Harald

2018-02-01

The purpose of this study was to investigate internal tumor volume density overwrite strategies to minimize intensity modulated proton therapy (IMPT) plan degradation of mobile lung tumors. Four planning paradigms were compared for nine lung cancer patients. Internal gross tumor volume (IGTV) and internal clinical target volume (ICTV) structures were defined encompassing their respective volumes in every 4DCT phase. The paradigms use different planning CT (pCT) created from the average intensity projection (AIP) of the 4DCT, overwriting the density within the IGTV to account for movement. The density overwrites were: (a) constant filling with 100 HU (C100) or (b) 50 HU (C50), (c) maximum intensity projection (MIP) across phases, and (d) water equivalent path length (WEPL) consideration from beam’s-eye-view. Plans were created optimizing dose-influence matrices calculated with fast GPU Monte Carlo (MC) simulations in each pCT. Plans were evaluated with MC on the 4DCTs using a model of the beam delivery time structure. Dose accumulation was performed using deformable image registration. Interplay effect was addressed applying 10 times rescanning. Significantly less DVH metrics degradation occurred when using MIP and WEPL approaches. Target coverage (D99≥slant 70 Gy(RBE)) was fulfilled in most cases with MIP and WEPL (D{{99}WEPL}=69.2+/- 4.0 Gy (RBE)), keeping dose heterogeneity low (D5-D{{95}WEPL}=3.9+/- 2.0 Gy(RBE)). The mean lung dose was kept lowest by the WEPL strategy, as well as the maximum dose to organs at risk (OARs). The impact on dose levels in the heart, spinal cord and esophagus were patient specific. Overall, the WEPL strategy gives the best performance and should be preferred when using a 3D static geometry for lung cancer IMPT treatment planning. Newly available fast MC methods make it possible to handle long simulations based on 4D data sets to perform studies with high accuracy and efficiency, even prior to individual treatment planning.

Grading the neuroendocrine tumors of the lung: an evidence-based proposal.

PubMed

Rindi, G; Klersy, C; Inzani, F; Fellegara, G; Ampollini, L; Ardizzoni, A; Campanini, N; Carbognani, P; De Pas, T M; Galetta, D; Granone, P L; Righi, L; Rusca, M; Spaggiari, L; Tiseo, M; Viale, G; Volante, M; Papotti, M; Pelosi, G

2014-02-01

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Feasibility of cell-free circulating tumor DNA testing for lung cancer.

PubMed

Santarpia, Mariacarmela; Karachaliou, Niki; González-Cao, Maria; Altavilla, Giuseppe; Giovannetti, Elisa; Rosell, Rafael

2016-01-01

Tumor tissue genotyping is used routinely for lung cancer to identify specific targetable oncogenic alterations, including EGFR mutations and ALK rearrangements. However, tumor tissue from a single biopsy is often insufficient for molecular testing, may offer a limited evaluation because of tumor heterogeneity and can be difficult to obtain. Cell-free circulating tumor DNA has been widely investigated as a potential surrogate for tissue biopsy for noninvasive assessment of tumor-related genomic alterations. New techniques have improved EGFR mutations detection in ctDNA, thus supporting the use of this liquid biopsy for predicting response to EGFR tyrosine kinase inhibitors (TKIs) and monitoring the emergence of resistance. The serial evaluation of ctDNA during treatment is feasible and can be used to track tumor changes in real time and for a wide range of clinically useful applications.

Tumoral cavitation in patients with non-small-cell lung cancer treated with antiangiogenic therapy using bevacizumab

PubMed Central

Nishino, Mizuki; Cryer, Sarah K.; Okajima, Yuka; Sholl, Lynette M.; Hatabu, Hiroto; Rabin, Michael S.; Jackman, David M.; Johnson, Bruce E.

2012-01-01

Abstract Rationale and objectives: To investigate the frequency and radiographic patterns of tumoral cavitation in patients with non-small cell lung cancer (NSCLC) treated with bevacizumab, and correlate the imaging findings with the pathology, clinical characteristics and outcome. Materials and methods: Seventy-two patients with NSCLC treated with bevacizumab therapy were identified retrospectively. Baseline and follow-up chest computed tomography scan were reviewed to identify tumoral cavitation and subsequent filling in of cavitation. Radiographic cavitation patterns were classified into 3 groups. The clinical and outcome data were correlated with cavity formation and patterns. Results: Out of 72 patients, 14 patients developed cavitation after the initiation of bevacizumab therapy (19%; median time to event, 1.5 months; range 1.0–24.8 months). Three radiographic patterns of tumoral cavitation were noted: (1) development of cavity within the dominant lung tumor (n = 8); (2) development of non-dominant cavitary nodules (n = 3); and (3) development of non-dominant cavitary nodules with adjacent interstitial abnormalities (n = 3). Eleven patients (79%) demonstrated subsequent filling in of cavitation (the time from the cavity formation to filling in; median 3.7 months; range 1.9–22.7 months). No significant difference was observed in the clinical characteristics, including smoking history, or in the survival between patients who developed cavitation and those who did not. Smoking history demonstrated a significant difference across 3 radiographic cavitation patterns (P = 0.006). Hemoptysis was noted in 1 patient with cavity formation and 4 patients without, with no significant difference between the 2 groups. Conclusion: Tumoral cavitation occurred in 19% in patients with NSCLC treated with bevacizumab and demonstrated 3 radiographic patterns. Subsequent filling in of cavitation was noted in the majority of cases. PMID:22743083

Intrafractional Baseline Shift or Drift of Lung Tumor Motion During Gated Radiation Therapy With a Real-Time Tumor-Tracking System.

PubMed

Takao, Seishin; Miyamoto, Naoki; Matsuura, Taeko; Onimaru, Rikiya; Katoh, Norio; Inoue, Tetsuya; Sutherland, Kenneth Lee; Suzuki, Ryusuke; Shirato, Hiroki; Shimizu, Shinichi

2016-01-01

To investigate the frequency and amplitude of baseline shift or drift (shift/drift) of lung tumors in stereotactic body radiation therapy (SBRT), using a real-time tumor-tracking radiation therapy (RTRT) system. Sixty-eight patients with peripheral lung tumors were treated with SBRT using the RTRT system. One of the fiducial markers implanted near the tumor was used for the real-time monitoring of the intrafractional tumor motion every 0.033 seconds by the RTRT system. When baseline shift/drift is determined by the system, the position of the treatment couch is adjusted to compensate for the shift/drift. Therefore, the changes in the couch position correspond to the baseline shift/drift in the tumor motion. The frequency and amount of adjustment to the couch positions in the left-right (LR), cranio-caudal (CC), and antero-posterior (AP) directions have been analyzed for 335 fractions administered to 68 patients. The average change in position of the treatment couch during the treatment time was 0.45 ± 2.23 mm (mean ± standard deviation), -1.65 ± 5.95 mm, and 1.50 ± 2.54 mm in the LR, CC, and AP directions, respectively. Overall the baseline shift/drift occurs toward the cranial and posterior directions. The incidence of baseline shift/drift exceeding 3 mm was 6.0%, 15.5%, 14.0%, and 42.1% for the LR, CC, AP, and for the square-root of sum of 3 directions, respectively, within 10 minutes of the start of treatment, and 23.0%, 37.6%, 32.5%, and 71.6% within 30 minutes. Real-time monitoring and frequent adjustments of the couch position and/or adding appropriate margins are suggested to be essential to compensate for possible underdosages due to baseline shift/drift in SBRT for lung cancers. Copyright © 2016 Elsevier Inc. All rights reserved.

Coincidence between malignant perivascular epithelioid cell tumor arising in the gastric serosa and lung adenocarcinoma.

PubMed

Yamada, Sohsuke; Nabeshima, Atsunori; Noguchi, Hirotsugu; Nawata, Aya; Nishii, Hisae; Guo, Xin; Wang, Ke-Yong; Hisaoka, Masanori; Nakayama, Toshiyuki

2015-01-28

A 4-mo history of both epigastralgia and back pain was presented in a 39-year-old male. Computed tomography showed right lung nodule and abdominal mass attached to the gastric wall, measuring approximately 30 mm and 70 mm in diameter. Since biopsy samples from the lung and abdomen revealed poorly differentiated adenocarcinoma and malignant tumor, clinicians first interpreted the abdominal mass as metastatic carcinoma, and a right lower lobectomy with following resection of the mass was performed. Gross examination of both lesions displayed gray-whitish to yellow-whitish cut surfaces with hemorrhagic and necrotic foci, and the mass attached to the serosa of the lesser curvature on the gastric body. On microscopic examination, the lung tumor was composed of a proliferation of highly atypical epithelial cells having abundant eosinophilic cytoplasm, predominantly arranged in an acinar or solid growth pattern with vessel permeation, while the abdominal tumor consisted of sheets or nests with markedly atypical epithelioid cells having pleomorphic nuclei and abundant eosinophilic to clear cytoplasm focally in a radial perivascular or infiltrative growth pattern. Immunohistochemically, the latter cells were positive for HMB45 or α-smooth muscle actin, but the former ones not. Therefore, we finally made a diagnosis of malignant perivascular epithelioid cell tumor (PEComa) arising in the gastric serosa, combined with primary lung adenocarcinoma. Furthermore, small papillary carcinoma of the thyroid gland was identified. The current case describes the coincidence of malignant PEComa with other carcinomas, posing a challenge in distinction from metastatic tumor disease.

Coincidence between malignant perivascular epithelioid cell tumor arising in the gastric serosa and lung adenocarcinoma

PubMed Central

Yamada, Sohsuke; Nabeshima, Atsunori; Noguchi, Hirotsugu; Nawata, Aya; Nishii, Hisae; Guo, Xin; Wang, Ke-Yong; Hisaoka, Masanori; Nakayama, Toshiyuki

2015-01-01

A 4-mo history of both epigastralgia and back pain was presented in a 39-year-old male. Computed tomography showed right lung nodule and abdominal mass attached to the gastric wall, measuring approximately 30 mm and 70 mm in diameter. Since biopsy samples from the lung and abdomen revealed poorly differentiated adenocarcinoma and malignant tumor, clinicians first interpreted the abdominal mass as metastatic carcinoma, and a right lower lobectomy with following resection of the mass was performed. Gross examination of both lesions displayed gray-whitish to yellow-whitish cut surfaces with hemorrhagic and necrotic foci, and the mass attached to the serosa of the lesser curvature on the gastric body. On microscopic examination, the lung tumor was composed of a proliferation of highly atypical epithelial cells having abundant eosinophilic cytoplasm, predominantly arranged in an acinar or solid growth pattern with vessel permeation, while the abdominal tumor consisted of sheets or nests with markedly atypical epithelioid cells having pleomorphic nuclei and abundant eosinophilic to clear cytoplasm focally in a radial perivascular or infiltrative growth pattern. Immunohistochemically, the latter cells were positive for HMB45 or α-smooth muscle actin, but the former ones not. Therefore, we finally made a diagnosis of malignant perivascular epithelioid cell tumor (PEComa) arising in the gastric serosa, combined with primary lung adenocarcinoma. Furthermore, small papillary carcinoma of the thyroid gland was identified. The current case describes the coincidence of malignant PEComa with other carcinomas, posing a challenge in distinction from metastatic tumor disease. PMID:25632212

[Granular Cell Tumor of the Lung - a Visual Diagnosis on Bronchoscopy?

PubMed

Keymel, S; Büter, S; Krüger, S

2018-05-22

A 38 years old patient presented with a progressive reduction of his general condition and weight loss. Chest imaging revealed consolidations and cavities suggesting a mycobacterial infection. For further diagnosis, a bronchoscopy was performed. In fact, a nontuberculous mycobacterial infection was found. As an incidental finding, we saw a white polypoid tumor in the middle lobe bronchus. The histology of this tumor revealed a granular cell tumor (GCT). The GCT is a rare tumor entity which occurs at different anatomical locations. In the lungs, the GCT may become symptomatic as it can cause bronchial obstruction. In chest imaging, it can manifest as infiltration, atelectasis or nodule. Likewise, GCT can be found as an incidental finding in bronchoscopy. First choice treatment is surgical resection of the tumor. © Georg Thieme Verlag KG Stuttgart · New York.

Real-time Non-invasive Spectral Imaging of Orthotopic Red Fluorescent Protein-expressing Lung Tumor Growth in Nude Mice.

PubMed

Zhang, Yong; Zhang, Nan; Zhao, Ming; Hoffman, Robert M

2015-07-01

Orthotopic implantation of cancer allows metastasis to occur. The most patient-like metastatic orthotopic models are developed with surgical orthotopic implantation using intact tissue in order to preserve the natural tissue structure of the tumor which contains both cancer cells and stroma. In the present study, we performed a simple thoracotomy by making an intercostal incision between the fourth and fifth ribs on the left side of the chest of nude mice. Lung tumor fragments expressing red fluorescent protein were then implanted on the left lung. It was possible to monitor tumor formation in the lung non-invasively by spectral imaging using the Maestro system with a liquid tunable filter. The model described here has high tumorigenicity in the lung (100%) and a low mortality rate (5%). This imageable nude mouse model using surgical orthotopic implantation of lung cancer will be useful for all types of longitudinal studies. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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

NASA Astrophysics Data System (ADS)

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.

Primary Lung Signet Ring Cell Carcinoma Presenting as a Cavitary Pancoast Tumor in a 32-Year-Old Man.

PubMed

Corvini, Michael; Koorji, Alysha; Sgroe, Erica; Nguyen, Uyen

2018-06-01

Signet ring cell carcinoma, a subtype of adenocarcinoma, is a rare cause of primary lung cancer. The authors report a case of primary lung signet ring cell carcinoma presenting as a cavitary Pancoast tumor in a 32-year-old male smoker. Beyond the rarity of primary lung signet ring cell carcinoma itself, the youth of the patient, his smoking status, the presence of cavitation, and the location of the tumor in the superior sulcus make it especially atypical.

Markerless EPID image guided dynamic multi-leaf collimator tracking for lung tumors

NASA Astrophysics Data System (ADS)

Rottmann, J.; Keall, P.; Berbeco, R.

2013-06-01

Compensation of target motion during the delivery of radiotherapy has the potential to improve treatment accuracy, dose conformity and sparing of healthy tissue. We implement an online image guided therapy system based on soft tissue localization (STiL) of the target from electronic portal images and treatment aperture adaptation with a dynamic multi-leaf collimator (DMLC). The treatment aperture is moved synchronously and in real time with the tumor during the entire breathing cycle. The system is implemented and tested on a Varian TX clinical linear accelerator featuring an AS-1000 electronic portal imaging device (EPID) acquiring images at a frame rate of 12.86 Hz throughout the treatment. A position update cycle for the treatment aperture consists of four steps: in the first step at time t = t0 a frame is grabbed, in the second step the frame is processed with the STiL algorithm to get the tumor position at t = t0, in a third step the tumor position at t = ti + δt is predicted to overcome system latencies and in the fourth step, the DMLC control software calculates the required leaf motions and applies them at time t = ti + δt. The prediction model is trained before the start of the treatment with data representing the tumor motion. We analyze the system latency with a dynamic chest phantom (4D motion phantom, Washington University). We estimate the average planar position deviation between target and treatment aperture in a clinical setting by driving the phantom with several lung tumor trajectories (recorded from fiducial tracking during radiotherapy delivery to the lung). DMLC tracking for lung stereotactic body radiation therapy without fiducial markers was successfully demonstrated. The inherent system latency is found to be δt = (230 ± 11) ms for a MV portal image acquisition frame rate of 12.86 Hz. The root mean square deviation between tumor and aperture position is smaller than 1 mm. We demonstrate the feasibility of real-time markerless DMLC

β-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice.

PubMed

Iskandar, Anita R; Liu, Chun; Smith, Donald E; Hu, Kang-Quan; Choi, Sang-Woon; Ausman, Lynne M; Wang, Xiang-Dong

2013-04-01

Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosamino-1-(3-pyridyl)-1-butanone (NNK)-initiated lung cancer in A/J mice. This tumor-promoting effect of nicotine was accompanied by significant reductions in survival probability and lung Sirtuin 1 (SIRT1) expression, which has been proposed as a tumor suppressor. The decreased level of SIRT1 was associated with increased levels of AKT phosphorylation and interleukin (il)-6 mRNA but decreased tumor suppressor p53 and retinoic acid receptor (RAR)-β mRNA levels in the lungs. Using this mouse model, we then determined whether β-cryptoxanthin (BCX), a xanthophyll that is strongly associated with a reduced risk of lung cancer in several cohort studies, can inhibit nicotine-induced emphysema and lung tumorigenesis. We found that BCX supplementation at two different doses was associated with reductions of the nicotine-promoted lung tumor multiplicity and volume, as well as emphysema in mice treated with both NNK and nicotine. Moreover, BCX supplementation restored the nicotine-suppressed expression of lung SIRT1, p53, and RAR-β to that of the control group, increased survival probability, and decreased the levels of lung il-6 mRNA and phosphorylation of AKT. The present study indicates that BCX is a preventive agent against emphysema and lung cancer with SIRT1 as a potential target. In addition, our study establishes a relevant animal lung cancer model for studying tumor growth within emphysematous microenvironments.

Dose enhancement in radiotherapy of small lung tumors using inline magnetic fields: A Monte Carlo based planning study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oborn, B. M., E-mail: brad.oborn@gmail.com; Ge, Y.; Hardcastle, N.

2016-01-15

Purpose: To report on significant dose enhancement effects caused by magnetic fields aligned parallel to 6 MV photon beam radiotherapy of small lung tumors. Findings are applicable to future inline MRI-guided radiotherapy systems. Methods: A total of eight clinical lung tumor cases were recalculated using Monte Carlo methods, and external magnetic fields of 0.5, 1.0, and 3 T were included to observe the impact on dose to the planning target volume (PTV) and gross tumor volume (GTV). Three plans were 6 MV 3D-CRT plans while 6 were 6 MV IMRT. The GTV’s ranged from 0.8 to 16 cm{sup 3}, whilemore » the PTV’s ranged from 1 to 59 cm{sup 3}. In addition, the dose changes in a 30 cm diameter cylindrical water phantom were investigated for small beams. The central 20 cm of this phantom contained either water or lung density insert. Results: For single beams, an inline magnetic field of 1 T has a small impact in lung dose distributions by reducing the lateral scatter of secondary electrons, resulting in a small dose increase along the beam. Superposition of multiple small beams leads to significant dose enhancements. Clinically, this process occurs in the lung tissue typically surrounding the GTV, resulting in increases to the D{sub 98%} (PTV). Two isolated tumors with very small PTVs (3 and 6 cm{sup 3}) showed increases in D{sub 98%} of 23% and 22%. Larger PTVs of 13, 26, and 59 cm{sup 3} had increases of 9%, 6%, and 4%, describing a natural fall-off in enhancement with increasing PTV size. However, three PTVs bounded to the lung wall showed no significant increase, due to lack of dose enhancement in the denser PTV volume. In general, at 0.5 T, the GTV mean dose enhancement is around 60% lower than that at 1 T, while at 3 T, it is 5%–60% higher than 1 T. Conclusions: Monte Carlo methods have described significant and predictable dose enhancement effects in small lung tumor plans for 6 MV radiotherapy when an external inline magnetic field is included. Results of

Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma

PubMed Central

Schneeberger, Valentina E.; Ren, Yuan; Luetteke, Noreen; Huang, Qingling; Chen, Liwei; Lawrence, Harshani R.; Lawrence, Nicholas J.; Haura, Eric B.; Koomen, John M.; Coppola, Domenico; Wu, Jie

2015-01-01

Epidermal growth factor receptor (EGFR) mutants drive lung tumorigenesis and are targeted for therapy. However, resistance to EGFR inhibitors has been observed, in which the mutant EGFR remains active. Thus, it is important to uncover mediators of EGFR mutant-driven lung tumors to develop new treatment strategies. The protein tyrosine phosphatase (PTP) Shp2 mediates EGF signaling. Nevertheless, it is unclear if Shp2 is activated by oncogenic EGFR mutants in lung carcinoma or if inhibiting the Shp2 PTP activity can suppress EGFR mutant-induced lung adenocarcinoma. Here, we generated transgenic mice containing a doxycycline (Dox)-inducible PTP-defective Shp2 mutant (tetO-Shp2CSDA). Using the rat Clara cell secretory protein (CCSP)-rtTA-directed transgene expression in the type II lung pneumocytes of transgenic mice, we found that the Gab1-Shp2 pathway was activated by EGFRL858R in the lungs of transgenic mice. Consistently, the Gab1-Shp2 pathway was activated in human lung adenocarcinoma cells containing mutant EGFR. Importantly, Shp2CSDA inhibited EGFRL858R-induced lung adenocarcinoma in transgenic animals. Analysis of lung tissues showed that Shp2CSDA suppressed Gab1 tyrosine phosphorylation and Gab1-Shp2 association, suggesting that Shp2 modulates a positive feedback loop to regulate its own activity. These results show that inhibition of the Shp2 PTP activity impairs mutant EGFR signaling and suppresses EGFRL858R-driven lung adenocarcinoma. PMID:25730908

Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer

PubMed Central

Herrmann, Amanda C.; Bernatchez, Chantale; Haymaker, Cara; Molldrem, Jeffrey J.; Hong, Waun Ki; Perez-Soler, Roman

2016-01-01

Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation. PMID:27467256

Inhalation of gas metal arc-stainless steel welding fume promotes lung tumorigenesis in A/J mice.

PubMed

Falcone, Lauryn M; Erdely, Aaron; Meighan, Terence G; Battelli, Lori A; Salmen, Rebecca; McKinney, Walter; Stone, Samuel; Cumpston, Amy; Cumpston, Jared; Andrews, Ronnee N; Kashon, Michael; Antonini, James M; Zeidler-Erdely, Patti C

2017-08-01

Epidemiologic studies suggest an increased risk of lung cancer with exposure to welding fumes, but controlled animal studies are needed to support this association. Oropharyngeal aspiration of collected "aged" gas metal arc-stainless steel (GMA-SS) welding fume has been shown by our laboratory to promote lung tumor formation in vivo using a two-stage initiation-promotion model. Our objective in this study was to determine whether inhalation of freshly generated GMA-SS welding fume also acts as a lung tumor promoter in lung tumor-susceptible mice. Male A/J mice received intraperitoneal (IP) injections of corn oil or the chemical initiator 3-methylcholanthrene (MCA; 10 µg/g) and 1 week later were exposed by whole-body inhalation to air or GMA-SS welding aerosols for 4 h/d × 4 d/w × 9 w at a target concentration of 40 mg/m 3 . Lung nodules were enumerated at 30 weeks post-initiation. GMA-SS fume significantly promoted lung tumor multiplicity in A/J mice initiated with MCA (16.11 ± 1.18) compared to MCA/air-exposed mice (7.93 ± 0.82). Histopathological analysis found that the increased number of lung nodules in the MCA/GMA-SS group were hyperplasias and adenomas, which was consistent with developing lung tumorigenesis. Metal deposition analysis in the lung revealed a lower deposited dose, approximately fivefold compared to our previous aspiration study, still elicited a significant lung tumorigenic response. In conclusion, this study demonstrates that inhaling GMA-SS welding fume promotes lung tumorigenesis in vivo which is consistent with the epidemiologic studies that show welders may be at an increased risk for lung cancer.

Metastatic potential of tumor-initiating cells in solid tumors.

PubMed

Adhikari, Amit S; Agarwal, Neeraj; Iwakuma, Tomoo

2011-01-01

The lethality of cancer is mainly caused by its properties of metastasis, drug resistance, and subsequent recurrence. Understanding the mechanisms governing these properties and developing novel strategies to overcome them will greatly improve the survival of cancer patients. Recent findings suggest that tumors are comprised of heterogeneous cell populations, and only a small fraction of these are tumorigenic with the ability to self-renew and produce phenotypically diverse tumor cell populations. Cells in this fraction are called tumor-initiating cells (TICs) or cancer stem cells (CSCs). TICs have been identified from many types of cancer. They share several similarities with normal adult stem cells including sphere-forming ability, self-renewability, and expression of stem cell surface markers and transcription factors. TICs have also been proposed to be responsible for cancer metastasis, however, scarce evidence for their metastatic potential has been provided. In this review article, we have attempted to summarize the studies which have examined the metastatic potential of TICs in solid tumors.

Highly sensitive detection of multiple tumor markers for lung cancer using gold nanoparticle probes and microarrays.

PubMed

Gao, Wanlei; Wang, Wentao; Yao, Shihua; Wu, Shan; Zhang, Honglian; Zhang, Jishen; Jing, Fengxiang; Mao, Hongju; Jin, Qinghui; Cong, Hui; Jia, Chunping; Zhang, Guojun; Zhao, Jianlong

2017-03-15

Assay of multiple serum tumor markers such as carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen (CYFRA21-1), and neuron specific enolase (NSE), is important for the early diagnosis of lung cancer. Dickkopf-1 (DKK1), a novel serological and histochemical biomarker, was recently reported to be preferentially expressed in lung cancer. Four target proteins were sandwiched by capture antibodies attached to microarrays and detection antibodies carried on modified gold nanoparticles. Optical signals generated by the sandwich structures were amplified by gold deposition with HAuCl 4 and H 2 O 2 , and were observable by microscopy or the naked eye. The four tumor markers were subsequently measured in 106 lung cancer patients and 42 healthy persons. The assay was capable of detecting multiple biomarkers in serum sample at concentration of <1 ng mL -1 in 1 h. Combined detection of the four tumor markers highly improved the sensitivity (to 87.74%) for diagnosis of lung cancer compared with sensitivity of single markers. A rapid, highly sensitive co-detection method for multiple biomarkers based on gold nanoparticles and microarrays was developed. In clinical use, it would be expected to improve the early diagnosis of lung cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

CIGB-300, an anti-CK2 peptide, inhibits angiogenesis, tumor cell invasion and metastasis in lung cancer models.

PubMed

Benavent Acero, Fernando; Capobianco, Carla S; Garona, Juan; Cirigliano, Stéfano M; Perera, Yasser; Urtreger, Alejandro J; Perea, Silvio E; Alonso, Daniel F; Farina, Hernan G

2017-05-01

Casein kinase 2 (CK2) is overexpressed in several types of cancer. It has more than 300 substrates mainly involved in DNA reparation and replication, chromatin remodeling and cellular growth. In recent years CK2 became an interesting target for anticancer drug development. CIGB-300 is a peptidic inhibitor of CK2 activity, designed to bind to the phospho-acceptor domain of CK2 substrates, impairing the correct phosphorylation by the enzyme. The aim of this work was to explore the antitumor effects of this inhibitor in preclinical lung cancer models. Human H125 and murine 3LL Lewis lung carcinoma cell lines were used to evaluate the effect of CIGB-300 treatment in vitro. For this purpose, adhesion, migration and invasion capabilities of cancer cells were tested. Proteolytic activity of tumor cell-secreted uPA and MMP after CIGB-300 incubation was also analyzed. In vivo anticancer efficacy of the peptide was evaluated using experimental and spontaneous lung colonization assays in C57BL/6 mice. Finally, in order to test the effect of CIGB-300 on tumor cell-induced angiogenesis, a modified Matrigel plug assay was conducted. We demonstrate that treatment with low micromolar concentrations of CIGB-300 caused a drastic reduction of adhesion, migration and invasion of lung cancer cells. Reduced invasiveness after CIGB-300 incubation was associated with decreased proteolytic activity of tumor cell-conditioned medium. In vivo, intravenous administration of CIGB-300 (10mg/kg) markly decreased lung colonization and metastasis development of 3LL cells. Interestingly, after 5days of systemic treatment with CIGB-300, tumor cell-driven neovascularization was significantly reduced in comparison to control group. Altogether our data suggest an important role of CK2 in lung tumor development, suggesting a potential use of CIGB-300 as a novel therapeutic agent against lung cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.

PubMed

Baker, Amanda F; Hanke, Neale T; Sands, Barbara J; Carbajal, Liliana; Anderl, Janet L; Garland, Linda L

2014-12-31

Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC.

Analysis of Tumor Vessel Supply in Lewis Lung Carcinoma in Mice by Fluorescent Microsphere Distribution and Imaging with Micro- and Flat-Panel Computed Tomography

PubMed Central

Savai, Rajkumar; Wolf, Joachim C.; Greschus, Susanne; Eul, Bastian G.; Schermuly, Ralph T.; Hänze, Jörg; Voswinckel, Robert; Langheinrich, Alexander C.; Grimminger, Friedrich; Traupe, Horst; Seeger, Werner; Rose, Frank

2005-01-01

In lung carcinomas the blood supply varies depending on tumor type and stage and can develop from pulmonary or bronchial circulation, or both. To examine this in vivo, primary bronchogenic Lewis lung carcinoma cells were intratracheally instilled in C57BL/6 mice. Within 7 days, histological examinations showed progressive tumor growth at the peripheral parenchymal region. The relative contribution of tumor blood supply via the pulmonary and systemic arteries was studied in detail using fluorescent microspheres (10 μm). When compared to healthy lung parenchyma (13:1), Lewis lung carcinoma tumor tissue (52:1) showed a fourfold increase in pulmonary to systemic microspheres, indicating that the pulmonary arteries are the predominant tumor-feeding vessels. After filling the vessels with a vascular cast, the microanatomy of vessels being derived from the pulmonary artery was visualized with micro computed tomography. Flat-panel volumetric computed tomography provided longitudinal visualization of tissue bridges between the growing tumor and the pulmonary vasculature. In this model of peripheral parenchymal malignancy, new imaging techniques allowed effective visualization of lung tumor growth and vascularization in living mice, demonstrating a pulmonary blood supply for lung tumors. PMID:16192630

Clot in Lung, Clot in Heart: A Case Report of Tumor-Like Thrombus in Right Atrium.

PubMed

Habibi, Roshanak; Altamirano, Alvaro J; Dadkhah, Shahriar

2017-01-01

Tumor-like formation of thrombus in the right atrial cavity is rare. It may be mistaken for a myxoma. The exact pathophysiology of an isolated thrombus in the heart is still unclear. Management to prevent complications such as pulmonary thromboembolism depends on the clinical judgment of a cardiologist. This report describes a 76-year-old woman with right atrial thrombus causing subsequent pulmonary thromboembolism in right lung. She initially presented to us with pulmonary embolism, and later, an incidental finding of a mass in her right atrium revealed an association of thrombus in heart with thrombus in lung. The challenging management was to resect this thrombus which was fixed to atrial septum, and a trial of anticoagulation did not resolve it. Exact management of such incidental findings in right heart cavities is not well established. Some cases may benefit from resection of such formed fixed thrombus.

Clot in Lung, Clot in Heart: A Case Report of Tumor-Like Thrombus in Right Atrium

PubMed Central

Habibi, Roshanak; Altamirano, Alvaro J; Dadkhah, Shahriar

2017-01-01

Tumor-like formation of thrombus in the right atrial cavity is rare. It may be mistaken for a myxoma. The exact pathophysiology of an isolated thrombus in the heart is still unclear. Management to prevent complications such as pulmonary thromboembolism depends on the clinical judgment of a cardiologist. This report describes a 76-year-old woman with right atrial thrombus causing subsequent pulmonary thromboembolism in right lung. She initially presented to us with pulmonary embolism, and later, an incidental finding of a mass in her right atrium revealed an association of thrombus in heart with thrombus in lung. The challenging management was to resect this thrombus which was fixed to atrial septum, and a trial of anticoagulation did not resolve it. Exact management of such incidental findings in right heart cavities is not well established. Some cases may benefit from resection of such formed fixed thrombus. PMID:28579859

Functional signaling pathway analysis of lung adenocarcinomas identifies novel therapeutic targets for KRAS mutant tumors

PubMed Central

Baldelli, Elisa; Bellezza, Guido; Haura, Eric B.; Crinó, Lucio; Cress, W. Douglas; Deng, Jianghong; Ludovini, Vienna; Sidoni, Angelo; Schabath, Matthew B.; Puma, Francesco; Vannucci, Jacopo; Siggillino, Annamaria; Liotta, Lance A.; Petricoin, Emanuel F.; Pierobon, Mariaelena

2015-01-01

Little is known about the complex signaling architecture of KRAS and the interconnected RAS-driven protein-protein interactions, especially as it occurs in human clinical specimens. This study explored the activated and interconnected signaling network of KRAS mutant lung adenocarcinomas (AD) to identify novel therapeutic targets. Thirty-four KRAS mutant (MT) and twenty-four KRAS wild-type (WT) frozen biospecimens were obtained from surgically treated lung ADs. Samples were subjected to laser capture microdissection and reverse phase protein microarray analysis to explore the expression/activation levels of 150 signaling proteins along with co-activation concordance mapping. An independent set of 90 non-small cell lung cancers (NSCLC) was used to validate selected findings by immunohistochemistry (IHC). Compared to KRAS WT tumors, the signaling architecture of KRAS MT ADs revealed significant interactions between KRAS downstream substrates, the AKT/mTOR pathway, and a number of Receptor Tyrosine Kinases (RTK). Approximately one-third of the KRAS MT tumors had ERK activation greater than the WT counterpart (p<0.01). Notably 18% of the KRAS MT tumors had elevated activation of the Estrogen Receptor alpha (ER-α) (p=0.02). This finding was verified in an independent population by IHC (p=0.03). KRAS MT lung ADs appear to have a more intricate RAS linked signaling network than WT tumors with linkage to many RTKs and to the AKT-mTOR pathway. Combination therapy targeting different nodes of this network may be necessary to treat this group of patients. In addition, for patients with KRAS MT tumors and activation of the ER-α, anti-estrogen therapy may have important clinical implications. PMID:26468985

Carbon nanotube based respiratory gated micro-CT imaging of a murine model of lung tumors with optical imaging correlation

NASA Astrophysics Data System (ADS)

Burk, Laurel M.; Lee, Yueh Z.; Heathcote, Samuel; Wang, Ko-han; Kim, William Y.; Lu, Jianping; Zhou, Otto

2011-03-01

Current optical imaging techniques can successfully measure tumor load in murine models of lung carcinoma but lack structural detail. We demonstrate that respiratory gated micro-CT imaging of such models gives information about structure and correlates with tumor load measurements by optical methods. Four mice with multifocal, Kras-induced tumors expressing firefly luciferase were imaged against four controls using both optical imaging and respiratory gated micro-CT. CT images of anesthetized animals were acquired with a custom CNT-based system using 30 ms x-ray pulses during peak inspiration; respiration motion was tracked with a pressure sensor beneath each animal's abdomen. Optical imaging based on the Luc+ signal correlating with tumor load was performed on a Xenogen IVIS Kinetix. Micro-CT images were post-processed using Osirix, measuring lung volume with region growing. Diameters of the largest three tumors were measured. Relationships between tumor size, lung volumes, and optical signal were compared. CT images and optical signals were obtained for all animals at two time points. In all lobes of the Kras+ mice in all images, tumors were visible; the smallest to be readily identified measured approximately 300 microns diameter. CT-derived tumor volumes and optical signals related linearly, with r=0.94 for all animals. When derived for only tumor bearing animals, r=0.3. The trend of each individual animal's optical signal tracked correctly based on the CT volumes. Interestingly, lung volumes also correlated positively with optical imaging data and tumor volume burden, suggesting active remodeling.

Anti-tumor activity of three ginsenoside derivatives in lung cancer is associated with Wnt/β-catenin signaling inhibition.

PubMed

Bi, Xiuli; Xia, Xichun; Mou, Teng; Jiang, Bowen; Fan, Dongdong; Wang, Peng; Liu, Yafei; Hou, Yue; Zhao, Yuqing

2014-11-05

Numerous compounds isolated from Ginseng have been shown to exhibit various biological activities, including antioxidant, anti-carcinogenic, anti-mutagenic, and anti-tumor activities. Recent research has focused on the potential values of these compounds in the prevention and treatment of human cancers. The anti-tumor activity of 25-hydroxyprotopanaxadiol (25-OH-PPD), a natural compound isolated from Panax ginseng, has been established in previous study. In the current study, we investigated the anti-tumor activity of three derivatives of 25-OH-PPD, namely xl, 1c, and 8b with respect to lung cancer. All three compounds significantly inhibited the growth of the human lung cancer cells A549 and H460. Oral administration of these compounds significantly inhibited the growth of xenograft tumors in mice without affecting body weight. Further mechanistic study demonstrated that these compounds could decrease the expression levels of β-catenin and its downstream targets Cyclin D1, CDK4, and c-myc in lung cancer cells. Taken together, the results suggested that the anti-growth activity exerted by these 25-OH-PPD derivatives against lung cancer cells probably involved β-catenin-mediated signaling pathway, a finding that could have important implication for chemotherapeutic strategy aiming at the treatment of lung cancer. Copyright © 2014 Elsevier B.V. All rights reserved.

Molecular Biology of Lung Cancer

PubMed Central

Nana-Sinkam, Serge Patrick

2013-01-01

Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics. PMID:23649444

Inhaled uranium ore dust and lung cancer risk in rats.

PubMed

Mitchel, R E; Jackson, J S; Heinmiller, B

1999-02-01

Using a nose-only inhalation system, male Sprague-Dawley rats were exposed 4.2 h d(-1), 5 days per week for 65 weeks to one of two concentrations of natural uranium ore dust aerosol (44% U, 50 mg m(-3) and 19 mg m(-3)) without significant radon content. After inhalation exposure ceased, the rats were allowed to live for their natural lifetime. Lung uranium burdens, measured at the time of death of each animal, declined exponentially after dust inhalation ceased, and the rate of decline was independent of the initial lung burden. Lymph node specific burdens ranged from 1 to 60 fold greater than the specific lung burden in the same animal. No lymph node tumors were observed. The frequency of primary malignant lung tumors was 0.016, 0.175 and 0.328 and primary non-malignant lung tumors 0.016, 0.135 and 0.131 in the control, low and high aerosol exposed groups, respectively. There was no difference in tumor latency between the groups. Absorbed dose to the lung was calculated for each animal in the study. The average doses for all the animals exposed to the low and high dust aerosol concentrations were 0.87 Gy and 1.64 Gy respectively, resulting in an average risk of malignant lung tumors of about 0.20 tumors per animal per Gy in both groups. The frequency of primary lung tumors was also calculated as a function of dose increment for both exposed groups individually and combined. The data indicate that, in spite of the above result, lung tumor frequency was not directly proportional to dose. However, when malignant lung tumor frequency was calculated as a function of dose rate (as measured by the lung burden at the end of dust inhalation) a direct linear relationship was seen (p < 0.01) suggesting dose rate may be a more important determinant of lung cancer risk than dose. Conversely, non-malignant lung tumors were significantly correlated with low lung burdens (p = 0.01). We conclude that chronic inhalation of natural uranium ore dust alone in rats creates a risk of

Two-stage model of radon-induced malignant lung tumors in rats: effects of cell killing

NASA Technical Reports Server (NTRS)

Luebeck, E. G.; Curtis, S. B.; Cross, F. T.; Moolgavkar, S. H.

1996-01-01

A two-stage stochastic model of carcinogenesis is used to analyze lung tumor incidence in 3750 rats exposed to varying regimens of radon carried on a constant-concentration uranium ore dust aerosol. New to this analysis is the parameterization of the model such that cell killing by the alpha particles could be included. The model contains parameters characterizing the rate of the first mutation, the net proliferation rate of initiated cells, the ratio of the rates of cell loss (cell killing plus differentiation) and cell division, and the lag time between the appearance of the first malignant cell and the tumor. Data analysis was by standard maximum likelihood estimation techniques. Results indicate that the rate of the first mutation is dependent on radon and consistent with in vitro rates measured experimentally, and that the rate of the second mutation is not dependent on radon. An initial sharp rise in the net proliferation rate of initiated cell was found with increasing exposure rate (denoted model I), which leads to an unrealistically high cell-killing coefficient. A second model (model II) was studied, in which the initial rise was attributed to promotion via a step function, implying that it is due not to radon but to the uranium ore dust. This model resulted in values for the cell-killing coefficient consistent with those found for in vitro cells. An "inverse dose-rate" effect is seen, i.e. an increase in the lifetime probability of tumor with a decrease in exposure rate. This is attributed in large part to promotion of intermediate lesions. Since model II is preferable on biological grounds (it yields a plausible cell-killing coefficient), such as uranium ore dust. This analysis presents evidence that a two-stage model describes the data adequately and generates hypotheses regarding the mechanism of radon-induced carcinogenesis.

MRI-guided tumor tracking in lung cancer radiotherapy

NASA Astrophysics Data System (ADS)

Cerviño, Laura I.; Du, Jiang; Jiang, Steve B.

2011-07-01

Precise tracking of lung tumor motion during treatment delivery still represents a challenge in radiation therapy. Prototypes of MRI-linac hybrid systems are being created which have the potential of ionization-free real-time imaging of the tumor. This study evaluates the performance of lung tumor tracking algorithms in cine-MRI sagittal images from five healthy volunteers. Visible vascular structures were used as targets. Volunteers performed several series of regular and irregular breathing. Two tracking algorithms were implemented and evaluated: a template matching (TM) algorithm in combination with surrogate tracking using the diaphragm (surrogate was used when the maximum correlation between the template and the image in the search window was less than specified), and an artificial neural network (ANN) model based on the principal components of a region of interest that encompasses the target motion. The mean tracking error ē and the error at 95% confidence level e95 were evaluated for each model. The ANN model led to ē = 1.5 mm and e95 = 4.2 mm, while TM led to ē = 0.6 mm and e95 = 1.0 mm. An extra series was considered separately to evaluate the benefit of using surrogate tracking in combination with TM when target out-of-plane motion occurs. For this series, the mean error was 7.2 mm using only TM and 1.7 mm when the surrogate was used in combination with TM. Results show that, as opposed to tracking with other imaging modalities, ANN does not perform well in MR-guided tracking. TM, however, leads to highly accurate tracking. Out-of-plane motion could be addressed by surrogate tracking using the diaphragm, which can be easily identified in the images.

Detachment-induced E-cadherin expression promotes 3D tumor spheroid formation but inhibits tumor formation and metastasis of lung cancer cells.

PubMed

Powan, Phattrakorn; Luanpitpong, Sudjit; He, Xiaoqing; Rojanasakul, Yon; Chanvorachote, Pithi

2017-11-01

The epithelial-to-mesenchymal transition is proposed to be a key mechanism responsible for metastasis-related deaths. Similarly, cancer stem cells (CSCs) have been proposed to be a key driver of tumor metastasis. However, the link between the two events and their control mechanisms is unclear. We used a three-dimensional (3D) tumor spheroid assay and other CSC-indicating assays to investigate the role of E-cadherin in CSC regulation and its association to epithelial-to-mesenchymal transition in lung cancer cells. Ectopic overexpression and knockdown of E-cadherin were found to promote and retard, respectively, the formation of tumor spheroids in vitro but had opposite effects on tumor formation and metastasis in vivo in a xenograft mouse model. We explored the discrepancy between the in vitro and in vivo results and demonstrated, for the first time, that E-cadherin is required as a component of a major survival pathway under detachment conditions. Downregulation of E-cadherin increased the stemness of lung cancer cells but had an adverse effect on their survival, particularly on non-CSCs. Such downregulation also promoted anoikis resistance and invasiveness of lung cancer cells. These results suggest that anoikis assay could be used as an alternative method for in vitro assessment of CSCs that involves dysregulated adhesion proteins. Our data also suggest that agents that restore E-cadherin expression may be used as therapeutic agents for metastatic cancers. Copyright © 2017 the American Physiological Society.

Lung Cancer: A Classic Example of Tumor Escape and Progression While Providing Opportunities for Immunological Intervention

PubMed Central

Jadus, Martin R.; Natividad, Josephine; Mai, Anthony; Ouyang, Yi; Lambrecht, Nils; Szabo, Sandor; Ge, Lisheng; Hoa, Neil; Dacosta-Iyer, Maria G.

2012-01-01

Lung cancers remain one of the most common and deadly cancers in the world today (12.5% of newly diagnosed cancers) despite current advances in chemo- and radiation therapies. Often, by the time these tumors are diagnosed, they have already metastasized. These tumors demonstrate the classic hallmarks of cancer in that they have advanced defensive strategies allowing them to escape various standard oncological treatments. Immunotherapy is making inroads towards effectively treating other fatal cancers, such as melanoma, glioblastoma multiforme, and castrate-resistant prostate cancers. This paper will cover the escape mechanisms of bronchogenic lung cancer that must be overcome before they can be successfully treated. We also review the history of immunotherapy directed towards lung cancers. PMID:22899945

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene-induced lung tumors in aged mice

USDA-ARS?s Scientific Manuscript database

Aging is often accompanied by a dramatic increase in cancer susceptibility. To gain insights into how aging affects tumor susceptibility, we generated a conditional mouse model in which oncogenic KrasG12D was activated specifically in lungs of young (3-5 months) and old (19-24 months) mice. Activati...

Targeting filamin A reduces K-RAS–induced lung adenocarcinomas and endothelial response to tumor growth in mice

PubMed Central

2012-01-01

Background Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. Methods First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. Results Knockout of Flna significantly reduced K-RAS–induced lung tumor formation and the proliferation of oncogenic K-RAS–expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. Conclusions We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics. PMID:22857000

Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor

PubMed Central

Chaudhri, Virendra K.; Salzler, Gregory G.; Dick, Salihah A.; Buckman, Melanie S.; Sordella, Raffaella; Karoly, Edward D.; Mohney, Robert; Stiles, Brendon M.; Elemento, Olivier; Altorki, Nasser K.; McGraw, Timothy E.

2013-01-01

SUMMARY Cancer cells undergo a metabolic reprogramming but little is known about metabolic alterations of other cells within tumors. We use mass spectrometry-based profiling and a metabolic pathway-based systems analysis to compare 21 primary human lung tumor cancer-associated fibroblast lines (CAFs) to “normal” fibroblast lines (NFs) generated from adjacent non-neoplastic lung tissue. CAFs are pro-tumorigenic, although the mechanisms by which CAFs support tumors have not been elucidated. We have identified several pathways whose metabolite abundance globally distinguished CAFs from NFs, suggesting that metabolic alterations are not limited to cancer cells. In addition, we found metabolic differences between CAFs from high and low glycolytic tumors that might reflect distinct roles of CAFs related to the tumor’s glycolytic capacity. One such change was an increase of dipeptides in CAFs. Dipeptides primarily arise from the breakdown of proteins. We found in CAFs an increase in basal macroautophagy which likely accounts for the increase in dipeptides. Furthermore, we demonstrate a difference between CAFs and NFs in the induction of autophagy promoted by reduced glucose. In sum, our data suggest increased autophagy may account for metabolic differences between CAFs and NFs and may play additional as yet undetermined roles in lung cancer. PMID:23475953

Quantitative Primary Tumor Indocyanine Green Measurements Predict Osteosarcoma Metastatic Lung Burden in a Mouse Model.

PubMed

Fourman, Mitchell S; Mahjoub, Adel; Mandell, Jon B; Yu, Shibing; Tebbets, Jessica C; Crasto, Jared A; Alexander, Peter E; Weiss, Kurt R

2018-03-01

Current preclinical osteosarcoma (OS) models largely focus on quantifying primary tumor burden. However, most fatalities from OS are caused by metastatic disease. The quantification of metastatic OS currently relies on CT, which is limited by motion artifact, requires intravenous contrast, and can be technically demanding in the preclinical setting. We describe the ability for indocyanine green (ICG) fluorescence angiography to quantify primary and metastatic OS in a previously validated orthotopic, immunocompetent mouse model. (1) Can near-infrared ICG fluorescence be used to attach a comparable, quantitative value to the primary OS tumor in our experimental mouse model? (2) Will primary tumor fluorescence differ in mice that go on to develop metastatic lung disease? (3) Does primary tumor fluorescence correlate with tumor volume measured with CT? Six groups of 4- to 6-week-old immunocompetent Balb/c mice (n = 6 per group) received paraphyseal injections into their left hindlimb proximal tibia consisting of variable numbers of K7M2 mouse OS cells. A hindlimb transfemoral amputation was performed 4 weeks after injection with euthanasia and lung extraction performed 10 weeks after injection. Histologic examination of lung and primary tumor specimens confirmed ICG localization only within the tumor bed. Mice with visible or palpable tumor growth had greater hindlimb fluorescence (3.5 ± 2.3 arbitrary perfusion units [APU], defined as the fluorescence pixel return normalized by the detector) compared with those with a negative examination (0.71 ± 0.38 APU, -2.7 ± 0.5 mean difference, 95% confidence interval -3.7 to -1.8, p < 0.001). A strong linear trend (r = 0.81, p < 0.01) was observed between primary tumor and lung fluorescence, suggesting that quantitative ICG tumor fluorescence is directly related to eventual metastatic burden. We did not find a correlation (r = 0.04, p = 0.45) between normalized primary tumor fluorescence and CT volumetric measurements. We

Intrafractional Baseline Shift or Drift of Lung Tumor Motion During Gated Radiation Therapy With a Real-Time Tumor-Tracking System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takao, Seishin; Miyamoto, Naoki; Matsuura, Taeko

2016-01-01

Purpose: To investigate the frequency and amplitude of baseline shift or drift (shift/drift) of lung tumors in stereotactic body radiation therapy (SBRT), using a real-time tumor-tracking radiation therapy (RTRT) system. Methods and Materials: Sixty-eight patients with peripheral lung tumors were treated with SBRT using the RTRT system. One of the fiducial markers implanted near the tumor was used for the real-time monitoring of the intrafractional tumor motion every 0.033 seconds by the RTRT system. When baseline shift/drift is determined by the system, the position of the treatment couch is adjusted to compensate for the shift/drift. Therefore, the changes in the couch positionmore » correspond to the baseline shift/drift in the tumor motion. The frequency and amount of adjustment to the couch positions in the left-right (LR), cranio-caudal (CC), and antero-posterior (AP) directions have been analyzed for 335 fractions administered to 68 patients. Results: The average change in position of the treatment couch during the treatment time was 0.45 ± 2.23 mm (mean ± standard deviation), −1.65 ± 5.95 mm, and 1.50 ± 2.54 mm in the LR, CC, and AP directions, respectively. Overall the baseline shift/drift occurs toward the cranial and posterior directions. The incidence of baseline shift/drift exceeding 3 mm was 6.0%, 15.5%, 14.0%, and 42.1% for the LR, CC, AP, and for the square-root of sum of 3 directions, respectively, within 10 minutes of the start of treatment, and 23.0%, 37.6%, 32.5%, and 71.6% within 30 minutes. Conclusions: Real-time monitoring and frequent adjustments of the couch position and/or adding appropriate margins are suggested to be essential to compensate for possible underdosages due to baseline shift/drift in SBRT for lung cancers.« less

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dzyubak, Oleksandr; Kincaid, Russell; Hertanto, Agung

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 secondmore » 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

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

PubMed

Dzyubak, Oleksandr; Kincaid, Russell; Hertanto, Agung; Hu, Yu-Chi; Pham, Hai; Rimner, Andreas; Yorke, Ellen; Zhang, Qinghui; Mageras, Gig S

2014-10-01

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. 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 registration, each CBCT was

Characterization of the cell of origin and propagation potential of the fibroblast growth factor 9-induced mouse model of lung adenocarcinoma

PubMed Central

Soejima, Kenzo; Kuroda, Aoi; Ishioka, Kota; Yasuda, Hiroyuki; Naoki, Katsuhiko; Shizuko, Kagawa; Hamamoto, Junko; Yin, Yongjun; Ornitz, David M.; Betsuyaku, Tomoko

2014-01-01

Fibroblast growth factor (FGF) 9 is essential for lung development and is highly expressed in a subset of human lung adenocarcinomas. We recently described a mouse model in which FGF9 expression in the lung epithelium caused proliferation of the airway epithelium at the terminal bronchioles and led to rapid development of adenocarcinoma. Here, we used this model to characterize the effects of prolonged FGF9 induction on the proximal and distal lung epithelia, and examined the propagation potential of FGF9-induced lung tumors. We show that prolonged FGF9 overexpression in the lung resulted in the development of adenocarcinomas arising from both alveolar type II and airway secretory cells in the lung parenchyma and airways, respectively. We found that tumor cells harbored tumor-propagating cells that were able to form secondary tumors in recipient mice regardless of FGF9 expression. However, the highest degree of tumor propagation was observed when unfractionated tumor cells were coadministered with autologous, tumor-associated mesenchymal cells. Although the initiation of lung adenocarcinomas was dependent on activation of the FGF9/FGF receptor (FGFR) 3 signaling axis, maintenance and propagation of the tumor was independent of this signaling. Activation of an alternative FGF/FGFR and the interaction with tumor stromal cells is likely to be responsible for the development of this independence. This study demonstrates the complex role of FGF/FGFR signaling in the initiation, growth, and propagation of lung cancer. Our findings suggest that analyzing the expressions of FGFs/FGFRs in human lung cancer will be a useful tool for guiding customized therapy. PMID:25413587

Bronchial and bronchovascular sleeve resection for treatment of central lung tumors.

PubMed

Lausberg, H F; Graeter, T P; Wendler, O; Demertzis, S; Ukena, D; Schäfers, H J

2000-08-01

To improve postoperative pulmonary reserve, we have employed parenchyma-sparing resections for central lung tumors irrespective of pulmonary function. The results of lobectomy, pneumonectomy, and sleeve resection were analyzed retrospectively. From October 1995 to June 1999, 422 typical lung resections were performed for lung cancer. Of these, 301 were lobectomies (group I), 81 were sleeve resections (group II), and 40 were pneumonectomies (group III). Operative mortality was 2% in group I, 1.2% in group II, and 7.5% in group III (group I and II vs. group III, p<0.03). Mean time of intubation was 1.0+/-4.1 days in group I, 0.9+/-1.3 days in group II, and 3.6+/-11.2 days in group III (groups I and II vs. group III, p<0.01). The incidence of bronchial complications was 1.3% in group I, none in group II, and 7.5% in group III (group I and II vs group III, p<0.001). After 2 years, survival was 64% in group I, 61.9% in group II, and 56.1% in group III (p = NS). Freedom from local disease recurrence was 92.1% in group I, 95.7% in group II, and 90.9% in group III after 2 years (p = NS). Sleeve resection is a useful surgical option for the treatment of central lung tumors, thus avoiding pneumonectomy with its associated risks. Morbidity, early mortality, long-term survival, and recurrence of disease after sleeve resection are similar to those seen after lobectomy.

Tumor initiation in human malignant melanoma and potential cancer therapies.

PubMed

Ma, Jie; Frank, Markus H

2010-02-01

Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanoma-initiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment.

Tumor Initiation in Human Malignant Melanoma and Potential Cancer Therapies

PubMed Central

Ma, Jie; Frank, Markus H.

2010-01-01

Cancer stem cells (CSCs), also known as tumor-initiating cells, have been identified in several human malignancies, including human malignant melanoma. The frequency of malignant melanoma-initiating cells (MMICs), which are identified by their expression of ATP-binding cassette (ABC) family member ABCB5, correlates with disease progression in human patients. Furthermore, targeted MMIC ablation through ABCB5 inhibits tumor initiation and growth in preclinical xenotransplantation models, pointing to potential therapeutic promise of the CSC concept. Recent advances also show that CSCs can exert pro-angiogenic roles in tumor growth and serve immunomodulatory functions related to the evasion of host anti-tumor immunity. Thus, MMICs might initiate and sustain tumorigenic growth not only as a result of CSC-intrinsic self-renewal, differentiation and proliferative capacity, but also based on pro-tumorigenic interactions with the host environment. PMID:20184545

Thyroid hormone receptor interactor 13 (TRIP13) overexpression associated with tumor progression and poor prognosis in lung adenocarcinoma.

PubMed

Li, Wei; Zhang, Gengyan; Li, Xiaojun; Wang, Xiaojing; Li, Qing; Hong, Lei; Shen, Yuangbing; Zhao, Chenling; Gong, Xiaomeng; Chen, Yuqing; Zhou, Jihong

2018-05-15

Thyroid hormone receptor interactor 13 (TRIP13) is an AAA + -ATPase that plays a key role in mitotic checkpoint complex inactivation and is associated with the progression of several cancers. However, its role in lung adenocarcinogenesis remains unknown. Here, we report that TRIP13 is highly overexpressed in multiple lung adenocarcinoma cell lines and tumor tissues. Clinically, TRIP13 expression is positively associated with tumor size, T-stage, and N-stage, and Kaplan-Meier analysis revealed that heightened TRIP13 expression is associated with lower overall survival. TRIP13 promotes lung adenocarcinoma cell proliferation, clonogenicity, and migration while inhibiting apoptosis and G2/M phase shift in vitro. Accordingly, TRIP13-silenced xenograft tumors displayed significant growth inhibition in vivo. Bioinformatics analysis demonstrated that TRIP13 interacts with a protein network associated with dsDNA break repair and PI3K/Akt signaling. TRIP13 upregulatesAkt Ser473 and downregulatesAkt Thr308 /mTOR Ser2448 activity, which suppresses accurate dsDNA break repair. TRIP13 also downregulates pro-apoptotic Bad Ser136 and cleaved caspase-3 while upregulating survivin. In conclusion, heightened TRIP13 expression appears to promote lung adenocarcinoma tumor progression and displays potential as a therapeutic target or biomarker for lung adenocarcinoma. Copyright © 2018 Elsevier Inc. All rights reserved.

The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification.

PubMed

Travis, William D; Brambilla, Elisabeth; Nicholson, Andrew G; Yatabe, Yasushi; Austin, John H M; Beasley, Mary Beth; Chirieac, Lucian R; Dacic, Sanja; Duhig, Edwina; Flieder, Douglas B; Geisinger, Kim; Hirsch, Fred R; Ishikawa, Yuichi; Kerr, Keith M; Noguchi, Masayuki; Pelosi, Giuseppe; Powell, Charles A; Tsao, Ming Sound; Wistuba, Ignacio

2015-09-01

The 2015 World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification. The most significant changes in this edition involve (1) use of immunohistochemistry throughout the classification, (2) a new emphasis on genetic studies, in particular, integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients, (3) a new classification for small biopsies and cytology similar to that proposed in the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (4) a completely different approach to lung adenocarcinoma as proposed by the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (5) restricting the diagnosis of large cell carcinoma only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories, (6) reclassifying squamous cell carcinomas into keratinizing, nonkeratinizing, and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemistry proof of squamous differentiation, (7) grouping of neuroendocrine tumors together in one category, (8) adding NUT carcinoma, (9) changing the term sclerosing hemangioma to sclerosing pneumocytoma, (10) changing the name hamartoma to "pulmonary hamartoma," (11) creating a group of PEComatous tumors that include (a) lymphangioleiomyomatosis, (b) PEComa, benign (with clear cell tumor as a variant) and (c) PEComa, malignant, (12) introducing the entity pulmonary myxoid sarcoma with an EWSR1-CREB1 translocation, (13) adding the entities myoepithelioma and myoepithelial carcinomas, which can show EWSR1 gene rearrangements, (14) recognition of usefulness of WWTR1-CAMTA1 fusions in diagnosis of epithelioid

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

PubMed

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.

Mdm2 overexpression and p14(ARF) inactivation are two mutually exclusive events in primary human lung tumors.

PubMed

Eymin, Béatrice; Gazzeri, Sylvie; Brambilla, Christian; Brambilla, Elisabeth

2002-04-18

Pathways involving p53 and pRb tumor suppressor genes are frequently deregulated during lung carcinogenesis. Through its location at the interface of these pathways, Mdm2 can modulate the function of both p53 and pRb genes. We have examined here the pattern of expression of Mdm2 in a series of 192 human lung carcinomas of all histological types using both immunohistochemical and Western blot analyses and four distinct antibodies mapping different epitopes onto the Mdm2 protein. Using Immunohistochemistry (IHC), Mdm2 was overexpressed as compared to normal lung in 31% (60 out of 192) of all tumors analysed, whatever their histological types. Western blotting was performed on 28 out of the 192 tumoral samples. Overexpression of p85/90, p74/76 and p57 Mdm2 isoforms was detected in 18% (5 out of 28), 25% (7 out of 28) and 39% (11 out of 28) of the cases respectively. Overall, overexpression of at least one isoform was observed in 14 out of 28 (50%) lung tumors and concomittant overexpression of at least two isoforms in 7 out of 28 (25%) cases. A good concordance (82%) was observed between immunohistochemical and Western blot data. Interestingly, a highly significant inverse relationship was detected between p14(ARF) loss and Mdm2 overexpression either in NSCLC (P=0.0089) or in NE lung tumors (P<0.0001). Furthermore, a Mdm2/p14(ARF) >1 ratio was correlated with a high grade phenotype among NE tumors overexpressing Mdm2 (P=0.0021). Taken together, these data strongly suggest that p14(ARF)and Mdm2 act on common pathway(s) to regulate p53 and/or pRb-dependent or independent functions and that the Mdm2 : p14(ARF) ratio might act as a rheostat in modulating the activity of both proteins.

Pattern of metastasis outside tumor-bearing segments in primary lung cancer: rationale for segmentectomy.

PubMed

Sakairi, Yuichi; Yoshino, Ichiro; Yoshida, Shigetoshi; Suzuki, Hidemi; Tagawa, Tetsuzo; Iwata, Takekazu; Mizobuchi, Teruaki

2014-05-01

Patterns of intrapulmonary metastasis, particularly metastasis outside tumor-bearing segments, were investigated in lung cancer patients to address the rationale for segmentectomy. In a consecutive series of patients who underwent resection of two or more pulmonary segments for primary lung cancer, intrapulmonary spread patterns, such as segmental/intersegmental node metastasis and pulmonary parenchymal metastasis, were pathologically examined. Eligible 244 lesions included 167 adenocarcinomas, 66 squamous cell carcinomas, and 11 large cell carcinomas. Pathologic stages included 0 to IA (n=111), IB (n=56), IIA (n=31), IIB (n=20), IIIA (n=23), and IIIB to IV (n=3); and N1 (n=26) and N2 (n=22). Intrapulmonary spread was observed in 24 cases (9.8%). Of these, metastasis outside tumor-bearing segments was only observed in 4 cases (1.6%), and such cancer spread was more frequently seen in cases with extrapulmonary (hilar to mediastinal) nodal metastasis (7.9%) than in cases without extrapulmonary metastasis (0.5%; p=0.01). Metastasis outside tumor-bearing segments was not observed in 64 tumors with pure or mixed ground glass opacity features on computed tomography. Although tumor location (peripheral or central/intermediate) was not related to the incidence of metastasis outside tumor-bearing segments, intrapulmonary spread was observed in only 1 of 52 peripheral small (≤20 mm) tumors. Metastasis outside tumor-bearing segments is rarely observed in cases with tumors (1) without extrapulmonary nodal metastasis and (2) with ground glass opacity or peripheral small (≤20 mm) features. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Development of New Mouse Lung Tumor Models Expressing EGFR T790M Mutants Associated with Clinical Resistance to Kinase Inhibitors

PubMed Central

Regales, Lucia; Balak, Marissa N.; Gong, Yixuan; Politi, Katerina; Sawai, Ayana; Le, Carl; Koutcher, Jason A.; Solit, David B.; Rosen, Neal; Zakowski, Maureen F.; Pao, William

2007-01-01

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 EGFRT790M 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. EGFRL858R+T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFRT790M-expressing animals develop tumors with longer latency than EGFRL858R+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 EGFRT790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations. PMID:17726540

Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

PubMed

Regales, Lucia; Balak, Marissa N; Gong, Yixuan; Politi, Katerina; Sawai, Ayana; Le, Carl; Koutcher, Jason A; Solit, David B; Rosen, Neal; Zakowski, Maureen F; Pao, William

2007-08-29

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. 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. 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.

Promotion of Tumor-Initiating Cells in Primary and Recurrent Breast Tumors

DTIC Science & Technology

2014-10-01

confer stemness . We hypothesize that inhibition of IKK/NF-κB will reduce or eliminate breast camcer TICs, blocking tumorigenesis. Furthermore, we...Korkaya H, Liu S, Wicha MS. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest. 2011 Oct;121(10):3804-9. Review...cells and sub- population of cells termed cancer stem cells or tumor-initiating cells (TICs).1 The primary characteristic of TICs is their ability to

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

PubMed

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.

Radiofrequency ablation and immunostimulant OK-432: combination therapy enhances systemic antitumor immunity for treatment of VX2 lung tumors in rabbits.

PubMed

Hamamoto, Shinichi; Okuma, Tomohisa; Yamamoto, Akira; Kageyama, Ken; Takeshita, Toru; Sakai, Yukimasa; Nishida, Norifumi; Matsuoka, Toshiyuki; Miki, Yukio

2013-05-01

To evaluate whether antitumor immunity is enhanced systemically by combining radiofrequency ablation (RFA) and local injection of an immunostimulant, OK-432. Experiments were approved by the institutional animal care committee. Experimental Japanese rabbits inoculated with VX2 tumors in the lung and the auricle were randomized into four groups of eight: control (supportive care), RFA (RFA of lung tumor), OK-432 (direct injection of OK-432 into lung tumor), and combination therapy (lung RFA and direct OK-432 injection into lung tumor). All procedures were performed 1 week after implantation of VX2 tumors (week 1). In addition, a VX2 tumor rechallenge test was performed in the RFA and combination therapy groups. Survival time was evaluated by means of the Kaplan-Meier method and by using the log-rank test for intergroup comparison. Mean auricle tumor volumes were calculated every week. Specific growth rates (SGRs) were calculated and compared by using the Mann-Whitney test. The median survival times of the control, RFA, OK-432, and combination therapy groups were 23, 36.5, 46.5, and 105 days, respectively. Survival was significantly prolonged in the combination therapy group when compared with the other three groups (P <.05). The mean auricle tumor volume decreased only in the combination therapy group. The mean auricle tumor volumes of the combination therapy group from week 1 to week 7 were 205, 339, 264, 227, 143, 127, and 115 mm(3). SGR in the combination therapy group became significantly smaller than those in the other three groups (P < .05). In the rechallenge test, the volume of all reimplanted tumors decreased. Combining RFA with local injection of immunostimulant OK-432 may lead to indirectly activation of systemic antitumor immunity. © RSNA, 2013.

Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis

PubMed Central

Calvo, A; Catena, R; Noble, MS; Carbott, D; Gil-Bazo, I; Gonzalez-Moreno, O; Huh, J-I; Sharp, R; Qiu, T-H; Anver, MR; Merlino, G; Dickson, RB; Johnson, MD; Green, JE

2009-01-01

Metastasis is the primary cause of death in patients with breast cancer. Overexpression of c-myc in humans correlates with metastases, but transgenic mice only show low rates of micrometastases. We have generated transgenic mice that overexpress both c-myc and vascular endothelial growth factor (VEGF) (Myc/VEGF) in the mammary gland, which develop high rates of pulmonary macrometastases. Gene expression profiling revealed a set of deregulated genes in Myc/VEGF tumors compared to Myc tumors associated with the increased metastatic phenotype. Cross-comparisons between this set of genes with a human breast cancer lung metastasis gene signature identified five common targets: tenascin-C (TNC), matrix metalloprotease-2, collagen-6-A1, mannosidase-α-1A and HLA-DPA1. Signaling blockade or knockdown of TNC in MDA-MB-435 cells resulted in a significant impairment of cell migration and anchorage-independent cell proliferation. Mice injected with clonal MDA-MB-435 cells with reduced expression of TNC demonstrated a significant decrease (P < 0.05) in (1) primary tumor growth; (2) tumor relapse after surgical removal of the primary tumor and (3) incidence of lung metastasis. Our results demonstrate that VEGF induces complex alterations in tissue architecture and gene expression. The TNC signaling pathway plays an important role in mammary tumor growth and metastases, suggesting that TNC may be a relevant target for therapy against metastatic breast cancer. PMID:18504437

3D tumor localization through real-time volumetric x-ray imaging for lung cancer radiotherapy.

PubMed

Li, Ruijiang; Lewis, John H; Jia, Xun; Gu, Xuejun; Folkerts, Michael; Men, Chunhua; Song, William Y; Jiang, Steve B

2011-05-01

To evaluate an algorithm for real-time 3D tumor localization from a single x-ray projection image for lung cancer radiotherapy. Recently, we have developed an algorithm for reconstructing volumetric images and extracting 3D tumor motion information from a single x-ray projection [Li et al., Med. Phys. 37, 2822-2826 (2010)]. We have demonstrated its feasibility using a digital respiratory phantom with regular breathing patterns. In this work, we present a detailed description and a comprehensive evaluation of the improved algorithm. The algorithm was improved by incorporating respiratory motion prediction. The accuracy and efficiency of using this algorithm for 3D tumor localization were then evaluated on (1) a digital respiratory phantom, (2) a physical respiratory phantom, and (3) five lung cancer patients. These evaluation cases include both regular and irregular breathing patterns that are different from the training dataset. For the digital respiratory phantom with regular and irregular breathing, the average 3D tumor localization error is less than 1 mm which does not seem to be affected by amplitude change, period change, or baseline shift. On an NVIDIA Tesla C1060 graphic processing unit (GPU) card, the average computation time for 3D tumor localization from each projection ranges between 0.19 and 0.26 s, for both regular and irregular breathing, which is about a 10% improvement over previously reported results. For the physical respiratory phantom, an average tumor localization error below 1 mm was achieved with an average computation time of 0.13 and 0.16 s on the same graphic processing unit (GPU) card, for regular and irregular breathing, respectively. For the five lung cancer patients, the average tumor localization error is below 2 mm in both the axial and tangential directions. The average computation time on the same GPU card ranges between 0.26 and 0.34 s. Through a comprehensive evaluation of our algorithm, we have established its accuracy in 3D

TH-AB-BRA-08: Simulated Tumor Tracking in An MRI Linac for Lung Tumor Lesions Using the Monaco Treatment Planning System

DOE Office of Scientific and Technical Information (OSTI.GOV)

Al-Ward, S; Kim, A; McCann, C

2016-06-15

Purpose: To simulate tumor tracking in an Elekta MRI-linac (MRL) and to compare this tracking method with our current ITV approach in terms of OAR sparing for lung cancer patients. Methods: Five SABR-NSCLC patients with central lung tumors were selected for reasons of potential enhancement of tumor-tissue delineation using MRI. The Monaco TPS was used to compare the current clinical ITV approach to a simulated, novel tracking method which used a 7MV MRL beam in the presence of an orthogonal 1.5 T magnetic field (4D-MRL method). In the simulated tracking scenario, achieved using the virtual couch shift (VCS), the PTVmore » was defined using an isotropic 5mm margin applied to the GTV of each phase, as acquired from an 8-phase amplitude-binned 4DCT. These VCS plans were optimized and weighted on each phase. The dose weighting was performed using the patient-specific breathing traces. The doses were accumulated on the inhale phase. The two methods were compared by assessing the OAR DVHs. Results: The 4D-MRL method resulted in a reduced target volume (by an average of 29% over all patients). The benefits of using an MRL tracking system depended on the tumor motion amplitude and the relative OAR motion (ROM) to the target. The reduction in mean doses to parallel organs was up to 3 Gy for the heart and 2.1 Gy for the lung. The reductions in maximum doses to serial organs were up to 9.4 Gy, 5.6 Gy, and 8.7 Gy for the esophagus, spinal cord, and the trachea, respectively. Serial organs benefited from MRL tracking when the ROM was ≥ 0.3 cm despite small tumor motion amplitude in some cases. Conclusions: This work demonstrated the potential benefit for an MRL tracking system to spare OARs in SABR-NSCLC patients with central tumors. The benefits are embodied in the target volume reduction. This project was made possible with the financial support of Elekta.« less

MiR-564 functions as a tumor suppressor in human lung cancer by targeting ZIC3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Bin; Jia, Lin; Guo, Qiaojuan

2015-11-27

Although miR-564 was reported to be dysregulated in human malignancy, the function and mechanism of miR-564 in tumorigenesis remains unknown. In the present study, we found that miR-564 frequently downregulated in lung cancer cells and significantly inhibited cell proliferation, cell cycle progression, motility, and the tumorigenicity of lung cancer cells. Moreover, we identified zic family member 3 (ZIC3) as a direct target of miR-564. ZIC3 overexpression impaired the suppressive effects of miR-564 on the capacity of lung cancer cells for proliferation and motility. Finally, we detected the expression level of miR-564 and ZIC3 protein in tissue specimens, and found amore » significant negative correlation between them. Patients with low levels of miR-564 showed a poorer overall survival. Taken together, our present study revealed the tumor suppressor role of miR-564, indicating restoration of miR-564 as a potential therapeutic strategy for the treatment of lung cancer. - Highlights: • MiR-564 inhibits cancer cell proliferation, cell cycle progression, migration, and invasion. • miR-564 suppresses the tumorigenicity of lung cancer cell in vivo. • ZIC3 is a direct and functional target of miR-564. • The expression of miR-564 was negatively correlated with ZIC3 protein in tumors. • Both low miR-564 and high ZIC3 was associated with tumor stage and prognosis.« less

WE-H-BRA-02: Radiobiological Modeling of Tumor Control Probability (TCP) and Radiation-Induced Pneumonitis (RP) for Lung Cancer Patients Treated with Monte Carlo-Based Lung SBRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, D; Sood, S; Shen, X

2016-06-15

Purpose: To present radiobiological modeling of TCP using tumor size-adjusted BED(s-BED)and PTV(D99) to lung SBRT patients treated with X-ray Voxel Monte Carlo(XVMC) algorithm, apply parameterized Lyman-NTCP model to predict grade-2 RP and subsequently, compare with clinical outcomes/observations. Methods: Dosimetric parameters and clinical follow-up for XVMC-based lung-SBRT patients were retrospectively evaluated. Patients were treated at Novalis-TX with hybrid(2 non-coplanar partial-arcs plus 3–6 static-beams)plan using HD-MLC/6MV-SRS-beam.For TCP,s-BED modelling was utilized: TCP=EXP[sBED-TCD50]/k/(1.0+EXP[sBED-TCD50]/k), where k=31Gy corresponding to TCD50=0Gy and s-BED was defined as BED10 minus 10 times the tumor diameter(in centimeters)by Ohri et al.(IJROBP,2012). For 2-yr local-control, we used more-realistic MC-computed PTVD99 as amore » predictive parameter, s-BED(D99).Due to relatively shorter median follow-up interval(12-months),Kaplan-Meier curves were generated to estimate 2-yr observed local-control and compared to predicted-rate by TCP modeling. For NTCP, we employed parameterized Lyman-NTCP model utilizing normal-lung DVH and α/β=3Gy fitted to predict grade-2 RP after lung-SBRT. Results: Total 108 patients (137 tumors) treated for 35–70Gy in 3–5 fractions, either primary-lung(n=74)or metastatic-lung(n=53)tumors were included.F or the given prescription dose with MC-computed MUs, 2-yr local-control rates with s-BED(D99) was 87±8%. Kaplan-Meier generated observed local-control rate at 2-yr was 87.5%,suggesting that PTV(D99) could be a potential predictor (p-value=0.38). Observed vs predicted TCP for primary-lung tumors and metastatic tumors were 97% vs 88±7% and 94% vs 86±9%.NTCP model predicted well for symptomatic-RP with predicted vs observed (3±5% vs 2%). Radiographic and clinically significant RP was observed in 13% and 2% of patients. Higher rates of radiographic change were observed in patients who received >50Gy compared to �

[Construction of 2-dimensional tumor microvascular architecture phenotype in non-small cell lung cancer].

PubMed

Liu, Jin-kang; Wang, Xiao-yi; Xiong, Zeng; Zhou, Hui; Zhou, Jian-hua; Fu, Chun-yan; Li, Bo

2008-08-01

To construct a technological platform of 2-dimensional tumor microvascular architecture phenotype (2D-TAMP) expression. Thirty samples of non-small cell lung cancer (NSCLC) were collected after surgery. The corresponding sections of tumor tissue specimens to the slice of CT perfusion imaging were selected. Immunohistochemical staining,Gomori methenamine silver stain, and electron microscope observation were performed to build a technological platform of 2D-TMAP expression by detecting the morphology and the integrity of basement membrane of microvasculature, microvascular density, various microvascular subtype, the degree of the maturity and lumenization of microvasculature, and the characteristics of immunogenetics of microvasculature. The technological platform of 2D-TMAP expression was constructed successfully. There was heterogeneity in 2D-TMAP expression of non-small cell lung cancer. The microvascular of NSCLC had certain characteristics. 2D-TMAP is a key technology that can be used to observe the overall state of micro-environment in tumor growth.

Impact of Anatomical Location on Value of CT-PET Co-Registration for Delineation of Lung Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fitton, Isabelle; Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Steenbakkers, Roel J.H.M.

2008-04-01

Purpose: To derive guidelines for the need to use positron emission tomography (PET) for delineation of the primary tumor (PT) according to its anatomical location in the lung. Methods and Materials: In 22 patients with non-small-cell lung cancer, thoracic X-ray computed tomography (CT) and PET were performed. Eleven radiation oncologists delineated the PT on the CT and on the CT-PET registered scans. The PTs were classified into two groups. In Group I patients, the PT was surrounded by lung or visceral pleura, without venous invasion, without extension to chest wall or the mediastinum over more than one quarter of itsmore » surface. In Group II patients, the PT invaded the hilar region, heart, great vessels, pericardium, mediastinum over more than one quarter of its surface and/or associated with atelectasis. A comparison of interobserver variability for each group was performed and expressed as a local standard deviation. Results: The comparison of delineations showed a good reproducibility for Group I, with an average SD of 0.4 cm on CT and an average SD of 0.3 cm on CT-PET (p = 0.1628). There was also a significant improvement with CT-PET for Group II, with an average SD of 1.3 cm on CT and SD of 0.4 cm on CT-PET (p = 0.0003). The improvement was mainly located at the atelectasis/tumor interface. At the tumor/lung and tumor/hilum interfaces, the observer variation was similar with both modalities. Conclusions: Using PET for PT delineation is mandatory to decrease interobserver variability in the hilar region, heart, great vessels, pericardium, mediastinum, and/or the region associated with atelectasis; however it is not essential for delineation of PT surrounded by lung or visceral pleura, without venous invasion or extension to the chest wall.« less

The European initiative for quality management in lung cancer care.

PubMed

Blum, Torsten G; Rich, Anna; Baldwin, David; Beckett, Paul; De Ruysscher, Dirk; Faivre-Finn, Corinne; Gaga, Mina; Gamarra, Fernando; Grigoriu, Bogdan; Hansen, Niels C G; Hubbard, Richard; Huber, Rudolf Maria; Jakobsen, Erik; Jovanovic, Dragana; Konsoulova, Assia; Kollmeier, Jens; Massard, Gilbert; McPhelim, John; Meert, Anne-Pascale; Milroy, Robert; Paesmans, Marianne; Peake, Mick; Putora, Paul-Martin; Scherpereel, Arnaud; Schönfeld, Nicolas; Sitter, Helmut; Skaug, Knut; Spiro, Stephen; Strand, Trond-Eirik; Taright, Samya; Thomas, Michael; van Schil, Paul E; Vansteenkiste, Johan F; Wiewrodt, Rainer; Sculier, Jean-Paul

2014-05-01

Lung cancer is the commonest cause of cancer-related death worldwide and poses a significant respiratory disease burden. Little is known about the provision of lung cancer care across Europe. The overall aim of the Task Force was to investigate current practice in lung cancer care across Europe. The Task Force undertook four projects: 1) a narrative literature search on quality management of lung cancer; 2) a survey of national and local infrastructure for lung cancer care in Europe; 3) a benchmarking project on the quality of (inter)national lung cancer guidelines in Europe; and 4) a feasibility study of prospective data collection in a pan-European setting. There is little peer-reviewed literature on quality management in lung cancer care. The survey revealed important differences in the infrastructure of lung cancer care in Europe. The European guidelines that were assessed displayed wide variation in content and scope, as well as methodological quality but at the same time there was relevant duplication. The feasibility study demonstrated that it is, in principle, feasible to collect prospective demographic and clinical data on patients with lung cancer. Legal obligations vary among countries. The European Initiative for Quality Management in Lung Cancer Care has provided the first comprehensive snapshot of lung cancer care in Europe.

Mesenchymal stem cells cancel azoxymethane-induced tumor initiation.

PubMed

Nasuno, Masanao; Arimura, Yoshiaki; Nagaishi, Kanna; Isshiki, Hiroyuki; Onodera, Kei; Nakagaki, Suguru; Watanabe, Shuhei; Idogawa, Masashi; Yamashita, Kentaro; Naishiro, Yasuyoshi; Adachi, Yasushi; Suzuki, Hiromu; Fujimiya, Mineko; Imai, Kohzoh; Shinomura, Yasuhisa

2014-04-01

The role of mesenchymal stem cells (MSCs) in tumorigenesis remains controversial. Therefore, our goal was to determine whether exogenous MSCs possess intrinsic antineoplastic or proneoplastic properties in azoxymethane (AOM)-induced carcinogenesis. Three in vivo models were studied: an AOM/dextran sulfate sodium colitis-associated carcinoma model, an aberrant crypt foci model, and a model to assess the acute apoptotic response of a genotoxic carcinogen (AARGC). We also performed in vitro coculture experiments. As a result, we found that MSCs partially canceled AOM-induced tumor initiation but not tumor promotion. Moreover, MSCs inhibited the AARGC in colonic epithelial cells because of the removal of O(6)-methylguanine (O(6) MeG) adducts through O(6) MeG-DNA methyltransferase activation. Furthermore, MSCs broadly affected the cell-cycle machinery, potentially leading to G1 arrest in vivo. Coculture of IEC-6 rat intestinal cells with MSCs not only arrested the cell cycle at the G1 phase, but also induced apoptosis. The anti-carcinogenetic properties of MSCs in vitro required transforming growth factor (TGF)-β signaling because such properties were completely abrogated by absorption of TGF-β under indirect coculture conditions. MSCs inhibited AOM-induced tumor initiation by preventing the initiating cells from sustaining DNA insults and subsequently inducing G1 arrest in the initiated cells that escaped from the AARGC. Furthermore, tumor initiation perturbed by MSCs might potentially dysregulate WNT and TGF-β-Smad signaling pathways in subsequent tumorigenesis. Obtaining a better understanding of MSC functions in colon carcinogenesis is essential before commencing the broader clinical application of promising MSC-based therapies for cancer-prone patients with inflammatory bowel disease. © AlphaMed Press.

Percutaneous thermal ablation of lung tumors - Radiofrequency, microwave and cryotherapy: Where are we going?

PubMed

Palussière, J; Catena, V; Buy, X

2017-09-01

Main indications of percutaneous pulmonary thermal ablation are early stage non-small cell lung carcinoma (NSCLC) for patients who are not amenable to surgery and slow-evolving localized metastatic disease, either spontaneous or following a general treatment. Radiofrequency ablation (RFA) is the most evaluated technique. This technique offers a local control rate ranging between 80 and 90% for tumors <3cm in diameter. Other more recently used ablation techniques such as microwaves and cryotherapy could overcome some limitations of RFA. One common characteristic of these techniques is an excellent tolerance with very few complications. This article reviews the differences between these techniques when applied to lung tumors, indications, results and complications. Future potential associations with immunotherapy will be discussed. Copyright © 2017. Published by Elsevier Masson SAS.

Cytosolic PhospholipaseA2 Inhibition with PLA-695 Radiosensitizes Tumors in Lung Cancer Animal Models

PubMed Central

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. PMID:23894523

Inflammatory myofibroblastic tumor of the lung with unique histological pattern and association with Sjögren's disease and systemic lupus erythematosus.

PubMed

Shlopov, Boris V; French, Samuel W

2011-10-01

Inflammatory myofibroblastic tumor (IMT) of the lung is a rare condition. Radiological properties and clinical presentation of this disease can mimic malignant process. We present a case of IMT of the lung in a 58 year old female patient with a single lung nodule. Tumor was unencapsulated, firm, and well circumscribed. Microscopically tumor had multinodular structure with single or multiple small blood vessels in the center of each nodule surrounded in circular pattern by connective tissue containing spindle cells embedded into the thick layers of extracellular matrix. Extracellular matrix was identified as type I and type III collagen fibrils embedded into type IV collagen and laminin. The tumor was surrounded by T-, B-lymphocytes and polyclonal plasma cells. Histological organization of this lesion's stromal component was unique, but cell composition was similar to inflammatory pseudotumor of the lung. In addition, tumor tissue sections exhibited strong positivity for IgG, weak positivity for IgA, 1Cq, but were negative for IgM, and C3. Mutational analysis of the EGFR, KRAS genes and ALK locus rearrangement were performed and did not reveal any mutations. This is the first report of an IMT associated with Sjögren's disease, systemic lupus erythematosus and Non-Hodgkin lymphoma developing in the lungs. Patient was clinically followed up for 18 months and no recurrence of the tumor observed. Copyright © 2011 Elsevier Inc. All rights reserved.

SU-E-J-23: An Accurate Algorithm to Match Imperfectly Matched Images for Lung Tumor Detection Without Markers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rozario, T; Bereg, S; Chiu, T

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 ofmore » 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

Implications of delayed initiation of radiotherapy: accelerated repopulation after induction chemotherapy for stage III non-small cell lung cancer.

PubMed

Chen, Chien P; Weinberg, Vivian K; Jahan, Thierry M; Jablons, David M; Yom, Sue S

2011-11-01

For patients with stage III non-small cell lung cancer treated with induction chemotherapy (ICT), delayed initiation of subsequent radiotherapy (RT) may allow for repopulation in the interval between treatment modalities and during the early phase of RT. We quantified the impact of postinduction RT timing by evaluating the pace of tumor regrowth. Institutionally approved retrospective review identified 21 analyzable patients with stage III non-small cell lung cancer who had platinum-based ICT followed by RT+/- chemotherapy from 2002 to 2009. Radiographic response was determined by RECIST criteria and the volume of the single largest tumor mass on the pre-ICT, post-ICT, and RT-planning computed tomography scans. After ICT, the median percent volume change from pre-ICT baseline was -41% (range -86 to +86%). By the RT-planning computed tomography scan, the median percent volume change from the post-ICT timepoint was +40% (range -11 to +311%) and the median volume change was +20 ml (range -4 to 102 ml); these changes were significant (p = 0.0002). Similar results were seen for tumor diameter. A correlation was observed between the amount of delay and degree of regrowth for percent volume (p = 0.0006) and percent diameter change (p = 0.003). A delay greater than 21 days produced greater increases in percent volume change (p = 0.002) and percent diameter (p = 0.055) than lesser delays. After ICT, tumor regrowth can occur within a few weeks. Radiation treatment planning should begin as soon as possible after the administration of ICT to maximize the benefits of cytoreduction.

RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation

PubMed Central

Morales, Mònica; Arenas, Enrique J; Urosevic, Jelena; Guiu, Marc; Fernández, Esther; Planet, Evarist; Fenwick, Robert Bryn; Fernández-Ruiz, Sonia; Salvatella, Xavier; Reverter, David; Carracedo, Arkaitz; Massagué, Joan; Gomis, Roger R

2014-01-01

In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme. PMID:24867881

“Sentinel” Circulating Tumor Cells Allow Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease

PubMed Central

Ilie, Marius; Hofman, Véronique; Long-Mira, Elodie; Selva, Eric; Vignaud, Jean-Michel; Padovani, Bernard; Mouroux, Jérôme; Marquette, Charles-Hugo; Hofman, Paul

2014-01-01

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. Migration of circulating tumor cells (CTCs) into the blood stream is an early event that occurs during carcinogenesis. We aimed to examine the presence of CTCs in complement to CT-scan in COPD patients without clinically detectable lung cancer as a first step to identify a new marker for early lung cancer diagnosis. The presence of CTCs was examined by an ISET filtration-enrichment technique, for 245 subjects without cancer, including 168 (68.6%) COPD patients, and 77 subjects without COPD (31.4%), including 42 control smokers and 35 non-smoking healthy individuals. CTCs were identified by cytomorphological analysis and characterized by studying their expression of epithelial and mesenchymal markers. COPD patients were monitored annually by low-dose spiral CT. CTCs were detected in 3% of COPD patients (5 out of 168 patients). The annual surveillance of the CTC-positive COPD patients by CT-scan screening detected lung nodules 1 to 4 years after CTC detection, leading to prompt surgical resection and histopathological diagnosis of early-stage lung cancer. Follow-up of the 5 patients by CT-scan and ISET 12 month after surgery showed no tumor recurrence. CTCs detected in COPD patients had a heterogeneous expression of epithelial and mesenchymal markers, which was similar to the corresponding lung tumor phenotype. No CTCs were detected in control smoking and non-smoking healthy individuals. CTCs can be detected in patients with COPD without clinically detectable lung cancer. Monitoring “sentinel” CTC-positive COPD patients may allow early diagnosis of lung cancer. PMID:25360587

Pneumothorax caused by cystic and nodular lung metastases from a malignant uterine perivascular epithelioid cell tumor (PEComa).

PubMed

Okamoto, Shouichi; Komura, Moegi; Terao, Yasuhisa; Kurisaki-Arakawa, Aiko; Hayashi, Takuo; Saito, Tsuyoshi; Togo, Shinsaku; Shiokawa, Akira; Mitani, Keiko; Kobayashi, Etsuko; Kumasaka, Toshio; Takahashi, Kazuhisa; Seyama, Kuniaki

2017-01-01

Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with immunoreactivity for both melanocytic and smooth muscle markers. PEComas occur at multiple sites, and malignant PEComas can undergo metastasis, recurrence and aggressive clinical courses. Although the lung is a common metastatic site of PEComas, they usually appear as multiple nodules but rarely become cystic or cavitary. Here, we describe a female patient whose lungs manifested multiple cystic, cavity-like and nodular metastases 3 years after the resection of uterine tumors tentatively diagnosed as epithelioid smooth muscle tumors with uncertain malignant potential. This patient's subsequent pneumothorax necessitated video-assisted thoracoscopic surgery, and examination of her resected lung specimens eventually led to correcting the diagnosis, i.e., to a PEComa harboring tuberous sclerosis complex 1 ( TSC1 ) loss-of-heterozygosity that originated in the uterus and then metastasized to the lungs. The administration of a gonadotropin-releasing hormone analogue later stabilized her clinical course. To the best of our knowledge, the present case is the first in the literature that associates PEComas with a TSC1 abnormality. Additionally, the pulmonary manifestations, including imaging appearance and pneumothorax, somewhat resembled those of lymphangioleiomyomatosis, a representative disease belonging to the PEComa family. Although PEComas are rare, clinicians, radiologists and pathologists should become aware of this disease entity, especially in the combined clinical setting of multiple cystic, cavity-like, nodular lesions on computed tomography of the chest and a past history of the tumor in the female reproductive system.

Lung transplantation from initially rejected donors after ex vivo lung reconditioning: the French experience.

PubMed

Sage, Edouard; Mussot, Sacha; Trebbia, Grégoire; Puyo, Philippe; Stern, Marc; Dartevelle, Philippe; Chapelier, Alain; Fischler, Marc

2014-11-01

Only 15% of brain death donors are considered suitable for lung transplantation (LTx). The normothermic ex vivo lung perfusion technique is used to potentially increase the availability of high-risk lung donors. We report our experience of LTx with initially rejected donors after ex vivo lung reconditioning (EVLR). From April 2011 to May 2013, we performed EVLR for 32 pairs of donor lungs deemed unsuitable for transplantation and rejected by the 11 French lung transplant teams. After EVLR, lungs with acceptable function were transplanted. During the same period, 81 double-lung transplantations (DLTx) were used as controls. During EVLR, 31 of 32 donor lungs recovered physiological function with a median PO2/FiO2 ratio increasing from 274 (range 162-404) mmHg to 511 (378-668) mmHg at the end of EVLR (P < 0.0001). Thirty-one DLTx were performed. The incidence of primary graft dysfunction 72 h after LTx was 9.5% in the EVLR group and 8.5% in the control group (P = 1). The median time of extubation, intensive care unit and hospital lengths of stay were 1, 9 and 37 days in the EVLR group and 1 (P = 0.17), 6 (P = 0.06) and 28 days (P = 0.09) in the control group, respectively. Thirty-day mortality rates were 3.3% (n = 1) in the EVLR group and 3.7% (n = 3) in the control group (P = 0.69). One-year survival rates were 93% in the EVLR group and 91% in the control group. EVLR is a reliable and repeatable technique that offers a significant increase of available donors. The results of LTx with EVLR lungs are similar to those obtained with conventional donors. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

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

EPA Science Inventory

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...

Markerless positional verification using template matching and triangulation of kV images acquired during irradiation for lung tumors treated in breath-hold

NASA Astrophysics Data System (ADS)

Hazelaar, Colien; Dahele, Max; Mostafavi, Hassan; van der Weide, Lineke; Slotman, Ben; Verbakel, Wilko

2018-06-01

�� +  triangulation using DTS  +  band-pass filtered images could accurately determine the position of stationary lung tumors. However, triangulation was less accurate/reliable for targets with continuous, gradual displacement in the lateral and vertical directions. This technique is therefore currently most suited to detect/monitor offsets occurring between initial setup and the start of treatment, inter-breath-hold variations, and tumors with predominantly longitudinal motion.

TH-AB-202-01: Daily Lung Tumor Motion Characterization On EPIDs Using a Markerless Tiling Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rozario, T; University of Texas at Dallas, Richardson, TX; Chiu, T

Purpose: Tracking lung tumor motion in real time allows for target dose escalation while simultaneously reducing dose to sensitive structures, thus increasing local control without increasing toxicity. We present a novel intra-fractional markerless lung tumor tracking algorithm using MV treatment beam images acquired during treatment delivery. Strong signals superimposed on the tumor significantly reduced the soft tissue resolution; while different imaging modalities involved introduce global imaging discrepancies. This reduced the comparison accuracies. A simple yet elegant Tiling algorithm is reported to overcome the aforementioned issues. Methods: MV treatment beam images were acquired continuously in beam’s eye view (BEV) by anmore » electronic portal imaging device (EPID) during treatment and analyzed to obtain tumor positions on every frame. Every frame of the MV image was simulated by a composite of two components with separate digitally reconstructed radiographs (DRRs): all non-moving structures and the tumor. This Titling algorithm divides the global composite DRR and the corresponding MV projection into sub-images called tiles. Rigid registration is performed independently on tile-pairs in order to improve local soft tissue resolution. This enables the composite DRR to be transformed accurately to match the MV projection and attain a high correlation value through a pixel-based linear transformation. The highest cumulative correlation for all tile-pairs achieved over a user-defined search range indicates the 2-D coordinates of the tumor location on the MV projection. Results: This algorithm was successfully applied to cine-mode BEV images acquired during two SBRT plans delivered five times with different motion patterns to each of two phantoms. Approximately 15000 beam’s eye view images were analyzed and tumor locations were successfully identified on every projection with a maximum/average error of 1.8 mm / 1.0 mm. Conclusion: Despite the presence

Isolation and (111)In-Oxine Labeling of Murine NK Cells for Assessment of Cell Trafficking in Orthotopic Lung Tumor Model.

PubMed

Malviya, Gaurav; Nayak, Tapan; Gerdes, Christian; Dierckx, Rudi A J O; Signore, Alberto; de Vries, Erik F J

2016-04-04

A noninvasive in vivo imaging method for NK cell trafficking is essential to gain further understanding of the pathogenesis of NK cell mediated immune response to the novel cancer treatment strategies, and to discover the homing sites and physiological distribution of NK cells. Although human NK cells can be labeled for in vivo imaging, little is known about the murine NK cell labeling and its application in animal models. This study describes the isolation and ex vivo radiolabeling of murine NK cells for the evaluation of cell trafficking in an orthotopic model of human lung cancer in mice. Scid-Tg(FCGR3A)Blt transgenic SCID mice were used to isolate NK cells from mouse splenocytes using the CD49b (DX5) MicroBeads positive selection method. The purity and viability of the isolated NK cells were confirmed by FACS analysis. Different labeling buffers and incubation times were evaluated to optimize (111)In-oxine labeling conditions. Functionality of the radiolabeled NK cell was assessed by (51)Cr-release assay. We evaluated physiological distribution of (111)In-oxine labeled murine NK cells in normal SCID mice and biodistribution in irradiated and nonirradiated SCID mice with orthotopic A549 human lung tumor lesions. Imaging findings were confirmed by histology. Results showed that incubation with 0.011 MBq of (111)In-oxine per million murine NK cells in PBS (pH 7.4) for 20 min is the best condition that provides optimum labeling efficiency without affecting cell viability and functionality. Physiological distribution in normal SCID mice demonstrated NK cells homing mainly in the spleen, while (111)In released from NK cells was excreted via kidneys into urine. Biodistribution studies demonstrated a higher lung uptake in orthotopic lung tumor-bearing mice than control mice. In irradiated mice, lung tumor uptake of radiolabeled murine NK cells decreased between 24 h and 72 h postinjection (p.i.), which was accompanied by tumor regression, while in nonirradiated mice

Tumor microenvironment is multifaceted.

PubMed

Sautès-Fridman, Catherine; Cherfils-Vicini, Julien; Damotte, Diane; Fisson, Sylvain; Fridman, Wolf Hervé; Cremer, Isabelle; Dieu-Nosjean, Marie-Caroline

2011-03-01

Cancer initiation, progression, and invasion occur in a complex and dynamic microenvironment which depends on the hosts and sites where tumors develop. Tumors arising in mucosal tissues may progress in an inflammatory context linked to local viral and/or bacterial infections. At the opposite, tumors developing in immunoprivileged sites are protected from microorganisms and grow in an immunosuppressive environment. In the present review, we summarize and present our recent data on the influence of infectious context and immune cell infiltration organization in human Non-Small Cell Lung Cancers (NSCLC) progression. We show that stimulation of tumor cells by TLR for viral ssRNA, such as TLR7/8, or bacteria, such as TLR4, promotes cell survival and induces chemoresistance. On the opposite, stimulation by TLR3, receptor for double-stranded viral RNA, decreases tumor cell viability and induces chemosensitivity in some lung tumor cell lines. Since fresh lung tumor cells exhibit a gene expression profile characteristic of TLR-stimulated lung tumor cell lines, we suspect that viral and bacterial influence may not only act on the host immune system but also directly on tumor growth and sensitivity to chemotherapy. The stroma of NSCLC contains tertiary lymphoid structures (or Tumor-induced Bronchus-Associated Lymphoid Tissues (Ti-BALT)) with mature DC, follicular DC, and T and B cells. Two subsets of immature DC, Langerhans cells (LC) and interstitial DC (intDC), were detected in the tumor nests and the stroma, respectively. Here, we show that the densities of the three DC subsets, mature DC, LC, and intDC, are highly predictive of disease-specific survival in a series of 74 early-stage NSCLC patients. We hypothesize that the mature DC may derive from local activation and migration of the immature DC--and especially LC which contact the tumor cells--to the tertiary lymphoid structures, after sampling and processing of the tumor antigens. In view of the prominent role of DC in

Development of an automated size-based filtration system for isolation of circulating tumor cells in lung cancer patients.

PubMed

Yagi, Satomi; Koh, Yasuhiro; Akamatsu, Hiroaki; Kanai, Kuninobu; Hayata, Atsushi; Tokudome, Nahomi; Akamatsu, Keiichiro; Endo, Katsuya; Nakamura, Seita; Higuchi, Masayuki; Kanbara, Hisashige; Nakanishi, Masanori; Ueda, Hiroki; Yamamoto, Nobuyuki

2017-01-01

Circulating tumor cells (CTCs), defined as tumor cells circulating in the peripheral blood of patients with solid tumors, are relatively rare. Diagnosis using CTCs is expected to help in the decision-making for precision cancer medicine. We have developed an automated microcavity array (MCA) system to detect CTCs based on the differences in size and deformability between tumor cells and normal blood cells. Herein, we evaluated the system using blood samples from non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients. To evaluate the recovery of CTCs, preclinical experiments were performed by spiking NSCLC cell lines (NCI-H820, A549, NCI-H23 and NCI-H441) into peripheral whole blood samples from healthy volunteers. The recovery rates were 70% or more in all cell lines. For clinical evaluation, 6 mL of peripheral blood was collected from 50 patients with advanced lung cancer and from 10 healthy donors. Cells recovered on the filter were stained. We defined CTCs as DAPI-positive, cytokeratin-positive, and CD45-negative cells under the fluorescence microscope. The 50 lung cancer patients had a median age of 72 years (range, 48-85 years); 76% had NSCLC and 20% had SCLC, and 14% were at stage III disease whereas 86% were at stage IV. One or more CTCs were detected in 80% of the lung cancer patients (median 2.5). A comparison of the CellSearch system with our MCA system, using the samples from NSCLC patients, confirmed the superiority of our system (median CTC count, 0 versus 11 for CellSearch versus MCA; p = 0.0001, n = 17). The study results suggest that our MCA system has good clinical potential for diagnosing CTCs in lung cancer.

Intra-observer and inter-observer agreements for the measurement of dual-input whole tumor computed tomography perfusion in patients with lung cancer: Influences of the size and inner-air density of tumors.

PubMed

Wang, Qingle; Zhang, Zhiyong; Shan, Fei; Shi, Yuxin; Xing, Wei; Shi, Liangrong; Zhang, Xingwei

2017-09-01

This study was conducted to assess intra-observer and inter-observer agreements for the measurement of dual-input whole tumor computed tomography perfusion (DCTP) in patients with lung cancer. A total of 88 patients who had undergone DCTP, which had proved a diagnosis of primary lung cancer, were divided into two groups: (i) nodules (diameter ≤3 cm) and masses (diameter >3 cm) by size, and (ii) tumors with and without air density. Pulmonary flow, bronchial flow, and pulmonary index were measured in each group. Intra-observer and inter-observer agreements for measurement were assessed using intraclass correlation coefficient, within-subject coefficient of variation, and Bland-Altman analysis. In all lung cancers, the reproducibility coefficient for intra-observer agreement (range 26.1-38.3%) was superior to inter-observer agreement (range 38.1-81.2%). Further analysis revealed lower agreements for nodules compared to masses. Additionally, inner-air density reduced both agreements for lung cancer. The intra-observer agreement for measuring lung cancer DCTP was satisfied, while the inter-observer agreement was limited. The effects of tumoral size and inner-air density to agreements, especially between two observers, should be emphasized. In future, an automatic computer-aided segment of perfusion value of the tumor should be developed. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

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

EPA Science Inventory

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...

Non-Small Cell Lung Cancer Cells Expressing CD44 Are Enriched for Stem Cell-Like Properties

PubMed Central

Leung, Elaine Lai-Han; Fiscus, Ronald R.; Tung, James W.; Tin, Vicky Pui-Chi; Cheng, Lik Cheung; Sihoe, Alan Dart-Loon; Fink, Louis M.; Ma, Yupo; Wong, Maria Pik

2010-01-01

Background The cancer stem cell theory hypothesizes that cancers are perpetuated by cancer stem cells (CSC) or tumor initiating cells (TIC) possessing self-renewal and other stem cell-like properties while differentiated non-stem/initiating cells have a finite life span. To investigate whether the hypothesis is applicable to lung cancer, identification of lung CSC and demonstration of these capacities is essential. Methodology/Principal Finding The expression profiles of five stem cell markers (CD34, CD44, CD133, BMI1 and OCT4) were screened by flow cytometry in 10 lung cancer cell lines. CD44 was further investigated by testing for in vitro and in vivo tumorigenecity. Formation of spheroid bodies and in vivo tumor initiation ability were demonstrated in CD44+ cells of 4 cell lines. Serial in vivo tumor transplantability in nude mice was demonstrated using H1299 cell line. The primary xenografts initiated from CD44+ cells consisted of mixed CD44+ and CD44− cells in similar ratio as the parental H1299 cell line, supporting in vivo differentiation. Semi-quantitative Real-Time PCR (RT-PCR) showed that both freshly sorted CD44+ and CD44+ cells derived from CD44+-initiated tumors expressed the pluripotency genes OCT4/POU5F1, NANOG, SOX2. These stemness markers were not expressed by CD44− cells. Furthermore, freshly sorted CD44+ cells were more resistant to cisplatin treatment with lower apoptosis levels than CD44− cells. Immunohistochemical analysis of 141 resected non-small cell lung cancers showed tumor cell expression of CD44 in 50.4% of tumors while no CD34, and CD133 expression was observed in tumor cells. CD44 expression was associated with squamous cell carcinoma but unexpectedly, a longer survival was observed in CD44-expressing adenocarcinomas. Conclusion/Significance Overall, our results demonstrated that stem cell-like properties are enriched in CD44-expressing subpopulations of some lung cancer cell lines. Further investigation is required to clarify

An Evaluation of Two Internal Surrogates for Determining the Three-Dimensional Position of Peripheral Lung Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spoelstra, Femke; Soernsen de Koste, John R. van; Vincent, Andrew

2009-06-01

Purpose: Both carina and diaphragm positions have been used as surrogates during respiratory-gated radiotherapy. We studied the correlation of both surrogates with three-dimensional (3D) tumor position. Methods and Materials: A total of 59 repeat artifact-free four-dimensional (4D) computed tomography (CT) scans, acquired during uncoached breathing, were identified in 23 patients with Stage I lung cancer. Repeat scans were co-registered to the initial 4D CT scan, and tumor, carina, and ipsilateral diaphragm were manually contoured in all phases of each 4D CT data set. Correlation between positions of carina and diaphragm with 3D tumor position was studied by use of log-likelihoodmore » ratio statistics. Models to predict 3D tumor position from internal surrogates at end inspiration (EI) and end expiration (EE) were developed, and model accuracy was tested by calculating SDs of differences between predicted and actual tumor positions. Results: Motion of both the carina and diaphragm significantly correlated with tumor motion, but log-likelihood ratios indicated that the carina was more predictive for tumor position. When craniocaudal tumor position was predicted by use of craniocaudal carina positions, the SDs of the differences between the predicted and observed positions were 2.2 mm and 2.4 mm at EI and EE, respectively. The corresponding SDs derived with the diaphragm positions were 3.7 mm and 3.9 mm at EI and EE, respectively. Prediction errors in the other directions were comparable. Prediction accuracy was similar at EI and EE. Conclusions: The carina is a better surrogate of 3D tumor position than diaphragm position. Because residual prediction errors were observed in this analysis, additional studies will be performed using audio-coached scans.« less

Lung carcinoma mimicking malignant lymphoma: report of three cases.

PubMed

Matsui, K; Kitagawa, M; Wakaki, K; Masuda, S

1993-10-01

Three cases of lung carcinomas with unusual histologic appearances that have received little or no comment in the literature are presented. They were initially confused with malignant lymphoma because of a diffuse proliferation of relatively monotonous cells simulating large-cell immunoblastic lymphoma. In each case, the possibility of malignant lymphoma was excluded with confidence after the immunohistochemical study (leucocyte common antigen negative and cytokeratins positive), although with conventional microscopy several foci of cohesive groups of tumor cells were observed. The tumors were ranked at the clinical stage II or III when they were initially discovered, but all patients died of disease within 1 year. The present three tumors show an aggressive behavior and could be classified into a peculiar variant of 'large cell' carcinoma. It is necessary for surgical pathologists to have an idea of these variants of lung carcinoma in order to avoid erroneous diagnosis.

SOX5 predicts poor prognosis in lung adenocarcinoma and promotes tumor metastasis through epithelial-mesenchymal transition

PubMed Central

Chen, Xin; Fu, Yufei; Xu, Hongfei; Teng, Peng; Xie, Qiong; Zhang, Yiran; Yan, Caochong; Xu, Yiqiao; Li, Chunqi; Zhou, Jianying; Ni, Yiming; Li, Weidong

2018-01-01

Lung cancer is the leading cause of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) promotes lung cancer progression and metastasis, especially in lung adenocarcinoma. Sex determining region Y-box protein 5 (SOX5) is known to stimulate the progression of various cancers. Here, we used immunohistochemical analysis to reveal that SOX5 levels were increased in 90 lung adenocarcinoma patients. The high SOX5 expression in lung adenocarcinoma and non-tumor counterparts correlated with the patients’ poor prognosis. Inhibiting SOX5 expression attenuated metastasis and progression in lung cancer cells, while over-expressing SOX5 accelerated lung adenocarcinoma progression and metastasis via EMT. An in vivo zebrafish xenograft cancer model also showed SOX5 knockdown was followed by reduced lung cancer cell proliferation and metastasis. Our results indicate SOX5 promotes lung adenocarcinoma tumorigenicity and can be a novel diagnosis and prognosis marker of the disease. PMID:29541384

A hierarchy of self-renewing tumor-initiating cell types in glioblastoma.

PubMed

Chen, Ruihuan; Nishimura, Merry C; Bumbaca, Stephanie M; Kharbanda, Samir; Forrest, William F; Kasman, Ian M; Greve, Joan M; Soriano, Robert H; Gilmour, Laurie L; Rivers, Celina Sanchez; Modrusan, Zora; Nacu, Serban; Guerrero, Steve; Edgar, Kyle A; Wallin, Jeffrey J; Lamszus, Katrin; Westphal, Manfred; Heim, Susanne; James, C David; VandenBerg, Scott R; Costello, Joseph F; Moorefield, Scott; Cowdrey, Cynthia J; Prados, Michael; Phillips, Heidi S

2010-04-13

The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation; however, instances of CD133(-) cells exhibiting similar properties have also been reported. Here, we show that some PTEN-deficient GBM tumors produce a series of CD133(+) and CD133(-) self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stemlike cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage. Copyright 2010 Elsevier Inc. All rights reserved.

Impaired Tumor-infiltrating T Cells in Patients with COPD Impacts Lung Cancer Response to PD-1 Blockade.

PubMed

Biton, Jérôme; Ouakrim, Hanane; Dechartres, Agnès; Alifano, Marco; Mansuet-Lupo, Audrey; Si, Han; Halpin, Rebecca; Creasy, Todd; Bantsimba-Malanda, Claudie; Arrondeau, Jennifer; Goldwasser, François; Boudou-Rouquette, Pascaline; Fournel, Ludovic; Roche, Nicolas; Burgel, Pierre-Régis; Goc, Jeremy; Devi-Marulkar, Priyanka; Germain, Claire; Dieu-Nosjean, Marie-Caroline; Cremer, Isabelle; Herbst, Ronald; Damotte, Diane

2018-03-08

Patients with chronic obstructive pulmonary disease (COPD) have a higher prevalence of lung cancer. The chronic inflammation associated with COPD probably promotes the earliest stages of carcinogenesis. However, once tumors have progressed to malignancy, the impact of COPD on the tumor immune microenvironment remains poorly defined, and its effects on immune-checkpoint blockers' efficacy are still unknown. To study the impact of COPD on the immune contexture of non-small cell lung cancer (NSCLC). We performed in depth immune profiling of lung tumors by immunohistochemistry and we determined its impact on patients' survival (n=435). Tumor-infiltrating T lymphocyte (TILs) exhaustion by flow cytometry (n=50) was also investigated. The effectiveness of an anti-PD-1 treatment (nivolumab) was evaluated in 39 advanced-stage NSCLC patients. All data were analyzed according to patients' COPD status. Measurments and Main Results: Remarkably, COPD severity is positively correlated with the coexpression of PD-1/TIM-3 by CD8 T cells. In agreement, we observed a loss of CD8 T cell-associated favorable clinical outcome in COPD+ patients. Interestingly, a negative prognostic value of PD-L1 expression by tumor cells was observed only in highly CD8 T cell-infiltrated tumors of COPD+ patients. Finally, data obtained on 39 advanced-stage NSCLC patients treated by an anti-PD-1 antibody showed longer progression free survival in COPD+ patients, and also that the association between the severity of smoking and the response to nivolumab was preferentially observed in COPD+ patients. COPD is associated with an increased sensitivity of CD8 TILs to immune escape mechanisms developed by tumors, thus suggesting a higher sensitivity to PD-1 blockade in patients with COPD.

EGFR Somatic Mutations in Lung Tumors: Radon Exposure and Passive-smoking in Former- and Never-smoking U.S. Women

PubMed Central

Taga, Masataka; Mechanic, Leah E.; Hagiwara, Nobutoshi; Vähäkangas, Kirsi H.; Bennett, William P.; Alavanja, Michael C. R.; Welsh, Judith A.; Khan, Mohammed A.; Lee, Adam; Diasio, Robert; Edell, Eric; Bungum, Aaron; Jang, Jin Sung; Yang, Ping; Jen, Jin; Harris, Curtis C.

2012-01-01

Background Lung cancer patients with mutations in EGFR tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke. Methods This hypothesis was investigated by analyzing EGFR mutations in seventy lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive-smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. Results Overall, the frequency of EGFR mutation was 41% [95% Confidence Interval (CI): 32-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. Conclusions The results suggest that EGFR mutations are common in female, never-smoking, lung cancer cases from the U.S, and EGFR mutations are unlikely due to exposure to radon or passive-smoking. PMID:22523180

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shiinoki, T; Hanazawa, H; Park, S

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.,more » 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.« less

Deformable registration of the inflated and deflated lung in cone-beam CT-guided thoracic surgery: Initial investigation of a combined model- and image-driven approach

PubMed Central

Uneri, Ali; Nithiananthan, Sajendra; Schafer, Sebastian; Otake, Yoshito; Stayman, J. Webster; Kleinszig, Gerhard; Sussman, Marc S.; Prince, Jerry L.; Siewerdsen, Jeffrey H.

2013-01-01

Purpose: Surgical resection is the preferred modality for curative treatment of early stage lung cancer, but localization of small tumors (<10 mm diameter) during surgery presents a major challenge that is likely to increase as more early-stage disease is detected incidentally and in low-dose CT screening. To overcome the difficulty of manual localization (fingers inserted through intercostal ports) and the cost, logistics, and morbidity of preoperative tagging (coil or dye placement under CT-fluoroscopy), the authors propose the use of intraoperative cone-beam CT (CBCT) and deformable image registration to guide targeting of small tumors in video-assisted thoracic surgery (VATS). A novel algorithm is reported for registration of the lung from its inflated state (prior to pleural breach) to the deflated state (during resection) to localize surgical targets and adjacent critical anatomy. Methods: The registration approach geometrically resolves images of the inflated and deflated lung using a coarse model-driven stage followed by a finer image-driven stage. The model-driven stage uses image features derived from the lung surfaces and airways: triangular surface meshes are morphed to capture bulk motion; concurrently, the airways generate graph structures from which corresponding nodes are identified. Interpolation of the sparse motion fields computed from the bounding surface and interior airways provides a 3D motion field that coarsely registers the lung and initializes the subsequent image-driven stage. The image-driven stage employs an intensity-corrected, symmetric form of the Demons method. The algorithm was validated over 12 datasets, obtained from porcine specimen experiments emulating CBCT-guided VATS. Geometric accuracy was quantified in terms of target registration error (TRE) in anatomical targets throughout the lung, and normalized cross-correlation. Variations of the algorithm were investigated to study the behavior of the model- and image-driven stages

Deformable registration of the inflated and deflated lung in cone-beam CT-guided thoracic surgery: initial investigation of a combined model- and image-driven approach.

PubMed

Uneri, Ali; Nithiananthan, Sajendra; Schafer, Sebastian; Otake, Yoshito; Stayman, J Webster; Kleinszig, Gerhard; Sussman, Marc S; Prince, Jerry L; Siewerdsen, Jeffrey H

2013-01-01

Surgical resection is the preferred modality for curative treatment of early stage lung cancer, but localization of small tumors (<10 mm diameter) during surgery presents a major challenge that is likely to increase as more early-stage disease is detected incidentally and in low-dose CT screening. To overcome the difficulty of manual localization (fingers inserted through intercostal ports) and the cost, logistics, and morbidity of preoperative tagging (coil or dye placement under CT-fluoroscopy), the authors propose the use of intraoperative cone-beam CT (CBCT) and deformable image registration to guide targeting of small tumors in video-assisted thoracic surgery (VATS). A novel algorithm is reported for registration of the lung from its inflated state (prior to pleural breach) to the deflated state (during resection) to localize surgical targets and adjacent critical anatomy. The registration approach geometrically resolves images of the inflated and deflated lung using a coarse model-driven stage followed by a finer image-driven stage. The model-driven stage uses image features derived from the lung surfaces and airways: triangular surface meshes are morphed to capture bulk motion; concurrently, the airways generate graph structures from which corresponding nodes are identified. Interpolation of the sparse motion fields computed from the bounding surface and interior airways provides a 3D motion field that coarsely registers the lung and initializes the subsequent image-driven stage. The image-driven stage employs an intensity-corrected, symmetric form of the Demons method. The algorithm was validated over 12 datasets, obtained from porcine specimen experiments emulating CBCT-guided VATS. Geometric accuracy was quantified in terms of target registration error (TRE) in anatomical targets throughout the lung, and normalized cross-correlation. Variations of the algorithm were investigated to study the behavior of the model- and image-driven stages by modifying

Automated measurements of metabolic tumor volume and metabolic parameters in lung PET/CT imaging

NASA Astrophysics Data System (ADS)

Orologas, F.; Saitis, P.; Kallergi, M.

2017-11-01

Patients with lung tumors or inflammatory lung disease could greatly benefit in terms of treatment and follow-up by PET/CT quantitative imaging, namely measurements of metabolic tumor volume (MTV), standardized uptake values (SUVs) and total lesion glycolysis (TLG). The purpose of this study was the development of an unsupervised or partially supervised algorithm using standard image processing tools for measuring MTV, SUV, and TLG from lung PET/CT scans. Automated metabolic lesion volume and metabolic parameter measurements were achieved through a 5 step algorithm: (i) The segmentation of the lung areas on the CT slices, (ii) the registration of the CT segmented lung regions on the PET images to define the anatomical boundaries of the lungs on the functional data, (iii) the segmentation of the regions of interest (ROIs) on the PET images based on adaptive thresholding and clinical criteria, (iv) the estimation of the number of pixels and pixel intensities in the PET slices of the segmented ROIs, (v) the estimation of MTV, SUVs, and TLG from the previous step and DICOM header data. Whole body PET/CT scans of patients with sarcoidosis were used for training and testing the algorithm. Lung area segmentation on the CT slices was better achieved with semi-supervised techniques that reduced false positive detections significantly. Lung segmentation results agreed with the lung volumes published in the literature while the agreement between experts and algorithm in the segmentation of the lesions was around 88%. Segmentation results depended on the image resolution selected for processing. The clinical parameters, SUV (either mean or max or peak) and TLG estimated by the segmented ROIs and DICOM header data provided a way to correlate imaging data to clinical and demographic data. In conclusion, automated MTV, SUV, and TLG measurements offer powerful analysis tools in PET/CT imaging of the lungs. Custom-made algorithms are often a better approach than the manufacturer�

Characterization of the cell of origin for small cell lung cancer

PubMed Central

Park, Kwon-Sik; Liang, Mei-Chih; Raiser, David M; Zamponi, Raffaella; Roach, Rebecca R; Curtis, Stephen J; Walton, Zandra; Schaffer, Bethany E; Roake, Caitlin M; Zmoos, Anne-Flore; Kriegel, Christina; Wong, Kwok-Kin

2011-01-01

Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer that affects more than 200,000 people worldwide every year with a very high mortality rate. Here, we used a mouse genetics approach to characterize the cell of origin for SCLC; in this mouse model, tumors are initiated by the deletion of the Rb and p53 tumor suppressor genes in the lung epithelium of adult mice. We found that mouse SCLCs often arise in the lung epithelium, where neuroendocrine cells are located, and that the majority of early lesions were composed of proliferating neuroendocrine cells. In addition, mice in which Rb and p53 are deleted in a variety of non-neuroendocrine lung epithelial cells did not develop SCLC. These data indicate that SCLC likely arises from neuroendocrine cells in the lung. PMID:21822053

Recommendations for dose calculations of lung cancer treatment plans treated with stereotactic ablative body radiotherapy (SABR)

NASA Astrophysics Data System (ADS)

Devpura, S.; Siddiqui, M. S.; Chen, D.; Liu, D.; Li, H.; Kumar, S.; Gordon, J.; Ajlouni, M.; Movsas, B.; Chetty, I. J.

2014-03-01

The purpose of this study was to systematically evaluate dose distributions computed with 5 different dose algorithms for patients with lung cancers treated using stereotactic ablative body radiotherapy (SABR). Treatment plans for 133 lung cancer patients, initially computed with a 1D-pencil beam (equivalent-path-length, EPL-1D) algorithm, were recalculated with 4 other algorithms commissioned for treatment planning, including 3-D pencil-beam (EPL-3D), anisotropic analytical algorithm (AAA), collapsed cone convolution superposition (CCC), and Monte Carlo (MC). The plan prescription dose was 48 Gy in 4 fractions normalized to the 95% isodose line. Tumors were classified according to location: peripheral tumors surrounded by lung (lung-island, N=39), peripheral tumors attached to the rib-cage or chest wall (lung-wall, N=44), and centrally-located tumors (lung-central, N=50). Relative to the EPL-1D algorithm, PTV D95 and mean dose values computed with the other 4 algorithms were lowest for "lung-island" tumors with smallest field sizes (3-5 cm). On the other hand, the smallest differences were noted for lung-central tumors treated with largest field widths (7-10 cm). Amongst all locations, dose distribution differences were most strongly correlated with tumor size for lung-island tumors. For most cases, convolution/superposition and MC algorithms were in good agreement. Mean lung dose (MLD) values computed with the EPL-1D algorithm were highly correlated with that of the other algorithms (correlation coefficient =0.99). The MLD values were found to be ~10% lower for small lung-island tumors with the model-based (conv/superposition and MC) vs. the correction-based (pencil-beam) algorithms with the model-based algorithms predicting greater low dose spread within the lungs. This study suggests that pencil beam algorithms should be avoided for lung SABR planning. For the most challenging cases, small tumors surrounded entirely by lung tissue (lung-island type), a Monte

Mechanical phenotyping of cells and extracellular matrix as grade and stage markers of lung tumor tissues.

PubMed

Panzetta, Valeria; Musella, Ida; Rapa, Ida; Volante, Marco; Netti, Paolo A; Fusco, Sabato

2017-07-15

The mechanical cross-talk between cells and the extra-cellular matrix (ECM) regulates the properties, functions and healthiness of the tissues. When this is disturbed it changes the mechanical state of the tissue components, singularly or together, and cancer, along with other diseases, may start and progress. However, the bi-univocal mechanical interplay between cells and the ECM is still not properly understood. In this study we show how a microrheology technique gives us the opportunity to evaluate the mechanics of cells and the ECM at the same time. The mechanical phenotyping was performed on the surgically removed tissues of 10 patients affected by adenocarcinoma of the lung. A correlation between the mechanics and the grade and stage of the tumor was reported and compared to the mechanical characteristics of the healthy tissue. Our findings suggest a sort of asymmetric modification of the mechanical properties of the cells and the extra-cellular matrix in the tumor, being the more compliant cell even though it resides in a stiffer matrix. Overall, the simultaneous mechanical characterization of the tissues constituents (cells and ECM) provided new support for diagnosis and offered alternative points of analysis for cancer mechanobiology. When the integrity of the mechanical cross-talk between cells and the extra-cellular matrix is disturbed cancer, along with other diseases, may initiate and progress. Here, we show how a new technique gives the opportunity to evaluate the mechanics of cells and the ECM at the same time. It was applied on surgically removed tissues of 10 patients affected by adenocarcinoma of the lung and a correlation between the mechanics and the grade and stage of the tumor was reported and compared to the mechanical characteristics of the healthy tissue. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The Microenvironment of Lung Cancer and Therapeutic Implications.

PubMed

Mittal, Vivek; El Rayes, Tina; Narula, Navneet; McGraw, Timothy E; Altorki, Nasser K; Barcellos-Hoff, Mary Helen

2016-01-01

The tumor microenvironment (TME) represents a milieu that enables tumor cells to acquire the hallmarks of cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. Concerted interactions between genetically altered tumor cells and genetically stable intratumoral stromal cells result in an "activated/reprogramed" stroma that promotes carcinogenesis by contributing to inflammation, immune suppression, therapeutic resistance, and generating premetastatic niches that support the initiation and establishment of distant metastasis. The lungs present a unique milieu in which tumors progress in collusion with the TME, as evidenced by regions of aberrant angiogenesis, acidosis and hypoxia. Inflammation plays an important role in the pathogenesis of lung cancer, and pulmonary disorders in lung cancer patients such as chronic obstructive pulmonary disease (COPD) and emphysema, constitute comorbid conditions and are independent risk factors for lung cancer. The TME also contributes to immune suppression, induces epithelial-to-mesenchymal transition (EMT) and diminishes efficacy of chemotherapies. Thus, the TME has begun to emerge as the "Achilles heel" of the disease, and constitutes an attractive target for anti-cancer therapy. Drugs targeting the components of the TME are making their way into clinical trials. Here, we will focus on recent advances and emerging concepts regarding the intriguing role of the TME in lung cancer progression, and discuss future directions in the context of novel diagnostic and therapeutic opportunities.

Using an external surrogate for predictor model training in real-time motion management of lung tumors.

PubMed

Rottmann, Joerg; Berbeco, Ross

2014-12-01

Precise prediction of respiratory motion is a prerequisite for real-time motion compensation techniques such as beam, dynamic couch, or dynamic multileaf collimator tracking. Collection of tumor motion data to train the prediction model is required for most algorithms. To avoid exposure of patients to additional dose from imaging during this procedure, the feasibility of training a linear respiratory motion prediction model with an external surrogate signal is investigated and its performance benchmarked against training the model with tumor positions directly. The authors implement a lung tumor motion prediction algorithm based on linear ridge regression that is suitable to overcome system latencies up to about 300 ms. Its performance is investigated on a data set of 91 patient breathing trajectories recorded from fiducial marker tracking during radiotherapy delivery to the lung of ten patients. The expected 3D geometric error is quantified as a function of predictor lookahead time, signal sampling frequency and history vector length. Additionally, adaptive model retraining is evaluated, i.e., repeatedly updating the prediction model after initial training. Training length for this is gradually increased with incoming (internal) data availability. To assess practical feasibility model calculation times as well as various minimum data lengths for retraining are evaluated. Relative performance of model training with external surrogate motion data versus tumor motion data is evaluated. However, an internal-external motion correlation model is not utilized, i.e., prediction is solely driven by internal motion in both cases. Similar prediction performance was achieved for training the model with external surrogate data versus internal (tumor motion) data. Adaptive model retraining can substantially boost performance in the case of external surrogate training while it has little impact for training with internal motion data. A minimum adaptive retraining data length of

A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors

PubMed Central

Jahchan, Nadine S; Dudley, Joel T; Mazur, Pawel K; Flores, Natasha; Yang, Dian; Palmerton, Alec; Zmoos, Anne-Flore; Vaka, Dedeepya; Tran, Kim QT; Zhou, Margaret; Krasinska, Karolina; Riess, Jonathan W; Neal, Joel W; Khatri, Purvesh; Park, Kwon S; Butte, Atul J; Sage, Julien

2013-01-01

Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate FDA-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs. PMID:24078773

MO-FG-CAMPUS-JeP2-02: Audiovisual Biofeedback Guided Respiratory-Gated MRI: An Investigation of Tumor Definition and Scan Time for Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, D; Pollock, S; Keall, P

Purpose: Breathing consistency variations can cause respiratory-related motion blurring and artifacts and increase in MRI scan time due to inadequate respiratory-gating and discarding of breathing cycles. In a previous study the concept of audiovisual biofeedback (AV) guided respiratory-gated MRI was tested with healthy volunteers and it demonstrated image quality improvement on anatomical structures and scan time reduction. This study tests the applicability of AV-guided respiratorygated MRI for lung cancer in a prospective patient study. Methods: Image quality and scan time were investigated in thirteen lung cancer patients who underwent two 3T MRI sessions. In the first MRI session (pre-treatment), respiratory-gatedmore » MR images with free breathing (FB) and AV were acquired at inhalation and exhalation. An RF navigator placed on the liver dome was employed for the respiratory-gated MRI. This was repeated in the second MRI session (mid-treatment). Lung tumors were delineated on each dataset. FB and AV were compared in terms of (1) tumor definition assessed by lung tumor contours and (2) intra-patient scan time variation using the total image acquisition time of inhalation and exhalation datasets from the first and second MRI sessions across 13 lung cancer patients. Results: Compared to FB AV-guided respiratory-gated MRI improved image quality for contouring tumors with sharper boundaries and less blurring resulted in the improvement of tumor definition. Compared to FB the variation of intra-patient scan time with AV was reduced by 48% (p<0.001) from 54 s to 28 s. Conclusion: This study demonstrated that AV-guided respiratorygated MRI improved the quality of tumor images and fixed tumor definition for lung cancer. These results suggest that audiovisual biofeedback breathing guidance has the potential to control breathing for adequate respiratory-gating for lung cancer imaging and radiotherapy.« less

The development of a 4D treatment planning methodology to simulate the tracking of central lung tumors in an MRI-linac.

PubMed

Al-Ward, Shahad M; Kim, Anthony; McCann, Claire; Ruschin, Mark; Cheung, Patrick; Sahgal, Arjun; Keller, Brian M

2018-01-01

Targeting and tracking of central lung tumors may be feasible on the Elekta MRI-linac (MRL) due to the soft-tissue visualization capabilities of MRI. The purpose of this work is to develop a novel treatment planning methodology to simulate tracking of central lung tumors with the MRL and to quantify the benefits in OAR sparing compared with the ITV approach. Full 4D-CT datasets for five central lung cancer patients were selected to simulate the condition of having 4D-pseudo-CTs derived from 4D-MRI data available on the MRL with real-time tracking capabilities. We used the MRL treatment planning system to generate two plans: (a) with a set of MLC-defined apertures around the target at each phase of the breathing ("4D-MRL" method); (b) with a fixed set of fields encompassing the maximum inhale and exhale of the breathing cycle ("ITV" method). For both plans, dose accumulation was performed onto a reference phase. To further study the potential benefits of a 4D-MRL method, the results were stratified by tumor motion amplitude, OAR-to-tumor proximity, and the relative OAR motion (ROM). With the 4D-MRL method, the reduction in mean doses was up to 3.0 Gy and 1.9 Gy for the heart and the lung. Moreover, the lung's V12.5 Gy was spared by a maximum of 300 cc. Maximum doses to serial organs were reduced by up to 6.1 Gy, 1.5 Gy, and 9.0 Gy for the esophagus, spinal cord, and the trachea, respectively. OAR dose reduction with our method depended on the tumor motion amplitude and the ROM. Some OARs with large ROMs and in close proximity to the tumor benefited from tracking despite small tumor amplitudes. We developed a novel 4D tracking methodology for the MRL for central lung tumors and quantified the potential dosimetric benefits compared with our current ITV approach. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

TU-H-CAMPUS-JeP2-02: Interobserver Variability of CT, PET-CT and MRI Based Primary Tumor Delineation for Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karki, K; Hugo, G; Saraiya, S

Purpose: Target delineation in lung cancer radiotherapy has, in general, large variability. MRI has so far not been investigated in detail for lung cancer delineation variability. The purpose of this study is to investigate delineation variability for lung tumors using MRI and compare it to CT alone and PET-CT based delineations. Methods: Seven physicians delineated the primary tumor volumes of nine patients for the following scenarios: (1) CT only; (2) post-contrast T1-weighted MRI registered with diffusion-weighted MRI; and (3) PET-CT fusion images. To compute interobserver variability, the median surface was generated from all observers’ contours and used as the referencemore » surface. A single physician labeled the interface types (tumor to lung, atelectasis (collapsed lung), hilum, mediastinum, or chest-wall) on the median surface. Volume variation (normalized to PET-CT volume), minimum distance (MD), and bidirectional local distance (BLD) between individual observers’ contours and the reference contour were measured. Results: CT- and MRI-based normalized volumes were 1.61±0.76 (mean±SD) and 1.38±0.44, respectively, both significantly larger than PET-CT (p<0.05, paired t-test). The overall uncertainty (root mean square of SD values over all points) of both BLD and MD measures of the observers for the interfaces were not significantly different (p>0.05, two-samples t-test) for all imaging modalities except between tumor-mediastinum and tumor-atelectasis in PET-CT. The largest mean overall uncertainty was observed for tumor-atelectasis interface, the smallest for tumor-mediastinum and tumor-lung interfaces for all modalities. The whole tumor uncertainties for both BLD and MD were not significantly different between any two modalities (p>0.05, paired t-test). Overall uncertainties for the interfaces using BLD were similar to using MD. Conclusion: Large volume variations were observed between the three imaging modalities. Contouring variability appeared

Critical roles of mucin-1 in sensitivity of lung cancer cells to tumor necrosis factor-alpha and dexamethasone.

PubMed

Xu, Menglin; Wang, Xiangdong

2017-08-01

Lung cancer is the leading cause of death from cancer. Mucins are glycoproteins with high molecular weight, responsible for cell growth, differentiation, and signaling, and were proposed to be correlated with gene heterogeneity of lung cancer. Here, we report aberrant expression of mucin genes and tumor necrosis factor receptors in lung adenocarcinoma tissues compared with normal tissues in GEO datasets. Mucin-1 (MUC1) gene was selected and considered as the target gene; furthermore, the expression pattern of adenocarcinomic cells (A549, H1650, or H1299 cells) was validated under the stimulation with tumor necrosis factor-alpha (TNFα) or dexamethasone (DEX), separately. MUC1 gene interference was done to A549 cells to show its role in sensitivity of lung cancer cells to TNFα and DEX. Results of our experiments indicate that MUC1 may regulate the influence of inflammatory mediators in effects of glucocorticoids (GCs), as a regulatory target to improve therapeutics. It shows the potential effect of MUC1 and GCs in lung adenocarcinoma (LADC), which may help in LADC treatment in the future.

Combined human papillomavirus typing and TP53 mutation analysis in distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma.

PubMed

Daher, Tamas; Tur, Mehmet Kemal; Brobeil, Alexander; Etschmann, Benjamin; Witte, Biruta; Engenhart-Cabillic, Rita; Krombach, Gabriele; Blau, Wolfgang; Grimminger, Friedrich; Seeger, Werner; Klussmann, Jens Peter; Bräuninger, Andreas; Gattenlöhner, Stefan

2018-06-01

In head and neck squamous cell carcinoma (HNSCC), the occurrence of concurrent lung malignancies poses a significant diagnostic challenge because metastatic HNSCC is difficult to discern from second primary lung squamous cell carcinoma (SCC). However, this differentiation is crucial because the recommended treatments for metastatic HNSCC and second primary lung SCC differ profoundly. We analyzed the origin of lung tumors in 32 patients with HNSCC using human papillomavirus (HPV) typing and targeted next generation sequencing of all coding exons of tumor protein 53 (TP53). Lung tumors were clearly identified as HNSCC metastases or second primary tumors in 29 patients, thus revealing that 16 patients had received incorrect diagnoses based on clinical and morphological data alone. The HPV typing and mutation analysis of all TP53 coding exons is a valuable diagnostic tool in patients with HNSCC and concurrent lung SCC, which can help to ensure that patients receive the most suitable treatment. © 2018 Wiley Periodicals, Inc.

Mutational analysis of multiple lung cancers: Discrimination between primary and metastatic lung cancers by genomic profile.

PubMed

Goto, Taichiro; Hirotsu, Yosuke; Mochizuki, Hitoshi; Nakagomi, Takahiro; Shikata, Daichi; Yokoyama, Yujiro; Oyama, Toshio; Amemiya, Kenji; Okimoto, Kenichiro; Omata, Masao

2017-05-09

In cases of multiple lung cancers, individual tumors may represent either a primary lung cancer or both primary and metastatic lung cancers. Treatment selection varies depending on such features, and this discrimination is critically important in predicting prognosis. The present study was undertaken to determine the efficacy and validity of mutation analysis as a means of determining whether multiple lung cancers are primary or metastatic in nature. The study involved 12 patients who underwent surgery in our department for multiple lung cancers between July 2014 and March 2016. Tumor cells were collected from formalin-fixed paraffin-embedded tissues of the primary lesions by using laser capture microdissection, and targeted sequencing of 53 lung cancer-related genes was performed. In surgically treated patients with multiple lung cancers, the driver mutation profile differed among the individual tumors. Meanwhile, in a case of a solitary lung tumor that appeared after surgery for double primary lung cancers, gene mutation analysis using a bronchoscopic biopsy sample revealed a gene mutation profile consistent with the surgically resected specimen, thus demonstrating that the tumor in this case was metastatic. In cases of multiple lung cancers, the comparison of driver mutation profiles clarifies the clonal origin of the tumors and enables discrimination between primary and metastatic tumors.

Identifying risk factors for refractory febrile neutropenia in patients with lung cancer.

PubMed

Fujita, Masaki; Tokunaga, Shoji; Ikegame, Satoshi; Harada, Eiji; Matsumoto, Takemasa; Uchino, Junji; Watanabe, Kentaro; Nakanishi, Yoichi

2012-02-01

Information about the development of febrile neutropenia in patients with solid tumors remains insufficient. In this study, we tried to identify the risk factors for refractory febrile neutropenia in patients with lung cancer. A total of 59 neutropenic fever episodes associated with anti-tumor chemotherapy for lung cancer were retrospectively analyzed. We compared patient characteristics according to their initial response to treatment with antibiotics. For 34 of 59 (58%) episodes a response to initial antibiotics was obtained whereas 25 of 59 (42%) were refractory to treatment. Multivariate analysis demonstrated independent risk factors for refractory febrile neutropenia with lung cancer. These risk factors were the severity of febrile neutropenia (odds ratio (OR) 6.11; 95% confidence interval (CI) 1.85-20.14) and C-reactive protein more than 10 mg/dl (OR 4.39; 95% CI 1.22-15.74). These factors could predict outcome for patients with lung cancer who develop refractory febrile neutropenia.

SU-E-J-136: Evaluation of a Non-Invasive Method on Lung Tumor Tracking.

PubMed

Zhao, T; White, B; Low, D

2012-06-01

to develop a non-invasive method to track lung motion in free-breathing patients. A free-breathing breathing model has been developed to use tidal volume and air flow rate as surrogates for lung trajectories. In this study, 4D CT data sets were acquired during simulation and were reconstructed into 10 phases. Total lung capacities were calculated from the reconstructed images. Continuous signals from the abdominal pneumatic belt were correlated to the volumes and were therefore converted into a curve of tidal volumes. Air flow rate were calculated as the first order derivative of the tidal volume curve. Lung trajectories in the 10 reconstructed images were obtained using B-Spline registration. Parameters of the free-breathing lung motion model were fit from the tidal volumes, airflow rates and lung trajectories using the simulation data. Patients were rescanned every week during the treatment. Prediction of lung trajectories from the model were given and compared to the actual positions in BEV. Trajectories of lung were predicted with residual error of 1.49mm at 95th percentile of all tracked points. Tracking was stable and reproducible over two weeks. Non-invasive tumor tracking based on a free-breathing lung motion model is feasible and stable over weeks. © 2012 American Association of Physicists in Medicine.

SU-F-R-44: Modeling Lung SBRT Tumor Response Using Bayesian Network Averaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diamant, A; Ybarra, N; Seuntjens, J

2016-06-15

Purpose: The prediction of tumor control after a patient receives lung SBRT (stereotactic body radiation therapy) has proven to be challenging, due to the complex interactions between an individual’s biology and dose-volume metrics. Many of these variables have predictive power when combined, a feature that we exploit using a graph modeling approach based on Bayesian networks. This provides a probabilistic framework that allows for accurate and visually intuitive predictive modeling. The aim of this study is to uncover possible interactions between an individual patient’s characteristics and generate a robust model capable of predicting said patient’s treatment outcome. Methods: We investigatedmore » a cohort of 32 prospective patients from multiple institutions whom had received curative SBRT to the lung. The number of patients exhibiting tumor failure was observed to be 7 (event rate of 22%). The serum concentration of 5 biomarkers previously associated with NSCLC (non-small cell lung cancer) was measured pre-treatment. A total of 21 variables were analyzed including: dose-volume metrics with BED (biologically effective dose) correction and clinical variables. A Markov Chain Monte Carlo technique estimated the posterior probability distribution of the potential graphical structures. The probability of tumor failure was then estimated by averaging the top 100 graphs and applying Baye’s rule. Results: The optimal Bayesian model generated throughout this study incorporated the PTV volume, the serum concentration of the biomarker EGFR (epidermal growth factor receptor) and prescription BED. This predictive model recorded an area under the receiver operating characteristic curve of 0.94(1), providing better performance compared to competing methods in other literature. Conclusion: The use of biomarkers in conjunction with dose-volume metrics allows for the generation of a robust predictive model. The preliminary results of this report demonstrate that it is

Significance of Fractionated Administration of Thalidomide Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis

PubMed Central

Masunaga, Shin-ichiro; Sanada, Yu; Moriwaki, Takahiro; Tano, Keizo; Sakurai, Yoshinori; Tanaka, Hiroki; Suzuki, Minoru; Kondo, Natsuko; Narabayashi, Masaru; Watanabe, Tsubasa; Nakagawa, Yosuke; Maruhashi, Akira; Ono, Koji

2014-01-01

Background The aim of this study was to evaluate the significance of fractionated administration of thalidomide combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. Methods B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2’-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after thalidomide treatment through a single or two consecutive daily intraperitoneal administrations up to a total dose of 400 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Results Thalidomide raised the sensitivity of the total cell population more remarkably than Q cells in both single and daily administrations. Daily administration of thalidomide elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. Conclusion Daily fractionated administration of thalidomide in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential. PMID:29147396

Baseline and On-Treatment Characteristics of Serum Tumor Markers in Stage IV Oncogene-Addicted Adenocarcinoma of the Lung.

PubMed

Noonan, Sinead A; Patil, Tejas; Gao, Dexiang; King, Gentry G; Thibault, Jessica R; Lu, Xian; Bunn, Paul A; Doebele, Robert C; Purcell, W Thomas; Barón, Anna E; Camidge, D Ross

2018-01-01

The role of serum tumor markers in the modern management of advanced NSCLC remains poorly described. A single-center retrospective analysis of available carcinoembryonic antigen, CA125, CA19.9, and CA27.29 levels at baseline and during treatment of stage IV lung adenocarcinoma by oncogenic driver was conducted. A total of 142 patients were analyzed (60 with anaplastic lymphoma kinase gene [ALK] rearrangement, 50 with EGFR mutation, four with ROS1 rearrangement, and 29 with KRAS mutation). Of these, 82% had at least one marker (95% if all four markers were measured), with CA27.29 being the most commonly increased and CA19.9 the rarest. Only CA27.29 differed significantly by oncogene (it was less common in KRAS) (p = 0.016). The median times to nadir during tyrosine kinase inhibitor (TKI) therapy in EGFR and ALK cases were 16.4 and 20 weeks, respectively. Of the 41 patients with EGFR mutation or ALK or ROS1 rearrangement, 24 (59%) demonstrated an initial increase within the first 4 weeks of TKI therapy, 58% of whom then had their levels fall below baseline. An increase in marker level of 10% or more from nadir occurred in 53% of systemic and 22% of central nervous system-only progression. Serum tumor markers are frequently increased in lung adenocarcinoma regardless of driver oncogene. Changes within the first 4 weeks of therapy may be misleading. Progression is associated with marker increases, especially in sites other than the central nervous system. Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

SU-E-T-06: 4D Particle Swarm Optimization to Enable Lung SBRT in Patients with Central And/or Large Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Modiri, A; Gu, X; Hagan, A

2015-06-15

Purpose: Patients presenting with large and/or centrally-located lung tumors are currently considered ineligible for highly potent regimens such as SBRT due to concerns of toxicity to normal tissues and organs-at-risk (OARs). We present a particle swarm optimization (PSO)-based 4D planning technique, designed for MLC tracking delivery, that exploits the temporal dimension as an additional degree of freedom to significantly improve OAR-sparing and reduce toxicity to levels clinically considered as acceptable for SBRT administration. Methods: Two early-stage SBRT-ineligible NSCLC patients were considered, presenting with tumors of maximum dimensions of 7.4cm (central-right lobe; 1.5cm motion) and 11.9cm (upper-right lobe; 1cm motion). Inmore » each case, the target and normal structures were manually contoured on each of the ten 4DCT phases. Corresponding ten initial 3D-conformal plans (Pt#1: 7-beams; Pt#2: 9-beams) were generated using the Eclipse planning system. Using 4D-PSO, fluence weights were optimized over all beams and all phases (70 and 90 apertures for Pt1&2, respectively). Doses to normal tissues and OARs were compared with clinicallyestablished lung SBRT guidelines based on RTOG-0236. Results: The PSO-based 4D SBRT plan yielded tumor coverage and dose—sparing for parallel and serial OARs within the SBRT guidelines for both patients. The dose-sparing compared to the clinically-delivered conventionallyfractionated plan for Patient 1 (Patient 2) was: heart Dmean = 11% (33%); lung V20 = 16% (21%); lung Dmean = 7% (20%); spinal cord Dmax = 5% (16%); spinal cord Dmean = 7% (33%); esophagus Dmax = 0% (18%). Conclusion: Truly 4D planning can significantly reduce dose to normal tissues and OARs. Such sparing opens up the possibility of using highly potent and effective regimens such as lung SBRT for patients who were conventionally considered SBRT non-eligible. Given the large, non-convex solution space, PSO represents an attractive, parallelizable tool to

Overexpression of Pokemon in non-small cell lung cancer and foreshowing tumor biological behavior as well as clinical results.

PubMed

Zhao, Zhi-Hong; Wang, Sheng-Fa; Yu, Liang; Wang, Ju; Chang, Hao; Yan, Wei-Li; Zhang, Jian; Fu, Kai

2008-10-01

Transcription factor Pokemon, a central regulation gene of the important tumor suppressor alternative reading frame (ARF), exerted its activity by acting upstream of many tumor-suppressing genes and proto-oncogenes. Its expression in non-small cell lung cancer (NSCLC) and its clinical significance remains unclear. The aim of this study was to investigate the expression of Pokemon in non-small cell lung cancer and to explore its correlation with the clinical pathological characteristics and its influence on patients' prognosis. Observe the expression of Pokemon in NSCLC and investigate its mechanism and clinical significance. Determine the expression of Pokemon in human NSCLC cell lines as well as 55 cases of NSCLC tumor tissues, tumor adjacent tissues and surrounding tissues by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, and analyze the relationship between Pokemon expression in NSCLC tumor tissues and clinicopathological features. Determine 62 NSCLC tumor tissues (5 years ago) and p14(ARF) expression with immunohistochemical technique, discuss the correlation between them and assess the effect of Pokemon on prognosis of patients with lung cancer. Pokemon mRNA and protein took on high expression in lung cancer cell lines, and the expression difference between cancer tissues, tumor adjacent tissues and surrounding tissues had statistical significance (P<0.05). Pokemon expression and p14(ARF) expression were negatively correlated (r=-0.287). The expression of Pokemon was determined not to be associated with the patient's sex, age, smoking condition, tumor differentiation degree, histology and lymph node metastasis condition. However, its relationship with TNM staging was established (P<0.05). Furthermore, it was shown that the survival rate of patients with negative Pokemon expression was significantly higher than that of those with positive Pokemon expression (P=0.004), therefore, the expression of Pokemon is believed to be an

Audiovisual biofeedback improves the correlation between internal/external surrogate motion and lung tumor motion.

PubMed

Lee, Danny; Greer, Peter B; Paganelli, Chiara; Ludbrook, Joanna Jane; Kim, Taeho; Keall, Paul

2018-03-01

Breathing management can reduce breath-to-breath (intrafraction) and day-by-day (interfraction) variability in breathing motion while utilizing the respiratory motion of internal and external surrogates for respiratory guidance. Audiovisual (AV) biofeedback, an interactive personalized breathing motion management system, has been developed to improve reproducibility of intra- and interfraction breathing motion. However, the assumption of the correlation of respiratory motion between surrogates and tumors is not always verified during medical imaging and radiation treatment. Therefore, the aim of the study was to test the hypothesis that the correlation of respiratory motion between surrogates and tumors is the same under free breathing without guidance (FB) and with AV biofeedback guidance for voluntary motion management. For 13 lung cancer patients receiving radiotherapy, 2D coronal and sagittal cine-MR images were acquired across two MRI sessions (pre- and mid-treatment) with two breathing conditions: (a) FB and (b) AV biofeedback, totaling 88 patient measurements. Simultaneously, the external respiratory motion of the abdomen was measured. The internal respiratory motion of the diaphragm and lung tumor was retrospectively measured from 2D coronal and sagittal cine-MR images. The correlation of respiratory motion between surrogates and tumors was calculated using Pearson's correlation coefficient for: (a) abdomen to tumor (abdomen-tumor) and (b) diaphragm to tumor (diaphragm-tumor). The correlations were compared between FB and AV biofeedback using several metrics: abdomen-tumor and diaphragm-tumor correlations with/without ≥5 mm tumor motion range and with/without adjusting for phase shifts between the signals. Compared to FB, AV biofeedback improved abdomen-tumor correlation by 11% (p = 0.12) from 0.53 to 0.59 and diaphragm-tumor correlation by 13% (p = 0.02) from 0.55 to 0.62. Compared to FB, AV biofeedback improved abdomen-tumor correlation by 17% (p = 0

Local Control and Toxicity in a Large Cohort of Central Lung Tumors Treated With Stereotactic Body Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Modh, Ankit; Rimner, Andreas; Williams, Eric

2014-12-01

Purpose: Stereotactic body radiation therapy (SBRT) in central lung tumors has been associated with higher rates of severe toxicity. We sought to evaluate toxicity and local control in a large cohort and to identify predictive dosimetric parameters. Methods and Materials: We identified patients who received SBRT for central tumors according to either of 2 definitions. Local failure (LF) was estimated using a competing risks model, and multivariate analysis (MVA) was used to assess factors associated with LF. We reviewed patient toxicity and applied Cox proportional hazard analysis and log-rank tests to assess whether dose-volume metrics of normal structures correlated with pulmonarymore » toxicity. Results: One hundred twenty-five patients received SBRT for non-small cell lung cancer (n=103) or metastatic lesions (n=22), using intensity modulated radiation therapy. The most common dose was 45 Gy in 5 fractions. Median follow-up was 17.4 months. Incidence of toxicity ≥ grade 3 was 8.0%, including 5.6% pulmonary toxicity. Sixteen patients (12.8%) experienced esophageal toxicity ≥ grade 2, including 50% of patients in whom PTV overlapped the esophagus. There were 2 treatment-related deaths. Among patients receiving biologically effective dose (BED) ≥80 Gy (n=108), 2-year LF was 21%. On MVA, gross tumor volume (GTV) was significantly associated with LF. None of the studied dose-volume metrics of the lungs, heart, proximal bronchial tree (PBT), or 2 cm expansion of the PBT (“no-fly-zone” [NFZ]) correlated with pulmonary toxicity ≥grade 2. There were no differences in pulmonary toxicity between central tumors located inside the NFZ and those outside the NFZ but with planning target volume (PTV) intersecting the mediastinum. Conclusions: Using moderate doses, SBRT for central lung tumors achieves acceptable local control with low rates of severe toxicity. Dosimetric analysis showed no significant correlation between dose to the lungs, heart, or NFZ

Early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study.

PubMed

Wallinder, Andreas; Ricksten, Sven-Erik; Silverborn, Martin; Hansson, Christoffer; Riise, Gerdt C; Liden, Hans; Jeppsson, Anders; Dellgren, Göran

2014-01-01

An increasing number of studies have shown that ex vivo lung perfusion (EVLP) is safe and that rejected donor lungs can be resuscitated and used for lung transplantation (LTx). Early clinical outcomes in patients transplanted with reconditioned lungs at our centre were reviewed and compared with those of contemporary non-EVLP controls. During 18 months starting January 2011, 11 pairs of donor lungs initially deemed unsuitable for transplantation underwent EVLP. Haemodynamic (pulmonary flow, vascular resistance and artery pressure) and respiratory (peak airway pressure and compliance) parameters were analysed during evaluation. Lungs that improved (n = 11) to meet International Society of Heart and Lung Transplantation criteria were transplanted and compared with patients transplanted with non-EVLP lungs (n = 47) during the same time period. Donor lungs were initially rejected due to either inferior PaO2/FiO2 ratio (n = 9), bilateral infiltrate on chest X-ray (n = 1) or ongoing extra corporeal membrane oxygenation (n = 1). The donor lungs improved from a mean PaO2/FiO2 ratio of 27.9 kPa in the donor to a mean of 59.6 kPa at the end of the EVLP (median improvement 28.4 kPa, range 21.0-50.7 kPa). Two single lungs were deemed unsuitable and not used for LTx. Eleven recipients from the regular waiting list underwent either single (n = 3) LTx or double (n = 8) LTx with EVLP-treated lungs. The median time to extubation (12 (range, 3-912) vs 6 (range, 2-1296) h) and median intensive care unit (ICU) stay (152 (range, 40-625) vs 48 (range, 22-1632) h) were longer in the EVLP group (P = 0.05 and P = 0.01, respectively). There were no differences in length of hospital stay (median 28 (range 25-93) vs 28 (18-209), P = 0.21). Two patients in the EVLP group and 6 in the control group had primary graft dysfunction >Grade 1 at 72 h postoperatively. Three patients in the control group died before discharge. All recipients of EVLP lungs were discharged alive from hospital. The use of

The Initial Immune Reaction to a New Tumor Antigen Is Always Stimulatory and Probably Necessary for the Tumor's Growth

PubMed Central

Prehn, Richmond T.

2010-01-01

All nascent neoplasms probably elicit at least a weak immune reaction. However, the initial effect of the weak immune reaction on a nascent tumor is always stimulatory rather than inhibitory to tumor growth, assuming only that exposure to the tumor antigens did not antedate the initiation of the neoplasm (as may occur in some virally induced tumors). This conclusion derives from the observation that the relationship between the magnitude of an adaptive immune reaction and tumor growth is not linear but varies such that while large quantities of antitumor immune reactants tend to inhibit tumor growth, smaller quantities of the same reactants are, for unknown reasons, stimulatory. Any immune reaction must presumably be small before it can become large; hence the initial reaction to the first presentation of a tumor antigen must always be small and in the stimulatory portion of this nonlinear relationship. In mouse-skin carcinogenesis experiments it was found that premalignant papillomas were variously immunogenic, but that the carcinomas that arose in them were, presumably because of induced immune tolerance, nonimmunogenic in the animal of origin. PMID:20811480

The initial immune reaction to a new tumor antigen is always stimulatory and probably necessary for the tumor's growth.

PubMed

Prehn, Richmond T

2010-01-01

All nascent neoplasms probably elicit at least a weak immune reaction. However, the initial effect of the weak immune reaction on a nascent tumor is always stimulatory rather than inhibitory to tumor growth, assuming only that exposure to the tumor antigens did not antedate the initiation of the neoplasm (as may occur in some virally induced tumors). This conclusion derives from the observation that the relationship between the magnitude of an adaptive immune reaction and tumor growth is not linear but varies such that while large quantities of antitumor immune reactants tend to inhibit tumor growth, smaller quantities of the same reactants are, for unknown reasons, stimulatory. Any immune reaction must presumably be small before it can become large; hence the initial reaction to the first presentation of a tumor antigen must always be small and in the stimulatory portion of this nonlinear relationship. In mouse-skin carcinogenesis experiments it was found that premalignant papillomas were variously immunogenic, but that the carcinomas that arose in them were, presumably because of induced immune tolerance, nonimmunogenic in the animal of origin.

Lung metastases

MedlinePlus

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 the bloodstream or lymphatic ...

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

PubMed Central

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

2015-01-01

Collagen-producing myofibroblast transdifferentiation is considered a crucial determinant in the formation of scar tissue in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Multiple resident pulmonary cell types and bone marrow-derived fibrocytes have been implicated as contributors to fibrotic lesions due to 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 IPF lungs, but has limited or no expression in normal human lungs. We also demonstrate that WT1-positive 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 transforming growth factor-α transgenic-mouse model demonstrated that fibrocytes do not transform into WT1-positive mesenchymal cells, but do augment accumulation of WT1-positive cells in severe fibrotic lung disease. Importantly, the number of WT1-positive cells in fibrotic lesions were 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-positive cell accumulation and severe fibrotic lung disease. PMID:26371248

Cysts mark the early stage of metastatic tumor development in non-small cell lung cancer

PubMed Central

Thakur, Chitra; Rapp, Ulf R.; Rudel, Thomas

2018-01-01

Identifying metastatic tumor growth at an early stage has been one of the biggest challenges in the treatment of lung cancer. By genetic lineage tracing approach in a conditional model of Non-Small Cell Lung Cancer (NSCLC) in mice, we demonstrate that cystic lesions represent an early stage of metastatic invasion. We generated a mouse model for NSCLC which incorporated a heritable DsRed fluorescent tag driven by the ubiquitous CAG promoter in the alveolar type II cells of the lung. We found early cystic lesions in a secondary organ (liver) that lacked the expression of bona fide lung makers namely Scgb1a1 and surfactant protein C Sftpc and were DsRed positive hence identifying lung as their source of origin. This demonstrates the significant potential of alveolar type II cells in orchestrating the process of metastasis, rendering it as one of the target cell types of the lung of therapeutic importance in human NSCLC. PMID:29464089

Uterine-Specific Loss of Tsc2 Leads to Myometrial Tumors in Both the Uterus and Lungs

PubMed Central

Prizant, Hen; Sen, Aritro; Light, Allison; Cho, Sung-Nam; DeMayo, Francesco J.; Lydon, John P.

2013-01-01

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells in the lungs, leading to functional loss and sometimes lung transplantation. Although the origin of LAM cells is unknown, several features of LAM provide clues. First, LAM cells contain inactivating mutations in genes encoding Tsc1 or Tsc2, proteins that limit mTORC1 activity. Second, LAM tumors recur after lung transplantation, suggesting a metastatic pathogenesis. Third, LAM is found almost exclusively in women. Finally, LAM shares features with uterine leiomyomas, benign tumors of myometrial cells. From these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop mouse models for leiomyoma and LAM, we targeted Tsc2 deletion primarily in uterine cells. In fact, nearly 100% of uteri from uterine-specific Tsc2 knockout mice developed myometrial proliferation and uterine leiomyomas by 12 and 24 weeks, respectively. Myometrial proliferation and mTORC1/S6 activity were abrogated by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy or aromatase inhibition. In ovariectomized Tsc2 null mice, mTORC1/S6 activity and myometrial growth were restored by estrogen but not progesterone. Thus, even without Tsc2, estrogen appears to be required for myometrial mTORC1/S6 signaling and proliferation. Finally, we found Tsc2 null myometrial tumors in lungs of older Tsc2 uterine-specific knockout females, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of LAM and leiomyomas and might lead to novel therapeutic strategies for both diseases. PMID:23820898

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

PubMed Central

Wang, Wan-Jhen; Wu, Yu-Sheng; Chen, Sherwin; Liu, Chi-Feng

2015-01-01

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. PMID:26167490

Metachronous Primary Adenocarcinoma of Lung During Adjuvant Imatinib Mesylate Therapy for Gastrointestinal Stromal Tumor of Stomach: A Case Report.

PubMed

Jiang, Meng-Jie; Weng, Shan-Shan; Cao, Ying; Li, Xiao-Fen; Wang, Liu-Hong; Xu, Jing-Hong; Yuan, Ying

2015-09-01

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in gastrointestinal tracts; however, the synchronous or metachronous coexistence of GIST with additional primary malignancy is not common.Here, we present an unusual case of gastric GIST with metachronous primary lung adenocarcinoma diagnosed during his adjuvant treatment with oral receptor tyrosine kinase inhibitor imatinib mesylate (400 mg daily). After 6-month use of imatinib, the patient suffered from dry cough and dyspnea. Subsequent lung biopsy demonstrated adenocarcinoma with diffuse interstitial changes.Our research emphasizes the possibility of an additional primary tumor with GIST, and reminds the clinicians to strengthen the surveillance of the additional cancer during the follow-up of GIST patients.

Tumor growth affects the metabonomic phenotypes of multiple mouse non-involved organs in an A549 lung cancer xenograft model.

PubMed

Xu, Shan; Tian, Yuan; Hu, Yili; Zhang, Nijia; Hu, Sheng; Song, Dandan; Wu, Zhengshun; Wang, Yulan; Cui, Yanfang; Tang, Huiru

2016-06-22

The effects of tumorigenesis and tumor growth on the non-involved organs remain poorly understood although many research efforts have already been made for understanding the metabolic phenotypes of various tumors. To better the situation, we systematically analyzed the metabolic phenotypes of multiple non-involved mouse organ tissues (heart, liver, spleen, lung and kidney) in an A549 lung cancer xenograft model at two different tumor-growth stages using the NMR-based metabonomics approaches. We found that tumor growth caused significant metabonomic changes in multiple non-involved organ tissues involving numerous metabolic pathways, including glycolysis, TCA cycle and metabolisms of amino acids, fatty acids, choline and nucleic acids. Amongst these, the common effects are enhanced glycolysis and nucleoside/nucleotide metabolisms. These findings provided essential biochemistry information about the effects of tumor growth on the non-involved organs.

Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors

PubMed Central

Kalra, Sean; Cleaver, Timothy G.; Merrick, Daniel; Wang, Xiao-Jing; Malkoski, Stephen P.

2015-01-01

Non-small cell lung cancer (NSCLC) is a common malignancy with a poor prognosis. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor suppressor loss. Smad4 is an established tumor suppressor in pancreatic and colon cancer, however, the consequences of Smad4 loss in lung cancer are largely unknown. We evaluated Smad4 expression in human NSCLC samples and examined Smad4 alterations in large NSCLC datasets and found that reduced Smad4 expression is common in human NSCLC and occurs through a variety of mechanisms including mutation, homozygous deletion, and heterozygous loss. We modeled Smad4 loss in lung cancer by deleting Smad4 in airway epithelial cells and found that Smad4 deletion both initiates and promotes lung tumor development. Interestingly, both Smad4−/− mouse tumors and human NSCLC samples with reduced Smad4 expression demonstrated increased DNA damage while Smad4 knockdown in lung cancer cells reduced DNA repair and increased apoptosis after DNA damage. In addition, Smad4 deficient NSCLC cells demonstrated increased sensitivity to both chemotherapeutics that inhibit DNA topoisomerase and drugs that block double strand DNA break repair by non-homologous end joining. In sum, these studies establish Smad4 as a lung tumor suppressor and suggest that the defective DNA repair phenotype of Smad4 deficient tumors can be exploited by specific therapeutic strategies. PMID:25893305

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

PubMed Central

2011-01-01

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. PMID:21943279

INDUCTION OF DNA ADDUCTS, TUMORS, AND KI-RAS ONCOGENE MUTATIONS IN STRAIN A/J MOUSE LUNG BY IP. ADMINISTRATION OF DIBENZ[A,H]ANTHRACENE

EPA Science Inventory

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...

An accurate algorithm to match imperfectly matched images for lung tumor detection without markers

PubMed Central

Rozario, Timothy; Bereg, Sergey; Yan, Yulong; Chiu, Tsuicheng; Liu, Honghuan; Kearney, Vasant; Jiang, Lan

2015-01-01

In order to locate lung tumors on kV projection images without internal markers, digitally reconstructed radiographs (DRRs) are created and compared with projection images. However, lung tumors always move due to respiration and their locations change on projection images while they are static on DRRs. In addition, global image intensity discrepancies exist between DRRs and projections due to their different image orientations, scattering, and noises. This adversely affects comparison accuracy. A simple but efficient comparison algorithm is reported to match imperfectly matched projection images and DRRs. The kV projection images were matched with different DRRs in two steps. Preprocessing was performed in advance to generate two sets of DRRs. The tumors were removed from the planning 3D CT for a single phase of planning 4D CT images using planning contours of tumors. DRRs of background and DRRs of tumors were generated separately for every projection angle. The first step was to match projection images with DRRs of background signals. This method divided global images into a matrix of small tiles and similarities were evaluated by calculating normalized cross‐correlation (NCC) between corresponding tiles on projections and DRRs. The tile configuration (tile locations) was automatically optimized to keep the tumor within a single projection tile that had a bad matching with the corresponding DRR tile. A pixel‐based linear transformation was determined by linear interpolations of tile transformation results obtained during tile matching. The background DRRs were transformed to the projection image level and subtracted from it. The resulting subtracted image now contained only the tumor. The second step was to register DRRs of tumors to the subtracted image to locate the tumor. This method was successfully applied to kV fluoro images (about 1000 images) acquired on a Vero (BrainLAB) for dynamic tumor tracking on phantom studies. Radiation opaque markers were

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schaake, Eva E.; Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam; Rossi, Maddalena M.G.

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 cancermore » 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 Catalog of Genes Homozygously Deleted in Human Lung Cancer and the Candidacy of PTPRD as a Tumor Suppressor Gene

PubMed Central

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

Changes in Functional Lung Regions During the Course of Radiation Therapy and Their Potential Impact on Lung Dosimetry for Non-Small Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meng, Xue; Department of Radiation Oncology, Shandong Cancer Hospital, Shandong University, Jinan; Frey, Kirk

2014-05-01

Purpose: To study changes in functional activity on ventilation (V)/perfusion (Q) single-photon emission computed tomography (SPECT) during radiation therapy (RT) and explore the impact of such changes on lung dosimetry in patients with non-small cell lung cancer (NSCLC). Methods and Materials: Fifteen NSCLC patients with centrally located tumors were enrolled. All patients were treated with definitive RT dose of ≥60 Gy. V/Q SPECT-CT scans were performed prior to and after delivery of 45 Gy of fractionated RT. SPECT images were used to define temporarily dysfunctional regions of lung caused by tumor or other potentially reversible conditions as B3. The functional lung (FL)more » was defined on SPECT by 2 separate approaches: FL1, a threshold of 30% of the maximum uptake of the patient's lung; and FL2, FL1 plus B3 region. The impact of changes in FL between initiation of RT and delivery of 45 Gy on lung dosimetry were analyzed. Results: Fourteen patients (93%) had larger FL2 volumes than FL1 pre-RT (P<.001). Dysfunctional lung became functional in 11 patients (73%) on V SPECT and in 10 patients (67%) on Q SPECT. The dosimetric parameters generated from CT-based anatomical lung had significantly lower values in FL1 than FL2, with a median reduction in the volume of lung receiving a dose of at least 20 Gy (V{sub 20}) of 3%, 5.6%, and mean lung dose of 0.95 and 1.55 on V and Q SPECT respectively. Conclusions: Regional ventilation and perfusion function improve significantly during RT in centrally located NSCLC. Lung dosimetry values vary notably between different definitions of functional lung.« less

Identification of tumor-initiating cells derived from two canine rhabdomyosarcoma cell lines.

PubMed

Kishimoto, Takuya Evan; Yashima, Shoko; Nakahira, Rei; Onozawa, Eri; Azakami, Daigo; Ujike, Makoto; Ochiai, Kazuhiko; Ishiwata, Toshiyuki; Takahashi, Kimimasa; Michishita, Masaki

2017-07-07

Cancer stem cells or tumor-initiating cells (TICs) are a small subpopulation of cells that have the capacity to self-renew, differentiate and initiate tumors. These cells may function in tumor initiation, aggression and recurrence. Whether spheres derived from canine rhabdomyosarcoma cells have stem cell-like properties is unclear. We induced sphere formation in the canine rhabdomyosarcoma cell lines, CMS-C and CMS-J, and characterized the spheres in vitro and in vivo. Sphere-forming cells were more resistant to vincristine, mitoxantrone and doxorubicin than adherent cells. Xenograft transplantation demonstrated that 1 × 10 3 sphere-forming cells derived from CMS-C were sufficient for tumor formation. The sphere assay showed that the sphere-forming cells were present in these tumors. These results suggest that the spheres derived from canine rhabdomyosarcoma cells may possess characteristics of TICs. This study provides the foundation for elucidating the contribution of TICs to rhabdomyosarcoma tumorigenesis.

Usefulness of Daily Fractionated Administration of Wortmannin Combined With γ-Ray Irradiation in Terms of Local Tumor Response and Lung Metastasis

PubMed Central

Masunaga, Shin-ichiro; Sakurai, Yoshinori; Tanaka, Hiroki; Suzuki, Minoru; Kondo, Natsuko; Narabayashi, Masaru; Tano, Keizo; Maruhashi, Akira; Ono, Koji

2013-01-01

Background To evaluate the usefulness of fractionated administration of wortmannin combined with γ-ray irradiation in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. Methods B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2’-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumor-bearing mice then received γ-ray irradiation after wortmannin treatment through a single or 4 consecutive daily intraperitoneal administrations up to a total dose of 4 mg/kg in combination with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH). Immediately after the irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (= P + Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. Results Wortmannin raised the sensitivity of Q cells more remarkably than the total cell population in both single and daily administrations. Daily administration of wortmannin elevated the sensitivity of both the total and Q cell populations, but especially the total cell population, compared with single administration. Daily administration, especially combined with MTH, decreased the number of lung metastases. Conclusion Daily fractionated administration of wortmannin in combination with γ-ray irradiation was thought to be more promising than single administration because of its potential to enhance local tumor response and repress lung metastatic potential. PMID:29147327

An alternative way to initiate Notch1 signaling in non-small cell lung cancer

PubMed Central

Yang, Yi-Lin; Jablons, David

2014-01-01

Non-small cell lung cancer (NSCLC) cells activate Notch1 signaling to promote cell proliferation and facilitate their survival. It now emerges that endothelial Delta-like ligand 4 (Dll4) may mediate Notch1 activation and inhibit tumor cell growth. PMID:25806306

Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model.

PubMed

Koskimaki, Jacob E; Karagiannis, Emmanouil D; Tang, Benjamin C; Hammers, Hans; Watkins, D Neil; Pili, Roberto; Popel, Aleksander S

2010-02-01

Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the alpha-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the alpha5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer.

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells.

PubMed

Testa, Ugo; Castelli, Germana; Pelosi, Elvira

2017-11-20

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells.

An Emerging Allee Effect Is Critical for Tumor Initiation and Persistence

PubMed Central

Böttger, Katrin; Hatzikirou, Haralambos; Voss-Böhme, Anja; Cavalcanti-Adam, Elisabetta Ada; Herrero, Miguel A.; Deutsch, Andreas

2015-01-01

Tumor cells develop different strategies to cope with changing microenvironmental conditions. A prominent example is the adaptive phenotypic switching between cell migration and proliferation. While it has been shown that the migration-proliferation plasticity influences tumor spread, it remains unclear how this particular phenotypic plasticity affects overall tumor growth, in particular initiation and persistence. To address this problem, we formulate and study a mathematical model of spatio-temporal tumor dynamics which incorporates the microenvironmental influence through a local cell density dependence. Our analysis reveals that two dynamic regimes can be distinguished. If cell motility is allowed to increase with local cell density, any tumor cell population will persist in time, irrespective of its initial size. On the contrary, if cell motility is assumed to decrease with respect to local cell density, any tumor population below a certain size threshold will eventually extinguish, a fact usually termed as Allee effect in ecology. These results suggest that strategies aimed at modulating migration are worth to be explored as alternatives to those mainly focused at keeping tumor proliferation under control. PMID:26335202

Early tumor shrinkage served as a prognostic factor for patients with stage III non-small cell lung cancer treated with concurrent chemoradiotherapy.

PubMed

Wei, Min; Ye, Qingqing; Wang, Xuan; Wang, Men; Hu, Yan; Yang, Yonghua; Yang, Jiyuan; Cai, Jun

2018-05-01

Lung cancer is the most common cause of cancer death. About 80% of patients are diagnosed at stage III in the non-small cell lung cancer (NSCLC). It is extremely important to understand the progression of this disease which has low survival times despite the advancing treatment modalities. We aimed to investigate the relationship between early tumor shrinkage (ETS) after initial concurrent chemoradiotherapy (C-CRT) and survival outcome in patients with stage III (NSCLC). A retrospective review of 103 patients with stage III NSCLC who had received C-CRT from January 2006 to October 2011 was performed. Patients were treated with systemic chemotherapy regimen of Cisplatin/Vp-16 and concurrent thoracic radiotherapy at a median dose of 66 Gy (range 60-70 Gy). All patients received a computed tomography (CT) examination before treatment. Also subsequently, chest CT scans were performed with the same imaging parameters at approximately 5 weeks after the initiation of treatment. ETS is here stratified by a decrease in tumor size ≥30% and <30% in the longest dimension of the target lesion within 5 weeks. Of the 103 patients, 59 ones showed a 30% decrease in tumor size, and the rest displayed a decrease of <30%. ETS showed no significant correlation with age, T classification, N classification, histological classification, smoking status, G classification, EGFR status, or acute pulmonary toxicity. In the current retrospective clinical study, Kaplan-Meier curves showed that patients with ETS ≥ 30% had a better progression-free survival and overall survival. The univariate and multivariate Cox regression analyses indicated that ETS < 30% was associated with a significantly increased risk of cancer-related death (P < .05) in stage IIINSCLC. ETS may be served as a useful prognostic factor to predict the outcome of stage III NSCLC patients treated with CCRT.

REGULATION OF LUNG CANCER METASTASIS BY Klf4-Numb-like SIGNALING

PubMed Central

Vaira, Valentina; Faversani, Alice; Martin, Nina M.; Garlick, David S.; Ferrero, Stefano; Nosotti, Mario; Kissil, Joseph L.; Bosari, Silvano; Altieri, Dario C.

2013-01-01

Metastatic traits appear to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor microRNA-296-5p (miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non-small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a "stemness" transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor-like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer PMID:23440423

JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer

PubMed Central

Song, Wenqiang; Ma, Yufang; Wang, Jialiang; Brantley-Sieders, Dana; Chen, Jin

2014-01-01

Recent genome-wide analyses in human lung cancer revealed that EPHA2 receptor tyrosine kinase is overexpressed in non-small cell lung cancer (NSCLC), and high levels of EPHA2 correlate with poor clinical outcome. However, the mechanistic basis for EPHA2-mediated tumor promotion in lung cancer remains poorly understood. Here we show that the JNK/c-JUN signaling mediates EPHA2-dependent tumor cell proliferation and motility. A screen of phospho-kinase arrays revealed a decrease in phospho-c-JUN levels in EPHA2 knockdown cells. Knockdown of EPHA2 inhibited p-JNK and p-c-JUN levels in approximately 50% of NSCLC lines tested. Treatment of parental cells with SP600125, a JNK inhibitor, recapitulated defects in EPHA2-deficient tumor cells; whereas constitutively activated JNK mutants were sufficient to rescue phenotypes. Knockdown of EPHA2 also inhibited tumor formation and progression in xenograft animal models in vivo. Furthermore, we investigated the role of EPHA2 in cancer stem-like cells. RNAi-mediated depletion of EPHA2 in multiple NSCLC lines decreased the ALDH positive cancer stem-like population and tumor spheroid formation in suspension. Depletion of EPHA2 in sorted ALDH positive populations markedly inhibited tumorigenicity in nude mice. Furthermore, analysis of a human lung cancer tissue microarray revealed a significant, positive association between EPHA2 and ALDH expression, indicating an important role for EPHA2 in human lung cancer stem-like cells. Collectively, these studies revealed a critical role of JNK signaling in EPHA2-dependent lung cancer cell proliferation and motility and a role for EPHA2 in cancer stem-like cell function, providing evidence for EPHA2 as a potential therapeutic target in NSCLC. PMID:24607842

Identification of tumor-initiating cells derived from two canine rhabdomyosarcoma cell lines

PubMed Central

KISHIMOTO, Takuya Evan; YASHIMA, Shoko; NAKAHIRA, Rei; ONOZAWA, Eri; AZAKAMI, Daigo; UJIKE, Makoto; OCHIAI, Kazuhiko; ISHIWATA, Toshiyuki; TAKAHASHI, Kimimasa; MICHISHITA, Masaki

2017-01-01

Cancer stem cells or tumor-initiating cells (TICs) are a small subpopulation of cells that have the capacity to self-renew, differentiate and initiate tumors. These cells may function in tumor initiation, aggression and recurrence. Whether spheres derived from canine rhabdomyosarcoma cells have stem cell-like properties is unclear. We induced sphere formation in the canine rhabdomyosarcoma cell lines, CMS-C and CMS-J, and characterized the spheres in vitro and in vivo. Sphere-forming cells were more resistant to vincristine, mitoxantrone and doxorubicin than adherent cells. Xenograft transplantation demonstrated that 1 × 103 sphere-forming cells derived from CMS-C were sufficient for tumor formation. The sphere assay showed that the sphere-forming cells were present in these tumors. These results suggest that the spheres derived from canine rhabdomyosarcoma cells may possess characteristics of TICs. This study provides the foundation for elucidating the contribution of TICs to rhabdomyosarcoma tumorigenesis. PMID:28529244

A Fast Neural Network Approach to Predict Lung Tumor Motion during Respiration for Radiation Therapy Applications

PubMed Central

Slama, Matous; Benes, Peter M.; Bila, Jiri

2015-01-01

During radiotherapy treatment for thoracic and abdomen cancers, for example, lung cancers, respiratory motion moves the target tumor and thus badly affects the accuracy of radiation dose delivery into the target. A real-time image-guided technique can be used to monitor such lung tumor motion for accurate dose delivery, but the system latency up to several hundred milliseconds for repositioning the radiation beam also affects the accuracy. In order to compensate the latency, neural network prediction technique with real-time retraining can be used. We have investigated real-time prediction of 3D time series of lung tumor motion on a classical linear model, perceptron model, and on a class of higher-order neural network model that has more attractive attributes regarding its optimization convergence and computational efficiency. The implemented static feed-forward neural architectures are compared when using gradient descent adaptation and primarily the Levenberg-Marquardt batch algorithm as the ones of the most common and most comprehensible learning algorithms. The proposed technique resulted in fast real-time retraining, so the total computational time on a PC platform was equal to or even less than the real treatment time. For one-second prediction horizon, the proposed techniques achieved accuracy less than one millimeter of 3D mean absolute error in one hundred seconds of total treatment time. PMID:25893194

A fast neural network approach to predict lung tumor motion during respiration for radiation therapy applications.

PubMed

Bukovsky, Ivo; Homma, Noriyasu; Ichiji, Kei; Cejnek, Matous; Slama, Matous; Benes, Peter M; Bila, Jiri

2015-01-01

During radiotherapy treatment for thoracic and abdomen cancers, for example, lung cancers, respiratory motion moves the target tumor and thus badly affects the accuracy of radiation dose delivery into the target. A real-time image-guided technique can be used to monitor such lung tumor motion for accurate dose delivery, but the system latency up to several hundred milliseconds for repositioning the radiation beam also affects the accuracy. In order to compensate the latency, neural network prediction technique with real-time retraining can be used. We have investigated real-time prediction of 3D time series of lung tumor motion on a classical linear model, perceptron model, and on a class of higher-order neural network model that has more attractive attributes regarding its optimization convergence and computational efficiency. The implemented static feed-forward neural architectures are compared when using gradient descent adaptation and primarily the Levenberg-Marquardt batch algorithm as the ones of the most common and most comprehensible learning algorithms. The proposed technique resulted in fast real-time retraining, so the total computational time on a PC platform was equal to or even less than the real treatment time. For one-second prediction horizon, the proposed techniques achieved accuracy less than one millimeter of 3D mean absolute error in one hundred seconds of total treatment time.

Combining Cell Type-Restricted Adenoviral Targeting with Immunostaining and Flow Cytometry to Identify Cells-of-Origin of Lung Cancer.

PubMed

Best, Sarah A; Kersbergen, Ariena; Asselin-Labat, Marie-Liesse; Sutherland, Kate D

2018-01-01

Lung cancers display considerable intertumoral heterogeneity, leading to the classification of distinct tumor subtypes. Our understanding of the genetic aberrations that underlie tumor subtypes has been greatly enhanced by recent genomic sequencing studies and state-of-the-art gene targeting technologies, highlighting evidence that distinct lung cancer subtypes may be derived from different "cells-of-origin". Here, we describe the intra-tracheal delivery of cell type-restricted Ad5-Cre viruses into the lungs of adult mice, combined with immunohistochemical and flow cytometry strategies for the detection of lung cancer-initiating cells in vivo.

Constitutive Androstane Receptor Ligands Modulate the Anti-Tumor Efficacy of Paclitaxel in Non-Small Cell Lung Cancer Cells

PubMed Central

Fukumasu, Heidge; Rochetti, Arina L.; Pires, Pedro R. L.; Silva, Edson R.; Mesquita, Ligia G.; Strefezzi, Ricardo F.; De Carvalho, Daniel D.; Dagli, Maria L.

2014-01-01

Background Lung tumors are the leading cause of cancer deaths worldwide and paclitaxel has proven to be useful for patients with lung cancer, however, acquired resistance is a major problem. To overcome this problem, one promising option is the use of Constitutive Androstane Receptor (CAR) ligands in combination with chemotherapeutics against cancer cells. Therefore, we wish to elucidate the effects of CAR ligands on the antineoplastic efficacy of paclitaxel in lung cancer cells. Methodology/Principal Findings Our results from cell viability assays exposing CAR agonist or inverse-agonist to mouse and human lung cancer cells modulated the antineoplastic effect of paclitaxel. The CAR agonists increased the effect of Paclitaxel in 6 of 7 lung cancer cell lines, whereas the inverse-agonist had no effect on paclitaxel cytotoxicity. Interestingly, the mCAR agonist TCPOBOP enhanced the expression of two tumor suppressor genes, namely WT1 and MGMT, which were additively enhanced in cells treated with CAR agonist in combination with paclitaxel. Also, in silico analysis showed that both paclitaxel and CAR agonist TCPOBOP docked into the mCAR structure but not the inverse agonist androstenol. Paclitaxel per se increases the expression of CAR in cancer cells. At last, we analyzed the expression of CAR in two public independent studies from The Cancer Genome Atlas (TCGA) of Non Small Cell Lung Cancer (NSCLC). CAR is expressed in variable levels in NSCLC samples and no association with overall survival was noted. Conclusions/Significance Taken together, our results demonstrated that CAR agonists modulate the antineoplastic efficacy of paclitaxel in mouse and human cancer cell lines. This effect was probably related by the enhanced expression of two tumor suppressor genes, viz. WT1 and MGMT. Most of NSCLC cases present CAR gene expression turning it possible to speculate the use of CAR modulation by ligands along with Paclitaxel in NSCLC therapy. PMID:24959746

Molecular biology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

PubMed

Nana-Sinkam, Serge Patrick; Powell, Charles A

2013-05-01

Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics.

SU-E-J-94: Positioning Errors Resulting From Using Bony Anatomy Alignment for Treating SBRT Lung Tumor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frame, C; Ding, G

Purpose: To quantify patient setups errors based on bony anatomy registration rather than 3D tumor alignment for SBRT lung treatments. Method: A retrospective study was performed for patients treated with lung SBRT and imaged with kV cone beam computed tomography (kV-CBCT) image-guidance. Daily CBCT images were registered to treatment planning CTs based on bony anatomy alignment and then inter-fraction tumor movement was evaluated by comparing shift in the tumor center in the medial-lateral, anterior-posterior, and superior-inferior directions. The PTV V100% was evaluated for each patient based on the average daily tumor displacement to assess the impact of the positioning errormore » on the target coverage when the registrations were based on bony anatomy. Of the 35 patients studied, 15 were free-breathing treatments, 10 used abdominal compression with a stereotactic body frame, and the remaining 10 were performed with BodyFIX vacuum bags. Results: For free-breathing treatments, the range of tumor displacement error is between 1–6 mm in the medial-lateral, 1–13 mm in the anterior-posterior, and 1–7 mm in the superior-inferior directions. These positioning errors lead to 6–22% underdose coverage for PTV - V100% . Patients treated with abdominal compression immobilization showed positional errors of 0–4mm mediallaterally, 0–3mm anterior-posteriorly, and 0–2 mm inferior-superiorly with PTV - V100% underdose ranging between 6–17%. For patients immobilized with the vacuum bags, the positional errors were found to be 0–1 mm medial-laterally, 0–1mm anterior-posteriorly, and 0–2 mm inferior-superiorly with PTV - V100% under dose ranging between 5–6% only. Conclusion: It is necessary to align the tumor target by using 3D image guidance to ensure adequate tumor coverage before performing SBRT lung treatments. The BodyFIX vacuum bag immobilization method has the least positioning errors among the three methods studied when bony anatomy is used for

Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells.

PubMed

Wang, Wendan; Belosay, Aashvini; Yang, Xujuan; Hartman, James A; Song, Huaxin; Iwaniec, Urszula T; Turner, Russell T; Churchwell, Mona I; Doerge, Daniel R; Helferich, William G

2016-06-01

Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Here we evaluate the effects of the aromatase inhibitor letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER-) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX + Letrozole, Intact, and Intact + Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 µg/g body weight. Tumor progression was monitored by bioluminescence imaging (BLI). Following necropsy, inoculated tibiae were scanned via µCT and bone response to tumor was scored from 0 (no ectopic mineralization/osteolysis) to 5 (extensive ectopic mineralization/osteolysis). OVX mice had higher tibial pathology scores indicative of more extensive bone destruction than intact mice, irrespective of letrozole treatment. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Furthermore, mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&E and Ki-67 staining, respectively. In conclusion, BC-inoculated OVX animals had higher tibia pathology scores than BC-inoculated intact animals and letrozole reduced BC metastases to lungs. These findings suggest that, by lowering systemic estrogen level and/or by interacting with the host organ, the aromatase inhibitor letrozole has the potential to reduce ER- BC metastasis to lung.

Non-Small-Cell Lung Cancer Molecular Signatures Recapitulate Lung Developmental Pathways

PubMed Central

Borczuk, Alain C.; Gorenstein, Lyall; Walter, Kristin L.; Assaad, Adel A.; Wang, Liqun; Powell, Charles A.

2003-01-01

Current paradigms hold that lung carcinomas arise from pleuripotent stem cells capable of differentiation into one or several histological types. These paradigms suggest lung tumor cell ontogeny is determined by consequences of gene expression that recapitulate events important in embryonic lung development. Using oligonucleotide microarrays, we acquired gene profiles from 32 microdissected non-small-cell lung tumors. We determined the 100 top-ranked marker genes for adenocarcinoma, squamous cell, large cell, and carcinoid using nearest neighbor analysis. Results were validated by immunostaining for 11 selected proteins using a tissue microarray representing 80 tumors. Gene expression data of lung development were accessed from a publicly available dataset generated with the murine Mu11k genome microarray. Self-organized mapping identified two temporally distinct clusters of murine orthologues. Supervised clustering of lung development data showed large-cell carcinoma gene orthologues were in a cluster expressed in pseudoglandular and canalicular stages whereas adenocarcinoma homologues were predominantly in a cluster expressed later in the terminal sac and alveolar stages of murine lung development. Representative large-cell genes (E2F3, MYBL2, HDAC2, CDK4, PCNA) are expressed in the nucleus and are associated with cell cycle and proliferation. In contrast, adenocarcinoma genes are associated with lung-specific transcription pathways (SFTPB, TTF-1), cell adhesion, and signal transduction. In sum, non-small-cell lung tumors histology gene profiles suggest mechanisms relevant to ontogeny and clinical course. Adenocarcinoma genes are associated with differentiation and glandular formation whereas large-cell genes are associated with proliferation and differentiation arrest. The identification of developmentally regulated pathways active in tumorigenesis provides insights into lung carcinogenesis and suggests early steps may differ according to the eventual tumor

Imaging a moving lung tumor with megavoltage cone beam computed tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gayou, Olivier, E-mail: ogayou@wpahs.org; Colonias, Athanasios

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 volumesmore » 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

Preparation, characterization, in vitro and in vivo anti-tumor effect of thalidomide nanoparticles on lung cancer.

PubMed

Chen, Long Xia; Ni, Xiao Ling; Zhang, Heng; Wu, Min; Liu, Jing; Xu, Shan; Yang, Ling Lin; Fu, Shao Zhi; Wu, Jingbo

2018-01-01

Thalidomide (THA) is an angiogenesis inhibitor and an efficient inhibitor of the tumor necrosis factor-α (TNF-α). However, the clinical application of THA has been limited due to hydrophobicity of the compound. To increase the water solubility of THA and in order to evaluate the anticancer abilities of this material on human lung carcinoma, methoxy poly(ethylene glycol)-poly(ε-caprolactone) nanoparticles loaded with THA (THA-NPs) were prepared. The synthesis of THA-NPs was carried out via a dialysis method with relative satisfactory encapsulation efficiency, loading capacity, size distribution, and zeta potential. A cytotoxicity assay demonstrated that THA-NPs inhibited the growth of cells in a dose-dependent manner. The evaluation of anti-tumor activity in vivo showed that THA-NPs could inhibit tumor growth and prolong the survival rate of tumor-bearing mice. Immunohistochemical analysis indicated that THA-NPs inhibited cell proliferation (Ki-67 positive rate, 32.8%±4.2%, P <0.01), and resulted in a decreased rate of the tumor tissue microvessel density (3.87%±0.77%, P <0.01), VEGF (26.67%±4.02%, P <0.01), and TNF-α (75.21±6.85 ng/mL, P <0.01). In general, the drug delivery system reported herein may shed light on future targeted therapy in lung cancer treatment.

Neuroendocrine Tumors of the Lung: Current Challenges and Advances in the Diagnosis and Management of Well-Differentiated Disease.

PubMed

Hendifar, Andrew E; Marchevsky, Alberto M; Tuli, Richard

2017-03-01

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies that arise from neuroendocrine cells throughout the body, most commonly originating from the lungs and gastrointestinal tract. Lung NETs can be classified as well differentiated (low-grade typical carcinoids [TCs] and intermediate-grade atypical carcinoids [ACs]) and poorly differentiated (high-grade large cell neuroendocrine carcinoma or SCLC). The incidence of these tumors is increasing, but disease awareness remains low among thoracic specialists, who are often involved in the diagnosis and early treatment for these patients. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and have a substantial impact on prognosis. However, lung NET classification and diagnosis, particularly for TCs/ACs, are complicated by several factors, including a variable natural history and nonspecific symptoms. Surgery remains the only curative option for TCs/ACs, but there is a lack of consensus between lung NET management guidelines regarding optimal treatment approaches in the unresectable/metastatic setting on account of the limited availability of high-level clinical evidence. As a result, a multidisciplinary approach to management of lung NETs is required to ensure a consistent and optimal level of care. RADIANT-4 is the first phase III trial involving a large subpopulation of patients with advanced well-differentiated lung NETs to report reductions in the risk for disease progression and death with everolimus over placebo. This led to the recent U.S. approval of everolimus-the first agent approved for advanced lung TCs/ACs. To further improve evidence-based care, additional randomized controlled trials in patients with lung carcinoids are needed. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

[Possible Significance of Bronchoalveolar Lavage Cytology at Initial Diagnosis and Follow-up of Lung Cancer].

PubMed

Grünewaldt, A; Hügel, C; Hermann, E; Wagner, T O F

2017-02-01

Bronchoalveolar lavage [BAL] is an important procedure in the diagnosis of a variety of lung diseases. While it has enormous value in the diagnostics of inflammatory parenchymal diseases, its significance in lung cancer is unclear. Keeping in mind that immune therapy (e. g. application of checkpoint inhibitors) is gaining importance in the management of lung carcinoma, it is important to know if there are typical cellular patterns in BAL of lung cancer patients. Methods  In a retrospective proof of principle-study, we analyzed 38 patients who underwent BAL at the initial diagnosis of lung cancer. Results  We observed an elevated level of CD25 lymphocytes as well as an increased expression of DR antigen, both signaling lymphocyte activation. We could not find a typical cytologic pattern of inflammatory cells in lung carcinoma patients. Sensitivity of BAL to malignant cells was rare, thus confirming earlier analysis. Conclusion  We could not demonstrate typical cellular patterns in BAL of lung cancer patients. Evaluation of specific microRNA patterns might play a supporting role in the initial diagnosis as well as follow-up of lung cancer patients. © Georg Thieme Verlag KG Stuttgart · New York.

FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival

PubMed Central

Heim, Lisanne; Trump, Sonja; Mittler, Susanne; Sopel, Nina; Andreev, Katerina; Ferrazzi, Fulvia; Ekici, Arif B.; Rieker, Ralf; Springel, Rebekka; Assmann, Vera L.; Lechmann, Matthias; Koch, Sonja; Engelhardt, Marina; Trufa, Denis I.; Sirbu, Horia; Hartmann, Arndt; Finotto, Susetta

2017-01-01

ABSTRACT Genome-wide association studies (GWAS) associated Family with sequence similarity 13, member A (FAM13A) with non-small cell lung cancer (NSCLC) occurrence. Here, we found increased numbers of FAM13A protein expressing cells in the tumoral region of lung tissues from a cohort of patients with NSCLC. Moreover, FAM13A inversely correlated with CTLA4 but directly correlated with HIF1α levels in the control region of these patients. Consistently, FAM13A RhoGAP was found to be associated with T cell effector molecules like HIF1α and Tbet and was downregulated in immunosuppressive CD4+CD25+Foxp3+CTLA4+ T cells. TGFβ, a tumor suppressor factor, as well as siRNA to FAM13A, suppressed both isoforms of FAM13A and inhibited tumor cell proliferation. RNA-Seq analysis confirmed this finding. Moreover, siRNA to FAM13A induced TGFβ levels. Finally, in experimental tumor cell migration, FAM13A was induced and TGFβ accelerated this process by inducing cell migration, HIF1α, and the FAM13A RhoGAP isoform. Furthermore, siRNA to FAM13A inhibited tumor cell proliferation and induced cell migration without affecting HIF1α. In conclusion, FAM13A is involved in tumor cell proliferation and downstream of TGFβ and HIF1α, FAM13A RhoGAP is associated with Th1 gene expression and lung tumor cell migration. These findings identify FAM13A as key regulator of NSCLC growth and progression. PMID:28197372

Results of initial low-dose computed tomographic screening for lung cancer.

PubMed

Church, Timothy R; Black, William C; Aberle, Denise R; Berg, Christine D; Clingan, Kathy L; Duan, Fenghai; Fagerstrom, Richard M; Gareen, Ilana F; Gierada, David S; Jones, Gordon C; Mahon, Irene; Marcus, Pamela M; Sicks, JoRean D; Jain, Amanda; Baum, Sarah

2013-05-23

Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. We describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST to inform and improve lung-cancer-screening programs. At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptomatic participants, 55 to 74 years of age, with a history of at least 30 pack-years of smoking. The participants were randomly assigned to undergo annual screening, with the use of either low-dose CT or chest radiography, for 3 years. Nodules or other suspicious findings were classified as positive results. This article reports findings from the initial screening examination. A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants (98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 participants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography group had a positive screening result; in the respective groups, 6369 participants (90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, including imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121 (5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively. The NLST initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancer is achievable at U.S. screening centers that

Based on an analysis of mode of action, styrene-induced mouse lung tumors are not a human cancer concern.

PubMed

Cruzan, George; Bus, James S; Andersen, Melvin E; Carlson, Gary P; Banton, Marcy I; Sarang, Satinder S; Waites, Robbie

2018-06-01

Based on 13 chronic studies, styrene exposure causes lung tumors in mice, but no tumor increases in other organs in mice or rats. Extensive research into the mode of action demonstrates the key events and human relevance. Key events are: metabolism of styrene by CYP2F2 in mouse lung club cells to ring-oxidized metabolites; changes in gene expression for metabolism of lipids and lipoproteins, cell cycle and mitotic M-M/G1 phases; cytotoxicity and mitogenesis in club cells; and progression to preneoplastic/neoplastic lesions in lung. Although styrene-7,8-oxide (SO) is a common genotoxic styrene metabolite in in vitro studies, the data clearly demonstrate that SO is not the proximate toxicant and that styrene does not induce a genotoxic mode of action. Based on complete attenuation of styrene short-term and chronic toxicity in CYP2F2 knockout mice and similar attenuation in CYP2F1 (humanized) transgenic mice, limited metabolism of styrene in human lung by CYP2F1, 2 + orders of magnitude lower SO levels in human lung compared to mouse lung, and lack of styrene-related increase in lung cancer in humans, styrene does not present a risk of cancer to humans. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Bone marrow-derived fibrocytes promote stem cell-like properties of lung cancer cells.

PubMed

Saijo, Atsuro; Goto, Hisatsugu; Nakano, Mayuri; Mitsuhashi, Atsushi; Aono, Yoshinori; Hanibuchi, Masaki; Ogawa, Hirohisa; Uehara, Hisanori; Kondo, Kazuya; Nishioka, Yasuhiko

2018-05-01

Cancer stem cells (CSCs) represent a minor population that have clonal tumor initiation and self-renewal capacity and are responsible for tumor initiation, metastasis, and therapeutic resistance. CSCs reside in niches, which are composed of diverse types of stromal cells and extracellular matrix components. These stromal cells regulate CSC-like properties by providing secreted factors or by physical contact. Fibrocytes are differentiated from bone marrow-derived CD14 + monocytes and have features of both macrophages and fibroblasts. Accumulating evidence has suggested that stromal fibrocytes might promote cancer progression. However, the role of fibrocytes in the CSC niches has not been revealed. We herein report that human fibrocytes enhanced the CSC-like properties of lung cancer cells through secreted factors, including osteopontin, CC-chemokine ligand 18, and plasminogen activator inhibitor-1. The PIK3K/AKT pathway was critical for fibrocytes to mediate the CSC-like functions of lung cancer cells. In human lung cancer specimens, the number of tumor-infiltrated fibrocytes was correlated with high expression of CSC-associated protein in cancer cells. These results suggest that fibrocytes may be a novel cell population that regulates the CSC-like properties of lung cancer cells in the CSC niches. Copyright © 2018. Published by Elsevier B.V.

Robotic anatomic segmentectomy of the lung: technical aspects and initial results.

PubMed

Pardolesi, Alessandro; Park, Bernard; Petrella, Francesco; Borri, Alessandro; Gasparri, Roberto; Veronesi, Giulia

2012-09-01

Robotic lobectomy with radical lymph node dissection is a new frontier of minimally invasive thoracic surgery. Series of sublobar anatomic resection for primary initial lung cancers or for metastasis using video-assisted thoracic surgery have been reported but no cases have been so far reported using the robot-assisted approach. We present the technique and surgical outcome of our initial experience. Clinical data of patients undergoing robotic lung anatomic segmentectomy were retrospectively reviewed. All cases were done using the DaVinci System. A 3- or 4-incision strategy with a 3-cm utility incision in the anterior fourth or fifth intercostal space was performed. Individual ligation and division of the hilar structures was performed using Hem-o-Lok (Teleflex Medical, Research Triangle Park, NC) or endoscopic staplers. The parenchyma was transected with endovascular staplers introduced by the bedside assistant mainly through the utility incision. Systematic mediastinal lymph node dissection or sampling was performed. From 2008 to 2010, 17 patients underwent a robot-assisted lung anatomic segmentectomy in two centers. There were 10 women and 7 men with a mean age of 68.2 years (range, 32 to 82). Mean duration of surgery was 189 minutes. There were no major intraoperative complications. Conversion to open procedure was never required. Postoperative morbidity rate was 17.6% with pneumonia in 1 case and prolonged air leaks in 2 patients. Median postoperative stay was 5 days (range, 2 to 14), and postoperative mortality was 0%. Final pathology was non-small cell lung cancer in 8 patient, typical carcinoids in 2, and lung metastases in 7. Robotic anatomic lung segmentectomy is feasible and safe procedure. Robotic system, by improving ergonomic, surgeon view and precise movements, may make minimally invasive segmentectomy easier to adopt and perform. Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Melanoma: Genetic Abnormalities, Tumor Progression, Clonal Evolution and Tumor Initiating Cells

PubMed Central

Castelli, Germana; Pelosi, Elvira

2017-01-01

Melanoma is an aggressive neoplasia issued from the malignant transformation of melanocytes, the pigment-generating cells of the skin. It is responsible for about 75% of deaths due to skin cancers. Melanoma is a phenotypically and molecularly heterogeneous disease: cutaneous, uveal, acral, and mucosal melanomas have different clinical courses, are associated with different mutational profiles, and possess distinct risk factors. The discovery of the molecular abnormalities underlying melanomas has led to the promising improvement of therapy, and further progress is expected in the near future. The study of melanoma precursor lesions has led to the suggestion that the pathway of tumor evolution implies the progression from benign naevi, to dysplastic naevi, to melanoma in situ and then to invasive and metastatic melanoma. The gene alterations characterizing melanomas tend to accumulate in these precursor lesions in a sequential order. Studies carried out in recent years have, in part, elucidated the great tumorigenic potential of melanoma tumor cells. These findings have led to speculation that the cancer stem cell model cannot be applied to melanoma because, in this malignancy, tumor cells possess an intrinsic plasticity, conferring the capacity to initiate and maintain the neoplastic process to phenotypically different tumor cells. PMID:29156643

Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake.

PubMed

Flavahan, William A; Wu, Qiulian; Hitomi, Masahiro; Rahim, Nasiha; Kim, Youngmi; Sloan, Andrew E; Weil, Robert J; Nakano, Ichiro; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Li, Meizhang; Lathia, Justin D; Rich, Jeremy N; Hjelmeland, Anita B

2013-10-01

Like all cancers, brain tumors require a continuous source of energy and molecular resources for new cell production. In normal brain, glucose is an essential neuronal fuel, but the blood-brain barrier limits its delivery. We now report that nutrient restriction contributes to tumor progression by enriching for brain tumor initiating cells (BTICs) owing to preferential BTIC survival and to adaptation of non-BTICs through acquisition of BTIC features. BTICs outcompete for glucose uptake by co-opting the high affinity neuronal glucose transporter, type 3 (Glut3, SLC2A3). BTICs preferentially express Glut3, and targeting Glut3 inhibits BTIC growth and tumorigenic potential. Glut3, but not Glut1, correlates with poor survival in brain tumors and other cancers; thus, tumor initiating cells may extract nutrients with high affinity. As altered metabolism represents a cancer hallmark, metabolic reprogramming may maintain the tumor hierarchy and portend poor prognosis.

MicroRNA-137 inhibits tumor growth and sensitizes chemosensitivity to paclitaxel and cisplatin in lung cancer

PubMed Central

Ge, Xin; Jiang, Cheng-Fei; Shi, Zhu-Mei; Li, Dong-Mei; Liu, Wei-Tao; Yu, Xiaobo; Shu, Yong-Qian

2016-01-01

Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. In this study, we explored miR-137's role in the chemosensitivity of lung cancer. We found that the expression level of miR-137 is down-regulated in the human lung cancer tissues and the resistant cells strains: A549/paclitaxel(A549/PTX) and A549/cisplatin (A549/CDDP) when compared with lung cancer A549 cells. Moreover, we found that overe-expression of miR-137 inhibited cell proliferation, migration, cell survival and arrest the cell cycle in G1 phase in A549/PTX and A549/CDDP. Furthermore, Repression of miR-137 significantly promoted cell growth, migration, cell survival and cell cycle G1/S transition in A549 cells. We further demonstrated that the tumor suppressive role of miR-137 was mediated by negatively regulating Nuclear casein kinase and cyclin-dependent kinase substrate1(NUCKS1) protein expression. Importantly, miR-137 inhibits A549/PTX, A549/CDDP growth and angiogenesis in vivo. Our study is the first to identify the tumor suppressive role of over-expressed miR-137 in chemosensitivity. Identification of a novel miRNA-mediated pathway that regulates chemosensitivity in lung cancer will facilitate the development of novel therapeutic strategies in the future. PMID:26989074

Survival after Radiofrequency Ablation in 122 Patients with Inoperable Colorectal Lung Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gillams, Alice, E-mail: alliesorting@gmail.com; Khan, Zahid; Osborn, Peter

2013-06-15

Purpose. To analyze the factors associated with favorable survival in patients with inoperable colorectal lung metastases treated with percutaneous image-guided radiofrequency ablation. Methods. Between 2002 and 2011, a total of 398 metastases were ablated in 122 patients (87 male, median age 68 years, range 29-90 years) at 256 procedures. Percutaneous CT-guided cool-tip radiofrequency ablation was performed under sedation/general anesthesia. Maximum tumor size, number of tumors ablated, number of procedures, concurrent/prior liver ablation, previous liver or lung resection, systemic chemotherapy, disease-free interval from primary resection to lung metastasis, and survival from first ablation were recorded prospectively. Kaplan-Meier analysis was performed, andmore » factors were compared by log rank test. Results. The initial number of metastases ablated was 2.3 (range 1-8); the total number was 3.3 (range 1-15). The maximum tumor diameter was 1.7 (range 0.5-4) cm, and the number of procedures was 2 (range 1-10). The major complication rate was 3.9 %. Overall median and 3-year survival rate were 41 months and 57 %. Survival was better in patients with smaller tumors-a median of 51 months, with 3-year survival of 64 % for tumors 2 cm or smaller versus 31 months and 44 % for tumors 2.1-4 cm (p = 0.08). The number of metastases ablated and whether the tumors were unilateral or bilateral did not affect survival. The presence of treated liver metastases, systemic chemotherapy, or prior lung resection did not affect survival. Conclusion. Three-year survival of 57 % in patients with inoperable colorectal lung metastases is better than would be expected with chemotherapy alone. Patients with inoperable but small-volume colorectal lung metastases should be referred for ablation.« less

Imaging macrophage distribution and density in mammary tumors and lung metastases using fluorine-19 MRI cell tracking.

PubMed

Makela, Ashley V; Foster, Paula J

2018-09-01

The presence of tumor-associated macrophages (TAMs) correlates with breast cancer progression and metastatic spread. Metastasis-associated macrophages (MAMs) are also recruited to distant sites, where they support metastatic growth. In this study, we demonstrate that in vivo fluorine-19 ( 19 F)-based MRI cell tracking can evaluate the density and distribution of macrophages within murine breast cancer tumors and associated metastases. Three murine breast cancer cell lines with different metastatic potentials (4T1, 168FARN, and 67NR) were implanted into the mammary fat pad in mice. In vivo whole body 19 F MRI was performed on tumor-bearing mice 24 hours post-intravenous injection of a perfluorocarbon (PFC) agent, which was taken up by macrophages in situ. TAMs were detected mainly in the periphery of primary tumors, and higher numbers of TAMs were detected in the more aggressive 4T1 tumors. Tumors had significantly greater 19 F spins/mm 3 when they were smaller, suggesting more TAM infiltration in early-stage tumors. 19 F signal was observed within lung metastases in mice with 4T1 tumors, and fluorescence microscopy confirmed the presence of PFC-positive macrophages. This study shows for the first time proof of the ability to use MRI cell tracking to visualize MAMs in the lungs. The ability to detect and monitor the number of TAMs in individual tumors with 19 F MRI would allow for identification of breast tumors with heavy infiltration of TAMs and could be used as a biomarker for decisions about how to best treat these patients as well as for monitoring responses to therapy. Magn Reson Med 80:1138-1147, 2018. © 2018 International Society for Magnetic Resonance in Medicine. © 2018 International Society for Magnetic Resonance in Medicine.

Serum carcinoembryonic antigen levels before initial treatment are associated with EGFR mutations and EML4- ALK fusion gene in lung adenocarcinoma patients.

PubMed

Wang, Wen-Tao; Li, Yin; Ma, Jie; Chen, Xiao-Bing; Qin, Jian-Jun

2014-01-01

Epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) define specific molecular subsets of lung adenocarcinomas with distinct clinical features. Our purpose was to analyze clinical features and prognostic value of EGFR gene mutations and the EML4-ALK fusion gene in lung adenocarcinoma. EGFR gene mutations and the EML4-ALK fusion gene were detected in 92 lung adenocarcinoma patients in China. Tumor marker levels before first treatment were measured by electrochemiluminescence immunoassay. EGFR mutations were found in 40.2% (37/92) of lung adenocarcinoma patients, being identified at high frequencies in never-smokers (48.3% vs. 26.5% in smokers; P=0.040) and in patients with abnormal serum carcinoembryonic antigen (CEA) levels before the initial treatment (58.3% vs. 28.6%, P=0.004). Multivariate analysis revealed that a higher serum CEA level before the initial treatment was independently associated with EGFR gene mutations (95%CI: 1.476~11.343, P=0.007). We also identified 8 patients who harbored the EML4-ALK fusion gene (8.7%, 8/92). In concordance with previous reports, younger age was a clinical feature for these (P=0.008). Seven of the positive cases were never smokers, and no coexistence with EGFR mutation was discovered. In addition, the frequency of the EML4-ALK fusion gene among patients with a serum CEA concentration below 5 ng/ml seemed to be higher than patients with a concentration over 5 ng/ml (P=0.021). No significant difference was observed for time to progression and overall survival between EML4-ALK-positive group and EML4-ALK-negative group or between patients with and without an EGFR mutation. The serum CEA level before the initial treatment may be helpful in screening population for EGFR mutations or EML4-ALK fusion gene presence in lung adenocarcinoma patients.