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Sample records for 1-3 brain metastasis

  1. Ion Channels in Brain Metastasis

    PubMed Central

    Klumpp, Lukas; Sezgin, Efe C.; Eckert, Franziska; Huber, Stephan M.

    2016-01-01

    Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial–mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood–brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation. PMID:27618016

  2. Ion Channels in Brain Metastasis.

    PubMed

    Klumpp, Lukas; Sezgin, Efe C; Eckert, Franziska; Huber, Stephan M

    2016-01-01

    Breast cancer, lung cancer and melanoma exhibit a high metastatic tropism to the brain. Development of brain metastases severely worsens the prognosis of cancer patients and constrains curative treatment options. Metastasizing to the brain by cancer cells can be dissected in consecutive processes including epithelial-mesenchymal transition, evasion from the primary tumor, intravasation and circulation in the blood, extravasation across the blood-brain barrier, formation of metastatic niches, and colonization in the brain. Ion channels have been demonstrated to be aberrantly expressed in tumor cells where they regulate neoplastic transformation, malignant progression or therapy resistance. Moreover, many ion channel modulators are FDA-approved drugs and in clinical use proposing ion channels as druggable targets for future anti-cancer therapy. The present review article aims to summarize the current knowledge on the function of ion channels in the different processes of brain metastasis. The data suggest that certain channel types involving voltage-gated sodium channels, ATP-release channels, ionotropic neurotransmitter receptors and gap junction-generating connexins interfere with distinct processes of brain metastazation. PMID:27618016

  3. Embracing rejection: Immunologic trends in brain metastasis.

    PubMed

    Farber, S Harrison; Tsvankin, Vadim; Narloch, Jessica L; Kim, Grace J; Salama, April K S; Vlahovic, Gordana; Blackwell, Kimberly L; Kirkpatrick, John P; Fecci, Peter E

    2016-07-01

    Brain metastases represent the most common type of brain tumor. These tumors offer a dismal prognosis and significantly impact quality of life for patients. Their capacity for central nervous system (CNS) invasion is dependent upon induced disruptions to the blood-brain barrier (BBB), alterations to the brain microenvironment, and mechanisms for escaping CNS immunosurveillance. In the emerging era of immunotherapy, understanding how metastases are influenced by the immunologic peculiarities of the CNS will be crucial to forging therapeutic advances. In this review, the immunology of brain metastasis is explored. PMID:27622023

  4. Blood–brain Barrier Remodeling during Brain Metastasis Formation

    PubMed Central

    Wrobel, Jagoda K; Toborek, Michal

    2016-01-01

    Our understanding of the process of metastatic progression has improved markedly over the past decades, yet metastasis remains the most enigmatic component of cancer pathogenesis. This lack of knowledge has serious health-related implications, since metastasis is responsible for 90% of all cancer-related mortalities. The brain is considered a sanctuary site for metastatic tumor growth, where the blood–brain barrier (BBB) and other components of the brain microenvironment, provide protection to the tumor cells from immune surveillance, chemotherapeutics and other potentially harmful substances. The interactions between tumor cells and the brain microenvironment, principally brain vascular endothelium, are the critical determinants in their progression toward metastasis, dormancy, or clearance. This review discusses current knowledge of the biology of metastatic progression, with a particular focus on the tumor cell migration and colonization in the brain.

  5. Blood–brain Barrier Remodeling during Brain Metastasis Formation

    PubMed Central

    Wrobel, Jagoda K; Toborek, Michal

    2016-01-01

    Our understanding of the process of metastatic progression has improved markedly over the past decades, yet metastasis remains the most enigmatic component of cancer pathogenesis. This lack of knowledge has serious health-related implications, since metastasis is responsible for 90% of all cancer-related mortalities. The brain is considered a sanctuary site for metastatic tumor growth, where the blood–brain barrier (BBB) and other components of the brain microenvironment, provide protection to the tumor cells from immune surveillance, chemotherapeutics and other potentially harmful substances. The interactions between tumor cells and the brain microenvironment, principally brain vascular endothelium, are the critical determinants in their progression toward metastasis, dormancy, or clearance. This review discusses current knowledge of the biology of metastatic progression, with a particular focus on the tumor cell migration and colonization in the brain. PMID:26837070

  6. Computational systems biology in cancer brain metastasis.

    PubMed

    Peng, Huiming; Tan, Hua; Zhao, Weiling; Jin, Guangxu; Sharma, Sambad; Xing, Fei; Watabe, Kounosuke; Zhou, Xiaobo

    2016-01-01

    Brain metastases occur in 20-40% of patients with advanced malignancies. A better understanding of the mechanism of this disease will help us to identify novel therapeutic strategies. In this review, we will discuss the systems biology approaches used in this area, including bioinformatics and mathematical modeling. Bioinformatics has been used for identifying the molecular mechanisms driving brain metastasis and mathematical modeling methods for analyzing dynamics of a system and predicting optimal therapeutic strategies. We will illustrate the strategies, procedures, and computational techniques used for studying systems biology in cancer brain metastases. We will give examples on how to use a systems biology approach to analyze a complex disease. Some of the approaches used to identify relevant networks, pathways, and possibly biomarkers in metastasis will be reviewed into details. Finally, certain challenges and possible future directions in this area will also be discussed.

  7. Brain metastasis: new opportunities to tackle therapeutic resistance.

    PubMed

    Seoane, Joan; De Mattos-Arruda, Leticia

    2014-09-12

    Brain metastasis is a devastating complication of cancer with unmet therapeutic needs. The incidence of brain metastasis has been rising in cancer patients and its response to treatment is limited due to the singular characteristics of brain metastasis (i.e., blood-brain-barrier, immune system, stroma). Despite improvements in the treatment and control of extracranial disease, the outcomes of patients with brain metastasis remain dismal. The mechanisms that allow tumor cells to promulgate metastases to the brain remain poorly understood. Further work is required to identify the molecular alterations inherent to brain metastasis in order to identify novel therapeutic targets and explicate the mechanisms of resistance to systemic therapeutics. In this article, we review current knowledge of the unique characteristics of brain metastasis, implications in therapeutic resistance, and the possibility of developing biomarkers to rationally guide the use of targeted agents.

  8. Brain metastasis from ovarian cancer: a systematic review.

    PubMed

    Pakneshan, Shabnam; Safarpour, Damoun; Tavassoli, Fattaneh; Jabbari, Bahman

    2014-08-01

    To review the existing literature on brain metastasis (BM) from ovarian cancer and to assess the frequency, anatomical, clinical and paraclinical information and factors associated with prognosis. Ovarian cancer is a rare cause of brain metastasis with a recently reported increasing prevalence. Progressive neurologic disability and poor prognosis is common. A comprehensive review on this subject has not been published previously. This systematic literature search used the Pubmed and Yale library. A total of 66 publications were found, 57 of which were used representing 591 patients with BM from ovarian cancer. The median age of the patients was 54.3 years (range 20-81). A majority of patients (57.3 %) had multiple brain lesions. The location of the lesion was cerebellar (30 %), frontal (20 %), parietal (18 %) and occipital (11 %). Extracranial metastasis was present in 49.8 % of cases involving liver (20.7 %), lung (20.4 %), lymph nodes (12.6 %), bones (6.6 %) and pelvic organs (4.3 %). The most common symptoms were weakness (16 %), seizures (11 %), altered mentality (11 %) visual disturbances (9 %) and dizziness (8 %). The interval from diagnosis of breast cancer to BM ranged from 0 to 133 months (median 24 months) and median survival was 8.2 months. Local radiation, surgical resection, stereotactic radiosurgery and medical therapy were used. Factors that significantly increased the survival were younger age at the time of ovarian cancer diagnosis and brain metastasis diagnosis, lower grade of the primary tumor, higher KPS score and multimodality treatment for the brain metastases. Ovarian cancer is a rare cause of brain metastasis. Development of brain metastasis among older patients and lower KPS score correlate with less favorable prognosis. The more prolonged survival after using multimodality treatment for brain metastasis is important due to potential impact on management of brain metastasis in future.

  9. Brain Metastasis in Patients With Adrenocortical Carcinoma: A Clinical Series

    PubMed Central

    Tageja, Nishant; Rosenberg, Avi; Mahalingam, Sowmya; Quezado, Martha; Velarde, Margarita; Edgerly, Maureen; Fojo, Tito

    2015-01-01

    Introduction: Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases. Objective: The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute. Methods: We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available. Results: The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, between 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up. Conclusion: Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario. PMID:25412413

  10. Non-coding RNAs in cancer brain metastasis.

    PubMed

    Wu, Kerui; Sharma, Sambad; Venkat, Suresh; Liu, Keqin; Zhou, Xiaobo; Watabe, Kounosuke

    2016-01-01

    More than 90% of cancer death is attributed to metastatic disease, and the brain is one of the major metastatic sites of melanoma, colon, renal, lung and breast cancers. Despite the recent advancement of targeted therapy for cancer, the incidence of brain metastasis is increasing. One reason is that most therapeutic drugs can't penetrate blood-brain-barrier and tumor cells find the brain as sanctuary site. In this review, we describe the pathophysiology of brain metastases to introduce the latest understandings of metastatic brain malignancies. This review also particularly focuses on non-coding RNAs and their roles in cancer brain metastasis. Furthermore, we discuss the roles of the extracellular vesicles as they are known to transport information between cells to initiate cancer cell-microenvironment communication. The potential clinical translation of non-coding RNAs as a tool for diagnosis and for treatment is also discussed in this review. At the end, the computational aspects of non-coding RNA detection, the sequence and structure calculation and epigenetic regulation of non-coding RNA in brain metastasis are discussed.

  11. Gene Expression Profiling of Breast Cancer Brain Metastasis

    PubMed Central

    Lee, Ji Yun; Park, Kyunghee; Lee, Eunjin; Ahn, TaeJin; Jung, Hae Hyun; Lim, Sung Hee; Hong, Mineui; Do, In-Gu; Cho, Eun Yoon; Kim, Duk-Hwan; Kim, Ji-Yeon; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2016-01-01

    The biology of breast cancer brain metastasis (BCBM) is poorly understood. We aimed to explore genes that are implicated in the process of brain metastasis of primary breast cancer (BC). NanoString nCounter Analysis covering 252 target genes was used for comparison of gene expression levels between 20 primary BCs that relapsed to brain and 41 BCBM samples. PAM50-based intrinsic subtypes such as HER2-enriched and basal-like were clearly over-represented in BCBM. A panel of 22 genes was found to be significantly differentially expressed between primary BC and BCBM. Five of these genes, CXCL12, MMP2, MMP11, VCAM1, and MME, which have previously been associated with tumor progression, angiogenesis, and metastasis, clearly discriminated between primary BC and BCBM. Notably, the five genes were significantly upregulated in primary BC compared to BCBM. Conversely, SOX2 and OLIG2 genes were upregulated in BCBM. These genes may participate in metastatic colonization but not in primary tumor development. Among patient-matched paired samples (n = 17), a PAM50 molecular subtype conversion was observed in eight cases (47.1%), with a trend toward unfavorable subtypes in patients with the distinct gene expression. Our findings, although not conclusive, reveal differentially expressed genes that might mediate the brain metastasis process. PMID:27340107

  12. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine.

    PubMed

    Kircher, David A; Silvis, Mark R; Cho, Joseph H; Holmen, Sheri L

    2016-01-01

    The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases. PMID:27598148

  13. Melanoma Brain Metastasis: Mechanisms, Models, and Medicine

    PubMed Central

    Kircher, David A.; Silvis, Mark R.; Cho, Joseph H.; Holmen, Sheri L.

    2016-01-01

    The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases. PMID:27598148

  14. Brain metastasis detection by resonant Raman optical biopsy method

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-hui; Cheng, Gangge; Zhou, Lixin; Zhang, Chunyuan; Pu, Yang; Li, Zhongwu; Liu, Yulong; Li, Qingbo; Wang, Wei; Alfano, Robert R.

    2014-03-01

    Resonant Raman (RR) spectroscopy provides an effective way to enhance Raman signal from particular bonds associated with key molecules due to changes on a molecular level. In this study, RR is used for detection of human brain metastases of five kinds of primary organs of lung, breast, kidney, rectal and orbital in ex-vivo. The RR spectra of brain metastases cancerous tissues were measured and compared with those of normal brain tissues and the corresponding primary cancer tissues. The differences of five types of brain metastases tissues in key bio-components of carotene, tryptophan, lactate, alanine and methyl/methylene group were investigated. The SVM-KNN classifier was used to categorize a set of RR spectra data of brain metastasis of lung cancerous tissues from normal brain tissue, yielding diagnostic sensitivity and specificity at 100% and 75%, respectively. The RR spectroscopy may provide new moleculebased optical probe tools for diagnosis and classification of brain metastatic of cancers.

  15. Integrated Genomic and Epigenomic Analysis of Breast Cancer Brain Metastasis

    PubMed Central

    Salhia, Bodour; Kiefer, Jeff; Ross, Julianna T. D.; Metapally, Raghu; Martinez, Rae Anne; Johnson, Kyle N.; DiPerna, Danielle M.; Paquette, Kimberly M.; Jung, Sungwon; Nasser, Sara; Wallstrom, Garrick; Tembe, Waibhav; Baker, Angela; Carpten, John; Resau, Jim; Ryken, Timothy; Sibenaller, Zita; Petricoin, Emanuel F.; Liotta, Lance A.; Ramanathan, Ramesh K.; Berens, Michael E.; Tran, Nhan L.

    2014-01-01

    The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies. PMID:24489661

  16. Primary mediastinal choriocarcinoma with brain metastasis in a female patient.

    PubMed

    Kuno, I; Matsumoto, Y; Kasai, M; Fukuda, T; Hashiguchi, Y; Ichimura, T; Yasui, T; Sumi, T

    2016-01-01

    Nongestational choriocarcinoma is very rare and carries a poor prognosis in female patients. In this report, the authors present a case of nongestational choriocarcinoma with brain metastasis in a female. A 58-year-old female with intermittent back pain was referred to a private hospital. On examination, a mediastinal tumor and a pancreatic tumor were detected. Endoscopic ultrasound-guided fine needle aspiration biopsy of the tumor was performed for histological evaluation. Pathological diagnosis was difficult because only a small amount of tissue was collected. Head MRI showed multiple metastatic tumors in the brain. The patient was diagnosed with primary mediastinal choriocarcinoma with brain metastasis. She was treated with one course of an etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine regimen, but her general condition gradually deteriorated, and she died on day 41. Nongestational choriocarcinoma is drug resistant, whereas gestational choriocarcinoma has better chemotherapeutic sensitivity. PMID:27172760

  17. Outcomes in patients with brain metastasis from esophageal carcinoma

    PubMed Central

    Kothari, Nishi; Mellon, Eric; Hoffe, Sarah E.; Frakes, Jessica; Shridhar, Ravi; Pimiento, Jose; Meredith, Ken; Tran, Nam D.; Saeed, Nadia

    2016-01-01

    Background Brain metastases from esophageal carcinoma have historically been rare and associated with poor prognosis. With improvements in systemic disease control, the incidence of brain metastases is expected to rise. To better inform management decisions, we sought to identify factors associated with survival in patients with brain metastasis from esophageal cancer. Methods We retrospectively identified 49 patients with brain metastasis from stage I–IV primary esophageal cancer treated with surgery, radiation, or a combination of modalities at our tertiary referral center between 1998 and 2015. Medical records were reviewed to collect demographic and clinical information. Results Median age at diagnosis of the primary esophageal cancer was 60 years. Forty-one (84%) patients were male and forty patients (82%) had adenocarcinoma. Median overall survival (MS) following esophageal cancer diagnosis was 24 months (range, 3–71 months), and median survival after the identification of brain metastases was 5 months (range, 1–52 months). On univariate analysis, only patients with poor Karnofsky performance status (KPS <70), recursive partitioning analysis (RPA) classification (III), or 3 or more brain metastases were found to have worsened survival after the diagnosis of brain metastases (all P<0.01). Factors not associated with survival were age, gender, histology (adenocarcinoma vs. other), palliative-intent treatment of the primary tumor, time to diagnosis of brain metastases from initial diagnosis, uncontrolled primary tumor at time of brain metastasis diagnosis, or extracranial metastases. On multivariate analysis (MVA, KPS excluded), patients with RPA class I (MS, 14.6 months) or II (MS, 5.0 months) disease had significantly improved overall survival compared to class III disease (MS, 1.6 months, P<0.01). Also on MVA, patients with 1 (MS, 10.7 months) or 2 (MS, 4.7 months) brain metastases had significantly improved overall survival compared to patients with 3

  18. Mouse Models of Brain Metastasis for Unravelling Tumour Progression.

    PubMed

    Soto, Manuel Sarmiento; Sibson, Nicola R

    2016-01-01

    Secondary tumours in the brain account for 40 % of triple negative breast cancer patients, and the percentage may be higher at the time of autopsy. The use of in vivo models allow us to recapitulate the molecular mechanisms potentially used by circulating breast tumour cells to proliferate within the brain.Metastasis is a multistep process that depends on the success of several stages including cell evasion from the primary tumour, distribution and survival within the blood stream and cerebral microvasculature, penetration of the blood-brain barrier and proliferation within the brain microenvironment. Cellular adhesion molecules are key proteins involved in all of the steps in the metastatic process. Our group has developed two different in vivo models to encompass both seeding and colonisation stages of the metastatic process: (1) haematogenous dissemination of tumour cells by direct injection into the left ventricle of the heart, and (2) direct implantation of the tumour cells into the mouse brain.This chapter describes, in detail, the practical implementation of the intracerebral model, which can be used to analyse tumour proliferation within a specific area of the central nervous system and tumour-host cell interactions. We also describe the use of immunohistochemistry techniques to identify, at the molecular scale, tumour-host cell interactions, which may open new windows for brain metastasis therapy.

  19. EGFR and HER2 signaling in breast cancer brain metastasis.

    PubMed

    Sirkisoon, Sherona R; Carpenter, Richard L; Rimkus, Tadas; Miller, Lance; Metheny-Barlow, Linda; Lo, Hui-Wen

    2016-01-01

    Breast cancer occurs in approximately 1 in 8 women and 1 in 37 women with breast cancer succumbed to the disease. Over the past decades, new diagnostic tools and treatments have substantially improved the prognosis of women with local diseases. However, women with metastatic disease still have a dismal prognosis without effective treatments. Among different molecular subtypes of breast cancer, the HER2-enriched and basal-like subtypes typically have higher rates of metastasis to the brain. Basal-like metastatic breast tumors frequently express EGFR. Consequently, HER2- and EGFR-targeted therapies are being used in the clinic and/or evaluated in clinical trials for treating breast cancer patients with brain metastases. In this review, we will first provide an overview of the HER2 and EGFR signaling pathways. The roles that EGFR and HER2 play in breast cancer metastasis to the brain will then be discussed. Finally, we will summarize the preclinical and clinical effects of EGFR- and HER2-targeted therapies on breast cancer metastasis.

  20. Surgical Resection Followed by Whole Brain Radiotherapy Versus Whole Brain Radiotherapy Alone for Single Brain Metastasis

    SciTech Connect

    Rades, Dirk Kieckebusch, Susanne; Haatanen, Tiina; Lohynska, Radka; Dunst, Juergen; Schild, Steven E.

    2008-04-01

    Purpose: To compare the outcome of surgical resection followed by whole brain radiotherapy (WBRT) with WBRT alone in patients treated for single brain metastasis. Methods and Materials: The data from 195 patients with single brain metastases were retrospectively evaluated. Of the 195 patients, 99 underwent resection of the metastasis followed by WBRT and 96 underwent WBRT alone. Seven additional potential prognostic factors were investigated: age, gender, Eastern Cooperative Oncology Group performance score, tumor type, interval between initial tumor diagnosis and WBRT, extracranial metastases, and recursive partitioning analysis class. Both treatment groups were well balanced for these factors. Results: On multivariate analysis, improved survival was associated with resection (relative risk [RR], 1.20; 95% confidence interval [CI], 1.11-1.31; p < 0.001), lower recursive partitioning analysis class (RR, 1.58; 95% CI, 1.22-2.06; p < 0.001), age {<=}61 years (RR, 1.79; 95% CI, 1.23-2.61; p = 0.002), Eastern Cooperative Oncology Group performance score of 0-1 (RR, 2.47; 95% CI, 1.70-3.59; p < 0.001), and the absence of extracranial metastases (RR, 1.99; 95% CI, 1.41-2.79; p < 0.001). Improved local control was associated with resection (RR, 1.25; 95% CI, 1.11-1.41; p < 0.001) and age {<=}61 years (RR, 1.77; 95% CI, 1.09-2.88; p = 0.020). Improved brain control distant from the original site was associated with lower recursive partitioning analysis class (RR, 1.65; 95% CI, 1.03-2.69; p < 0.035), age {<=}61 years (RR, 1.81; 95% CI, 1.12-2.96; p = 0.016), and the absence of extracranial metastases (RR, 2.42; 95% CI, 1.52-3.88; p < 0.001). Improved control within the entire brain was associated with surgery (RR, 1.24; 95% CI, 1.12-1.38; p < 0.001) and age {<=}61 years (RR, 1.83; 95% CI, 1.21-2.77; p = 0.004). Conclusion: In patients with a single brain metastasis, the addition of resection to WBRT improved survival, local control at the original metastatic site, and

  1. Whole-brain radiation therapy of brain metastasis.

    PubMed

    Sahgal, Arjun; Soliman, Hany; Larson, David A

    2012-01-01

    The purpose of this report was to review the role of whole brain radiotherapy (WBRT) in the management of brain metastases. In particular, we review the role of WBRT as a prophylactic therapy, and the role of surgery and stereotactic radiousurgery (SRS) with respect to WBRT, by discussing the relevant randomized controlled trials. WBRT is associated with toxicities and this may influence the decision to use WBRT and, therefore, we review both the acute side effects of WBRT and the more serious late side effects of neurocognitive impairment and leukoencephalopathy. As patients are living longer with brain metastases the role of WBRT is moving forward; however, using modern radiation technology we may be able to reduce the morbidity of this therapy. We present an extreme case of re-re-treatment WBRT with hippocampal sparing and simultaneous integrated boosts to multiple lesions as one of the future directions under evaluation. PMID:22236670

  2. Brain Metastasis-Initiating Cells: Survival of the Fittest

    PubMed Central

    Singh, Mohini; Manoranjan, Branavan; Mahendram, Sujeivan; McFarlane, Nicole; Venugopal, Chitra; Singh, Sheila K.

    2014-01-01

    Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only months. Despite the high rate of BM-associated mortality, very little research is conducted in this area. Lack of research and staggeringly low patient survival is indicative that a novel approach to BMs and their treatment is needed. The ability of a small subset of primary tumor cells to produce macrometastases is reminiscent of brain tumor-initiating cells (BTICs) or cancer stem cells (CSCs) hypothesized to form primary brain tumors. BTICs are considered stem cell-like due to their self-renewal and differentiation properties. Similar to the subset of cells forming metastases, BTICs are most often a rare subpopulation. Based on the functional definition of a TIC, cells capable of forming a BM could be considered to be brain metastasis-initiating cells (BMICs). These putative BMICs would not only have the ability to initiate tumor growth in a secondary niche, but also the machinery to escape the primary tumor, migrate through the circulation, and invade the neural niche. PMID:24857921

  3. Brain metastasis-initiating cells: survival of the fittest.

    PubMed

    Singh, Mohini; Manoranjan, Branavan; Mahendram, Sujeivan; McFarlane, Nicole; Venugopal, Chitra; Singh, Sheila K

    2014-05-22

    Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only months. Despite the high rate of BM-associated mortality, very little research is conducted in this area. Lack of research and staggeringly low patient survival is indicative that a novel approach to BMs and their treatment is needed. The ability of a small subset of primary tumor cells to produce macrometastases is reminiscent of brain tumor-initiating cells (BTICs) or cancer stem cells (CSCs) hypothesized to form primary brain tumors. BTICs are considered stem cell-like due to their self-renewal and differentiation properties. Similar to the subset of cells forming metastases, BTICs are most often a rare subpopulation. Based on the functional definition of a TIC, cells capable of forming a BM could be considered to be brain metastasis-initiating cells (BMICs). These putative BMICs would not only have the ability to initiate tumor growth in a secondary niche, but also the machinery to escape the primary tumor, migrate through the circulation, and invade the neural niche.

  4. Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer.

    PubMed

    Wu, Kerui; Fukuda, Koji; Xing, Fei; Zhang, Yingyu; Sharma, Sambad; Liu, Yin; Chan, Michael D; Zhou, Xiaobo; Qasem, Shadi A; Pochampally, Radhika; Mo, Yin-Yuan; Watabe, Kounosuke

    2015-04-10

    Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis.

  5. αB-crystallin Expression in Breast Cancer is Associated with Brain Metastasis

    PubMed Central

    Voduc, K. David; Nielsen, Torsten O.; Perou, Charles M.; Harrell, J. Chuck.; Fan, Cheng; Kennecke, Hagen; Minn, Andy J.

    2016-01-01

    Background/Objectives The molecular chaperone αB-crystallin is expressed in estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 “triple-negative” breast carcinomas and promotes brain and lung metastasis. We examined αB-crystallin expression in primary breast carcinomas with metastatic data to evaluate its association with prognosis and site-specific metastases. Methods αB-crystallin gene (CRYAB) expression was examined using publically available global-gene expression data (n=855 breast tumors) with first site of distant metastasis information (“855Met”). αB-crystallin protein expression was determined by immunohistochemistry using the clinically annotated tissue microarray (n=3987 breast tumors) from British Columbia Cancer Agency (BCCA). Kaplan-Meier and multivariable Cox regression analyses were used to evaluate the prognostic value of αB-crystallin. Multivariable logistic regression analysis was used to evaluate risks of αB-crystallin and other markers for site of metastasis. Results In the 855Met dataset, αB-crystallin gene (CRYAB) expression was an independent predictor of brain as the first distant site of relapse (HR = 1.2, (95% CI 1.0-1.4), P = 0.021). In the BCCA series, αB-crystallin protein expression was an independent prognostic marker of poor breast cancer specific survival (HR = 1.3, (95% CI 1.1-1.6), P = 0.014). Among patients with metastases, αB-crystallin was the strongest independent predictor of brain metastasis (OR = 2.99 (95% CI 1.83-4.89), P < 0.0001) and the only independent predictor of brain as the first site of distant metastasis (OR = 3.15 (95% CI1.43-6.95), P = 0.005). αB-crystallin was also associated with worse survival (3.0 versus 4.7 months, P = 0.007). Conclusions αB-crystallin is a promising biomarker to identify breast cancer patients at high risk for early relapse in the brain, independent of ER and HER2 status.

  6. Serpins promote cancer cell survival and vascular co-option in brain metastasis.

    PubMed

    Valiente, Manuel; Obenauf, Anna C; Jin, Xin; Chen, Qing; Zhang, Xiang H-F; Lee, Derek J; Chaft, Jamie E; Kris, Mark G; Huse, Jason T; Brogi, Edi; Massagué, Joan

    2014-02-27

    Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

  7. Epigenomic landscape of melanoma progression to brain metastasis: unexplored therapeutic alternatives.

    PubMed

    Marzese, Diego M; Witz, Isaac P; Kelly, Daniel F; Hoon, Dave S B

    2015-01-01

    Melanoma brain metastasis is a complication with rising incidence. Despite the high rate of somatic mutations driving the initial stages of melanocyte transformation, the brain colonization requires a phenotypic reprogramming that is, in part, influenced by epigenomic modifications. This special report summarizes recent findings in the epigenomic landscape of melanoma progression to brain metastasis, with particular emphasis on the clinical utility of DNA methylation, chromatin modifications and ncRNA expression as theragnostic markers, as well as the significance of the metastatic microenvironment on melanoma brain metastasis epigenome.

  8. [Complete remission of brain metastasis of bladder cancer treated by M-VAC therapy].

    PubMed

    Nakagawa, S; Nakao, M; Toyoda, K; Nukui, M; Takada, H; Ebisui, K

    1989-02-01

    A case of brain metastasis from transitional cell carcinoma of the bladder that attained complete remission by methotrexate-vinblastine-adriamycin-cisplatin (M-VAC) therapy was reported. The patient was a 53-year-old male, already treated with total cystectomy and CAP therapy against pulmonary metastasis, which disappeared completely. At 8 months after complete remission of pulmonary metastasis, brain metastasis was found. One course of M-VAC therapy brought a complete remission persisting for 7 months. He is alive with no relapse.

  9. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S.

    PubMed

    Sevenich, Lisa; Bowman, Robert L; Mason, Steven D; Quail, Daniela F; Rapaport, Franck; Elie, Benelita T; Brogi, Edi; Brastianos, Priscilla K; Hahn, William C; Holsinger, Leslie J; Massagué, Joan; Leslie, Christina S; Joyce, Johanna A

    2014-09-01

    Metastasis remains the most common cause of death in most cancers, with limited therapies for combating disseminated disease. While the primary tumour microenvironment is an important regulator of cancer progression, it is less well understood how different tissue environments influence metastasis. We analysed tumour-stroma interactions that modulate organ tropism of brain, bone and lung metastasis in xenograft models. We identified a number of potential modulators of site-specific metastasis, including cathepsin S as a regulator of breast-to-brain metastasis. High cathepsin S expression at the primary site correlated with decreased brain metastasis-free survival in breast cancer patients. Both macrophages and tumour cells produce cathepsin S, and only the combined depletion significantly reduced brain metastasis in vivo. Cathepsin S specifically mediates blood-brain barrier transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B. Pharmacological inhibition of cathepsin S significantly reduced experimental brain metastasis, supporting its consideration as a therapeutic target for this disease.

  10. Pertuzumab, trastuzumab and docetaxel reduced the recurrence of brain metastasis from breast cancer: a case report.

    PubMed

    Senda, Noriko; Yamaguchi, Ayane; Nishimura, Hideaki; Shiozaki, Toshiki; Tsuyuki, Shigeru

    2016-03-01

    The CLEOPATRA trial reported the survival benefit of pertuzumab with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients. However, there are a few case reports concerning the effects of a pertuzumab-containing regimen on brain metastases. A 55-year-old woman, who underwent curative surgery for breast cancer after neoadjuvant chemotherapy 5 years previously, developed repeated solitary brain metastasis in her right occipital lobe. Whole brain radiation therapy, stereotactic radiosurgery and 3 times of surgical resection were performed. Lapatinib and capecitabine plus tamoxifen were administered. The metastasis recurred in the stump of the previous surgery. Pertuzumab with trastuzumab plus docetaxel was initiated as second-line chemotherapy. A complete response of the brain metastasis was achieved, which persisted for 5 months. Pertuzumab with trastuzumab plus docetaxel was effective in reducing the brain metastases from breast cancer. Further studies are warranted to confirm the effect of this regimen on brain metastases.

  11. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain.

    PubMed

    Chen, Jinyu; Lee, Ho-Jeong; Wu, Xuefeng; Huo, Lei; Kim, Sun-Jin; Xu, Lei; Wang, Yan; He, Junqing; Bollu, Lakshmi R; Gao, Guang; Su, Fei; Briggs, James; Liu, Xiaojing; Melman, Tamar; Asara, John M; Fidler, Isaiah J; Cantley, Lewis C; Locasale, Jason W; Weihua, Zhang

    2015-02-01

    Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells, but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the nonoxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBP) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients.

  12. Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation.

    PubMed

    Wolff, Gretchen; Davidson, Sarah J; Wrobel, Jagoda K; Toborek, Michal

    2015-08-01

    Tumor cell extravasation into the brain requires passage through the blood-brain barrier, which is a highly protected microvascular environment fortified with tight junction (TJ) proteins. TJ integrity can be regulated under physiological and pathophysiological conditions. There is evidence that exercise can modulate oxidation status within the brain microvasculature and protect against tumor cell extravasation and metastasis formation. In order to study these events, mature male mice were given access to voluntary exercise on a running wheel (exercise) or access to a locked wheel (sedentary) for five weeks. The average running distance was 9.0 ± 0.2 km/day. Highly metastatic tumor cells (murine Lewis lung carcinoma) were then infused into the brain microvasculature through the internal carotid artery. Analyses were performed at early stage (48 h) and late stage (3 weeks) post tumor cell infusion. Immunohistochemical analysis revealed fewer isolated tumor cells extravasating into the brain at both 48 h and 3 weeks post surgery in exercised mice. Occludin protein levels were reduced in the sedentary tumor group, but maintained in the exercised tumor group at 48 h post tumor cell infusion. These results indicate that voluntary exercise may participate in modulating blood-brain barrier integrity thereby protecting the brain during metastatic progression.

  13. Brain metastasis from a lung mucoepidermoid carcinoma mimicking a brain abscess

    PubMed Central

    Saito, Taiichi; Ujiie, Hiroshi; Kadoyama, Shigeru; Higa, Takashi; Shiono, Saori; Teramoto, Akira

    2015-01-01

    Background: Mucoepidermoid carcinoma (MEC) is a rare tumor of the lung that accounts for 0.1–0.2% of all pulmonary tumors. To the best of our knowledge, brain metastasis from lung MEC is rare and magnetic resonance imaging (MRI) findings of this lesion have not been documented. Case Description: We herein report the case of a 72-year-old male. MRI revealed a left parietal tumor showing ring enhancement with medium gadolinium contrast and an evident high intensity area in the nonenhanced central portion on diffusion-weighted images (DWI) mimicking a brain abscess. Histologically, MEC is composed of a mixture of different cell types including mucin-secreting glandular cells and squamous cells. Accordingly, we suggest that the high DWI signal can be explained by the development of intracellular and intraluminal mucin, which have a high viscosity. Conclusion: Further accumulation of cases with brain metastasis from MEC is needed to establish the characteristic image findings, which would lead to prompt and adequate treatment. PMID:26167374

  14. A case report of gastric cancer with brain metastasis: Rare peripheral nervous system symptoms

    PubMed Central

    YANG, GE-LIANG; LUO, TIAN-HANG; ZHANG, HUI-QING; LING, CHANG-QUAN; LI, BAI

    2016-01-01

    Gastric cancer with brain metastasis is rare. The present study reports a case of gastric cancer with isolated brain metastasis 1 year after gastrectomy. To the best of our knowledge, there have been no prior reports of solitary brain metastasis from gastric cancer with peripheral nervous system symptoms. A distal gastrectomy was performed on a 60-year-old male patient with gastric cancer in November 2012. Postoperative pathological analysis revealed a moderately differentiated adenocarcinoma with tumor invasion into the serosa and metastasis to one dissected lymph node. No abnormalities were found at follow-up examination. However, a tumor representing metastasis to the brain was recognized by a cranial enhanced magnetic resonance imaging examination 1 year after gastrectomy, which was performed when the patient exhibited numbness and thigmesthesia. The patient was administered 30 Gy of stereotactic radiotherapy, delivered in 5 fractions. The patient succumbed to disease 10 months subsequent to undergoing radiotherapy. This case report suggests that gastric cancer may re-present as brain metastasis with peripheral nervous system symptoms. PMID:27073571

  15. Tumor-targeting Salmonella typhimurium A1-R arrests growth of breast-cancer brain metastasis.

    PubMed

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

    2015-02-20

    Brain metastasis is a morbid, treatment-resistant, end-stage frequent occurrence in breast cancer patients. The aim of this study was to evaluate the efficacy of tumor-targeting Salmonella typhimurium A1-R on breast cancer brain metastases. High brain-metastatic variants of murine 4T1 breast cancer cells expressing red fluorescent protein (RFP) were injected orthotopically in the mammary fat pad in non-transgenic nude mice or in the left ventricle of non-transgenic nude mice and transgenic nude mice expressing nestin-driven green fluorescent protein (ND-GFP). ND-GFP mice express GFP in nascent blood vessels. In the orthotopically-injected mice, the primary tumor was surgically-resected in order to allow brain metastasis to develop. At various time points, the tumors and vasculature in the brain were imaged by confocal and stereo fluorescence microscopy. Some of the breast cancer cells that reached the brain extravasated and grew perivascularly and some of the cells proliferated within the vasculature. S. typhimurium A1-R significantly inhibited brain metastasis in both metastatic models and increased survival of the orthotopically-transplanted, primary-tumor-resected mice (p<0.05). The results of the present study suggest the clinical potential of bacterial therapy of breast cancer brain metastasis.

  16. Metastasis

    SciTech Connect

    Weller, R.E.

    1991-10-01

    Distant metastasis of primary neoplasms is the main factor that limits the success of antineoplastic therapy. It can be regarded as an early or late event in the neoplastic process, and varies considerably with tumor type. The metastatic potential of a given tumor greatly influences prognosis. Tumor metastasis is not a single neoplastic event, rather, it involves several major steps: invasion of cells from the primary tumor into tissue, and penetration of blood and lymph vessels; release of tumor cell emboli into the circulation; arrest of the emboli in capillary beds of distant organs; invasion of the wall of the arresting vessel, infiltration into adjacent tissue, and multiplication; and growth of vascularized stroma into the new tumor as proliferating tumor cells invade the distant organ. Lodgement and invasion are complex events that are not fully defined. Arrest and lodgement appears to require a thromboembolic event in which the metastatic embolis (1 cell) contacts vascular endothelium and adheres to the wall with thrombis formation following aggregation of platelets and fibrin to the tumor cell(s). Invasion may involve: formation of collagenases by tumor cells; mechanical disruption; chemotactic factors. Metastatic patterns depend on the route of metastasis, tumor type, and target organ (favored soil). In general, carcinomas metastasize via lymphatics and sarcomas via hematogenous routes. Others, melanoma, mast cell tumors, etc., show mixed patterns. This knowledge is important when one is attempting to prognostically stage a tumor, especially when thoracic radiographs are negative. The question of enlarged regional lymph nodes will be discussed in lecture relative to specific tumor types. 4 refs., 1 tab.

  17. Brain metastasis in lung cancer: Building a molecular and systems-level understanding to improve outcomes.

    PubMed

    Ebben, Johnathan D; You, Ming

    2016-09-01

    Lung cancer is a clinically difficult disease with rising disease burden around the world. Unfortunately, most lung cancers present at a clinically advanced stage. Of these cancers, many also present with brain metastasis which complicates the clinical picture. This review summarizes current knowledge on the molecular basis of lung cancer brain metastases. We start from the clinical perspective, aiming to provide a clinical context for a significant problem that requires much deeper scientific investigation. We review new research governing the metastatic process, including tumor cell signaling, establishment of a receptive tumor niches in the brain and evaluate potential new therapeutic options that take advantage of these new scientific advances. Lung cancer remains the largest single cause of cancer mortality in the United States (Siegel et al., 2015). This continues to be the clinical picture despite significant advances in therapy, including the advent of targeted molecular therapies and newly adopted immunotherapies for certain subtypes of lung cancer. In the vast majority of cases, lung cancer presents as advanced disease; in many instances, this advanced disease state is intimately associated with micro and macrometastatic disease (Goldberg et al., 2015). For both non-small cell lung cancer and small cell lung cancer patients, the predominant metastatic site is the brain, with up to 68% of patients with mediastinal lymph node metastasis eventually demonstrating brain metastasis (Wang et al., 2009).The frequency (incidence) of brain metastasis is highest in lung cancers, relative to other common epithelial malignancies (Schouten et al., 2002). Other studies have attempted to predict the risk of brain metastasis in the setting of previously non-metastatic disease. One of the largest studies to do this, analyzing historical data from 1973 to 2011 using the SEER database revealed a 9% risk of patients with previously non-metastatic NSCLC developing brain

  18. Pathogenesis of Breast Cancer Metastasis to Brain: a Comprehensive Approach to the Signaling Network.

    PubMed

    Tayyeb, Bahrami; Parvin, Mehdipour

    2016-01-01

    There is a general consensus that breast cancer is a rising trend disease in the world. It is one of the most common cancer types and is the leading cause of death among women's cancers. There are several reasons for this high rate of mortality including metastasis which is responsible for about 90 % of cancer-related mortality. Therefore, recognition and understanding of metastatic process is important, and by considering the key role of pathophysiological route in metastasis as a multistep cascade of "invasion-metastasis," it might modify and improve our insight toward this complex phenomenon. Moreover, it can provide novel approaches for designing advanced targeted therapies. The present work aimed to review the published papers regarding molecular basis of metastatic process of breast cancer to brain metastasis, especially related genes and signaling network. Furthermore, the use of molecular aspects of metastatic breast cancer to brain was discussed in horizon of future treatment of breast cancer.

  19. Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer.

    PubMed

    Lee, Ji Yun; Park, Kyunghee; Lim, Sung Hee; Kim, Hae Su; Yoo, Kwai Han; Jung, Ki Sun; Song, Haa-Na; Hong, Mineui; Do, In-Gu; Ahn, TaeJin; Lee, Se Kyung; Bae, Soo Youn; Kim, Seok Won; Lee, Jeong Eon; Nam, Seok Jin; Kim, Duk-Hwan; Jung, Hae Hyun; Kim, Ji-Yeon; Ahn, Jin Seok; Im, Young-Hyuck; Park, Yeon Hee

    2015-12-22

    Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple-negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0-7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment.

  20. Serpins promote cancer cell survival and vascular co-option in brain metastasis.

    PubMed

    Valiente, Manuel; Obenauf, Anna C; Jin, Xin; Chen, Qing; Zhang, Xiang H-F; Lee, Derek J; Chaft, Jamie E; Kris, Mark G; Huse, Jason T; Brogi, Edi; Massagué, Joan

    2014-02-27

    Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers. PMID:24581498

  1. Epigenetic silencing of miR-145-5p contributes to brain metastasis

    PubMed Central

    Donzelli, Sara; Mori, Federica; Bellissimo, Teresa; Sacconi, Andrea; Casini, Beatrice; Frixa, Tania; Roscilli, Giuseppe; Aurisicchio, Luigi; Facciolo, Francesco; Pompili, Alfredo; Carosi, Maria Antonia; Pescarmona, Edoardo; Segatto, Oreste; Pond, Greg; Muti, Paola; Telera, Stefano; Strano, Sabrina; Yarden, Yosef; Blandino, Giovanni

    2015-01-01

    Brain metastasis is a major cause of morbidity and mortality of lung cancer patients. We assessed whether aberrant expression of specific microRNAs could contribute to brain metastasis. Comparison of primary lung tumors and their matched metastatic brain disseminations identified shared patterns of several microRNAs, including common down-regulation of miR-145-5p. Down-regulation was attributed to methylation of miR-145's promoter and affiliated elevation of several protein targets, such as EGFR, OCT-4, MUC-1, c-MYC and, interestingly, tumor protein D52 (TPD52). In line with these observations, restored expression of miR-145-5p and selective depletion of individual targets markedly reduced in vitro and in vivo cancer cell migration. In aggregate, our results attribute to miR-145-5p and its direct targets pivotal roles in malignancy progression and in metastasis. PMID:26440147

  2. Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy

    PubMed Central

    Martínez-Aranda, Antonio; Hernández, Vanessa; Picón, Cristina; Modolell, Ignasi; Sierra, Angels

    2013-01-01

    Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents. PMID:23591844

  3. [Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis].

    PubMed

    Song, Qi; Jiao, Shunchang; Li, Fang

    2016-08-20

    Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients' quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work. PMID:27561803

  4. Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis.

    PubMed

    Liu, Yi; Liu, Yong-Shuo; Wu, Peng-Fei; Li, Qiang; Dai, Wu-Min; Yuan, Shuai; Xu, Zhi-Hua; Liu, Ting-Ting; Miao, Zi-Wei; Fang, Wen-Gang; Chen, Yu-Hua; Li, Bo

    2015-09-01

    Small cell lung cancer is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing to brain early. However, the cellular and molecular basis is poorly known. Here, we provided evidence to reveal the role of annexin A1 in small cell lung cancer metastasis to brain. Firstly, the elevated annexin A1 serum levels in small cell lung cancer patients were associated with brain metastasis. The levels of annexin A1 were also upregulated in NCI-H446 cells, a small cell lung cancer cell line, upon migration into the mice brain. More interestingly, annexin A1 was secreted by NCI-H446 cells in a time-dependent manner when co-culturing with human brain microvascular endothelial cells, which was identified with the detections of annexin A1 in the co-cultured cellular supernatants by ELISA and western blot. Further results showed that blockage of annexin A1 in the co-cultured cellular supernatants using a neutralized antibody significantly inhibited NCI-H446 cells adhesion to brain endothelium and its transendothelial migration. Conversely, the addition of Ac2-26, an annexin A1 mimic peptide, enhanced these effects. Furthermore, knockdown of annexin A1 in NCI-H446 cells prevented its transendothelial migration in vitro and metastasis to mice brain in vivo. Our data showed that small cell lung cancer cell in brain microvasculature microenvironment could express much more annexin A1 and release it outside, which facilitated small cell lung cancer cell to gain malignant properties of entry into brain. These findings provided a potential target for the management of SCLC brain metastasis. PMID:26135980

  5. Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis.

    PubMed

    Liu, Yi; Liu, Yong-Shuo; Wu, Peng-Fei; Li, Qiang; Dai, Wu-Min; Yuan, Shuai; Xu, Zhi-Hua; Liu, Ting-Ting; Miao, Zi-Wei; Fang, Wen-Gang; Chen, Yu-Hua; Li, Bo

    2015-09-01

    Small cell lung cancer is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing to brain early. However, the cellular and molecular basis is poorly known. Here, we provided evidence to reveal the role of annexin A1 in small cell lung cancer metastasis to brain. Firstly, the elevated annexin A1 serum levels in small cell lung cancer patients were associated with brain metastasis. The levels of annexin A1 were also upregulated in NCI-H446 cells, a small cell lung cancer cell line, upon migration into the mice brain. More interestingly, annexin A1 was secreted by NCI-H446 cells in a time-dependent manner when co-culturing with human brain microvascular endothelial cells, which was identified with the detections of annexin A1 in the co-cultured cellular supernatants by ELISA and western blot. Further results showed that blockage of annexin A1 in the co-cultured cellular supernatants using a neutralized antibody significantly inhibited NCI-H446 cells adhesion to brain endothelium and its transendothelial migration. Conversely, the addition of Ac2-26, an annexin A1 mimic peptide, enhanced these effects. Furthermore, knockdown of annexin A1 in NCI-H446 cells prevented its transendothelial migration in vitro and metastasis to mice brain in vivo. Our data showed that small cell lung cancer cell in brain microvasculature microenvironment could express much more annexin A1 and release it outside, which facilitated small cell lung cancer cell to gain malignant properties of entry into brain. These findings provided a potential target for the management of SCLC brain metastasis.

  6. Control of the blood-brain barrier function in cancer cell metastasis.

    PubMed

    Blecharz, Kinga G; Colla, Ruben; Rohde, Veit; Vajkoczy, Peter

    2015-10-01

    Cerebral metastases are the most common brain neoplasms seen clinically in the adults and comprise more than half of all brain tumours. Actual treatment options for brain metastases that include surgical resection, radiotherapy and chemotherapy are rarely curative, although palliative treatment improves survival and life quality of patients carrying brain-metastatic tumours. Chemotherapy in particular has also shown limited or no activity in brain metastasis of most tumour types. Many chemotherapeutic agents used systemically do not cross the blood-brain barrier (BBB), whereas others may transiently weaken the BBB and allow extravasation of tumour cells from the circulation into the brain parenchyma. Increasing evidence points out that the interaction between the BBB and tumour cells plays a key role for implantation and growth of brain metastases in the central nervous system. The BBB, as the tightest endothelial barrier, prevents both early detection and treatment by creating a privileged microenvironment. Therefore, as observed in several in vivo studies, precise targetting the BBB by a specific transient opening of the structure making it permeable for therapeutic compounds, might potentially help to overcome this difficult clinical problem. Moreover, a better understanding of the molecular features of the BBB, its interrelation with metastatic tumour cells and the elucidation of cellular mechanisms responsible for establishing cerebral metastasis must be clearly outlined in order to promote treatment modalities that particularly involve chemotherapy. This in turn would substantially expand the survival and quality of life of patients with brain metastasis, and potentially increase the remission rate. Therefore, the focus of this review is to summarise the current knowledge on the role and function of the BBB in cancer metastasis.

  7. DNA Double-Strand Break Repair Genes and Oxidative Damage in Brain Metastasis of Breast Cancer

    PubMed Central

    Evans, Lynda; Duchnowska, Renata; Reed, L. Tiffany; Palmieri, Diane; Qian, Yongzhen; Badve, Sunil; Sledge, George; Gril, Brunilde; Aladjem, Mirit I.; Fu, Haiqing; Flores, Natasha M.; Gökmen-Polar, Yesim; Biernat, Wojciech; Szutowicz-Zielińska, Ewa; Mandat, Tomasz; Trojanowski, Tomasz; Och, Waldemar; Czartoryska-Arlukowicz, Bogumiła; Jassem, Jacek; Mitchell, James B.

    2014-01-01

    Background Breast cancer frequently metastasizes to the brain, colonizing a neuro-inflammatory microenvironment. The molecular pathways facilitating this colonization remain poorly understood. Methods Expression profiling of 23 matched sets of human resected brain metastases and primary breast tumors by two-sided paired t test was performed to identify brain metastasis–specific genes. The implicated DNA repair genes BARD1 and RAD51 were modulated in human (MDA-MB-231-BR) and murine (4T1-BR) brain-tropic breast cancer cell lines by lentiviral transduction of cDNA or short hairpin RNA (shRNA) coding sequences. Their functional contribution to brain metastasis development was evaluated in mouse xenograft models (n = 10 mice per group). Results Human brain metastases overexpressed BARD1 and RAD51 compared with either matched primary tumors (1.74-fold, P < .001; 1.46-fold, P < .001, respectively) or unlinked systemic metastases (1.49-fold, P = .01; 1.44-fold, P = .008, respectively). Overexpression of either gene in MDA-MB-231-BR cells increased brain metastases by threefold to fourfold after intracardiac injections, but not lung metastases upon tail-vein injections. In 4T1-BR cells, shRNA-mediated RAD51 knockdown reduced brain metastases by 2.5-fold without affecting lung metastasis development. In vitro, BARD1- and RAD51-overexpressing cells showed reduced genomic instability but only exhibited growth and colonization phenotypes upon DNA damage induction. Reactive oxygen species were present in tumor cells and elevated in the metastatic neuro-inflammatory microenvironment and could provide an endogenous source of genotoxic stress. Tempol, a brain-permeable oxygen radical scavenger suppressed brain metastasis promotion induced by BARD1 and RAD51 overexpression. Conclusions BARD1 and RAD51 are frequently overexpressed in brain metastases from breast cancer and may constitute a mechanism to overcome reactive oxygen species–mediated genotoxic stress in the metastatic

  8. Management of brain metastasis: past lessons, modern management, and future considerations.

    PubMed

    Koay, Eugene; Sulman, Erik P

    2012-02-01

    Brain metastasis is a major challenge for patients, physicians, and the broader health care system, with approximately 170,000 new cases per year. After a diagnosis of brain metastasis, patients have a poor prognosis, but modern management has made significant advances in the past two decades to improve palliative efficacy and patient survival through a multidisciplinary approach. A number of factors must be taken into consideration in the treatment approach, including the number of intracranial lesions, the control of extracranial disease, and the patient's overall health, while weighing the benefits of treatment against the toxicities, both acute and chronic. With quality of life as an emphasis, emerging concepts for modern management of brain metastasis have sought to minimize long-term toxicities. The economic impact of such strategies for patients and the health care system has been demonstrated in some studies, but has not been a consistent area of focus. Each of these strategies, as well as novel therapeutics, has embraced the concept of personalized treatment. This review will discuss the current knowledge of modern multidisciplinary management of brain metastasis and look forward to emerging concepts.

  9. Brain metastasis from pheochromocytoma in a patient with multiple endocrine neoplasia type 2A.

    PubMed

    Gentile, S; Rainero, I; Savi, L; Rivoiro, C; Pinessi, L

    2001-12-01

    Neurological involvement in multiple endocrine neoplasia (MEN) syndrome is uncommon. Notalgia paresthetica (pruritus localized in an area between D2 and D6 dermatomes) is the neurological symptom more frequently described in patients with MEN 2A. The authors report the unusual case of a MEN 2A patient with a brain metastasis from a pheochromocytoma. PMID:11677427

  10. Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation

    PubMed Central

    Li, Jin-Rui; Zhang, Ye

    2016-01-01

    Background The brain is a metastatic organ that is most prone to lung adenocarcinoma (LAC). However, the prognosis of patients with brain metastasis remains very poor. In this study, we evaluated the efficacy of icotinib plus whole brain radiation therapy (WBRT) for treating patients with brain metastasis from epidermal growth factor receptor (EGFR)-mutated LAC. Methods All patients received standard WBRT administered to the whole brain in 30 Gy in 10 daily fractions. Each patient was also instructed to take 125 mg icotinib thrice per day beginning from the first day of the WBRT. After completing the WBRT, maintenance icotinib was administered until the disease progressed or intolerable adverse effects were observed. Cranial progression-free survival (CPFS) and overall survival (OS) times were the primary endpoints. Results A total of 43 patients were enrolled in this study. Two patients (4.7%) presented a complete response (CR), whereas 20 patients (46.5%) presented a partial response (PR). The median CPFS and OS times were 11.0 and 15.0 months, respectively. The one-year CPFS rate was 40.0% for the patients harboring EGFR exon 19 deletion and 16.7% for the patients with EGFR exon 21 L858R (P=0.027). Conclusions The concurrent administration of icotinib and WBRT exhibited favorable effects on the patients with brain metastasis. EGFR exon 19 deletion was predictive of a long CPFS following icotinib plus WBRT. PMID:27499937

  11. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer.

    PubMed

    Chen, Qing; Boire, Adrienne; Jin, Xin; Valiente, Manuel; Er, Ekrem Emrah; Lopez-Soto, Alejandro; Jacob, Leni S; Patwa, Ruzeen; Shah, Hardik; Xu, Ke; Cross, Justin R; Massagué, Joan

    2016-05-26

    Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions meclofenamate and tonabersat break this paracrine loop, and we provide proof-of-principle that these drugs could be used to treat established brain metastasis. PMID:27225120

  12. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain

    PubMed Central

    Chen, Jinyu; Lee, Ho-Jeong; Wu, Xuefeng; Huo, Lei; Kim, Sun-Jin; Xu, Lei; Wang, Yan; He, Junqing; Bollu, Lakshmi Reddy; Gao, Guang; Su, Fei; Briggs, James; Liu, Xiaojing; Melman, Tamar; Asara, John M.; Fidler, Isaiah J.; Cantley, Lewis C.; Locasale, Jason W.; Weihua, Zhang

    2014-01-01

    Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain-metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the non-oxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBPs) in brain metastatic cells reduced their viability and improved the survival of metastasis-bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis, and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients. PMID:25511375

  13. [Brain metastasis from papillary thyroid carcinoma with acute intracerebral hemorrhage: a surgical case report].

    PubMed

    Chonan, Masashi; Mino, Masaki; Yoshida, Masahiro; Sakamoto, Kazuhiro

    2012-05-01

    We report a rare case of brain metastasis from papillary thyroid carcinoma with intracerebral hemorrhage. A 79-year-old woman presented with sudden headache and monoplegia of the right upper limb 10 years after diagnosis of thyroid papillary adenocarcinoma. Despite the known metastatic lesions in the cervical lymph nodes and lungs, she had been well for 10 years since thyroidectomy, focal irradiation and internal radiation of 131I. CT demonstrated intracerebral hemorrhage in the left temporal lobe. Magnetic resonance imaging showed marked signal heterogeneity. She underwent radical surgery on the day of the onset and the histological diagnosis was metastatic brain tumor of thyroid papillary carcinoma. Postoperative course was uneventful, and the monoplegia was improved. Papillary thyroid carcinoma has a relatively benign course, and surgical removal of the brain metastasis is able to contribute to longer survival times for patients.

  14. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth.

    PubMed

    Zhang, Lin; Zhang, Siyuan; Yao, Jun; Lowery, Frank J; Zhang, Qingling; Huang, Wen-Chien; Li, Ping; Li, Min; Wang, Xiao; Zhang, Chenyu; Wang, Hai; Ellis, Kenneth; Cheerathodi, Mujeeburahiman; McCarty, Joseph H; Palmieri, Diane; Saunus, Jodi; Lakhani, Sunil; Huang, Suyun; Sahin, Aysegul A; Aldape, Kenneth D; Steeg, Patricia S; Yu, Dihua

    2015-11-01

    The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during

  15. Management of solitary metastasis to the brain: the role of elective brain irradiation following complete surgical resection. [/sup 60/Co; x-rays

    SciTech Connect

    Dosoretz, D.E.; Blitzer, P.H.; Russell, A.H.; Wang, C.C.

    1980-12-01

    We examined the records of 33 patients who presented with the clinico-radiological diagnosis of solitary brain metastasis and no other evidence of tumor dissemination. Length of survival of patients and patterns of treatment failure were analyzed according to the treatment modalities that were used. Both groups were comparable regarding major parameters that affect response and survival in patients with brain metastasis. There did not appear to be any significant advantage to the use of irradiation following excision, at least at the doses employed in this study. We advocate the use of higher doses of irradiation in any curative attempt following total excision of a solitary brain metastasis.

  16. SU-E-T-56: Brain Metastasis Treatment Plans for Contrast-Enhanced Synchrotron Radiation Therapy

    SciTech Connect

    Obeid, L; Adam, J; Tessier, A; Vautrin, M; Benkebil, M; Sihanath, R

    2014-06-01

    Purpose: Iodine-enhanced radiotherapy is an innovative treatment combining the selective accumulation of an iodinated contrast agent in brain tumors with irradiations using monochromatic medium energy x-rays. The aim of this study is to compare dynamic stereotactic arc-therapy and iodineenhanced SSRT. Methods: Five patients bearing brain metastasis received a standard helical 3D-scan without iodine. A second scan was acquired 13 min after an 80 g iodine infusion. Two SSRT treatment plans (with/without iodine) were performed for each patient using a dedicated Monte Carlo (MC) treatment planning system (TPS) based on the ISOgray TPS. Ten coplanar beams (6×6 cm2, shaped with collimator) were simulated. MC statistical error objective was less than 5% in the 50% isodose. The dynamic arc-therapy plan was achieved on the Iplan Brainlab TPS. The treatment plan validation criteria were fixed such that 100% of the prescribed dose is delivered at the beam isocentre and the 70% isodose contains the whole target volume. The comparison elements were the 70% isodose volume, the average and maximum doses delivered to organs at risk (OAR): brainstem, optical nerves, chiasma, eyes, skull bone and healthy brain parenchyma. Results: The stereotactic dynamic arc-therapy remains the best technique in terms of dose conformation. Iodine-enhanced SSRT presents similar performances to dynamic arc-therapy with increased brainstem and brain parenchyma sparing. One disadvantage of SSRT is the high dose to the skull bone. Iodine accumulation in metastasis may increase the dose by 20–30%, allowing a normal tissue sparing effect at constant prescribed dose. Treatment without any iodine enhancement (medium-energy stereotactic radiotherapy) is not relevant with degraded HDVs (brain, parenchyma and skull bone) comparing to stereotactic dynamic arc-therapy. Conclusion: Iodine-enhanced SSRT exhibits a good potential for brain metastasis treatment regarding the dose distribution and OAR criteria.

  17. Afatinib in Treatment-Naive Patients With EGFR-Mutated Lung Adenocarcinoma With Brain Metastasis: A Case Series.

    PubMed

    Li, Shih-Hong; Hsieh, Meng-Heng; Fang, Yueh-Fu

    2015-10-01

    Tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) were previously the standard first-line treatments for lung cancers with activating EGFR mutations. The first-generation reversible EGFR TKIs, gefitinib and erlotinib, demonstrated substantial efficacy in the treatment of brain metastases from EGFR-mutated lung adenocarcinoma. However, the efficacy of afatinib, the second-generation irreversible EGFR TKI, as the first-line treatment in lung adenocarcinoma patients with brain metastasis has yet to be evaluated.Here, we report cases of 3 patients who received afatinib alone as the first-line treatment in combination with whole-brain radiotherapy or following surgical resection of brain metastases. All 3 patients had EGFR L858R mutation. The first patient had lung adenocarcinoma with brain metastasis and no neurologic symptoms. After consultation, she received afatinib as a first-line treatment. Chest computed tomography and brain magnetic resonance imaging (MRI) showed partial response. The second patient had lung adenocarcinoma accompanied with a metastatic brain lesion associated with seizures. This patient received whole-brain radiotherapy and afatinib treatment following brain MRI and subsequently showed significant regression of the brain metastasis. The third patient had strabismus of the right eye, and brain MRI showed a single tumor at the cerebellar pontine angle. This patient underwent surgical resection of the tumor followed by afatinib treatment. He refused adjuvant radiotherapy after surgery for brain metastasis. The brain MRI showed no recurrent brain metastasis, and the patient had relatively less neurologic deficiency.This series of 3 cases indicate that afatinib may be an appropriate first-line treatment alternative in patients having lung adenocarcinoma with EGFR mutations. Further retrospective analyses and prospective clinical trials are required to substantiate the efficacy of afatinib in the treatment of brain

  18. Low Expression of Slit2 and Robo1 is Associated with Poor Prognosis and Brain-specific Metastasis of Breast Cancer Patients.

    PubMed

    Qin, Fengxia; Zhang, Huikun; Ma, Li; Liu, Xiaoli; Dai, Kun; Li, Wenliang; Gu, Feng; Fu, Li; Ma, Yongjie

    2015-09-24

    Brain metastasis is a significant unmet clinical problem in breast cancer treatment. It is always associated with poor prognosis and high morbidity. Recently, Slit2/Robo1 pathway has been demonstrated to be involved in the progression of breast carcinoma. However, until present, there are no convincing reports that suggest whether the Slit2/Robo1 axis has any role in brain metastasis of breast cancer. In this study, we investigated the correlation between Slit2/Robo1 signaling and breast cancer brain metastasis for the first time. Our results demonstrated that (1) Invasive ductal carcinoma patients with low expression of Slit2 or Robo1 exhibited worse prognosis and brain-specific metastasis, but not liver, bone or lung. (2) Lower expression of Slit2 and Robo1 were observed in patients with brain metastasis, especially in their brain metastasis tumors, compared with patients without brain metastasis. (3) The interval from diagnosis of breast cancer to brain metastasis and brain metastasis to death were both much shorter in patients with low expression of Slit2 or Robo1 compared with the high expression group. Overall, our findings indicated that Slit2/Robo1 axis possibly be regarded as a significant clinical parameter for predicting brain metastasis in breast cancer patients.

  19. Analysis of radiation therapy in a model of triple-negative breast cancer brain metastasis.

    PubMed

    Smart, DeeDee; Garcia-Glaessner, Alejandra; Palmieri, Diane; Wong-Goodrich, Sarah J; Kramp, Tamalee; Gril, Brunilde; Shukla, Sudhanshu; Lyle, Tiffany; Hua, Emily; Cameron, Heather A; Camphausen, Kevin; Steeg, Patricia S

    2015-10-01

    Most cancer patients with brain metastases are treated with radiation therapy, yet this modality has not yet been meaningfully incorporated into preclinical experimental brain metastasis models. We applied two forms of whole brain radiation therapy (WBRT) to the brain-tropic 231-BR experimental brain metastasis model of triple-negative breast cancer. When compared to sham controls, WBRT as 3 Gy × 10 fractions (3 × 10) reduced the number of micrometastases and large metastases by 87.7 and 54.5 %, respectively (both p < 0.01); whereas a single radiation dose of 15 Gy × 1 (15 × 1) was less effective, reducing metastases by 58.4 % (p < 0.01) and 47.1 % (p = 0.41), respectively. Neuroinflammation in the adjacent brain parenchyma was due solely to a reaction from metastases, and not radiotherapy, while adult neurogenesis in brains was adversely affected following both radiation regimens. The nature of radiation resistance was investigated by ex vivo culture of tumor cells that survived initial WBRT ("Surviving" cultures). The Surviving cultures surprisingly demonstrated increased radiosensitivity ex vivo. In contrast, re-injection of Surviving cultures and re-treatment with a 3 × 10 WBRT regimen significantly reduced the number of large and micrometastases that developed in vivo, suggesting a role for the microenvironment. Micrometastases derived from tumor cells surviving initial 3 × 10 WBRT demonstrated a trend toward radioresistance upon repeat treatment (p = 0.09). The data confirm the potency of a fractionated 3 × 10 WBRT regimen and identify the brain microenvironment as a potential determinant of radiation efficacy. The data also nominate the Surviving cultures as a potential new translational model for radiotherapy.

  20. Endoscopy-verified occult subependymal dissemination of glioblastoma and brain metastasis undetected by MRI: prognostic significance

    PubMed Central

    Iacoangeli, Maurizio; Di Rienzo, Alessandro; Colasanti, Roberto; Zizzi, Antonio; Gladi, Maurizio; Alvaro, Lorenzo; Nocchi, Niccolò; Di Somma, Lucia Giovanna Maria; Scarpelli, Marina; Scerrati, Massimo

    2012-01-01

    Although various prognostic indices exist for patients with malignant brain tumors, the prognostic significance of the subependymal spread of intracranial tumors is still a matter of debate. In this paper, we report the cases of two intraventricular lesions, a recurrent glioblastoma multiforme (GBM) and a brain metastasis, each successfully treated with a neuroendoscopic approach. Thanks to this minimally invasive approach, we achieved good therapeutic results: we obtained a histological diagnosis; we controlled intracranial hypertension by treating the associated hydrocephalus and, above all, compared with a microsurgical approach, we reduced the risks related to dissection and brain retraction. Moreover, in both cases, neuroendoscopy enabled us to identify an initial, precocious subependymal tumor spreading below the threshold of magnetic resonance imaging (MRI) detection. This finding, undetected in pre-operative MRI scans, was then evident during follow-up neuroimaging studies. In light of these data, a neuroendoscopic approach might play a leading role in better defining the prognosis and optimally tailored management protocols for GBM and brain metastasis. PMID:23271915

  1. RPA classification has prognostic significance for surgically resected single brain metastasis

    SciTech Connect

    Tendulkar, Rahul D.; Liu, Stephanie W.; Barnett, Gene H.; Vogelbaum, Michael A.; Toms, Steven A.; Jin Tao; Suh, John H.

    2006-11-01

    Purpose: To retrospectively evaluate prognostic factors that correlate with overall survival among patients with a surgically resected single brain metastasis. Methods and Materials: An Institutional Review Board-approved database of Cleveland Clinic Brain Tumor Institute was queried for patients with a single brain metastasis treated by surgical resection between February 1984 and January 2004. The primary endpoint was overall survival from the date of surgery by the Kaplan-Meier method. Results: A total of 271 patients were included. Statistically significant variables for improved survival on multivariate analysis included age <65 years, lack of extracranial metastases, control of primary tumor, histology (non-small-cell lung carcinoma), and use of stereotactic radiosurgery. The median survival for all patients was 10.2 months. Survival of patients in recursive partitioning analysis (RPA) class 1 was better (21.4 months) than those in RPA class 2 (9.0 months, p < 0.001), RPA class 3 (8.9 months, p = 0.15), or the combined group of RPA classes 2 and 3 (9.0 months, p < 0.001). Patients had a median survival of 10.6 months after documented gross total resection and 8.7 months after subtotal resection, which approached statistical significance (p 0.07). Those who were treated with stereotactic radiosurgery had a median survival of 17.1 months, which was greater than patients who were not treated with stereotactic radiosurgery (8.9 months, p = 0.006). Conclusions: This analysis supports the prognostic significance of the RPA classification in patients with a single brain metastasis who undergo surgical resection and adjuvant therapy. RPA class 1 patients have a very favorable prognosis with a median survival of 21.4 months.

  2. Stereotactic Radiotherapy for Cervical Spinal Intramedullary Metastasis and Multiple Brain Metastases: A Case Report.

    PubMed

    Mori, Yoshimasa; Kawamura, Toshiki; Ohshima, Yukihiko; Takeuchi, Arisa; Mori, Toshie; Ishiguchi, Tuneo

    2016-01-01

    A case of cervical (C) spinal intramedullary metastasis and multiple small brain metastases from papillary thyroid carcinoma was presented. Spinal metastasis caused posterior neck and left shoulder pain, dysesthesia in both legs, and motor weakness in both legs and left arm, though the brain metastases were asymptomatic. Both the spinal and brain metastases were successfully treated by frameless stereotactic radiotherapy (SRT)/stereotactic radiosurgery (SRS). The patient's symptoms were almost entirely relieved within two months. A 76-year-old woman was diagnosed as having a thyroid tumor and lung metastasis by roentgenography and computed tomography. Biopsy of the thyroid tumor extending into the mediastinum revealed papillary thyroid carcinoma. She underwent surgical resection of thyroid with dissection of the mediastinum lymph node area. Internal oral radioisotope therapy was not effective for the multiple small lung metastases. She did well for 15 months, but later developed posterior neck and left shoulder pain and dysesthesia in the right leg and then dysesthesia and motor weakness in both legs. Then she experienced weakness in the left upper extremity. Magnetic resonance imaging (MRI) disclosed a small cervical spinal intramedullary mass lesion at the level of C6 and C7 on the left side as well as nine small brain lesions. The cervical spinal intramedullary metastatic tumor was treated by volumetric modulated arc radiotherapy (VMAT) SRT and the nine small brain metastatic tumors were treated by dynamic conformal arc (DCA) SRS uneventfully. A total dose of 39 Gy (100% dose) was delivered in 13 fractions for the spinal lesion (prescription, D95=95% dose; maximum dose=46.3 Gy). Single fraction SRS of 22 Gy (prescription, D95=100% dose) was performed for each of the nine small brain tumors. The spinal tumor was decreased in size on follow-up MRI two months after SRT. Three of the nine brain lesions had disappeared and six were decreased in size on

  3. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth

    PubMed Central

    Yao, Jun; Lowery, Frank J.; Zhang, Qingling; Huang, Wen-Chien; Li, Ping; Li, Min; Wang, Xiao; Zhang, Chenyu; Wang, Hai; Ellis, Kenneth; Cheerathodi, Mujeeburahiman; McCarty, Joseph H.; Palmieri, Diane; Saunus, Jodi; Lakhani, Sunil; Huang, Suyun; Sahin, Aysegul A.; Aldape, Kenneth D.; Steeg, Patricia S.; Yu, Dihua

    2016-01-01

    Summary Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites1. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs2. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth3,4. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important tumor suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. PTEN level in PTEN-loss brain metastatic tumor cells is restored after leaving brain microenvironment. This brain microenvironment-dependent, reversible PTEN mRNA and protein down-regulation is epigenetically regulated by microRNAs (miRNAs) from astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting miRNAs to metastatic tumor cells, while astrocyte-specific depletion of PTEN-targeting miRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumor cells leads to an increased secretion of cytokine chemokine (C-C motif) ligand 2 (CCL2), which recruits Iba1+ myeloid cells that reciprocally enhance outgrowth of brain metastatic tumor cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumor cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic

  4. Comparative analysis of survival, treatment, cost and resource use among patients newly diagnosed with brain metastasis by initial primary cancer.

    PubMed

    Ray, Saurabh; Dacosta-Byfield, Stacey; Ganguli, Arijit; Bonthapally, Vijayveer; Teitelbaum, April

    2013-08-01

    Brain metastases are a frequent complication of many systemic cancers and portend a poor prognosis. This retrospective analysis of health claims data compared survival, treatment and health care utilization and costs in patients with brain metastasis by primary tumor site. Adult commercial and Medicare Advantage enrollees newly diagnosed with brain metastasis in 01 Jan 2004 through 30 Apr 2010 were identified. Inclusion required at least 2 claims that identified the same primary cancer site prior to diagnosis of brain metastasis and no evidence of primary brain tumors. Health care utilization rates and costs were calculated at the patient level for each month of follow-up. Differences among primary cancer site cohorts were assessed by ANOVA (continuous variables), Chi square test (proportions) and the Poisson distribution (utilization rates). The primary cancer cohorts comprised 1,031 lung cancer, 93 melanoma and 395 female breast cancer patients. During the 6 months prior to brain metastasis diagnosis, 59 % of lung cancer patients had no evidence of lymph node involvement or other metastatic disease compared to 55 and 42 % of melanoma and breast cancer patients (P < 0.001). Survival after brain metastasis diagnosis was less than 3 months for 52, 43 and 39 % for lung cancer, breast cancer and melanoma, respectively (P < 0.001). Melanoma patients had the highest rate of inpatient stays and outpatient visits (P ≤ 0.003). Total monthly all-cause costs were: melanoma, $23,426; breast cancer $19,708; lung cancer, $17,007 (P = 0.003). Health care utilization and costs after brain metastasis diagnosis were substantial and differed by primary tumor site.

  5. miR-509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF-α.

    PubMed

    Xing, F; Sharma, S; Liu, Y; Mo, Y-Y; Wu, K; Zhang, Y-Y; Pochampally, R; Martinez, L A; Lo, H-W; Watabe, K

    2015-09-10

    The median survival time of breast cancer patients with brain metastasis is less than 6 months, and even a small metastatic lesion often causes severe neurological disabilities. Because of the location of metastatic lesions, a surgical approach is limited and most chemotherapeutic drugs are ineffective owing to the blood brain barrier (BBB). Despite this clinical importance, the molecular basis of the brain metastasis is poorly understood. In this study, we have isolated RNA from samples obtained from primary breast tumors and also from brain metastatic lesions followed by microRNA profiling analysis. Our results revealed that the miR-509 is highly expressed in the primary tumors, whereas the expression of this microRNA is significantly decreased in the brain metastatic lesions. MicroRNA target prediction and the analysis of cytokine array for the cells ectopically expressed with miR-509 demonstrated that this microRNA was capable of modulating the two genes essential for brain invasion, RhoC and TNF-α that affect the invasion of cancer cells and permeability of BBB, respectively. Importantly, high levels of TNF-α and RhoC-induced MMP9 were significantly correlated with brain metastasis-free survival of breast cancer patients. Furthermore, the results of our in vivo experiments indicate that miR-509 significantly suppressed the ability of cancer cells to metastasize to the brain. These findings suggest that miR-509 has a critical role in brain metastasis of breast cancer by modulating the RhoC-TNF-α network and that this miR-509 axis may represent a potential therapeutic target or serve as a prognostic tool for brain metastasis.

  6. P08.10SINGLE BRAIN METASTASIS 9 YEARS AFTER ORTHOTOPIC LIVER TRANSPLANT WITH HISTOLOGICAL NEGATIVE EXPIANTED LIVER: CASE REPORT

    PubMed Central

    Fornaro, R.; Agnoletti, A.; Specchia, F.M. Calamo; Garbossa, D.; Lanotte, M.; Ducati, A.

    2014-01-01

    We describe the case of a 67 years old man, that underwent orthotopic liver transplant (OLT) in 2004 for cirrhosis. Native liver hystological examination was negative for focal hepatocarcinoma (HCC) areas. In 2008, during regular follow up, pulmonary lesions were found and diagnosed as hepatocarcinoma metastasis.In 2013, patient accused vertigo and dizziness: neuroimaging showed a cerebellar lesion. Hystological diagnosis was HCC metastases. The peculiarity is the onset of lung metastasis after transplant, with negative analysis on native liver, and brain metastasis after stable disease. This case is also relevant due to long survival related to the unavailability of many oncologic therapies in transplanted patients.

  7. Clinical Significance of KISS1 Protein Expression for Brain Invasion and Metastasis

    PubMed Central

    Ulasov, Ilya V.; Kaverina, Natalya V.; Pytel, Peter; Thaci, Bart; Liu, FeiFei; Hurst, Douglas R.; Welch, Danny R.; Sattar, Husein A.; Olopade, Olufunmilayo I.; Baryshnikov, Anatoly Y.; Kadagidze, Zaira G.; Lesniak, Maciej S.

    2013-01-01

    BACKGROUND Metastases to the brain represent a feared complication and contribute to the morbidity and mortality of breast cancer. Despite improvements in therapy, prognostic factors for development of metastases are lacking. KISS1 is a metastasis suppressor that demonstrates inhibition of metastases formation in several types of cancer. The purpose of this study was to determine the importance of KISS1 expression in breast cancer progression and the development of intracerebral lesions. METHODS In this study, we performed a comparative analysis of 47 brain metastases and 165 primary breast cancer specimens by using the antihuman KISS1 antibody. To compare KISS1 expression between different groups, we used a 3-tier score and the automated score computer software (ACIS) evaluation. To reveal association between mRNA and protein expression, we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. Significance of immunohistochemistry stainings was correlated with clinicopathological data. RESULTS We identified that KISS1 expression is significantly higher in primary breast cancer compared with brain metastases (P < .05). The mRNA analysis performed on 33 selected ductal carcinoma brain metastatic lesions and 36 primary ductal carcinomas revealed a statistically significant down-regulation of KISS1 protein in metastatic cases (P = .04). Finally, we observed a significant correlation between expression of KISS1 and metastasis-free survival (P = .04) along with progression of breast cancer and expression of KISS1 in primary breast cancer specimens (P = .044). CONCLUSIONS In conclusion, our study shows that breast cancer expresses KISS1. Cytoplasmic expression of KISS1 may be used as a prognostic marker for increased risk of breast cancer progression. PMID:21928364

  8. Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption.

    PubMed

    Kobus, Thiele; Zervantonakis, Ioannis K; Zhang, Yongzhi; McDannold, Nathan J

    2016-09-28

    HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the brain. We investigated whether we could improve the response by temporary disruption of the BBB using focused ultrasound in combination with microbubbles. To study this, we inoculated 30 nude rats with HER2-positive cells derived from a brain metastasis of a breast cancer patient (MDA-MB-361). The animals were divided into three groups: a control-group that received no treatment; an antibody-only group that received six weekly treatments of trastuzumab and pertuzumab; and an ultrasound+antibody group that received trastuzumab and pertuzumab in combination with six weekly sessions of BBB disruption using focused ultrasound. In two animals, the leakiness of the tumors before disruption was evaluated using contrast-enhanced T1-weighted magnetic resonance imaging and found that the tumors were not leaky. The same technique was used to evaluate the effectiveness of BBB disruption, which was successful in all sessions. The tumor in the control animals grew exponentially with a growth constant of 0.042±0.011mm(3)/day. None of the antibody-only animals responded to the treatment and the growth constant was 0.033±0.009mm(3)/day during the treatment period. Four of the ten animals in the ultrasound+antibody-group showed a response to the treatment with an average growth constant of 0.010±0.007mm(3)/day, compared to a growth constant 0.043±0.013mm(3)/day for the six non-responders. After the treatment period, the tumors in all groups grew at similar rates. As the tumors were not leaky before BBB disruption and there were no responders in the antibody-only group, these results show that at least in some cases disruption of the BBB is necessary for a response to the antibodies in

  9. Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells.

    PubMed

    Lee, Hsueh-Te; Xue, Jianfei; Chou, Ping-Chieh; Zhou, Aidong; Yang, Phillip; Conrad, Charles A; Aldape, Kenneth D; Priebe, Waldemar; Patterson, Cam; Sawaya, Raymond; Xie, Keping; Huang, Suyun

    2015-04-30

    Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

  10. Differential interaction of ADP-ribosylation factors 1, 3, and 5 with rat brain Golgi membranes.

    PubMed

    Tsai, S C; Adamik, R; Haun, R S; Moss, J; Vaughan, M

    1992-10-01

    Six mammalian ADP-ribosylation factors (ARFs) identified by cDNA cloning were expressed as recombinant proteins (rARFs) that stimulated cholera toxin ADP-ribosyltransferase activity. Microsequencing of soluble ARFs I and II (sARFs I and II), purified from bovine brain, established that they are ARFs 1 and 3, respectively. Rabbit antibodies (IgG) against sARF II reacted similarly with ARFs 1, 2, and 3 (class I) on Western blots. ARFs 1 and 3 were distinguished by their electrophoretic mobilities. Antiserum against rARF 5 cross-reacted partially with rARF 4 but not detectably with rARF 6 and minimally with class I ARFs. Guanosine 5'-O-(3-thiotriphosphate) (GTP[gamma S]) increased recovery of ARF activity and immunoreactivity in organelle fractions separated by density gradient centrifugation, after incubation of rat brain homogenate with ATP and a regenerating system. ARF 1 accumulated in microsomes plus Golgi and Golgi fractions, whereas ARF 5 seemed to localize more specifically in Golgi; the smaller increment in ARF 3 was distributed more evenly among fractions. On incubation of Golgi with a crude ARF fraction, GTP[gamma S], and an ATP-regenerating system, association of ARF activity with Golgi increased with increasing ATP concentration paralleled by increases in immunoreactive ARFs 1 and 5 and, to a lesser degree, ARF 3. Golgi incubated with GTP[gamma S] and purified ARF 1 or 3 bound more ARF 1 than ARF 3. Based on immunoreactivity and assay of ARF activity, individual ARFs 1, 3, and 5 appeared to behave independently and selectively in their GTP-dependent association with Golgi in vitro.

  11. Differential interaction of ADP-ribosylation factors 1, 3, and 5 with rat brain Golgi membranes.

    PubMed Central

    Tsai, S C; Adamik, R; Haun, R S; Moss, J; Vaughan, M

    1992-01-01

    Six mammalian ADP-ribosylation factors (ARFs) identified by cDNA cloning were expressed as recombinant proteins (rARFs) that stimulated cholera toxin ADP-ribosyltransferase activity. Microsequencing of soluble ARFs I and II (sARFs I and II), purified from bovine brain, established that they are ARFs 1 and 3, respectively. Rabbit antibodies (IgG) against sARF II reacted similarly with ARFs 1, 2, and 3 (class I) on Western blots. ARFs 1 and 3 were distinguished by their electrophoretic mobilities. Antiserum against rARF 5 cross-reacted partially with rARF 4 but not detectably with rARF 6 and minimally with class I ARFs. Guanosine 5'-O-(3-thiotriphosphate) (GTP[gamma S]) increased recovery of ARF activity and immunoreactivity in organelle fractions separated by density gradient centrifugation, after incubation of rat brain homogenate with ATP and a regenerating system. ARF 1 accumulated in microsomes plus Golgi and Golgi fractions, whereas ARF 5 seemed to localize more specifically in Golgi; the smaller increment in ARF 3 was distributed more evenly among fractions. On incubation of Golgi with a crude ARF fraction, GTP[gamma S], and an ATP-regenerating system, association of ARF activity with Golgi increased with increasing ATP concentration paralleled by increases in immunoreactive ARFs 1 and 5 and, to a lesser degree, ARF 3. Golgi incubated with GTP[gamma S] and purified ARF 1 or 3 bound more ARF 1 than ARF 3. Based on immunoreactivity and assay of ARF activity, individual ARFs 1, 3, and 5 appeared to behave independently and selectively in their GTP-dependent association with Golgi in vitro. Images PMID:1409634

  12. Expression of metastasis-associated protein 3 in human brain glioma related to tumor prognosis.

    PubMed

    Shan, Shouqin; Hui, Guangyan; Hou, Fanggao; Shi, Hua; Zhou, Guoqing; Yan, Han; Wang, Lu; Liu, Jinfeng

    2015-10-01

    Glioma represents a disparate group of tumors characterized by high invasion ability, and therefore it is of clinical significance to identify molecular markers and therapeutic targets for better clinical management. Previously, metastasis-associated protein family (MTA) is considered to promote tumor cell invasion and metastasis of human malignancies. Recently, the newly identified MTA3 has been shown to play conflicting roles in human malignancies, while the expression pattern and potential clinical significance of MTA3 in human glioma have not been addressed yet. In the present study, we investigated the protein expression of MTA3 by immunohistochemistry assay and analyzed its association with glioma prognosis in 186 cases of patients. Results showed that MTA3 expression was decreased in glioma compared with that in normal brain (P < 0.05). In addition, tumors with high MTA3 expression were more likely to be of low WHO grade (P = 0.005) and reserve of body function (P = 0.014). Survival analysis showed that decreased MTA3 expression was independently associated with unfavorable overall survival of patients (P < 0.001). These results provide the first evidence that MTA3 expression was decreased in human glioma and negatively associated with prognosis of patients, suggesting that MTA3 may play a tumor suppressor role in glioma.

  13. Peptic ulcer disease and other complications in patients receiving dexamethasone palliation for brain metastasis

    SciTech Connect

    Penzner, R.D.; Lipsett, J.A.

    1982-11-01

    A retrospective analysis was done of 106 patients who received radiation therapy for brain metastasis. Dexamethasone therapy was instituted in 97 patients. Peptic ulcer disease developed in 5 of 89 patients (5.6 percent) who received a dosage of at least 12 mg a day, but did not occur in patients who received a lower dose or in those who did not receive steroids. The interval between institution of dexamethasone therapy and the development of peptic ulcer disease ranged from three to nine weeks. Two patients had perforated ulcers, one of whom required surgical resection. Peptic ulcer disease contributed to the general deterioration and death of three of the five patients. Overall, in 14 of the 89 patients (15.7 percent) a complication of steroid therapy developed in the form of peptic ulcer disease, steroid myopathy or diabetes mellitus (or a combination of these).

  14. CAVEOLIN-1 expression in brain metastasis from lung cancer predicts worse outcome and radioresistance, irrespective of tumor histotype.

    PubMed

    Duregon, Eleonora; Senetta, Rebecca; Pittaro, Alessandra; Verdun di Cantogno, Ludovica; Stella, Giulia; De Blasi, Pierpaolo; Zorzetto, Michele; Mantovani, Cristina; Papotti, Mauro; Cassoni, Paola

    2015-10-01

    Brain metastases develop in one-third of patients with non-small-cell lung cancer and are associated with a dismal prognosis, irrespective of surgery or chemo-radiotherapy. Pathological markers for predicting outcomes after surgical resection and radiotherapy responsiveness are still lacking. Caveolin 1 has been associated with chemo- and radioresistance in various tumors, including non-small-cell lung cancer. Here, caveolin 1 expression was assessed in a series of 69 brain metastases from non-small-cell lung cancer and matched primary tumors to determine its role in predicting survival and radiotherapy responsiveness. Only caveolin 1 expression in brain metastasis was associated with poor prognosis and an increased risk of death (log rank test, p = 0.015). Moreover, in the younger patients (median age of <54 years), caveolin 1 expression neutralized the favorable effect of young age on survival compared with the older patients. Among the radiotherapy-treated patients, an increased risk of death was detected in the group with caveolin 1-positive brain metastasis (14 out of 22 patients, HR=6.839, 95% CI 1.849 to 25.301, Wald test p = 0.004). Overall, caveolin 1 expression in brain metastasis from non-small-cell lung cancer is independently predictive of worse outcome and radioresistance and could become an additional tool for personalized therapy in the critical subset of brain-metastatic non-small-cell lung cancer patients.

  15. Deploying swarm intelligence in medical imaging identifying metastasis, micro-calcifications and brain image segmentation.

    PubMed

    al-Rifaie, Mohammad Majid; Aber, Ahmed; Hemanth, Duraiswamy Jude

    2015-12-01

    This study proposes an umbrella deployment of swarm intelligence algorithm, such as stochastic diffusion search for medical imaging applications. After summarising the results of some previous works which shows how the algorithm assists in the identification of metastasis in bone scans and microcalcifications on mammographs, for the first time, the use of the algorithm in assessing the CT images of the aorta is demonstrated along with its performance in detecting the nasogastric tube in chest X-ray. The swarm intelligence algorithm presented in this study is adapted to address these particular tasks and its functionality is investigated by running the swarms on sample CT images and X-rays whose status have been determined by senior radiologists. In addition, a hybrid swarm intelligence-learning vector quantisation (LVQ) approach is proposed in the context of magnetic resonance (MR) brain image segmentation. The particle swarm optimisation is used to train the LVQ which eliminates the iteration-dependent nature of LVQ. The proposed methodology is used to detect the tumour regions in the abnormal MR brain images. PMID:26577158

  16. Brain metastasis from cutaneous squamous cell carcinoma of the dorsum. Case report.

    PubMed

    Salvati, Maurizio; Caroli, Emanuela; Paone, Cristina; Frati, Alessandro; Ferrante, Luigi; Giangaspero, Felice; Delfini, Roberto

    2005-06-01

    The majority of cutaneous squamous cell carcinoma (SCC) are diagnosed early and cured using local treatment, although a minority of cases metastasize to regional structures. In this report the authors describe an unknown feature of skin SCC, namely, distant brain metastasis. This 54-year-old man, who had undergone surgery for moderately differentiated SCC of the dorsum (T2NOM0 stage), was admitted to our institution 11 months later with headache, vomiting, and ataxia. A magnetic resonance image documented a cerebellar lesion, which was totally removed. Results of histological studies revealed SCC. The patient received whole-brain radiotherapy (30 Gy over 2 weeks using a linear accelerator). A metastatic work-up showed enlarged inguinal and para-aortic lymph nodes that were histologically examined using excisional biopsy. Inguinal lymph nodes were tumor-positive and were dissected. The patient was subjected to two cycles of chemotherapy with cisplatin (75 mg/m2). After 3 months, a significant reduction in the size of the para-aortic lymph nodes was documented on control computerized tomography studies. Although the described case is unique, knowledge of the potential for this uncommon behavior in cutaneous SCC may be useful, especially because of its increasing incidence.

  17. Expression of high affinity folate receptor in breast cancer brain metastasis.

    PubMed

    Leone, José Pablo; Bhargava, Rohit; Theisen, Brian K; Hamilton, Ronald L; Lee, Adrian V; Brufsky, Adam M

    2015-10-01

    High affinity folate receptor (HFR) can be overexpressed in breast cancer and is associated with poor prognosis, however the expression in breast cancer brain metastases (BCBM) is unknown. The aim of this study was to analyze the rate of HFR expression in BCBM and its role in the prognosis of this high-risk cohort. We analyzed 19 brain metastasis (BM) and 13 primary tumors (PT) from a total of 25 patients. HFR status was assessed by immunohistochemistry. Median follow-up was 4.2 years (range 0.6-18.5). HFR was positive in 4/19 BM (21.1%) and in 1/13 PT (7.7%). Positive samples had low H-scores (range 1-50). 56% of patients had apocrine differentiation. OS was similar between patients with positive HFR (median OS 48 months) and negative HFR (median OS 69 months) (P = 0.25); and between patients with apocrine differentiation (median OS 63 months) and those without apocrine differentiation (median OS 69 months) (P = 0.49). To the best of our knowledge, this is the first analysis of HFR expression in BCBM. While previous studies associated the presence of HFR with worse prognosis; in our cohort HFR was positive in only 21.1% of BM with low levels of positivity. Neither HFR nor apocrine features had impact in OS.

  18. Analysis of peptides in prohormone convertase 1/3 null mouse brain using quantitative peptidomics

    PubMed Central

    Wardman, Jonathan H.; Zhang, Xin; Gagnon, Sandra; Castro, Leandro M.; Zhu, Xiaorong; Steiner, Donald F.; Day, Robert; Fricker, Lloyd D.

    2010-01-01

    Neuropeptides are produced from larger precursors by limited proteolysis, first by endopeptidases and then by carboxypeptidases. Major endopeptidases required for these cleavages include prohormone convertase (PC) 1/3 and PC2. In the present study, quantitative peptidomics analysis was used to characterize the specific role PC1/3 plays in this process. Peptides isolated from hypothalamus, amygdala, and striatum of PC1/3 null mice were compared to those from heterozygous and wild-type mice. Extracts were labeled with stable isotopic tags and fractionated by HPLC, after which relative peptide levels were determined using tandem mass spectrometry. In total, 92 peptides were found, of which 35 were known neuropeptides or related peptides derived from 15 distinct secretory pathway proteins: 7B2, chromogranin A and B, cocaine- and amphetamine-regulated transcript, procholecystokinin, proenkephalin, promelanin concentrating hormone, proneurotensin, propituitary adenylate cyclase-activating peptide, proSAAS, prosomatosatin, provasoactive intestinal peptide, provasopressin, secretogranin III, and VGF. Among the peptides derived from these proteins, ~1/3 were decreased in the PC1/3 null mice relative to wild-type mice, ~1/3 showed no change, and ~1/3 increased in PC1/3 null. Cleavage sites were analyzed in peptides that showed no change or that decreased in PC1/3 mice, and these results were compared with peptides that showed no change or decreased in previous peptidomic studies with PC2 null mice. Analysis of these sites showed that while PC1/3 and PC2 have overlapping substrate preferences, there are particular cleavage site residues that distinguish peptides preferred by each PC. PMID:20412386

  19. Stereotactic Irradiation of the Postoperative Resection Cavity for Brain Metastasis: A Frameless Linear Accelerator-Based Case Series and Review of the Technique

    SciTech Connect

    Kelly, Paul J.; Alexander, Brian M.; Hacker, Fred; Marcus, Karen J.; Weiss, Stephanie E.

    2012-01-01

    Purpose: Whole-brain radiation therapy (WBRT) is the standard of care after resection of a brain metastasis. However, concern regarding possible neurocognitive effects and the lack of survival benefit with this approach has led to the use of stereotactic radiosurgery (SRS) to the resection cavity in place of WBRT. We report our initial experience using an image-guided linear accelerator-based frameless stereotactic system and review the technical issues in applying this technique. Methods and Materials: We retrospectively reviewed the setup accuracy, treatment outcome, and patterns of failure of the first 18 consecutive cases treated at Brigham and Women's Hospital. The target volume was the resection cavity without a margin excluding the surgical track. Results: The median number of brain metastases per patient was 1 (range, 1-3). The median planning target volume was 3.49 mL. The median prescribed dose was 18 Gy (range, 15-18 Gy) with normalization ranging from 68% to 85%. In all cases, 99% of the planning target volume was covered by the prescribed dose. The median conformity index was 1.6 (range, 1.41-1.92). The SRS was delivered with submillimeter accuracy. At a median follow-up of 12.7 months, local control was achieved in 16/18 cavities treated. True local recurrence occurred in 2 patients. No marginal failures occurred. Distant recurrence occurred in 6/17 patients. Median time to any failure was 7.4 months. No Grade 3 or higher toxicity was recorded. A long interval between initial cancer diagnosis and the development of brain metastasis was the only factor that trended toward a significant association with the absence of recurrence (local or distant) (log-rank p = 0.097). Conclusions: Frameless stereotactic irradiation of the resection cavity after surgery for a brain metastasis is a safe and accurate technique that offers durable local control and defers the use of WBRT in select patients. This technique should be tested in larger prospective studies.

  20. Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary?

    PubMed

    Toyokawa, Gouji; Seto, Takashi; Takenoyama, Mitsuhiro; Ichinose, Yukito

    2015-12-01

    Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity through its rearrangement in non-small cell lung cancer (NSCLC), and patients (pts) with ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib, and ceritinib, than with chemotherapy. Despite the excellent efficacy of ALK inhibitors, resistance to these drugs is inevitably encountered in most ALK-rearranged pts. Cases of resistance are subtyped into three groups, i.e., systemic, oligo, and central nervous system (CNS) types, with the CNS being used to be considered a sanctuary. With regard to the management of CNS lesions in pts with ALK+ NSCLC, a growing body of evidence has gradually demonstrated the intracranial (IC) efficacy of ALK inhibitor (ALKi) in ALK+ NSCLC pts with brain metastases (BMs). Although the efficacy of crizotinib for the CNS lesions remains controversial, a recent retrospective investigation of ALK+ pts with BM enrolled in PROFILE 1005 and PROFILE 1007 demonstrated that crizotinib is associated with a high disease control rate for BM. However, BM comprises the most common site of progressive disease in pts with or without baseline BMs, which is a serious problem for crizotinib. Furthermore, alectinib can be used to achieve strong and long-lasting inhibitory effects on BM. In addition to alectinib, the IC efficacy of other next-generation ALK inhibitors, such as ceritinib, AP26113 and PF-06463922, has been demonstrated. In this article, we review the latest evidence regarding the BM and IC efficacy of ALK inhibitors in pts with ALK+ NSCLC.

  1. Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastasis

    PubMed Central

    Johung, Kimberly L.; Yeh, Norman; Desai, Neil B.; Williams, Terence M.; Lautenschlaeger, Tim; Arvold, Nils D.; Ning, Matthew S.; Attia, Albert; Lovly, Christine M.; Goldberg, Sarah; Beal, Kathryn; Yu, James B.; Kavanagh, Brian D.; Chiang, Veronica L.; Camidge, D. Ross

    2016-01-01

    Purpose We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non–small-cell lung cancer (NSCLC) and brain metastasis. Patients and Methods A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling. Results Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001). Conclusion Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease. PMID:26438117

  2. Poorly Differentiated Neuroendocrine Tumor of the Esophagus with Hypertrophic Osteoarthropathy and Brain Metastasis: A Success Story.

    PubMed

    Saif, Muhammad W; Vethody, Chandra

    2016-01-01

    Neuroendocrine carcinomas (NECs) of the esophagus are very rare. The majority of the patients with NECs present with metastasis. Paraneoplastic syndromes, such as syndrome of inappropriate secretion of anti-diuretic hormone and watery diarrhea-hypokalemia-achlorhydria syndrome, have been reported in previous reports. Esophageal NECs are related to a poor prognosis. A 38-year-old male with the histologic diagnosis of esophageal NEC, which initially manifested as hypertrophic osteoarthropathy (HOA), later developed brain metastases. He was initially treated with neoadjuvant chemotherapy consisting of cisplatin and etoposide followed by a partial esophagectomy in November 2009. At follow-up in February 2010, he complained of a headache that prompted imaging. MRI of the brain revealed a left frontal lobe lesion. Subsequently, he underwent a craniotomy and resection of the lesion. Pathological analysis revealed that the lesion was consistent with metastatic disease from the primary esophageal NEC. The patient underwent 40 Gy whole brain radiotherapy (WBRT), followed by two weeks of stereotactic radiation (SRS) to the tumor bed for an additional 12 Gy. During this time, his tumor marker neuron-specific enolase (NSE) initially dropped but later increased, which led us to offer him radiotherapy to the remaining esophagus to be followed by localized radiation to areas immediately adjacent to the surgical site, followed by six cycles of systemic chemotherapy consisting of cisplatin and irinotecan. Finally, his NSE normalized around the end of systemic chemotherapy. Surveillance imaging in 2015 - six years from initial diagnosis - showed no evidence of cancer. Of interest, treatment of the esophageal NEC also led to clinical resolution of his musculoskeletal symptoms, including his HOA. High-grade esophageal NECs are rare, aggressive, and have a poor prognosis. HOA can be a presenting sign associated with a high-grade esophageal NEC. The predominant site of metastatic

  3. Poorly Differentiated Neuroendocrine Tumor of the Esophagus with Hypertrophic Osteoarthropathy and Brain Metastasis: A Success Story

    PubMed Central

    Vethody, Chandra

    2016-01-01

    Neuroendocrine carcinomas (NECs) of the esophagus are very rare. The majority of the patients with NECs present with metastasis. Paraneoplastic syndromes, such as syndrome of inappropriate secretion of anti-diuretic hormone and watery diarrhea-hypokalemia-achlorhydria syndrome, have been reported in previous reports. Esophageal NECs are related to a poor prognosis. A 38-year-old male with the histologic diagnosis of esophageal NEC, which initially manifested as hypertrophic osteoarthropathy (HOA), later developed brain metastases. He was initially treated with neoadjuvant chemotherapy consisting of cisplatin and etoposide followed by a partial esophagectomy in November 2009. At follow-up in February 2010, he complained of a headache that prompted imaging. MRI of the brain revealed a left frontal lobe lesion. Subsequently, he underwent a craniotomy and resection of the lesion. Pathological analysis revealed that the lesion was consistent with metastatic disease from the primary esophageal NEC. The patient underwent 40 Gy whole brain radiotherapy (WBRT), followed by two weeks of stereotactic radiation (SRS) to the tumor bed for an additional 12 Gy. During this time, his tumor marker neuron-specific enolase (NSE) initially dropped but later increased, which led us to offer him radiotherapy to the remaining esophagus to be followed by localized radiation to areas immediately adjacent to the surgical site, followed by six cycles of systemic chemotherapy consisting of cisplatin and irinotecan. Finally, his NSE normalized around the end of systemic chemotherapy. Surveillance imaging in 2015 - six years from initial diagnosis - showed no evidence of cancer. Of interest, treatment of the esophageal NEC also led to clinical resolution of his musculoskeletal symptoms, including his HOA. High-grade esophageal NECs are rare, aggressive, and have a poor prognosis. HOA can be a presenting sign associated with a high-grade esophageal NEC. The predominant site of metastatic

  4. A clinical analysis of brain metastasis in gynecologic cancer: a retrospective multi-institute analysis.

    PubMed

    Kim, Young Zoon; Kwon, Jae Hyun; Lim, Soyi

    2015-01-01

    This study analyzes the clinical characteristics of the brain metastasis (BM) of gynecologic cancer based on the type of cancer. In addition, the study examines the factors influencing the survival. Total 61 BM patients of gynecologic cancer were analyzed retrospectively from January 2000 to December 2012 in terms of clinical and radiological characteristics by using medical and radiological records from three university hospitals. There were 19 (31.1%) uterine cancers, 32 (52.5%) ovarian cancers, and 10 (16.4%) cervical cancers. The mean interval to BM was 25.4 months (21.6 months in ovarian cancer, 27.8 months in uterine cancer, and 33.1 months in cervical cancer). The mean survival from BM was 16.7 months (14.1 months in ovarian cancer, 23.3 months in uterine cancer, and 8.8 months in cervical cancer). According to a multivariate analysis of factors influencing survival, type of primary cancer, Karnofsky performance score, status of primary cancer, recursive partitioning analysis class, and treatment modality, particularly combined therapies, were significantly related to the overall survival. These results suggest that, in addition to traditional prognostic factors in BM, multiple treatment methods such as neurosurgery and combined chemoradiotherapy may play an important role in prolonging the survival for BM patients of gynecologic cancer.

  5. Prognostic factors and survival of patients with brain metastasis from breast cancer who underwent craniotomy.

    PubMed

    Leone, José Pablo; Lee, Adrian V; Brufsky, Adam M

    2015-07-01

    Brain metastasis (BM) in patients with breast cancer is a catastrophic event that results in poor prognosis. Identification of prognostic factors associated with breast cancer brain metastases (BCBM) could help to identify patients at risk. The aim of this study was to assess clinical characteristics, prognostic factors, and survival of patients with BCBM who had craniotomy and resection in a series of patients treated with modern multimodality therapy. We analyzed 42 patients with BCBM who underwent resection. Patients were diagnosed with breast cancer between April 1994 and May 2010. Cox proportional hazards regression was selected to describe factors associated with time to BM, survival from the date of first recurrence, and overall survival (OS). Median age was 51 years (range 24-74). Median follow-up was 4.2 years (range 0.6-18.5). The proportion of the biological subtypes of breast cancer was ER+/HER2- 25%, ER+/HER2+ 15%, ER-/HER2+ 30%, and ER-/HER2- 30%. Median OS from the date of primary diagnosis was 5.74 years. Median survival after diagnosis of BM was 1.33 years. In multivariate Cox regression analyses, stage was the only factor associated with shorter time to the development of BM (P = 0.033), whereas age was the only factor associated with survival from the date of recurrence (P = 0.027) and with OS (P = 0.037). Stage at primary diagnosis correlated with shorter time to the development of BM, while age at diagnosis was associated with shorter survival in BCBM. None of the other clinical factors had influence on survival.

  6. The combination of weekly trastuzumab plus vinorelbine may be preferable regimen in HER-2 positive breast cancer patients with brain metastasis.

    PubMed

    Mutlu, Hasan; Büyükçelik, Abdullah

    2015-08-01

    Brain metastasis is one of the most important life-threatening conditions in patients with metastatic HER-2 positive breast cancer. A lot of conventional chemotherapeutic and antibody-based regimens used routinely in treatment of the patients with breast cancer are not effective due to blood-brain barrier. In our cases, we reported on three HER-2 positive breast cancer patients with brain metastasis who were offered a combination of weekly trastuzumab plus vinorelbine after brain metastasis. In our cases, the progression-free survival were 12, 16 and 9 months for Case 1, Case 2 and Case 3, respectively. In Case 1, there was no progression in the brain. In Case 3, we did not detect any progress but the patient died due to cerebrovascular embolic events. After local treatment, the combination of weekly trastuzumab plus vinorelbine may be an effective alternative regimen in HER-2 positive breast cancer patients with brain metastases.

  7. Absolute perfusion measurements and associated iodinated contrast agent time course in brain metastasis: a study for contrast-enhanced radiotherapy.

    PubMed

    Obeid, Layal; Deman, Pierre; Tessier, Alexandre; Balosso, Jacques; Estève, François; Adam, Jean-François

    2014-04-01

    Contrast-enhanced radiotherapy is an innovative treatment that combines the selective accumulation of heavy elements in tumors with stereotactic irradiations using medium energy X-rays. The radiation dose enhancement depends on the absolute amount of iodine reached in the tumor and its time course. Quantitative, postinfusion iodine biodistribution and associated brain perfusion parameters were studied in human brain metastasis as key parameters for treatment feasibility and quality. Twelve patients received an intravenous bolus of iodinated contrast agent (CA) (40 mL, 4 mL/s), followed by a steady-state infusion (160 mL, 0.5 mL/s) to ensure stable intratumoral amounts of iodine during the treatment. Absolute iodine concentrations and quantitative perfusion maps were derived from 40 multislice dynamic computed tomography (CT) images of the brain. The postinfusion mean intratumoral iodine concentration (over 30 minutes) reached 1.94 ± 0.12 mg/mL. Reasonable correlations were obtained between these concentrations and the permeability surface area product and the cerebral blood volume. To our knowledge, this is the first quantitative study of CA biodistribution versus time in brain metastasis. The study shows that suitable and stable amounts of iodine can be reached for contrast-enhanced radiotherapy. Moreover, the associated perfusion measurements provide useful information for the patient recruitment and management processes.

  8. Optical pathology of human brain metastasis of lung cancer using combined resonance Raman and spatial frequency spectroscopies

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-hui; Pu, Yang; Cheng, Gangge; Zhou, Lixin; Chen, Jun; Zhu, Ke; Alfano, Robert R.

    2016-03-01

    Raman spectroscopy has become widely used for diagnostic purpose of breast, lung and brain cancers. This report introduced a new approach based on spatial frequency spectra analysis of the underlying tissue structure at different stages of brain tumor. Combined spatial frequency spectroscopy (SFS), Resonance Raman (RR) spectroscopic method is used to discriminate human brain metastasis of lung cancer from normal tissues for the first time. A total number of thirty-one label-free micrographic images of normal and metastatic brain cancer tissues obtained from a confocal micro- Raman spectroscopic system synchronously with examined RR spectra of the corresponding samples were collected from the identical site of tissue. The difference of the randomness of tissue structures between the micrograph images of metastatic brain tumor tissues and normal tissues can be recognized by analyzing spatial frequency. By fitting the distribution of the spatial frequency spectra of human brain tissues as a Gaussian function, the standard deviation, σ, can be obtained, which was used to generate a criterion to differentiate human brain cancerous tissues from the normal ones using Support Vector Machine (SVM) classifier. This SFS-SVM analysis on micrograph images presents good results with sensitivity (85%), specificity (75%) in comparison with gold standard reports of pathology and immunology. The dual-modal advantages of SFS combined with RR spectroscopy method may open a new way in the neuropathology applications.

  9. The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer

    PubMed Central

    DENG, YANMING; FENG, WEINENG; WU, JING; CHEN, ZECHENG; TANG, YICONG; ZHANG, HUA; LIANG, JIANMIAO; XIAN, HAIBING; ZHANG, SHUNDA

    2014-01-01

    It has been demonstrated that erlotinib is effective in treating patients with brain metastasis from non-small-cell lung cancer. However, the number of studies determining the erlotinib concentration in these patients is limited. The purpose of this study was to measure the concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung carcinoma. Six patients were treated with the standard recommended daily dose of erlotinib (150 mg) for 4 weeks. All the patients had previously received chemotherapy, but no brain radiotherapy. At the end of the treatment period, blood plasma and cerebrospinal fluid samples were collected and the erlotinib concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The average erlotinib concentration in the blood plasma and the cerebrospinal fluid was 717.7±459.7 and 23.7±13.4 ng/ml, respectively. The blood-brain barrier permeation rate of erlotinib was found to be 4.4±3.2%. In patients with partial response (PR), stable disease (SD) and progressive disease (PD), the average concentrations of erlotinib in the cerebrospinal fluid were 35.5±19.0, 19.1±8.7 and 16.4±5.9 ng/ml, respectively. In addition, the efficacy rate of erlotinib for metastatic brain lesions was 33.3%, increasing to 50% in patients with EGFR mutations. However, erlotinib appeared to be ineffective in cases with wild-type EGFR. In conclusion, a relatively high concentration of erlotinib was detected in the cerebrospinal fluid of patients with brain metastases from non-small-cell lung cancer. Thus, erlotinib may be considered as a treatment option for this patient population. PMID:24649318

  10. Lapatinib-loaded human serum albumin nanoparticles for the prevention and treatment of triple-negative breast cancer metastasis to the brain

    PubMed Central

    Wan, Xu; Zheng, Xiaoyao; Pang, Xiaoyin; Pang, Zhiqing; Zhao, Jingjing; Zhang, Zheming; Jiang, Tao; Xu, Wei; Zhang, Qizhi; Jiang, Xinguo

    2016-01-01

    Brain metastasis from triple-negative breast cancer (TNBC) has continued to lack effective clinical treatments until present. However, the feature of epidermal growth factor receptor (EGFR) frequently overexpressed in TNBC offers the opportunity to employ lapatinib, a dual-tyrosine kinase inhibitor of human epidermal growth factor receptor-2 (HER2) and EGFR, in the treatment of brain metastasis of TNBC. Unfortunately, the low oral bioavailability of lapatinib and drug efflux by blood-brain barrier have resulted in low drug delivery efficiency into the brain and limited therapeutic effects for patients with brain metastasis in clinical trials. To overcome such disadvantages, we developed lapatinib-loaded human serum albumin (HSA) nanoparticles, named LHNPs, by modified nanoparticle albumin-bound (Nab) technology. LHNPs had a core-shell structure and the new HSA/phosphatidylcholine sheath made LHNPs stable in bloodstream. Compared to free lapatinib, LHNPs could inhibit the adhesion, migration and invasion ability of high brain-metastatic 4T1 cells more effectively in vitro. Tissue distribution following intravenous administration revealed that LHNPs (i.v., 10 mg/kg) achieved increased delivery to the metastatic brain at 5.43 and 4.36 times the levels of Tykerb (p.o., 100 mg/kg) and lapatinib solution (LS, i.v., 10 mg/kg), respectively. Compared to the marketed Tykerb group, LHNPs had markedly better inhibition effects on brain micrometastasis and significantly extended the median survival time of 4T1 brain metastatic mice in consequence. The improved anti-tumor efficacy of LHNPs could be partly ascribed to down-regulating metastasis-related proteins. Therefore, these results clearly indicated that LHNPs could become a promising candidate for clinical applications against brain metastasis of TNBC. PMID:27086917

  11. Clinicopathological significance of N-cadherin and VEGF in advanced gastric cancer brain metastasis and the effects of metformin in preclinical models.

    PubMed

    Jun, Kyong-Hwa; Lee, Jung Eun; Kim, Se Hoon; Jung, Ji-Han; Choi, Hyun-Joo; Kim, Young Il; Chin, Hyung-Min; Yang, Seung-Ho

    2015-10-01

    Gastric cancer is the second most common cause of cancer-related death worldwide. Although brain metastasis is a rare complication of gastric cancer, no standard therapy for gastric cancer brain metastasis has been established. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate such markers. A case-control study of patients newly diagnosed with gastric cancer who had developed brain metastasis during follow-up, was conducted. These patients were compared with patients who had advanced gastric cancer but no evidence of brain metastasis. Immunohistochemistry was used to analyze the expression of E-cadherin, N-cadherin, MSS1, claudin-3, claudin-4, Glut1, clusterin, ITGB4, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and p53. The expression of VEGF tended to be higher in the case group (33.3 vs. 0%, p=0.055). Median survival was significantly correlated with vascular invasion (12 vs. 33 months, p=0.008) and N-cadherin expression (36 vs. 12 months, p=0.027). We also investigated the effects of metformin in tumor-bearing mouse models. VEGF expression was decreased and E-cadherin increased in the metformin‑treated group when compared with the control group. The expression of the mesenchymal marker MMP9 was decreased in the metformin-treated group. Brain metastasis of advanced gastric cancer was associated with the expression of VEGF. Metformin treatment may be useful for modulating the metastatic capacity by reducing VEGF expression and blocking epithelial-to-mesenchymal transition.

  12. STAT3 pathway regulates lung-derived brain metastasis initiating cell capacity through miR-21 activation.

    PubMed

    Singh, Mohini; Garg, Neha; Venugopal, Chitra; Hallett, Robin; Tokar, Tomas; McFarlane, Nicole; Mahendram, Sujeivan; Bakhshinyan, David; Manoranjan, Branavan; Vora, Parvez; Qazi, Maleeha; Arpin, Carolynn C; Page, Brent; Haftchenary, Sina; Rosa, David A; Lai, Ping-Shan; Gómez-Biagi, Rodolfo F; Ali, Ahmed M; Lewis, Andrew; Geletu, Mulu; Murty, Naresh K; Hassell, John A; Jurisica, Igor; Gunning, Patrick T; Singh, Sheila K

    2015-09-29

    Brain metastases (BM) represent the most common tumor to affect the adult central nervous system. Despite the increasing incidence of BM, likely due to consistently improving treatment of primary cancers, BM remain severely understudied. In this study, we utilized patient-derived stem cell lines from lung-to-brain metastases to examine the regulatory role of STAT3 in brain metastasis initiating cells (BMICs). Annotation of our previously described BMIC regulatory genes with protein-protein interaction network mapping identified STAT3 as a novel protein interactor. STAT3 knockdown showed a reduction in BMIC self-renewal and migration, and decreased tumor size in vivo. Screening of BMIC lines with a library of STAT3 inhibitors identified one inhibitor to significantly reduce tumor formation. Meta-analysis identified the oncomir microRNA-21 (miR-21) as a target of STAT3 activity. Inhibition of miR-21 displayed similar reductions in BMIC self-renewal and migration as STAT3 knockdown. Knockdown of STAT3 also reduced expression of known downstream targets of miR-21. Our studies have thus identified STAT3 and miR-21 as cooperative regulators of stemness, migration and tumor initiation in lung-derived BM. Therefore, STAT3 represents a potential therapeutic target in the treatment of lung-to-brain metastases. PMID:26314961

  13. Pazopanib-mediated long-term disease stabilization after resection of a uterine leiomyosarcoma metastasis to the brain: A case report.

    PubMed

    Inoue, Kayo; Tsubamoto, Hiroshi; Tomogane, Yusuke; Kamihigashi, Mariko; Shibahara, Hiroaki

    2016-08-01

    A 48-year-old woman underwent a total abdominal hysterectomy after preoperative diagnosis of multiple uterine leiomyomas. The histopathological diagnosis was leiomyosarcoma (LMS). After 47 months, multiple lung metastases were detected and resected. The patient was also diagnosed with pelvic bone metastasis and received six cycles of adjuvant chemotherapy with gemcitabine plus docetaxel and local radiation therapy to control the pain. Seventy-seven months from the initial diagnosis, she had a headache and developed left hemiparesis and aphasia. Imaging studies detected a solitary brain metastasis in the right frontal lobe. The patient underwent a craniotomy and resection of the lesion, which was a confirmed metastasis from uterine LMS by histopathology. One month after the craniotomy, the patient experienced lower abdominal pain, and a pelvic metastasis was detected. She was prescribed oral pazopanib (800 mg per day). For twelve months, she remained asymptomatic, but gradually, pelvic pain increased due to pelvic mass growth. After 14 months of pazopanib treatment, pazopanib was discontinued. To date, for 18 months after the brain surgery, she is alive with disease, and the brain metastasis has not recurred. PMID:27617285

  14. The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma.

    PubMed

    Li, Bo; Sun, Suo-Zhu; Yang, Ming; Shi, Jian-Ling; Xu, Wei; Wang, Xi-Fan; Song, Mao-Min; Chen, Huo-Ming

    2015-08-01

    To explore the correlation between epidermal growth factor receptor (EGFR) mutation status and the risk of brain metastasis (BM) in patients with lung adenocarcinoma, the clinical data of 100 patients with pathologically confirmed lung adenocarcinoma and known EGFR mutation status at exon 18, 19, 20, or 21 were analyzed retrospectively. The incidence of BM was similar between patients with wild-type EGFR and those with EGFR mutations (p = 0.48). However, among patients with EGFR mutations, the incidence of BM was significantly higher in patients with mutation at exon 19 than in patients with mutation at other sites (p = 0.007). Besides, among patients with heterochronous BM, 66.7 % had EGFR mutations. Regarding brain-metastasis-free survival (BMFS), patients with EGFR sensitive mutations (mutation at exon 19/21/and dual mutation) had significantly shorter BMFS compared with patients with wild-type EGFR (p = 0.018). For patients treated only with chemotherapy, BM was an unfavorable prognostic factor. Patients with BM had worse overall survival compared with those without BM (p = 0.035). However, in patients with BM and EGFR sensitive mutations, those treated with tyrosine kinase inhibitors (TKIs) had significantly longer overall survival compared with those treated with chemotherapy only (p = 0.0081). In conclusion, among patients with EGFR mutations, those mutated at exon 19 had the highest incidence of BM. Furthermore, patients with EGFR mutations are more likely to develop heterochronous BM. The BMFS was significantly shorter in patients with EGFR sensitive mutations. TKIs improved the survival of patients with lung adenocarcinoma and BM who harbored EGFR sensitive mutations.

  15. Comparison of Clinical Outcomes of Surgery Followed by Local Brain Radiotherapy and Surgery Followed by Whole Brain Radiotherapy in Patients With Single Brain Metastasis: Single-Center Retrospective Analysis

    SciTech Connect

    Hashimoto, Kenji; Narita, Yoshitaka; Miyakita, Yasuji; Ohno, Makoto; Sumi, Minako; Mayahara, Hiroshi; Kayama, Takamasa; Shibui, Soichiro

    2011-11-15

    Purpose: Data comparing the clinical outcomes of local brain radiotherapy (LBRT) and whole brain RT (WBRT) in patients with a single brain metastasis after tumor removal are limited. Patients and Methods: A retrospective analysis was performed to compare the patterns of treatment failure, cause of death, progression-free survival, median survival time, and Karnofsky performance status for long-term survivors among patients who underwent surgery followed by either LBRT or WBRT between 1990 and 2008 at the National Cancer Center Hospital. Results: A total of 130 consecutive patients were identified. The median progression-free survival period among the patients who received postoperative LBRT (n = 64) and WBRT (n = 66) was 9.7 and 11.5 months, respectively (p = .75). The local recurrence rates (LBRT, 9.4% vs. WBRT, 12.1%) and intracranial new metastasis rate (LBRT, 42.2% vs. WBRT, 33.3%) were similar in each arm. The incidence of leptomeningeal metastasis was also equivalent (LBRT, 9.4% vs. WBRT, 10.6%). The median survival time for the LBRT and WBRT patients was 13.9 and 16.7 months, respectively (p = .88). A neurologic cause of death was noted in 35.6% of the patients in the LBRT group and 36.7% of the WBRT group (p = .99). The Karnofsky performance status at 2 years was comparable between the two groups. Conclusions: The clinical outcomes of LBRT and WBRT were similar. A prospective evaluation is warranted.

  16. A Study Evaluating INIPARIB in Combination With Chemotherapy to Treat Triple Negative Breast Cancer Brain Metastasis

    ClinicalTrials.gov

    2016-02-17

    Estrogen Receptor Negative (ER-Negative) Breast Cancer; Progesterone Receptor Negative (PR-Negative) Breast Cancer; Human Epidermal Growth Factor Receptor 2 Negative (HER2-Negative) Breast Cancer; Brain Metastases

  17. Metastasis Infiltration: An Investigation of the Postoperative Brain-Tumor Interface

    SciTech Connect

    Raore, Bethwel; Schniederjan, Matthew; Prabhu, Roshan; Brat, Daniel J.; Shu, Hui-Kuo; Olson, Jeffrey J.

    2011-11-15

    Purpose: This study aims to evaluate brain infiltration of metastatic tumor cells past the main tumor resection margin to assess the biological basis for the use of stereotactic radiosurgery treatment of the tumor resection cavity and visualized resection edge or clinical target volume. Methods and Materials: Resection margin tissue was obtained after gross total resection of a small group of metastatic lesions from a variety of primary sources. The tissue at the border of the tumor and brain tissue was carefully oriented and processed to evaluate the presence of tumor cells within brain tissue and their distance from the resection margin. Results: Microscopic assessment of the radially oriented tissue samples showed no tumor cells infiltrating the surrounding brain tissue. Among the positive findings were reactive astrocytosis observed on the brain tissue immediately adjacent to the tumor resection bed margin. Conclusions: The lack of evidence of metastatic tumor cell infiltration into surrounding brain suggests the need to target only a narrow depth of the resection cavity margin to minimize normal tissue injury and prevent treatment size-dependent stereotactic radiosurgery complications.

  18. [A Case of Brain Metastasis from Rectal Cancer with Synchronous Liver and Lung Metastases after Multimodality Treatment--A Case Report].

    PubMed

    Udagawa, Masaru; Tominaga, Ben; Kobayashi, Daisuke; Ishikawa, Yuuya; Watanabe, Shuuichi; Adikrisna, Rama; Okamoto, Hiroyuki; Yabata, Eiichi

    2015-11-01

    We report a case of brain metastasis from rectal cancer a long time after the initial resection. A 62-year-old woman, diagnosed with lower rectal cancer with multiple synchronous liver and lung metastases, underwent abdominoperineal resection after preoperative radiochemotherapy (40 Gy at the pelvis, using the de Gramont regimen FL therapy: 1 kur). The histological diagnosis was a moderately differentiated adenocarcinoma. Various regimens of chemotherapy for unresectable and metastatic colorectal cancer were administered, and a partial response was obtained; thereby, the metastatic lesions became resectable. The patient underwent partial resection of the liver and lung metastases. Pathological findings confirmed that both the liver and lung lesions were metastases from the rectal cancer. A disease-free period occurred for several months; however, there were recurrences of the lung metastases, so we started another round of chemotherapy. After 8 months, she complained of vertigo and dizziness. A left cerebellar tumor about 3 cm in diameter was revealed by MRI and neurosurgical excision was performed. Pathological findings confirmed a cerebellar metastasis from the rectal cancer. Twenty months after resection of the brain tumor, the patient complained of a severe headache. A brain MRI showed hydrocephalia, and carcinomatous meningitis from rectal cancer was diagnosed by a spinal fluid cytology test. A ventriculo-peritoneal shunt was inserted, but the cerebrospinal pressure did not decreased and she died 20 months after the first surgery. Although brain metastasis from colorectal cancer is rare, the number of patients with brain metastasis is thought to increase in the near future. Chemotherapy for colorectal cancer is effective enough to prolong the survival period even if multiple metastases have occurred. However, after a long survival period with lung metastases such as in our case, there is a high probability of developing brain metastases.

  19. Detection of brain metastasis with 68Ga-labeled PSMA ligand PET/CT: a novel radiotracer for imaging of prostate carcinoma.

    PubMed

    Chakraborty, Partha Sarathi; Kumar, Rajiv; Tripathi, Madhavi; Das, Chandan Jyoti; Bal, Chandrasekhar

    2015-04-01

    Brain metastasis in prostate cancer is rare and not expected at initial presentation especially when the patient is asymptomatic for the same. A 45-year-old male patient undergoing initial evaluation for newly diagnosed prostatic adenocarcinoma was referred to our department for 99mTc-MDP bone scintigraphy. As part of the study protocol, he also underwent Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68(HBED-CC)] (68Ga-PSMA) PET/CT, which revealed tracer accumulation in brain lesions, apart from localization in the primary, lymph node, and bone metastases. A subsequent MR evaluation confirmed brain metastases.

  20. Neurocognitive Function of Patients with Brain Metastasis Who Received Either Whole Brain Radiotherapy Plus Stereotactic Radiosurgery or Radiosurgery Alone

    SciTech Connect

    Aoyama, Hidefumi . E-mail: hao@radi.med.hokudai.ac.jp; Tago, Masao; Kato, Norio; Toyoda, Tatsuya; Kenjyo, Masahiro; Hirota, Saeko; Shioura, Hiroki; Inomata, Taisuke; Kunieda, Etsuo; Hayakawa, Kazushige; Nakagawa, Keiichi; Kobashi, Gen; Shirato, Hiroki

    2007-08-01

    Purpose: To determine how the omission of whole brain radiotherapy (WBRT) affects the neurocognitive function of patients with one to four brain metastases who have been treated with stereotactic radiosurgery (SRS). Methods and Materials: In a prospective randomized trial between WBRT+SRS and SRS alone for patients with one to four brain metastases, we assessed the neurocognitive function using the Mini-Mental State Examination (MMSE). Of the 132 enrolled patients, MMSE scores were available for 110. Results: In the baseline MMSE analyses, statistically significant differences were observed for total tumor volume, extent of tumor edema, age, and Karnofsky performance status. Of the 92 patients who underwent the follow-up MMSE, 39 had a baseline MMSE score of {<=}27 (17 in the WBRT+SRS group and 22 in the SRS-alone group). Improvements of {>=}3 points in the MMSEs of 9 WBRT+SRS patients and 11 SRS-alone patients (p = 0.85) were observed. Of the 82 patients with a baseline MMSE score of {>=}27 or whose baseline MMSE score was {<=}26 but had improved to {>=}27 after the initial brain treatment, the 12-, 24-, and 36-month actuarial free rate of the 3-point drop in the MMSE was 76.1%, 68.5%, and 14.7% in the WBRT+SRS group and 59.3%, 51.9%, and 51.9% in the SRS-alone group, respectively. The average duration until deterioration was 16.5 months in the WBRT+SRS group and 7.6 months in the SRS-alone group (p = 0.05). Conclusion: The results of the present study have revealed that, for most brain metastatic patients, control of the brain tumor is the most important factor for stabilizing neurocognitive function. However, the long-term adverse effects of WBRT on neurocognitive function might not be negligible.

  1. Assessment of the Molecular Expression and Structure of Gangliosides in Brain Metastasis of Lung Adenocarcinoma by an Advanced Approach Based on Fully Automated Chip-Nanoelectrospray Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Zamfir, Alina D.; Serb, Alina; Vukeli, Željka; Flangea, Corina; Schiopu, Catalin; Fabris, Dragana; Kalanj-Bognar, Svjetlana; Capitan, Florina; Sisu, Eugen

    2011-12-01

    Gangliosides (GGs), sialic acid-containing glycosphingolipids, are known to be involved in the invasive/metastatic behavior of brain tumor cells. Development of modern methods for determination of the variations in GG expression and structure during neoplastic cell transformation is a priority in the field of biomedical analysis. In this context, we report here on the first optimization and application of chip-based nanoelectrospray (NanoMate robot) mass spectrometry (MS) for the investigation of gangliosides in a secondary brain tumor. In our work a native GG mixture extracted and purified from brain metastasis of lung adenocarcinoma was screened by NanoMate robot coupled to a quadrupole time-of-flight MS. A native GG mixture from an age-matched healthy brain tissue, sampled and analyzed under identical conditions, served as a control. Comparative MS analysis demonstrated an evident dissimilarity in GG expression in the two tissue types. Brain metastasis is characterized by many species having a reduced N-acetylneuraminic acid (Neu5Ac) content, however, modified by fucosylation or O-acetylation such as Fuc-GM4, Fuc-GM3, di- O-Ac-GM1, O-Ac-GM3. In contrast, healthy brain tissue is dominated by longer structures exhibiting from mono- to hexasialylated sugar chains. Also, significant differences in ceramide composition were discovered. By tandem MS using collision-induced dissociation at low energies, brain metastasis-associated GD3 (d18:1/18:0) species as well as an uncommon Fuc-GM1 (d18:1/18:0) detected in the normal brain tissue could be structurally characterized. The novel protocol was able to provide a reliable compositional and structural characterization with high analysis pace and at a sensitivity situated in the fmol range.

  2. Relationship Between Neurocognitive Function and Quality of Life After Whole-Brain Radiotherapy in Patients With Brain Metastasis

    SciTech Connect

    Li Jing; Bentzen, Soren M.; Li Jialiang; Renschler, Markus; Mehta, Minesh P.

    2008-05-01

    Purpose: To examine the relationship between neurocognitive function (NCF) and quality of life (QOL) in patients with brain metastases after whole-brain radiotherapy. Patients and Methods: A total of 208 patients from the whole-brain radiotherapy arm of a Phase III trial (PCI-P120-9801), who underwent regular NCF and QOL (ADL [activities of daily living] and FACT-Br [Functional Assessment of Cancer Therapy-Brain-specific]) testing, were analyzed. Spearman's rank correlation was calculated between NCF and QOL, using each patient's own data, at each time point. To test the hypothesis that NCF declines before QOL changes, the predictive effect of NCF from previous visits on QOL was studied with a linear mixed-effects model. Neurocognitive function or QOL deterioration was defined relative to each patient's own baseline. Lead or lag time, defined as NCF deterioration before or after the date of QOL decline, respectively, was computed. Results: At baseline, all NCF tests showed statistically significant correlations with ADL, which became stronger at 4 months. A similar observation was made with FACT-Br. Neurocognitive function scores from previous visits predicted ADL (p < 0.05 for seven of eight tests) or FACT-Br. Scores on all eight NCF tests deteriorated before ADL decline (net lead time 9-153 days); and scores on six of eight NCF tests deteriorated before FACT-Br (net lead time 9-82 days). Conclusions: Neurocognitive function and QOL are correlated. Neurocognitive function scores from previous visits are predictive of QOL. Neurocognitive function deterioration precedes QOL decline. The sequential association between NCF and QOL decline suggests that delaying NCF deterioration is a worthwhile treatment goal in brain metastases patients.

  3. Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin

    PubMed Central

    Bosch-Barrera, Joaquim; Sais, Elia; Cañete, Noemí; Marruecos, Jordi; Cuyàs, Elisabet; Izquierdo, Angel; Porta, Rut; Haro, Manel; Brunet, Joan; Pedraza, Salvador; Menendez, Javier A.

    2016-01-01

    Despite multimodal treatment approaches, the prognosis of brain metastases (BM) from non-small cell lung cancer (NSCLC) remains poor. Untreated patients with BM have a median survival of about 1 month, with almost all patients dying from neurological causes. We herein present the first report describing the response of BM from NSCLC patients to an oral nutraceutical product containing silibinin, a flavonoid extracted from the seeds of the milk thistle. We present evidence of how the use of the silibinin-based nutraceutical Legasil® resulted in significant clinical and radiological improvement of BM from NSCLC patients with poor performance status that progressed after whole brain radiotherapy and chemotherapy. The suppressive effects of silibinin on progressive BM, which involved a marked reduction of the peritumoral brain edema, occurred without affecting the primary lung tumor outgrowth in NSCLC patients. Because BM patients have an impaired survival prognosis and are in need for an immediate tumor control, the combination of brain radiotherapy with silibinin-based nutraceuticals might not only alleviate BM edema but also prove local control and time for either classical chemotherapeutics with immunostimulatory effects or new immunotherapeutic agents such as checkpoint blockers to reveal their full therapeutic potential in NSCLC BM patients. New studies aimed to illuminate the mechanistic aspects underlying the regulatory effects of silibinin on the cellular and molecular pathobiology of BM might expedite the entry of new formulations of silibinin into clinical testing for progressive BM from lung cancer patients. PMID:26959886

  4. In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain.

    PubMed

    Heyn, Chris; Ronald, John A; Ramadan, Soha S; Snir, Jonatan A; Barry, Andrea M; MacKenzie, Lisa T; Mikulis, David J; Palmieri, Diane; Bronder, Julie L; Steeg, Patricia S; Yoneda, Toshiyuki; MacDonald, Ian C; Chambers, Ann F; Rutt, Brian K; Foster, Paula J

    2006-11-01

    Metastasis (the spread of cancer from a primary tumor to secondary organs) is responsible for most cancer deaths. The ability to follow the fate of a population of tumor cells over time in an experimental animal would provide a powerful new way to monitor the metastatic process. Here we describe a magnetic resonance imaging (MRI) technique that permits the tracking of breast cancer cells in a mouse model of brain metastasis at the single-cell level. Cancer cells that were injected into the left ventricle of the mouse heart and then delivered to the brain were detectable on MR images. This allowed the visualization of the initial delivery and distribution of cells, as well as the growth of tumors from a subset of these cells within the whole intact brain volume. The ability to follow the metastatic process from the single-cell stage through metastatic growth, and to quantify and monitor the presence of solitary undivided cells will facilitate progress in understanding the mechanisms of brain metastasis and tumor dormancy, and the development of therapeutics to treat this disease. PMID:17029229

  5. Clinical surveillance compared with clinical and magnetic resonance imaging surveillance for brain metastasis: a feasibility survey

    PubMed Central

    Yiu, K.C.Y.; Greenspoon, J.N.

    2016-01-01

    Introduction After stereotactic radiosurgery (srs) for brain metastases, patients are routinely monitored with magnetic resonance imaging (mri). The high rate of new brain metastases after srs treatment alone might not be as concerning with modern mri and target localization treatment. Intensive surveillance might induce anxiety, lowering the patient’s quality of life (qol). The present work is the feasibility component of a prospective study evaluating the role of surveillance mri on qol in patients with limited (1–3) brain metastases. Methods Patients with limited brain metastases treated with srs alone, an Eastern Cooperative Oncology Group performance status of 2 or less, and documented stability in treated lesions, with no new lesions seen on mri at weeks 6–10 after srs, were eligible. All were asked about their interest in participating in the control (mri and clinical surveillance) or the experimental arm (symptom-directed mri and clinical surveillance). If 33% or more agreed to participate in the experimental arm, it would be considered feasible to conduct the prospective study. Results From November 2014 to July 2015, 45% of patients (10 of 22) agreed to participate in the experimental arm. Subgroup analyses found that the decision to participate has no statistically significant association with time of presentation (p = 0.696), display of symptoms (p = 0.840), age (p = 0.135), or number of lesions (p = 0.171). Conclusions Results show that it is feasible to conduct the prospective cohort study. Because of the small sample size, we are limited in the conclusions able to be drawn in the subgroup analyses. However, the future study would allow for a better understanding of the attitudes of patients toward mri and its effect on qol. PMID:27803601

  6. Concomitant treatment of brain metastasis with Whole Brain Radiotherapy [WBRT] and Temozolomide [TMZ] is active and improves Quality of Life

    PubMed Central

    Addeo, Raffaele; Caraglia, Michele; Faiola, Vincenzo; Capasso, Elena; Vincenzi, Bruno; Montella, Liliana; Guarrasi, Rosario; Caserta, Luigi; Del Prete, Salvatore

    2007-01-01

    Background Brain metastases (BM) represent one of the most frequent complications related to cancer, and their treatment continues to evolve. We have evaluated the activity, toxicity and the impact on Quality of Life (QoL) of a concomitant treatment with whole brain radiotherapy (WBRT) and Temozolomide (TMZ) in patients with brain metastases from solid tumors in a prospective Simon two stage study. Methods Fifty-nine patients were enrolled and received 30 Gy WBRT with concomitant TMZ (75 mg/m2/day) for ten days, and subsequently TMZ (150 mg/m2/day) for up to six cycles. The primary end points were clinical symptoms and radiologic response. Results Five patients had a complete response, 21 patients had a partial response, while 18 patients had stable disease. The overall response rate (45%) exceeded the target activity per study design. The median time to progression was 9 months. Median overall survival was 13 months. The most frequent toxicities included grade 3 neutropenia (15%) and anemia (13%), and only one patient developed a grade 4 thrombocytopenia. Age, Karnofsky performance status, presence of extracranial metastases and the recursive partitioning analysis (RPA) were found to be predictive factors for response in patients. Overall survival (OS) and progression-free survival (PFS) were dependent on age and on the RPA class. Conclusion We conclude that this treatment is well tolerated, with an encouraging objective response rate, and a significant improvement in quality of life (p < 0.0001) demonstrated by FACT-G analysis. All patients answered the questionnaires and described themselves as 'independent' and able to act on their own initiatives. Our study found a high level of satisfaction for QoL, this provides useful information to share with patients in discussions regarding chemotherapy treatment of these lesions. PMID:17254350

  7. Lack of adrenomedullin in mouse endothelial cells results in defective angiogenesis, enhanced vascular permeability, less metastasis, and more brain damage

    PubMed Central

    Ochoa-Callejero, Laura; Pozo-Rodrigálvarez, Andrea; Martínez-Murillo, Ricardo; Martínez, Alfredo

    2016-01-01

    Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. AM plays critical roles in blood vessels, including regulation of vascular stability and permeability. To elucidate the autocrine/paracrine function of AM in endothelial cells (EC) in vivo, a conditional knockout of AM in EC (AMEC-KO) was used. The amount of vascularization of the matrigel implants was lower in AMEC-KO mice indicating a defective angiogenesis. Moreover, ablation of AM in EC revealed increased vascular permeability in comparison with wild type (WT) littermates. In addition, AMEC-KO lungs exhibited significantly less tumor growth than littermate WT mice using a syngeneic model of metastasis. Furthermore, following middle cerebral artery permanent occlusion, there was a significant infarct size decrease in animals lacking endothelial AM when compared to their WT counterparts. AM is an important regulator of EC function, angiogenesis, tumorigenesis, and brain response to ischemia. Studies of AM should bring novel approaches to the treatment of vascular diseases. PMID:27640364

  8. Lack of adrenomedullin in mouse endothelial cells results in defective angiogenesis, enhanced vascular permeability, less metastasis, and more brain damage.

    PubMed

    Ochoa-Callejero, Laura; Pozo-Rodrigálvarez, Andrea; Martínez-Murillo, Ricardo; Martínez, Alfredo

    2016-01-01

    Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. AM plays critical roles in blood vessels, including regulation of vascular stability and permeability. To elucidate the autocrine/paracrine function of AM in endothelial cells (EC) in vivo, a conditional knockout of AM in EC (AM(EC-KO)) was used. The amount of vascularization of the matrigel implants was lower in AM(EC-KO) mice indicating a defective angiogenesis. Moreover, ablation of AM in EC revealed increased vascular permeability in comparison with wild type (WT) littermates. In addition, AM(EC-KO) lungs exhibited significantly less tumor growth than littermate WT mice using a syngeneic model of metastasis. Furthermore, following middle cerebral artery permanent occlusion, there was a significant infarct size decrease in animals lacking endothelial AM when compared to their WT counterparts. AM is an important regulator of EC function, angiogenesis, tumorigenesis, and brain response to ischemia. Studies of AM should bring novel approaches to the treatment of vascular diseases. PMID:27640364

  9. Stereotactic radiosurgery for brain metastasis in non-small cell lung cancer

    PubMed Central

    Won, Yong Kyun; Lee, Ja Young; Kang, Young Nam; Jang, Ji Sun; Kang, Jin-Hyoung; Jung, So-Lyoung; Sung, Soo Yoon; Jo, In Young; Park, Hee Hyun; Lee, Dong-Soo; Chang, Ji Hyun; Lee, Yun Hee

    2015-01-01

    Purpose Stereotactic radiosurgery (SRS) has been introduced for small-sized single and oligo-metastases in the brain. The aim of this study is to assess treatment outcome, efficacy, and prognostic variables associated with survival and intracranial recurrence. Materials and Methods This study retrospectively reviewed 123 targets in 64 patients with non-small cell lung cancer (NSCLC) treated with SRS between January 2006 and December 2012. Treatment responses were evaluated using magnetic resonance imaging. Overall survival (OS) and intracranial progression-free survival (IPFS) were determined. Results The median follow-up was 13.9 months. The median OS and IPFS were 14.1 and 8.9 months, respectively. Fifty-seven patients died during the follow-up period. The 5-year local control rate was achieved in 85% of 108 evaluated targets. The 1- and 2-year OS rates were 55% and 28%, respectively. On univariate analysis, primary disease control (p < 0.001), the Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs. 2; p = 0.002), recursive partitioning analysis class (1 vs. 2; p = 0.001), and age (<65 vs. ≥65 years; p = 0.036) were significant predictive factors for OS. Primary disease control (p = 0.041) and ECOG status (p = 0.017) were the significant prognostic factors for IPFS. Four patients experienced radiation necrosis. Conclusion SRS is a safe and effective local treatment for brain metastases in patients with NSCLC. Uncontrolled primary lung disease and ECOG status were significant predictors of OS and intracranial failure. SRS might be a tailored treatment option along with careful follow-up of the intracranial and primary lung disease status. PMID:26484304

  10. Estimating the need for palliative radiotherapy for brain metastasis: a benchmarking approach.

    PubMed

    Kong, W; Jarvis, C; Mackillop, W J

    2015-02-01

    Palliative radiotherapy (PRT) is useful in the management of many patients with brain metastases, but the need for this treatment in the general cancer population is unknown. The objective of this study was to estimate the appropriate rate of use of PRT for brain metastases (PRT.Br). Ontario's population-based cancer registry was used to identify patients who died of cancer. Radiotherapy records from all the province's radiotherapy centres were linked to Ontario's cancer registry to identify patients who received PRT.Br in the last 2 years of life. Multivariate analysis was used to identify social and health system-related barriers to the use of PRT.Br and to identify a subpopulation of patients with unimpeded access to PRT.Br. The rate of use of PRT.Br was measured in this benchmark subpopulation. The benchmark rate was standardised to the case mix of the overall cancer population. The study population included 231,397 patients who died of cancer in Ontario between 1998 and 2007. Overall, 13,944 patients received at least one course of PRT.Br in the last 2 years of life (6.0%). Multivariate analysis showed that the use of PRT.Br was strongly associated with: the availability of radiotherapy at the diagnosing hospital; the socioeconomic status of the community where the patient lived; and the distance from his/her home to the nearest radiotherapy centre. The benchmark subpopulation was defined as patients diagnosed in a hospital with radiotherapy facilities on site and who resided in a high income community, within 50 km of the nearest radiotherapy centre. The standardised benchmark rate of PRT.Br was 8.0% (95% confidence interval 7.5%, 8.5%). The overall shortfall between the actual rate and the benchmark was 25%, but varied by primary cancer site: lung, 27.6%; melanoma, 19.4%; breast, 13.9%. The magnitude of the shortfall in the use of PRT.Br varied widely across the province. At least 8.0% of patients who die of cancer require PRT.Br at least once in the last 2

  11. Overexpression of microRNA-95-3p suppresses brain metastasis of lung adenocarcinoma through downregulation of cyclin D1.

    PubMed

    Hwang, Su Jin; Lee, Hye Won; Kim, Hye Ree; Song, Hye Jin; Lee, Dong Heon; Lee, Hong; Shin, Chang Hoon; Joung, Je-Gun; Kim, Duk-Hwan; Joo, Kyeung Min; Kim, Hyeon Ho

    2015-08-21

    Despite great efforts to improve survival rates, the prognosis of lung cancer patients is still very poor, mainly due to high invasiveness. We developed brain metastatic PC14PE6/LvBr4 cells through intracardiac injection of lung adenocarcinoma PC14PE6 cells. Western blot and RT-qPCR analyses revealed that PC14PE6/LvBr4 cells had mesenchymal characteristics and higher invasiveness than PC14PE6 cells. We found that cyclin D1 was upregulated, miR-95-3p was inversely downregulated, and pri-miR-95 and its host gene, ABLIM2, were consistently decreased in PC14PE6/LvBr4 cells. MiR-95-3p suppressed cyclin D1 expression through direct binding to the 3' UTR of cyclin D1 mRNA and suppressed invasiveness, proliferation, and clonogenicity of PC14PE6/LvBr4 cells. Ectopic cyclin D1 reversed miR-95-3p-mediated inhibition of invasiveness and clonogenicity, demonstrating cyclin D1 downregulation is involved in function of miR-95-3p. Using bioluminescence imaging, we found that miR-95-3p suppressed orthotopic tumorigenicity and brain metastasis in vivo and increased overall survival and brain metastasis-free survival. Consistent with in vitro metastatic cells, the levels of miR-95-3p, pri-miR-95, and ABLIM2 mRNA were decreased in brain metastatic tissues compared with lung cancer tissues and higher cyclin D1 expression was involved in poor prognosis. Taken together, our results demonstrate that miR-95-3p is a potential therapeutic target for brain metastasis of lung adenocarcinoma cells.

  12. Blockage of the Upregulation of Voltage-Gated Sodium Channel Nav1.3 Improves Outcomes after Experimental Traumatic Brain Injury

    PubMed Central

    Huang, Xian-jian; Li, Wei-ping; Lin, Yong; Feng, Jun-feng; Jia, Feng

    2014-01-01

    Abstract Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Nav1.3 expression occurs in the rat cortex at 2 h and 12 h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Nav1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Nav1.3 or artificial cerebrospinal fluid (aCSF) at 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h post-TBI, Nav1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups (p<0.01). However, the Nav1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group (p<0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region (p<0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group (p<0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group (p<0.01). However, latency in the aCSF group was significantly higher than in the ODN group (p<0.05). Our in vivo Nav1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Nav1.3 expression in the brain may improve outcomes following TBI. PMID:24313291

  13. Overall and disease-free survival greater than 12 years in metastatic non-small cell lung cancer after linear accelerator-based stereotactic radiosurgery for solitary brain metastasis.

    PubMed

    Scorsetti, Marta; Alongi, Filippo; Navarria, Piera; Cortinovis, Diego; Bidoli, Paolo

    2012-01-01

    The best treatment approach for solitary brain metastasis is not well defined and there is no consensus on this issue. It is still being debated whether patients with isolated brain metastasis should undergo surgical resection or stereotactic radiosurgery, and which patients should receive adjuvant whole brain radiotherapy. The median survival in patients with single or multiple metastatic lesions who underwent only stereotactic radiosurgery improved from two-three months to nine months. To the best of our knowledge this is the first report on patients treated with linear accelerator-based stereotactic radiosurgery alone where an overall survival of more than 12 years was obtained, maintaining good quality of life in three cases of solitary brain metastasis from non-small cell lung cancer. In addition to the case reports, we present a brief literature review on this topic. PMID:22677999

  14. Whole Brain Radiotherapy With Hippocampal Avoidance and Simultaneous Integrated Boost for 1-3 Brain Metastases: A Feasibility Study Using Volumetric Modulated Arc Therapy

    SciTech Connect

    Hsu, Fred; Carolan, Hannah; Nichol, Alan; Cao, Fred; Nuraney, Nimet; Lee, Richard; Gete, Ermias; Wong, Frances; Schmuland, Moira; Heran, Manraj; Otto, Karl

    2010-04-15

    Purpose: To evaluate the feasibility of using volumetric modulated arc therapy (VMAT) to deliver whole brain radiotherapy (WBRT) with hippocampal avoidance and a simultaneous integrated boost (SIB) for one to three brain metastases. Methods and Materials: Ten patients previously treated with stereotactic radiosurgery for one to three brain metastases underwent repeat planning using VMAT. The whole brain prescription dose was 32.25 Gy in 15 fractions, and SIB doses to brain metastases were 63 Gy to lesions >=2.0 cm and 70.8 Gy to lesions <2.0 cm in diameter. The mean dose to the hippocampus was kept at <6 Gy{sub 2}. Plans were optimized for conformity and target coverage while minimizing hippocampal and ocular doses. Plans were evaluated on target coverage, prescription isodose to target volume ratio, conformity number, homogeneity index, and maximum dose to prescription dose ratio. Results: Ten patients had 18 metastases. Mean values for the brain metastases were as follows: conformity number = 0.73 +- 0.10, target coverage = 0.98 +- 0.01, prescription isodose to target volume = 1.34 +- 0.19, maximum dose to prescription dose ratio = 1.09 +- 0.02, and homogeneity index = 0.07 +- 0.02. For the whole brain, the mean target coverage and homogeneity index were 0.960 +- 0.002 and 0.39 +- 0.06, respectively. The mean hippocampal dose was 5.23 +- 0.39 Gy{sub 2}. The mean treatment delivery time was 3.6 min (range, 3.3-4.1 min). Conclusions: VMAT was able to achieve adequate whole brain coverage with conformal hippocampal avoidance and radiosurgical quality dose distributions for one to three brain metastases. The mean delivery time was under 4 min.

  15. Long-Term Survival in Patients With Synchronous, Solitary Brain Metastasis From Non-Small-Cell Lung Cancer Treated With Radiosurgery

    SciTech Connect

    Flannery, Todd W.; Suntharalingam, Mohan; Regine, William F.; Chin, Lawrence S.; Krasna, Mark J.; Shehata, Michael K.; Edelman, Martin J.; Kremer, Marnie; Patchell, Roy A.; Kwok, Young

    2008-09-01

    Purpose: To report the outcome of patients with synchronous, solitary brain metastasis from non-small-cell lung cancer (NSCLC) treated with gamma knife stereotactic radiosurgery (GKSRS). Patients and Methods: Forty-two patients diagnosed with synchronous, solitary brain metastasis from NSCLC were treated with GKSRS between 1993 and 2006. The median Karnofsky performance status (KPS) was 90. Patients had thoracic Stage I-III disease (American Joint Committee on Cancer 2002 guidelines). Definitive thoracic therapy was delivered to 26/42 (62%) patients; 9 patients underwent chemotherapy and radiation, 12 patients had surgical resection, and 5 patients underwent preoperative chemoradiation and surgical resection. Results: The median overall survival (OS) was 18 months. The 1-, 2-, and 5-year actuarial OS rates were 71.3%, 34.1%, and 21%, respectively. For patients who underwent definitive thoracic therapy, the median OS was 26.4 months compared with 13.1 months for those who had nondefinitive therapy, and the 5-year actuarial OS was 34.6% vs. 0% (p < 0.0001). Median OS was significantly longer for patients with a KPS {>=}90 vs. KPS < 90 (27.8 months vs. 13.1 months, p < 0.0001). The prognostic factors significant on multivariate analysis were definitive thoracic therapy (p = 0.020) and KPS (p = 0.001). Conclusions: This is one of the largest series of patients diagnosed with synchronous, solitary brain metastasis from NSCLC treated with GKSRS. Definitive thoracic therapy and KPS significantly impacted OS. The 5-year OS of 21% demonstrates the potential for long-term survival in patients treated with GKSRS; therefore, patients with good KPS should be considered for definitive thoracic therapy.

  16. Ultra-high resolution polarization-sensitive optical coherence microscopy for brain imaging at 6 um, 3.4 um and 1.3 um resolution (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Wang, Hui; Akkin, Taner; Magnain, Caroline V.; Yaseen, Mohammad A.; Cramer, Avilash; Wang, Ruopeng; Sakadžic, Sava; Boas, David A.

    2016-03-01

    Neuroanatomical pathways form the basis for functional activity of brain circuits. In the past, we developed a polarization-sensitive optical coherence tomography with serial scanning to achieve large-scale brain imaging. The system was able to visualize 3D fiber tracts of ~20 um in diameter. To investigate the neuroanatomical pathways at finer scales, we have now built a polarization-maintaining fiber based ultra-high resolution polarization-sensitive optical coherence microscope (PS-OCM) at 1300 nm. The PS-OCM has an axial resolution of 3.5 um in tissue. The detection setup consists of two spectrometers, acquiring spectral interference on orthogonal polarization channels. With a single measurement, the setup generates four contrasts: reflectivity, cross-polarization, retardance and optic axis orientation. To investigate the capability of PS-OCM at different resolutions, we used three microscope objectives that yield lateral resolutions of 6.0 um, 3.4 um and 1.3 um. Blocks of formalin fixed mouse brain and human brain were scanned. The cross-polarization and retardance images clearly depict the neuronal fiber structures, which are comparable with that generated by the maximum projection of volumetric reflectivity data. The optic axis orientation quantifies the in-plane fiber orientation. With the lateral resolution of 1.3 um, the retardance contrast is weak in white matter due to the shallow depth of focus. Overall, the ultra-high resolution PS-OCM provides a new tool to reveal neuroanatomical maps in the brain at cellular resolution.

  17. A Rare Cause of Bowel Obstruction: Peritoneal Metastases in Osteosarcoma at the Tibia in a Young Female Patient with Brain Metastasis. Case Report.

    PubMed

    Badiu, Dumitru Cristinel; Manea, Cristina Alexandra; Porojan, Vlad; Paraschiv, Marius; Mehedintu, Claudia; Coman, Ionut Simion; Grigorean, Valentin Titus

    2016-01-01

    Osteosarcomas are the most frequent primary malignant bone tumors in children and adolescents. Like brain metastases in osteosarcomas, the bowel metastases are very rare. We present the case of a 23-year-old female patient, diagnosed and operated in 2008 of osteosarcoma at the tibia, for which she had sessions of neoadjuvant and adjuvant chemotherapy, but presented lungs metastases for which she underwent surgery in 2014. Then, in March 2015, she was diagnosed with an intracranial expansive process, an osteosarcoma metastasis, for which a total ablation of the tumor was performed during the early postoperatory period, being transferred to the General Surgery Clinic for abdominal pain, abdominal distention, vomiting, and lack of intestinal transit regarding faeces and intestinal gas. Both clinically and imagistically, the diagnosis was of bowel obstruction. This was the reason for performing surgery, thus discovering a bowel obstruction secondary to a metastasis of the terminal ileum and liver metastases that were confirmed as osteosarcoma metastases from an anatomopathological and immunohistochemical point of view. The bowel metastases and the osteosarcoma brain metastases are very rare entities and, their association, most often with young patients, is exceptional. However, bowel metastases must be taken into account as a possible cause of bowel obstruction in patients with osteosarcoma. PMID:27452942

  18. Pharmacologic inhibition of MLK3 kinase activity blocks the in vitro migratory capacity of breast cancer cells but has no effect on breast cancer brain metastasis in a mouse xenograft model.

    PubMed

    Rhoo, Kun Hyoe; Granger, Megan; Sur, Joynita; Feng, Changyong; Gelbard, Harris A; Dewhurst, Stephen; Polesskaya, Oksana

    2014-01-01

    Brain metastasis of breast cancer is an important clinical problem, with few therapeutic options and a poor prognosis. Recent data have implicated mixed lineage kinase 3 (MLK3) in controlling the in vitro migratory capacity of breast cancer cells, as well as the metastasis of MDA-MB-231 breast cancer cells from the mammary fat pad to distant lymph nodes in a mouse xenograft model. We therefore set out to test whether MLK3 plays a role in brain metastasis of breast cancer cells. To address this question, we used a novel, brain penetrant, MLK3 inhibitor, URMC099. URMC099 efficiently inhibited the migration of breast cancer cells in an in vitro cell monolayer wounding assay, and an in vitro transwell migration assay, but had no effect on in vitro cell growth. We also tested the effect of URMC099 on tumor formation in a mouse xenograft model of breast cancer brain metastasis. This analysis showed that URMC099 had no effect on the either the frequency or size of breast cancer brain metastases. We conclude that pharmacologic inhibition of MLK3 by URMC099 can reduce the in vitro migratory capacity of breast cancer cells, but that it has no effect on either the frequency or size of breast cancer brain metastases, in a mouse xenograft model.

  19. SU-E-QI-21: Iodinated Contrast Agent Time Course In Human Brain Metastasis: A Study For Stereotactic Synchrotron Radiotherapy Clinical Trials

    SciTech Connect

    Obeid, L; Esteve, F; Adam, J; Tessier, A; Balosso, J

    2014-06-15

    Purpose: Synchrotron stereotactic radiotherapy (SSRT) is an innovative treatment combining the selective accumulation of heavy elements in tumors with stereotactic irradiations using monochromatic medium energy x-rays from a synchrotron source. Phase I/II clinical trials on brain metastasis are underway using venous infusion of iodinated contrast agents. The radiation dose enhancement depends on the amount of iodine in the tumor and its time course. In the present study, the reproducibility of iodine concentrations between the CT planning scan day (Day 0) and the treatment day (Day 10) was assessed in order to predict dose errors. Methods: For each of days 0 and 10, three patients received a biphasic intravenous injection of iodinated contrast agent (40 ml, 4 ml/s, followed by 160 ml, 0.5 ml/s) in order to ensure stable intra-tumoral amounts of iodine during the treatment. Two volumetric CT scans (before and after iodine injection) and a multi-slice dynamic CT of the brain were performed using conventional radiotherapy CT (Day 0) or quantitative synchrotron radiation CT (Day 10). A 3D rigid registration was processed between images. The absolute and relative differences of absolute iodine concentrations and their corresponding dose errors were evaluated in the GTV and PTV used for treatment planning. Results: The differences in iodine concentrations remained within the standard deviation limits. The 3D absolute differences followed a normal distribution centered at zero mg/ml with a variance (∼1 mg/ml) which is related to the image noise. Conclusion: The results suggest that dose errors depend only on the image noise. This study shows that stable amounts of iodine are achievable in brain metastasis for SSRT treatment in a 10 days interval.

  20. A Melanoma Brain Metastasis with a Donor-Patient Hybrid Genome following Bone Marrow Transplantation: First Evidence for Fusion in Human Cancer

    PubMed Central

    Duvall, Eric; Spoelstra, Nicole; Klump, Vincent; Sznol, Mario; Cooper, Dennis; Spritz, Richard A.; Chang, Joseph T.; Pawelek, John M.

    2013-01-01

    Background Tumor cell fusion with motile bone marrow-derived cells (BMDCs) has long been posited as a mechanism for cancer metastasis. While there is much support for this from cell culture and animal studies, it has yet to be confirmed in human cancer, as tumor and marrow-derived cells from the same patient cannot be easily distinguished genetically. Methods We carried out genotyping of a metastatic melanoma to the brain that arose following allogeneic bone-marrow transplantation (BMT), using forensic short tandem repeat (STR) length-polymorphisms to distinguish donor and patient genomes. Tumor cells were isolated free of leucocytes by laser microdissection, and tumor and pre-transplant blood lymphocyte DNAs were analyzed for donor and patient alleles at 14 autosomal STR loci and the sex chromosomes. Results All alleles in the donor and patient pre-BMT lymphocytes were found in tumor cells. The alleles showed disproportionate relative abundances in similar patterns throughout the tumor, indicating the tumor was initiated by a clonal fusion event. Conclusions Our results strongly support fusion between a BMDC and a tumor cell playing a role in the origin of this metastasis. Depending on the frequency of such events, the findings could have important implications for understanding the generation of metastases, including the origins of tumor initiating cells and the cancer epigenome. PMID:23840523

  1. Activity of pemetrexed-based regimen as first-line chemotherapy for advanced non-small cell lung cancer with asymptomatic inoperable brain metastasis: a retrospective study.

    PubMed

    Zhu, Weiyou; Røe, Oluf Dimitri; Wu, Chen; Li, Wei; Guo, Renhua; Gu, Yanhong; Liu, Yiqian; Shu, Yongqian; Chen, Xiaofeng

    2015-08-01

    This retrospective study was conducted to assess the efficacy of combination of pemetrexed and cisplatin/carboplatin as first-line treatment in inoperable and asymptomatic brain metastasis (BM) from non-small cell lung cancer (NSCLC). A total of 30 patients with adenocarcinoma were included. Nine patients had solitary, and 21 patients had multiple BM. At evaluation after two cycles, the complete response (CR) rate, partial response (PR) rate, and stable disease (SD) for brain lesions was 0, 33.3, and 46.7%, respectively. The overall CR, PR, and SD were 0, 23.3, and 46.7%, respectively. The median time to tumour progression of BM (TTP-BM) was 6.0 months (95% CI 4.068-7.932). The median progression-free survival (PFS) and overall survival (OS) were 5.0 months (95% CI 4.197-5.803) and 11.0 months (95% CI 7.398-14.602), respectively. Pemetrexed has comparable activity on brain lesions as on extracranial tumours in advanced lung adenocarcinoma patients with inoperable and asymptomatic BM.

  2. [Biology of cancer metastasis].

    PubMed

    Robert, Jacques

    2013-04-01

    Metastatic dissemination represents the true cause of the malignant character of cancers. Its targeting is much more difficult than that of cell proliferation, because metastasis, like angiogenesis, involves a number of complex interactions between tumour and stroma; the contribution of adhesion and motility pathways is added to that of proliferation and survival pathways. Long distance extension, discontinuous in respect to the primitive tumour, is a major feature of cancer and the main cause of patients' death. Cancer cells use two main dissemination pathways: the lymphatic pathway, leading to the invasion of the lymph nodes draining the organs where the tumour evolves; and the blood pathway, leading to the invasion of distant organs such as liver, brain, bone or lung. Metastasis is inscribed within the properties of the primitive tumour, as shown by the comparative molecular analysis of the primitive tumour and its own metastases: their similarity is always more important than what could be expected from the general activation of "metastasis genes" or the inhibition of "metastasis suppressor genes". Among the signalling pathways involved in metastasis, one can mention the integrin pathway, the transforming growth factor beta (TGFβ) pathway, the chemokine pathway, the dependence receptor pathway and many others. These pathways allow the possibility of therapeutic targeting, thanks to therapeutic antibodies or small molecules inhibiting the kinases involved in these signalling pathways, but not a single properly anti-metastatic drug has yet been proposed: the complexity and the diversity of the processes allowing metastasis emergence, as well as the fact that the activation mechanisms are more often epigenetic than genetic and are generally physiological processes misled by the malignant cell, render especially difficult the therapeutic approach of metastasis.

  3. Palbociclib in Treating Patients With Metastatic HER-2 Positive or Triple-Negative Breast Cancer With Brain Metastasis

    ClinicalTrials.gov

    2016-05-26

    Breast Carcinoma Metastatic in the Brain; Estrogen Receptor Negative; HER2/Neu Negative; HER2/Neu Positive; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

  4. Feasibility on using composite gel-alanine dosimetry on the validation of a multiple brain metastasis radiosurgery VMAT technique

    NASA Astrophysics Data System (ADS)

    Pavoni, J. F.; Neves-Junior, W. F. P.; Silveira, M. A.; Ramos, P. A. M. M.; Haddad, C. M. K.; Baffa, O.

    2015-01-01

    This work presents an end-to-end test using a composite Gel-Alanine phantom, in order to validate 3-dimensionally the dose distribution delivered by a single isocenter VMAT technique on the simultaneous treatment of multiple brain metastases. The results obtained with the gel and alanine dosimeters are consistent with the expected by the treatment planning system, showing the potential of this multidosimetric approach and validating dosimetrically the multiple brain metastases treatment using VMAT.

  5. Discordance of Mutation Statuses of Epidermal Growth Factor Receptor and K-ras between Primary Adenocarcinoma of Lung and Brain Metastasis.

    PubMed

    Rau, Kun-Ming; Chen, Han-Ku; Shiu, Li-Yen; Chao, Tsai-Ling; Lo, Yi-Ping; Wang, Chin-Chou; Lin, Meng-Chih; Huang, Chao-Cheng

    2016-01-01

    Mutations on epidermal growth factor receptor (EGFR) of adenocarcinomas of lung have been found to be associated with increased sensitivity to EGFR tyrosine kinase inhibitors and K-ras mutations may correlate with primary resistance. We aimed to explore the discordant mutation statuses of EGFR and K-ras between primary tumors and matched brain metastases in adenocarcinomas of lung. We used a sensitive Scorpion ARMS method to analyze EGFR mutation, and Sanger sequencing followed by allele-specific real-time polymerase chain reaction to analyze K-ras mutation. Forty-nine paired tissues with both primary adenocarcinoma of lung and matched brain metastasis were collected. Thirteen patients (26.5%) were discordant for the status of EGFR between primary and metastatic sites. K-ras gene could be checked in paired specimens from 33 patients, thirteen patients (39.6%) were discordant for the status of K-ras. In primary lung adenocarcinoma, there were 14 patients of mutant EGFR had mutant K-ras synchronously. This study revealed that the status of EGFR mutation in lung adenocarcinomas is relatively consistent between primary and metastatic sites compared to K-ras mutation. However, there are still a few cases of adenocarcinoma of lung showing discordance for the status of EGFR mutation. Repeated analysis of EGFR mutation is highly recommended if tissue from metastatic or recurrent site is available for the evaluation of target therapy. PMID:27070580

  6. The Application of Lean Thinking to the Care of Patients With Bone and Brain Metastasis With Radiation Therapy

    PubMed Central

    Kim, Christopher S.; Hayman, James A.; Billi, John E.; Lash, Kathy; Lawrence, Theodore S.

    2007-01-01

    Purpose Patients with bone and brain metastases are among the most symptomatic nonemergency patients treated by radiation oncologists. Treatment should begin as soon as possible after the request is generated. We tested the hypothesis that the operational improvement method based on lean thinking could help streamline the treatment of our patients referred for bone and brain metastases. Methods University of Michigan Health System has adopted lean thinking as a consistent approach to quality and process improvement. We applied the principles and tools of lean thinking, especially value as defined by the customer, value stream mapping processes, and one piece flow, to improve the process of delivering care to patients referred for bone or brain metastases. Results and Conclusion The initial evaluation of the process revealed that it was rather chaotic and highly variable. Implementation of the lean thinking principles permitted us to improve the process by cutting the number of individual steps to begin treatment from 27 to 16 and minimize variability by applying standardization. After an initial learning period, the percentage of new patients with brain or bone metastases receiving consultation, simulation, and treatment within the same day rose from 43% to nearly 95%. By implementing the ideas of lean thinking, we improved the delivery of clinical care for our patients with bone or brain metastases. We believe these principles can be applied to much of the care administered throughout our and other health care delivery areas. PMID:20859409

  7. Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis.

    PubMed

    Dun, Matthew D; Chalkley, Robert J; Faulkner, Sam; Keene, Sheridan; Avery-Kiejda, Kelly A; Scott, Rodney J; Falkenby, Lasse G; Cairns, Murray J; Larsen, Martin R; Bradshaw, Ralph A; Hondermarck, Hubert

    2015-09-01

    Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and l-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation.

  8. Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis*

    PubMed Central

    Dun, Matthew D.; Chalkley, Robert J.; Faulkner, Sam; Keene, Sheridan; Avery-Kiejda, Kelly A.; Scott, Rodney J.; Falkenby, Lasse G.; Cairns, Murray J.; Larsen, Martin R.; Bradshaw, Ralph A.; Hondermarck, Hubert

    2015-01-01

    Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231-BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase-2, the S100 calcium-binding protein A4, and l-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation. PMID:26041846

  9. Secondary Analysis of RTOG 9508, a Phase 3 Randomized Trial of Whole-Brain Radiation Therapy Versus WBRT Plus Stereotactic Radiosurgery in Patients With 1-3 Brain Metastases; Poststratified by the Graded Prognostic Assessment (GPA)

    SciTech Connect

    Sperduto, Paul W.; Shanley, Ryan; Luo, Xianghua; Andrews, David; Werner-Wasik, Maria; Valicenti, Richard; Bahary, Jean-Paul; Souhami, Luis; Won, Minhee; Mehta, Minesh

    2014-11-01

    Purpose: Radiation Therapy Oncology Group (RTOG) 9508 showed a survival advantage for patients with 1 but not 2 or 3 brain metastasis (BM) treated with whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) versus WBRT alone. An improved prognostic index, the graded prognostic assessment (GPA) has been developed. Our hypothesis was that if the data from RTOG 9508 were poststratified by the GPA, the conclusions may vary. Methods and Materials: In this analysis, 252 of the 331 patients were evaluable by GPA. Of those, 211 had lung cancer. Breast cancer patients were excluded because the components of the breast GPA are not in the RTOG database. Multiple Cox regression was used to compare survival between treatment groups, adjusting for GPA. Treatment comparisons within subgroups were performed with the log-rank test. A free online tool ( (brainmetgpa.com)) simplified GPA use. Results: The fundamental conclusions of the primary analysis were confirmed in that there was no survival benefit overall for patients with 1 to 3 metastases; however, there was a benefit for the subset of patients with GPA 3.5 to 4.0 (median survival time [MST] for WBRT + SRS vs WBRT alone was 21.0 versus 10.3 months, P=.05) regardless of the number of metastases. Among patients with GPA 3.5 to 4.0 treated with WBRT and SRS, the MST for patients with 1 versus 2 to 3 metastases was 21 and 14.1 months, respectively. Conclusions: This secondary analysis of predominantly lung cancer patients, consistent with the original analysis, shows no survival advantage for the group overall when treated with WBRT and SRS; however, in patients with high GPA (3.5-4), there is a survival advantage regardless of whether they have 1, 2, or 3 BM. This benefit did not extend to patients with lower GPA. Prospective validation of this survival benefit for patients with multiple BM and high GPA when treated with WBRT and SRS is warranted.

  10. The reciprocal interactions between astrocytes and prostate cancer cells represent an early event associated with brain metastasis.

    PubMed

    de Oliveira Barros, Eliane Gouvêa; Palumbo, Antonio; Mello, Pedro Lucas Prado; de Mattos, Rômulo Medina; da Silva, Julianna Henriques; Pontes, Bruno; Viana, Nathan Bessa; do Amaral, Rackele Ferreira; Lima, Flavia Regina Souza; da Costa, Nathalia Meireles; Palmero, Celia Yelimar; Miranda-Alves, Leandro; Takiya, Christina Maeda; Nasciutti, Luiz Eurico

    2014-04-01

    Tumor establishment, growth, and survival are supported by interactions with microenvironment components. Here, we investigated whether the interactions between prostate cancer cells and cortical astrocytes are associated to a potential role for astrocytes in tumor establishment. We demonstrate that astrocytes interact in vitro with prostatic cancers cells derived from different metastatic sites. Astrocytes and their secreted extracellular matrix, stimulate DU145 cell (a brain-derived prostate tumor cell line) proliferation while inhibiting cell death and modulating the expression of several genes related to prostate cancer progression, suggesting the activation of EMT process in these cells. In contrast, DU145 cells and their conditioned medium inhibited cell proliferation and induced cell death of astrocytes. On the other hand, the astrocytes were unable to significantly induce an increment of LNCaP cell (a lymph node-derived prostate tumor cell line) proliferative activity. In addition, LNCaP cells were also unable to induce cell death of astrocytes. Thus, we believe that DU145 cells, but not LNCaP cells, present an even more aggressive behavior when interacting with astrocytes. These results provide an important contribution to the elucidation of the cellular mechanisms involved in the brain microenvironment colonization.

  11. A multimodality imaging model to track viable breast cancer cells from single arrest to metastasis in the mouse brain

    PubMed Central

    Parkins, Katie M.; Hamilton, Amanda M.; Makela, Ashley V.; Chen, Yuanxin; Foster, Paula J.; Ronald, John A.

    2016-01-01

    Cellular MRI involves sensitive visualization of iron-labeled cells in vivo but cannot differentiate between dead and viable cells. Bioluminescence imaging (BLI) measures cellular viability, and thus we explored combining these tools to provide a more holistic view of metastatic cancer cell fate in mice. Human breast carcinoma cells stably expressing Firefly luciferase were loaded with iron particles, injected into the left ventricle, and BLI and MRI were performed on days 0, 8, 21 and 28. The number of brain MR signal voids (i.e., iron-loaded cells) on day 0 significantly correlated with BLI signal. Both BLI and MRI signals decreased from day 0 to day 8, indicating a loss of viable cells rather than a loss of iron label. Total brain MR tumour volume on day 28 also correlated with BLI signal. Overall, BLI complemented our sensitive cellular MRI technologies well, allowing us for the first time to screen animals for successful injections, and, in addition to MR measures of cell arrest and tumor burden, provided longitudinal measures of cancer cell viability in individual animals. We predict this novel multimodality molecular imaging framework will be useful for evaluating the efficacy of emerging anti-cancer drugs at different stages of the metastatic cascade. PMID:27767185

  12. The reciprocal interactions between astrocytes and prostate cancer cells represent an early event associated with brain metastasis.

    PubMed

    de Oliveira Barros, Eliane Gouvêa; Palumbo, Antonio; Mello, Pedro Lucas Prado; de Mattos, Rômulo Medina; da Silva, Julianna Henriques; Pontes, Bruno; Viana, Nathan Bessa; do Amaral, Rackele Ferreira; Lima, Flavia Regina Souza; da Costa, Nathalia Meireles; Palmero, Celia Yelimar; Miranda-Alves, Leandro; Takiya, Christina Maeda; Nasciutti, Luiz Eurico

    2014-04-01

    Tumor establishment, growth, and survival are supported by interactions with microenvironment components. Here, we investigated whether the interactions between prostate cancer cells and cortical astrocytes are associated to a potential role for astrocytes in tumor establishment. We demonstrate that astrocytes interact in vitro with prostatic cancers cells derived from different metastatic sites. Astrocytes and their secreted extracellular matrix, stimulate DU145 cell (a brain-derived prostate tumor cell line) proliferation while inhibiting cell death and modulating the expression of several genes related to prostate cancer progression, suggesting the activation of EMT process in these cells. In contrast, DU145 cells and their conditioned medium inhibited cell proliferation and induced cell death of astrocytes. On the other hand, the astrocytes were unable to significantly induce an increment of LNCaP cell (a lymph node-derived prostate tumor cell line) proliferative activity. In addition, LNCaP cells were also unable to induce cell death of astrocytes. Thus, we believe that DU145 cells, but not LNCaP cells, present an even more aggressive behavior when interacting with astrocytes. These results provide an important contribution to the elucidation of the cellular mechanisms involved in the brain microenvironment colonization. PMID:24488147

  13. Response of 9L rat brain tumor multicellular spheroids to single and fractionated doses of 1,3-bis(2-chloroethyl)-1-nitrosourea.

    PubMed

    Sano, Y; Hoshino, T; Barker, M; Deen, D F

    1984-02-01

    This study was designed to examine the relative effect of each of four fractions of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against 9L rat brain tumor multicellular spheroids and to compare the results of the cell survival and growth delay assays. Similar levels of cell kill resulted when BCNU was administered either as single fractions of 1.5, 3.0, 4.5, or 6.0 micrograms/ml for 1 hr or as one to four fractions of 1.5 micrograms/ml that were administered sequentially for 1 hr each. Survival was increased if the assay was delayed until 24 hr after drug treatment, which indicates that 9L cells in spheroids recover from BCNU-induced potentially lethal damage. When BCNU was administered in 1.5-micrograms/ml fractions, plating efficiencies depended markedly on the interval between the fractions. The 12-hr protocol produced an overall higher cell kill. Fractionation schedules of 24 and 36 hr produced less cell kill than did the other schedules. Survival plateaued for the last three treatments with BCNU in the 36-hr schedule. Cells in S phase at the time of administration of the initial 1.5-micrograms/ml fraction of BCNU moved into G1- and G2-M phases by 12 hr after treatment. For time periods longer than 12 hr, cells began to appear in the BCNU-resistant S phase. Thus, the movement of cells into the drug-sensitive and -resistant phases after the first fraction correlates well with the corresponding overall cytotoxic effect produced by treatment with the combined BCNU (1.5 micrograms/ml) fractions. For a higher concentration (3.0 micrograms/ml for 1 hr), maximum cell kill was reached within the 12- to 18-hr interval, after which cell kill plateaued. Cells were not found in the S-phase fraction 12 to 36 hr after the first treatment with 3.0 micrograms/ml; maximum cell kill for the fractionated protocols resulted at these times. Therefore, BCNU, which is classified as a cell cycle-nonspecific drug, can induce a partial synchrony in 9L spheroid cells, which determines

  14. Swept-source optical coherence tomography powered by a 1.3-μm vertical cavity surface emitting laser enables 2.3-mm-deep brain imaging in mice in vivo

    PubMed Central

    Choi, Woo June; Wang, Ruikang K.

    2015-01-01

    Abstract. We report noninvasive, in vivo optical imaging deep within a mouse brain by swept-source optical coherence tomography (SS-OCT), enabled by a 1.3-μm vertical cavity surface emitting laser (VCSEL). VCSEL SS-OCT offers a constant signal sensitivity of 105 dB throughout an entire depth of 4.25 mm in air, ensuring an extended usable imaging depth range of more than 2 mm in turbid biological tissue. Using this approach, we show deep brain imaging in mice with an open-skull cranial window preparation, revealing intact mouse brain anatomy from the superficial cerebral cortex to the deep hippocampus. VCSEL SS-OCT would be applicable to small animal studies for the investigation of deep tissue compartments in living brains where diseases such as dementia and tumor can take their toll. PMID:26447860

  15. Swept-source optical coherence tomography powered by a 1.3-μm vertical cavity surface emitting laser enables 2.3-mm-deep brain imaging in mice in vivo

    NASA Astrophysics Data System (ADS)

    Choi, Woo June; Wang, Ruikang K.

    2015-10-01

    We report noninvasive, in vivo optical imaging deep within a mouse brain by swept-source optical coherence tomography (SS-OCT), enabled by a 1.3-μm vertical cavity surface emitting laser (VCSEL). VCSEL SS-OCT offers a constant signal sensitivity of 105 dB throughout an entire depth of 4.25 mm in air, ensuring an extended usable imaging depth range of more than 2 mm in turbid biological tissue. Using this approach, we show deep brain imaging in mice with an open-skull cranial window preparation, revealing intact mouse brain anatomy from the superficial cerebral cortex to the deep hippocampus. VCSEL SS-OCT would be applicable to small animal studies for the investigation of deep tissue compartments in living brains where diseases such as dementia and tumor can take their toll.

  16. Definitive Chemoradiation Therapy Following Surgical Resection or Radiosurgery Plus Whole-Brain Radiation Therapy in Non-Small Cell Lung Cancer Patients With Synchronous Solitary Brain Metastasis: A Curative Approach

    SciTech Connect

    Parlak, Cem; Mertsoylu, Hüseyin; Güler, Ozan Cem; Onal, Cem; Topkan, Erkan

    2014-03-15

    Purpose/Objectives: The aim of this study was to evaluate the impact of definitive thoracic chemoradiation therapy following surgery or stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT) on the outcomes of patients with non-small cell lung cancer (NSCLC) with synchronous solitary brain metastasis (SSBM). Methods and Materials: A total of 63 NSCLC patients with SSBM were retrospectively evaluated. Patients were staged using positron emission tomography-computed tomography in addition to conventional staging tools. Thoracic radiation therapy (TRT) with a total dose of 66 Gy in 2 Gy fractions was delivered along with 2 cycles of cisplatin-based chemotherapy following either surgery plus 30 Gy of WBRT (n=33) or SRS plus 30 Gy of WBRT (n=30) for BM. Results: Overall, the treatment was well tolerated. All patients received planned TRT, and 57 patients (90.5%) were also able to receive 2 cycles of chemotherapy. At a median follow-up of 25.3 months (7.1-52.1 months), the median months of overall, locoregional progression-free, neurological progression-free, and progression-free survival were 28.6, 17.7, 26.4, and 14.6, respectively. Both univariate and multivariate analyses revealed that patients with a T1-T2 thoracic disease burden (P=.001), a nodal stage of N0-N1 (P=.003), and no weight loss (P=.008) exhibited superior survival. Conclusions: In the present series, surgical and radiosurgical treatments directed toward SSBM in NSCLC patients were equally effective. The similarities between the present survival outcomes and those reported in other studies for locally advanced NSCLC patients indicate the potentially curative role of definitive chemoradiation therapy for highly selected patients with SSBM.

  17. Metastasis of Pregnancy-Associated Breast Cancer (Suspected to Be Hereditary Breast and Ovarian Cancer) to the Brain, Diagnosed at 18 Weeks' Gestation: A Case Report and Review of the Literature

    PubMed Central

    Okuda, Tomohiro; Yamamoto, Sakura; Matsuo, Seiki; Kataoka, Hisashi; Kitawaki, Jo

    2016-01-01

    We report a case of pregnancy-associated breast cancer with metastasis to the brain, likely resulting from hereditary breast and ovarian cancer (HBOC). A 35-year-old woman (gravida 2, para 0-1-0-1) underwent a right mastectomy and right axillary dissection after a cesarean section at 30 years of age; her mother died at 47 years of age due to breast cancer. Histopathological examination indicated an invasive ductal carcinoma with triple-negative cancer (cancer stage 2B [pT3N0M0]). The patient refused adjuvant therapy because of the risk of infertility. After 4 years, she became pregnant naturally. At 18 weeks' gestation, she experienced aphasia and dyslexia due to brain metastasis. The pregnancy was terminated at 21 weeks' gestation after thorough counseling. Her family history, young-onset disease, and histopathological findings suggested HBOC. She declined genetic testing for BRCA1/2, though genetic counseling was provided. In cases of pregnancy-related breast cancer, consideration must be given to whether the pregnancy should be continued and to posttreatment fertility. HBOC should also be considered. Genetic counseling should be provided and the patient should be checked for the BRCA mutation, as it is meaningful for the future of any potential children. Genetic counseling should be provided even if the cancer is advanced or recurrent. PMID:26981296

  18. Robotic radiosurgery for the treatment of 1-3 brain metastases: a pragmatic application of cost-benefit analysis using willingness-to-pay.

    PubMed

    Greenspoon, Jeffrey Noah; Whitton, Anthony; Whelan, Timothy; Sharieff, Waseem; Wright, James; Sussman, Jonathan; Gafni, Amiram

    2013-12-01

    With the emergence of radiosurgery as a new radiotherapeutic technique, health care decision makers are required to incorporate community need, cost and patient preferences when allocating radiosurgery resources. Conventional patient utility measures would not reflect short term preferences and would therefore not inform decision makers when allocating radiosurgery treatment units. The goal of this article is to demonstrate the feasibility of cost-benefit analysis to elicit the yearly net monetary benefit of robotic radiosurgery. To calculate the yearly incremental cost of robotic radiosurgery as compared to fixed gantry radiosurgery we used direct local cost data. We assumed a standard 10 year replacement and 5% amortization rate. Decision boards summarizing the clinical scenario of brain metastases and the difference between robotic and fixed gantry radiosurgery in terms of immobilization, comfort and treatment time were then presented to a sample of 18 participants. Participants who preferred robotic radiosurgery were randomly assigned to either a low ($1) or high ($5) starting point taxation based willingness-to-pay algorithm. The yearly incremental cost of providing robotic radiosurgery was $99,177 CAD. The mean community yearly willingness-to-pay for robotic radiosurgery was $2,300,000 CAD, p = 0.03. The calculated yearly net societal benefit for robotic radiosurgery was $2,200,823 CAD. Among participants who preferred robotic radiosurgery there was no evidence of starting point bias, p = 0.8. We have shown through this pilot study that it is feasible to perform cost-benefit analysis to evaluate new technologies in Radiation Oncology. Cost-benefit analysis offers an analytic method to evaluate local preferences and provide accountability when allocating limited healthcare resources.

  19. Brain

    MedlinePlus

    ... will return after updating. Resources Archived Modules Updates Brain Cerebrum The cerebrum is the part of the ... the outside of the brain and spinal cord. Brain Stem The brain stem is the part of ...

  20. Factors Affecting the Risk of Brain Metastasis in Small Cell Lung Cancer With Surgery: Is Prophylactic Cranial Irradiation Necessary for Stage I-III Disease?

    SciTech Connect

    Gong Linlin; Wang, Q.I.; Zhao Lujun; Yuan Zhiyong; Li Ruijian; Wang Ping

    2013-01-01

    Purpose: The use of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) with surgical resection has not been fully identified. This study undertook to assess the factors affecting the risk of brain metastases in patients with stage I-III SCLC after surgical resection. The implications of PCI treatment for these patients are discussed. Methods and Materials: One hundred twenty-six patients treated with surgical resection for stage I-III SCLC from January 1998-December 2009 were retrospectively analyzed to elucidate the risk factors of brain metastases. Log-rank test and Cox regression model were used to determine the risk factors of brain metastases. Results: The median survival time for this patient population was 34 months, and the 5-year overall survival rate was 34.9%. For the whole group, 23.0% (29/126) of the patients had evidence of metastases to brain. Pathologic stage not only correlated with overall survival but also significantly affected the risk of brain metastases. The 5-year survival rates for patients with pathologic stages I, II, and III were 54.8%, 35.6%, and 14.1%, respectively (P=.001). The frequency of brain metastases in patients with pathologic stages I, II, and III were 6.25% (2/32), 28.2% (11/39), and 29.1% (16/55) (P=.026), respectively. A significant difference in brain metastases between patients with complete resection and incomplete resection was also observed (20.5% vs 42.9%, P=.028). The frequency of brain metastases was not found to be correlated with age, sex, pathologic type, induction chemotherapy, adjuvant chemotherapy, or adjuvant radiation therapy. Conclusions: Stage I SCLC patients with complete resection had a low incidence of brain metastases and a favorable survival rate. Stage II-III disease had a higher incidence of brain metastases. Thus, PCI might have a role for stage II-III disease but not for stage I disease.

  1. Cancer stem cells and metastasis.

    PubMed

    Sampieri, Katia; Fodde, Riccardo

    2012-06-01

    Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity but also with an innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in cancer patients. Operationally, CSCs are defined by their tumour-propagating ability when serially transplanted into immune-compromised mice and by their capacity to fully recapitulate the original heterogeneity of cell types observed in the primary lesions they are derived from. CSCs were first identified in haematopoietic malignancies and later in a broad spectrum of solid tumours including those of the breast, colon and brain. Notably, several CSC characteristics are relevant to metastasis, such as motility, invasiveness and, as mentioned above, resistance to DNA damage-induced apoptosis. Here, we have reviewed the current literature on the relation between CSCs and metastasis formation. Preliminary studies on cancer cell lines and patient-derived material suggest a rate-limiting role for stem-like cells in the processes of tumour cell dissemination and metastasis formation. However, additional studies are needed to deliver formal proof of their identity as the cell of origin of recurrences at distant organ sites. Nevertheless, several studies have already provided pre-clinical evidence of the efficacy of novel therapies directed against disseminated CSCs.

  2. Tumour exosome integrins determine organotropic metastasis.

    PubMed

    Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Tesic Mark, Milica; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M; Dumont-Cole, Vanessa D; Kramer, Kimberly; Wexler, Leonard H; Narendran, Aru; Schwartz, Gary K; Healey, John H; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H; Grandgenett, Paul M; Hollingsworth, Michael A; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K; Jarnagin, William R; Brady, Mary S; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J; Bissell, Mina J; Garcia, Benjamin A; Kang, Yibin; Rajasekhar, Vinagolu K; Ghajar, Cyrus M; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David

    2015-11-19

    Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

  3. Tumour exosome integrins determine organotropic metastasis

    PubMed Central

    Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Mark, Milica Tesic; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E.; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M.; Dumont-Cole, Vanessa D.; Kramer, Kimberly; Wexler, Leonard H.; Narendran, Aru; Schwartz, Gary K.; Healey, John H.; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H.; Grandgenett, Paul M.; Hollingsworth, Michael A.; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K.; Jarnagin, William R.; Brady, Mary S.; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J.; Bissell, Mina J.; Garcia, Benjamin A.; Kang, Yibin; Rajasekhar, Vinagolu K.; Ghajar, Cyrus M.; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David

    2015-01-01

    Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis. PMID:26524530

  4. Low expression of dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin-related protein in lung cancer and significant correlations with brain metastasis and natural killer cells.

    PubMed

    Liu, Xiaoli; Zhang, Hua; Su, Lijie; Yang, Peng; Xin, Zhiqiang; Zou, Junwei; Ren, Shuangyi; Zuo, Yunfei

    2015-09-01

    Dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin-related protein (DC-SIGNR) is a type II transmembrane protein which has been reported to bind a variety of pathogens as well as participate in immunoregulation. But the association between the level of DC-SIGNR and lung cancer is unknown. To investigate the clinical diagnostic significance of DC-SIGNR in lung cancer, we investigated serum DC-SIGNR levels in 173 lung cancer patients and 134 healthy individuals using enzyme-linked immunosorbent assay (ELISA). Results showed that serum DC-SIGNR levels in lung cancer patients were lower than that in healthy controls (P = 0.0003). A cut-off value of 3.8998 ng/L for DC-SIGNR predicted the presence of lung cancer with 78.03% sensitivity and 49.25% specificity (area under the curve = 0.6212, P = 0.0003). Strikingly, serum DC-SIGNR levels were significantly higher in lung cancer patients with brain metastasis compared to those without metastasis (P = 0.0283). Moreover, the serum concentrations of DC-SIGNR in lung cancer patients also correlated significantly with serum natural killer cells percentage (P = 0.0017). In addition, immunohistochemistry assay demonstrated that the expression of DC-SIGNR in lung tissues of 31 lung cancer patients and 13 tuberculosis patients was significantly lower than that in 18 normal lung tissues (P = 0.0418, 0.0289), and there is no significant difference between tuberculosis tissues and lung cancer tissues (P = 0.2696). These results suggest that DC-SIGNR maybe a promising biological molecule that has the potential for clinical research of lung cancer, whereas its underlying roles are needed to be investigated in further studies.

  5. Brain metastasis model in athymic nude mice using a novel MUC1-secreting human breast-cancer cell line, MA11.

    PubMed

    Rye, P D; Norum, L; Olsen, D R; Garman-Vik, S; Kaul, S; Fodstad, O

    1996-11-27

    The MA11 human breast-cancer cell line was established with cells isolated from a bone-marrow sample using immunomagnetic beads conjugated to the anti-MUC1 antibody BM-2. The cell line showed a selective preference for metastasising to the brain in athymic nude mice. Following injection of MA11 cells into the left ventricle of the heart, brain metastases developed in 87% (20/23) animals, with a mean latency until development of neurological symptoms of 65 days. Necropsy and histological examination revealed tumour nodules of varying sizes throughout the brain, invading both grey and white matter of both hemispheres, and with extensive involvement of the cerebellum. MRI spin-echo images indicated brain lesions in some animals that were subsequently confirmed by histology. Three mice showed small tumour nodules (1-2 mm) in the lung, and 2 had solitary lesions (< 1 mm) within the spinal cord. Metastases were not detected in bone, liver, adrenal gland, kidney, spleen or heart. The human MUC1 mucin, as determined by a europium-based immunoradiometric assay, was detected in the serum of 9/11 animals that showed histological evidence of brain metastases. The mucin could not be found in mouse serum samples taken before day 46. The concentration range of MUC1 observed was from <1 to >50 U/ml, and did not appear to correlate with the size or number of tumours as determined from histological sections. This new model provides an opportunity to study the mechanisms of clinically relevant organ-selective metastases and may be of use in evaluating novel treatment for brain metastases in breast cancer.

  6. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer.

    PubMed

    Peters, Solange; Bexelius, Christin; Munk, Veronica; Leighl, Natasha

    2016-04-01

    This systematic review aims to improve understanding of the burden of disease associated with brain metastases from non-small-cell lung cancer (NSCLC) in terms of survival, quality of life (QoL) and economic impact. PubMed/MEDLINE, Cochrane collaboration and EMBASE databases were searched for articles published in English from 2000 to 2014. Of 3288 abstracts retrieved, 3156 were eliminated without a full-text review. Of the 132 articles that received a full-text review, a final set of 93 articles was included in an initial literature analysis. In order to homogenize the patient populations evaluated, we included entries that were either entirely composed of NSCLC patients or that had >50% of NSCLC patients in the total study population. From the studies identified in this systematic review, median OS and PFS varied based on the type of treatment received, although whole-brain radiotherapy (WBRT) was associated with the shortest OS and PFS durations. Regimens incorporating targeted therapy in molecularly selected patients were associated with the longest OS and PFS durations. QoL findings varied among studies, generally WBRT resulted in stable or worsening QoL scores rather than improvements. Healthcare costs were increased following diagnosis of brain metastases regardless of treatment. The findings from this review highlight the need for more effective treatments of brain metastases from NSCLC that improve survival function, QoL and potentially decrease costs. PMID:27019457

  7. The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer.

    PubMed

    Peters, Solange; Bexelius, Christin; Munk, Veronica; Leighl, Natasha

    2016-04-01

    This systematic review aims to improve understanding of the burden of disease associated with brain metastases from non-small-cell lung cancer (NSCLC) in terms of survival, quality of life (QoL) and economic impact. PubMed/MEDLINE, Cochrane collaboration and EMBASE databases were searched for articles published in English from 2000 to 2014. Of 3288 abstracts retrieved, 3156 were eliminated without a full-text review. Of the 132 articles that received a full-text review, a final set of 93 articles was included in an initial literature analysis. In order to homogenize the patient populations evaluated, we included entries that were either entirely composed of NSCLC patients or that had >50% of NSCLC patients in the total study population. From the studies identified in this systematic review, median OS and PFS varied based on the type of treatment received, although whole-brain radiotherapy (WBRT) was associated with the shortest OS and PFS durations. Regimens incorporating targeted therapy in molecularly selected patients were associated with the longest OS and PFS durations. QoL findings varied among studies, generally WBRT resulted in stable or worsening QoL scores rather than improvements. Healthcare costs were increased following diagnosis of brain metastases regardless of treatment. The findings from this review highlight the need for more effective treatments of brain metastases from NSCLC that improve survival function, QoL and potentially decrease costs.

  8. 1,3-Butadiene

    Integrated Risk Information System (IRIS)

    1,3 - Butadiene ; CASRN 106 - 99 - 0 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic E

  9. 1,3-Dichloropropene

    Integrated Risk Information System (IRIS)

    1,3 - Dichloropropene ( DCP ) ; CASRN 542 - 75 - 6 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Non

  10. 1,3-Dichlorobenzene

    Integrated Risk Information System (IRIS)

    1,3 - Dichlorobenzene ; CASRN 541 - 73 - 1 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinog

  11. Intraorbital metastasis from solitary fibrous tumor.

    PubMed

    Patel, Mrinali M; Jakobiec, Frederick A; Zakka, Fouad R; Du, Rose; Annino, Donald J; Borboli-Gerogiannis, Sheila; Daniels, Anthony B

    2013-01-01

    Solitary fibrous tumor (SFT) is a rare spindle cell tumor of mesenchymal origin that usually arises from pleura or pericardium but can also arise from many extraserosal sites. Although more than 50 cases of primary SFT of the orbit have been reported, there are no reports to date of a malignant nonophthalmic SFT metastasizing in the orbital soft tissues (although sphenoid wing bony involvement has been reported). The authors report here the first case of a patient with intraorbital metastasis of a CD34-positive malignant SFT. The patient was a 57-year-old man with a history of malignant pleural SFT and a prior kidney metastasis. He presented with the rapid appearance of proptosis and massive conjunctival chemosis preventing eyelid closure, and he was found to have a well-circumscribed metastasis to his lateral rectus muscle. Surgical excision cured his ocular symptoms, although he died 3 months later from brain and widespread metastases.

  12. Labeling by ( sup 3 H)1,3-di(2-tolyl)guanidine of two high affinity binding sites in guinea pig brain: Evidence for allosteric regulation by calcium channel antagonists and pseudoallosteric modulation by sigma ligands

    SciTech Connect

    Rothman, R.B.; Reid, A.; Mahboubi, A.; Kim, C.H.; De Costa, B.R.; Jacobson, A.E.; Rice, K.C. )

    1991-02-01

    Equilibrium binding studies with the sigma receptor ligand ({sup 3}H)1,3-di(2-tolyl)guanidine (({sup 3}H)DTG) demonstrated two high affinity binding sites in membranes prepared from guinea pig brain. The apparent Kd values of DTG for sites 1 and 2 were 11.9 and 37.6 nM, respectively. The corresponding Bmax values were 1045 and 1423 fmol/mg of protein. Site 1 had high affinity for (+)-pentazocine, haloperidol, (R)-(+)-PPP, carbepentane, and other sigma ligands, suggesting a similarity with the dextromethorphan/sigma 1 binding site described by Musacchio et al. (Life Sci. 45:1721-1732 (1989)). Site 2 had high affinity for DTG and haloperidol (Ki = 36.1 nM) and low affinity for most other sigma ligands. Kinetic experiments demonstrated that ({sup 3}H)DTG dissociated in a biphasic manner from both site 1 and site 2. DTG and haloperidol increased the dissociation rate of ({sup 3}H)DTG from site 1 and site 2, demonstrating the presence of pseudoallosteric interactions. Inorganic calcium channel blockers such as Cd2+ selectively increased the dissociation rate of ({sup 3}H)DTG from site 2, suggesting an association of this binding site with calcium channels.

  13. Targeting Breast Cancer Metastasis

    PubMed Central

    Jin, Xin; Mu, Ping

    2015-01-01

    Metastasis is the leading cause of breast cancer-associated deaths. Despite the significant improvement in current therapies in extending patient life, 30–40% of patients may eventually suffer from distant relapse and succumb to the disease. Consequently, a deeper understanding of the metastasis biology is key to developing better treatment strategies and achieving long-lasting therapeutic efficacies against breast cancer. This review covers recent breakthroughs in the discovery of various metastatic traits that contribute to the metastasis cascade of breast cancer, which may provide novel avenues for therapeutic targeting. PMID:26380552

  14. Brain metastasis of ALK positive anaplastic large cell lymphoma after a long-term disease free survival in an old adult

    PubMed Central

    Wang, Cai-Xia; Wang, Hai; Li, Jie; Ma, Heng-Hui; Yu, Bo; Shi, Shan-Shan; Zhou, Xiao-Jun; Shi, Qun-Li

    2014-01-01

    Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma composed of CD30-positive cells and now recognized as three different entities: primary cutaneous ALCL, primary systemic anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL and primary ALK-negative (ALK-) ALCL. ALK+ ALCL is supposed to have a better prognosis than ALK- ALCL. It is rarely metastasized to other sites, especially to the central nervous system (CNS). Herein, we present a rare case of systemic ALK+ ALCL which metastasized to the brain after a long-term disease free survival in an adult. Neuroimaging revealed a well-enhanced mass in the left frontal lobe. And it was completely resected. The results of the pathological and immunohistochemical studies were consistent with the metastasized ALK+ ALCL. The clinical findings, pathologic characteristics and treatment are described. PMID:24696735

  15. An unusual intracranial metastasis of osteosarcoma.

    PubMed

    Chang, J W; Howng, S L; Sun, Z M; Kuo, T H; Duh, C C

    1994-12-01

    Intracranial metastasis is unusual in osteosarcoma. A case of osteosarcoma was presented with a large intracranial "stone" which was a subdural convexity metastasis. Smaller epidural metastases over other areas were noted also in brain CT scan. Using the radiographs and bone scans, many other lesions at bones, the mediastinum, pleura, perirenal space, and adrenal gland were detected simultaneously. This condition might result from either early metastases or multifocal osteosarcomas. Because many of the above lesion sites were not frequent locations of primary osteosarcoma and had been reported as metastatic targets of osteosarcoma. So the explanation of a very malignant osteosarcoma with early metastases may be more appropriate for this case. The baseball-like tumor in the subdural space with marked compression of the brain surface was grossly totally excised. Histopathologic examination confirmed the diagnosis of osteosarcoma. Postoperatively, the man's condition improved dramatically, though only for two months. He died 5 months later. Reports of such metastatic osteosarcomas are reviewed.

  16. Solitary brain metastasis of an occult and stable small-cell lung cancer in a schizophrenic patient: a 3-year control.

    PubMed

    Jesien-Lewandowicz, Emilia; Spych, Michal; Fijuth, Jacek; Kordek, Radzislaw

    2010-08-01

    Small-cell lung cancer is a highly aggressive carcinoma, with poorer prognosis in patients with brain metastases. We present the case of a 49-year-old woman diagnosed with a cerebellar tumour which, following surgery, was revealed to be a metastatic small-cell lung carcinoma. Subsequent CT and PET scanning showed a small, isolated 8 mm nodule in the upper lobe of the right lung. The patient was suffering from schizophrenia and has been treated with clozapine for 17 years. Because of the unusual presentation, there was no therapy given for the primary tumour at the time, and systemic therapy or surgery was discussed. However, 18 months later, the nodule was slightly larger (14 mm), and surgery was performed. On pathology examination, the tumour was presented as a typical small-cell carcinoma. Standard chest irradiation with systemic chemotherapy was given. At the time of writing, 39 months after diagnosis of metastatic small-cell carcinoma, the patient is disease free. However, this case is unusual in that a long-term observation of a small stable primary tumour in the lung took place without any therapy being given. This case strongly supports the thesis that small-cell lung cancer may comprise a heterogeneous group of tumours with different biological properties. The proapoptotic effect of clozapine may be also taken into account.

  17. Cutaneous metastasis: An unusual presenting feature of urologic malignancies

    PubMed Central

    Menon, Arun Ramdas; Thomas, Anju Sussanna; Suresh, Nivedita; Shashidhar, Shashank Malagi

    2016-01-01

    Urological malignancies are well known for their ability to metastasize widely. The incidence of cutaneous metastasis from all urologic malignancies has been reported to be 0.73–1.3% with the primary most commonly being renal cell carcinoma followed by carcinoma bladder, adenocarcinoma prostate, and testicular germ cell tumor in decreasing order of frequency. Metastasis to the skin is unusual and has been predominantly reported as a late manifestation of the disease. We describe two patients with urologic malignancies who had cutaneous metastasis as their initial presenting feature. PMID:27453667

  18. Combined Therapy for Distant Metastasis of Sacral Chordoma

    PubMed Central

    Özkal, Birol; Yaldız, Can; Temiz, Peyker; Temiz, Cüneyt

    2015-01-01

    Chordomas are known as rare primary malign tumours that have formed from primitive notochord remains. Sacral chordomas grow slowly but locally and aggressively. Chordomas are locally invasive and have low tendency to metastasis and have a poor prognosis in long-term follow-up. Metastasis may be seen in a rate of 5–40% of the chordomas. Metastasis of chordomas is common in liver, lung, lymph nodes, peritoneum, and brain. The treatment approaches, including surgery, have been discussed in the literature before. Susceptibility to radiotherapy and chemotherapy is controversial in these tumours. The success of surgical treatment affects survival directly. In this report, we will report a sacral chordoma case in which an intraperitoneal distant metastasis occurred and discuss the surgical approach. PMID:25649759

  19. Imaging TGFβ Signaling in Mouse Models of Cancer Metastasis.

    PubMed

    Kang, Yibin

    2016-01-01

    Metastatic spread of cancer cells from the primary tumors to distant vital organs, such as lung, liver, brain, and bone, is responsible for the majority of cancer-related deaths. Development of metastatic lesions is critically dependent on the interaction of tumor cells with the stromal microenvironment. As a multifunctional paracrine signaling factor that is abundantly produced by both tumor and stromal cells, TGFβ has been well established as an important mediator of tumor-stromal interaction during cancer metastasis. Imaging the in vivo dynamic of TGFβ signaling activity during cancer metastasis is critical for understanding the pathogenesis of the disease, and for the development of effective anti-metastasis treatments. In this chapter, I describe several xenograft methods to introduce human breast cancer cells into nude mice in order to generate spontaneous and experimental metastases, as well as the luciferase-based bioluminescence imaging method for quantitative imaging analysis of TGFβ signaling in tumor cells during metastasis.

  20. Tumour progression and metastasis

    PubMed Central

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour’s survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible. PMID:26913068

  1. Tumour progression and metastasis.

    PubMed

    Arvelo, Francisco; Sojo, Felipe; Cotte, Carlos

    2016-01-01

    The two biological mechanisms that determine types of malignancy are infiltration and metastasis, for which tumour microenvironment plays a key role in developing and establishing the morphology, growth and invasiveness of a malignancy. The microenvironment is formed by complex tissue containing the extracellular matrix, tumour and non-tumour cells, a signalling network of cytokines, chemokines, growth factors, and proteases that control autocrine and paracrine communication among individual cells, facilitating tumour progression. During the development of the primary tumour, the tumour stroma and continuous genetic changes within the cells makes it possible for them to migrate, having to count on a pre-metastatic niche receptor that allows the tumour's survival and distant growth. These niches are induced by factors produced by the primary tumour; if it is eradicated, the active niches become responsible for activating the latent disseminated cells. Due to the importance of these mechanisms, the strategies that develop tumour cells during tumour progression and the way in which the microenvironment influences the formation of metastasis are reviewed. It also suggests that the metastatic niche can be an ideal target for new treatments that make controlling metastasis possible.

  2. A 1,3-Dihydro-1,3-azaborine Debuts

    PubMed Central

    Xu, Senmiao; Zakharov, Lev N.

    2011-01-01

    We present the first synthesis and characterization of a 1,3-dihydro-1,3-azaborine, a long-sought BN isostere of benzene. 1,3-Dihydro-1,3-azaborine is a stable structural motif with considerable aromatic character as evidenced by structural analysis and its reaction chemistry. Single crystal X-ray analysis indicates bonding consistent with significant electron delocalization. 1,3-Dihydro-1,3-azaborines also undergo nucleophilic substitutions at boron and electrophilic aromatic substitution reactions. In view of the versatility and impact of aromatic compounds in the biomedical field and in materials science, the present study further expands the available chemical space of arenes via BN/CC isosterism. PMID:22091703

  3. [Bone metastasis and RANKL].

    PubMed

    Nakashima, Tomoki

    2014-08-01

    The mice with a disruption of Rank or Rankl exhibit normal mammary development during puberty, but their mammary epithelium fails to proliferate and form lobuloalveolar structures during pregnancy, resulting in the death of newborns. Hormone replacement therapy is associated with an increased risk of breast cancer. Importantly, specific deletion of RANK in mammary epithelium cells prevents both the onset and progression of medroxyprogesterone acetate (MPA) -driven mammary cancer and impairs self-renewal of breast cancer stem cells. Furthermore, RANK is highly expressed in several cancer cells. Functionally, it has been shown that RANKL can stimulate the directed migration of mammary epithelial cells as well as prostate cancer and melanoma cells toward a source of RANKL. In an in vivo metastasis model, OPG reduced the tumor burden in bones and ameliorated clinical paralysis, but did not affect the frequency of the spread of metastases into other tissues. These findings show that the RANK/RANKL system is crucial for mammary development, breast tumorigenesis and bone metastasis.

  4. [Pancreas pseudocyst or metastasis?].

    PubMed

    Gyorffy, Hajnalka; Tihanyi, Tibor; Gyökeres, Tibor; Zsirka-Klein, Attila; Kádár, Péter; Kaszás, Ilona; Kovács, Margit

    2005-10-23

    The authors review a case of a 24-year-old male patient hospitalised for repeated acute abdominal symptoms. His medical history included no diseases worth of mentioning. By imaging techniques (abdominal US and CT scan) a cystic lesion, measuring 40 x 35 x 30 mm in diameter was found, and was diagnosed as pseudocyst in the region of the tail of the pancreas. Jejunal feeding was introduced. The lesion did not improve and the second CT scan suggested a suspicion of pancreatic cystadenoma. Three months after first presentation the surgical resection was performed. The tumour, however, was found independent of the pancreas (90 x 80 x 50 mm). Both histologically and immunohistochemically the lesion proved to be the metastasis of a germ cell (yolk-sac) tumour. Following the morphological diagnosis, detailed urological and medical check up was performed. A previously nonpalpable small tumour was found in the left testis which was radically resected. The testicular tumour measuring 9 x 9 x 5 mm in diameter was diagnosed as embryonal carcinoma. Later on the patient underwent chemotherapy. He has been undergoing close oncological followup. Clinically, he is disease free. Authors emphasize the importance of imaging techniques and fine needle aspiration cytology in the case of retroperitoneal masses in young males. The possibility of a metastasis, especially of germ cell origin, should be excluded (not only by physical examination, but by ultrasound of testis also) in case of retroperitoneal cystic tumours even with unusual morphology.

  5. Extraneural Glioblastoma Multiforme Vertebral Metastasis

    PubMed Central

    Goodwin, C. Rory; Liang, Lydia; Abu-Bonsrah, Nancy; Hdeib, Alia; Elder, Benjamin D.; Kosztowski, Thomas; Bettegowda, Chetan; Laterra, John; Burger, Peter; Sciubba, Daniel M.

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis. PMID:26704201

  6. Extraneural Glioblastoma Multiforme Vertebral Metastasis.

    PubMed

    Goodwin, C Rory; Liang, Lydia; Abu-Bonsrah, Nancy; Hdeib, Alia; Elder, Benjamin D; Kosztowski, Thomas; Bettegowda, Chetan; Laterra, John; Burger, Peter; Sciubba, Daniel M

    2016-05-01

    Glioblastoma multiforme (GBM) is the most common malignant central nervous system tumor; however, extraneural metastasis is uncommon. Of those that metastasize extraneurally, metastases to the vertebral bodies represent a significant proportion. We present a review of 28 cases from the published literature of GBM metastasis to the vertebra. The mean age at presentation was 38.4 years with an average overall survival of 26 months. Patients were either asymptomatic with metastasis discovered at autopsy or presented with varying degrees of pain, weakness of the extremities, or other neurologic deficits. Of the cases that included the time to spinal metastasis, the average time was 26.4 months with a reported survival of 10 months after diagnosis of vertebral metastasis. A significant number of patients had no treatments for their spinal metastasis, although the intracranial lesions were treated extensively with surgery and/or adjuvant therapy. With increasing incremental gains in the survival of patients with GBM, clinicians will encounter patients with extracranial metastasis. As such, this review presents timely information concerning the presentation and outcomes of patients with vertebral metastasis. PMID:26704201

  7. Mandible metastasis of hepatocellular carcinoma.

    PubMed

    Niedzielska, Iwona; Langowska-Adamczyk, Helena; Pajak, Jacek; Kajor, Maciej; Niedzielski, Zbigniew; Gołka, Dariusz

    2004-01-01

    Metastases to oral cavity are very uncommon. We present a case of hepatocellular carcinoma (HCC) metastasis to the jaw. The x-ray examination and clinical picture of the lesion were not characteristic. The gingival metastasis may mimic other benign and malignant conditions which affect jaw and therefore the histopathological examination is necessary to make an ultimate diagnosis.

  8. Isolated omental metastasis of renal cell carcinoma after extraperitoneal open partial nephrectomy: A case report

    PubMed Central

    Acar, Ömer; Mut, Tuna; Sağlıcan, Yeşim; Sag, Alan Alper; Falay, Okan; Selcukbiricik, Fatih; Tabak, Levent; Esen, Tarık

    2016-01-01

    Introduction Metachronous metastatic spread of clinically localized renal cell carcinoma (RCC) affects almost 1/3 of the patients. They occur most frequently in lung, liver, bone and brain. Isolated omental metastasis of RCC has not been reported so far. Case presentation A 62-year-old patient previously diagnosed and treated due to pulmonary sarcoidosis has developed an omental metastatic lesion 13 years after having undergone open extraperitoneal partial nephrectomy for T1 clear-cell RCC. Constitutional symptoms and imaging findings that were attributed to the presence of a sarcomatoid paraneoplastic syndrome triggered by the development this metastatic focus complicated the diagnostic work-up. Biopsy of the [18F]-fluorodeoxyglucose (+) lesions confirmed the diagnosis of metastatic RCC and the patient was managed by the resection of the omental mass via near-total omentectomy followed by targeted therapy with a tyrosine kinase inhibitor. Discussion Late recurrence of RCC has been reported to occur in 10–20% of the patients within 20 years. Therefore lifelong follow up of RCC has been advocated by some authors. Diffuse peritoneal metastases have been reported in certain RCC subtypes with adverse histopathological features. However, isolated omental metastasis without any sign of peritoneal involvement is an extremely rare condition. Conclusion To our knowledge, this is the first reported case of metachronously developed, isolated omental metastasis of an initially T1 clear-cell RCC. Constitutional symptoms, despite a long interval since nephrectomy, should raise the possibility of a paraneoplastic syndrome being associated with metastatic RCC. Morphological and molecular imaging studies together with histopathological documentation will be diagnostic. PMID:26874583

  9. Molecular Mechanisms of Bone Metastasis.

    PubMed

    Weidle, Ulrich H; Birzele, Fabian; Kollmorgen, Gwendlyn; Rüger, Rüdiger

    2016-01-01

    Metastasis of breast and prostate cancer as well as multiple myeloma to the bones represents a significant medical problem. We herein discuss the molecular basis of the creation of pre-metastatic niches, the process of bone metastasis and the phenomenon of tumor dormancy in the bone marrow as well as its regulation. We describe the identification and validation of genes mediating bone metastasis by use of pre-clinical models of bone metastasis. Additionally, we discuss the role of small integrin binding N-linked glycoproteins (SIBLINGS), the chemokine/chemokine receptor CXCL12/CXCR4 pathway and the role of micro RNAs (miRNAs) as mediators of bone metastasis. Finally, we summarize clinical achievements for the treatment of bone metastases.

  10. Imaging of ocular melanoma metastasis.

    PubMed

    Balasubramanya, Rashmi; Selvarajan, Santosh Kumar; Cox, Mougnyan; Joshi, Ganesh; Deshmukh, Sandeep; Mitchell, Donald G; O'Kane, Patrick

    2016-09-01

    Ocular melanoma is the most common adult primary intraocular tumour. Although <1% of patients have metastatic disease at the time of initial diagnosis, most will develop metastasis at varying lengths of time. Metastasis surveillance is therefore critical in the follow-up of patients with ocular melanoma. Liver is the most common site of metastasis and prognosis is based on the treatment of liver metastasis. Hence, imaging of liver metastasis is vital. MRI is the most specific modality for imaging liver metastasis and is at least as sensitive as CT. Extrahepatic metastasis such as retroperitoneal nodules and bone metastases are also better evaluated on MRI. Gadolinium-based contrast agents are extremely helpful for detecting liver lesions. In particular, newer hepatobiliary contrast agents which offer an additional hepatobiliary phase of excretion help in the detection of even tiny liver metastases. Diffusion-weighted imaging is helpful when an i.v. contrast cannot be administered. Treated lesions are also better evaluated with MRI. CT is useful for evaluating lung nodules, large liver metastasis or in patients in whom MRI is medically contraindicated. The disadvantage lies in its inability to detect small liver metastasis and the radiation dose involved. The lesions treated with iodized oil as part of chemoembolization procedures can be followed on CT. Ultrasound can be used only for detecting hepatic metastases. However, it is heavily operator dependent, technically challenging and time consuming especially in patients who are large. Extrahepatic metastasis cannot be seen on ultrasound. Its utility is primarily for the biopsy of liver lesions. Positron emission tomography (PET)-CT can detect lung nodules and large liver lesions but is insensitive to small liver lesions. Moreover, the high radiation dose is a major disadvantage. PMID:27168029

  11. Hypoxic control of metastasis

    PubMed Central

    Rankin, Erinn B.; Giaccia, Amato J.

    2016-01-01

    Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease. PMID:27124451

  12. Transformation of Merkel cell carcinoma to ganglioneuroblastoma in intracranial metastasis.

    PubMed

    Lach, Boleslaw; Joshi, Sangeeta S; Murty, Naresh; Huq, Nasimul

    2014-09-01

    Merkel cell carcinoma is an aggressive neuroendocrine tumor occasionally demonstrating aberrant differentiation to other epithelial and nonepithelial cell lines. We describe a case of Merkel cell carcinoma displaying unique patterns of differentiation in the primary focus and brain metastasis. The skin primary was almost uniformly small cell carcinoma positive for epithelial and neuroendocrine markers, with a few glial fibrillary acidic protein- and cytokeratin 20-positive cells. The neoplasm contained giant cells immunoreactive for neurofilament and negative for epithelial markers. The neck lymph node metastasis was a typical neuroendocrine Merkel cell carcinoma positive for cytokeratin 20. A solitary dural intracranial metastasis displayed features of aggressive ganglioneuroblastoma, expressing many neuronal antigens with no evidence of glial or epithelial differentiation. After total gross resection, the tumor recurred within 3 months, and the patient developed skeletal metastases and died 6 months after craniotomy. PMID:24996688

  13. Gastric adenocarcinoma with prostatic metastasis.

    PubMed

    Roshni, S; Anoop, Tm; Preethi, Tr; Shubanshu, G; Lijeesh, Al

    2014-06-01

    Metastasis of gastric adenocarcinoma to the prostate gland is extremely rare. Herein, we report a case of gastric adenocarcinoma in a 56-year-old man with prostatic metastasis diagnosed through the analysis of biopsy specimens from representative lesions in the stomach and prostate gland. Immunohistochemistry of the prostatic tissue showed positive staining for cytokeratin 7 and negative staining for prostate-specific antigen (PSA), whereas the serum PSA level was normal, confirming the diagnosis of prostatic metastasis from carcinoma of the stomach. PMID:25061542

  14. Gastric Adenocarcinoma with Prostatic Metastasis

    PubMed Central

    Roshni, S; Preethi, TR; Shubanshu, G; Lijeesh, AL

    2014-01-01

    Metastasis of gastric adenocarcinoma to the prostate gland is extremely rare. Herein, we report a case of gastric adenocarcinoma in a 56-year-old man with prostatic metastasis diagnosed through the analysis of biopsy specimens from representative lesions in the stomach and prostate gland. Immunohistochemistry of the prostatic tissue showed positive staining for cytokeratin 7 and negative staining for prostate-specific antigen (PSA), whereas the serum PSA level was normal, confirming the diagnosis of prostatic metastasis from carcinoma of the stomach. PMID:25061542

  15. Bone resorption, metastasis, and diphosphonates

    SciTech Connect

    Garattini, S.

    1985-01-01

    This book contains 17 selections. Some of the titles are: Radiotherapy of Bone Lesions; Methodological Problems; Treatment of Bone Metastasis with Antiresorptive Drugs; Control of Bone Cancer Pain; and Chemotherapy of Bone Metastases.

  16. 1,3,5-Trinitrobenzene

    Integrated Risk Information System (IRIS)

    1,3,5 - Trinitrobenzene ; CASRN 99 - 35 - 4 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcino

  17. Medullary metastasis of a malignant peripheral nerve sheath tumor: A case report

    PubMed Central

    Hagi, Tomohito; Nakamura, Tomoki; Yokoji, Ayumu; Matsumine, Akihiko; Sudo, Akihiro

    2016-01-01

    The present study reports a case of medullary metastasis without lung metastasis that occurred as a result of a malignant peripheral nerve sheath tumor (MPNST). An 81-year-old woman presented with a MPNST in the left brachial plexus, arising from the cervical nerve root. The patient underwent carbon ion radiotherapy; however, tumor recurrence was identified in the left shoulder. Subsequently, the patient underwent wide excision. Three weeks subsequent to surgery, imbalance and dysarthria developed suddenly. Dysphagia emerged and left upper limb pain disappeared on the day after symptom development. Magnetic resonance imaging (MRI) revealed that this was due to metastasis to the medulla. Five days subsequent to the onset of dysarthria, the patient succumbed due to respiratory failure. To the best of our knowledge, no previous cases of medullary metastasis arising from a MPNST in the absence of lung metastasis have been reported. MRI is a useful examination tool for the identification of brain metastases; however, the high cost of MRI as a routine examination must be considered due to the rarity of brain metastases. Therefore, methods to detect brain metastasis warrant further investigation. PMID:27588138

  18. Features and prognostic impact of distant metastasis in patients with stage IV lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis.

    PubMed

    Fujimoto, Daichi; Ueda, Hiroyuki; Shimizu, Ryoko; Kato, Ryoji; Otoshi, Takehiro; Kawamura, Takahisa; Tamai, Koji; Shibata, Yumi; Matsumoto, Takeshi; Nagata, Kazuma; Otsuka, Kyoko; Nakagawa, Atsushi; Otsuka, Kojiro; Katakami, Nobuyuki; Tomii, Keisuke

    2014-06-01

    Mutated epidermal growth factor receptor (EGFR) and signaling pathways were associated with multiple brain and intra-pulmonary metastases, oncogenic progression and metastasis. However, features of metastasis to other organs and the independent prognostic influence of metastatic lesions were not elucidated in patients with lung cancer harboring EGFR mutations. Between January 2007 and April 2012, we treated 277 patients diagnosed with stage IV lung adenocarcinoma. Studied were 246 patients with available tumor EGFR mutation data who also underwent radiographic evaluation of lung, abdominal, brain, and bone metastases. The EGFR mutated group (N = 98) had significantly more metastatic lesions in the brain and bone than the wild-type group (N = 148): brain, 3 (1-93) versus 2 (1-32) median (range), P = 0.023; bone, 3 (1-43) versus 2 (1-27), P = 0.035, respectively. In addition, EGFR mutations were significantly more frequent in patients with multiple than non-multiple lung metastases (24/40 vs. 12/42, P = 0.004). Multivariate analysis showed that bone metastasis was a significant independent negative predictive factor of overall survival (OS) in patients with mutated [hazard ratio (HR) 2.04; 95 % confidence interval (CI) 1.17-3.64; P = 0.011] and wild-type EGFR (HR 2.09; 95 % CI 1.37-3.20; P < 0.001). In conclusion, patients with mutated EGFR had more lung, brain, and bone metastases, and bone metastasis was an independent negative predictor of OS.

  19. Lymph node metastasis and lymph vascular space invasion in microinvasive squamous cell carcinoma of the uterine cervix.

    PubMed

    Lee, K B M; Lee, J M; Park, C Y; Lee, K B; Cho, H Y; Ha, S Y

    2006-01-01

    The objective of this study was to determine whether the depth of invasion was related to lymph vascular space invasion (LVSI) and lymph node metastasis and whether there was a correlation between LVSI and lymph node metastasis in stage IA cervical cancer. The medical records, including surgical notes and pathologic reports, of 202 patients with microinvasive squamous cell carcinoma of the uterine cervix were reviewed retrospectively. There was a positive correlation between the depth of invasion and the LVSI, and the incidence of lymph node metastasis was slightly higher than those reported hitherto for stage IA1 cervical cancer, especially in the depth of invasion of 1-3 mm group. However, among four patients with lymph node metastasis, only two patients had positive LVSI. There was no definite correlation between LVSI and lymph node metastasis. LVSI could not identify the patients with high risk for lymph node metastasis.

  20. Modeling metastasis in the mouse

    PubMed Central

    Bos, Paula D.; Nguyen, Don X.; Massagué, Joan

    2010-01-01

    Metastasis is a complex clinical and biological problem presently under intense study, and several model systems are in use to experimentally recapitulate and dissect the various steps of the metastatic process. Genetically engineered mouse models provide faithful renditions of events in tumor progression, angiogenesis, and local invasion that set the stage for metastasis, whereas engrafting of human or mouse tumor tissues into mouse hosts has been successfully exploited to investigate metastatic dissemination and colonization of distant organs. Real-time, high-resolution microscopy in live animals, and comprehensive genetic and molecular profiling are effective tools to interrogate diverse metastatic cancer cell phenotypes as well as the metastatic tumor microenvironment in different organs. By integrating the information obtained with these complementary approaches the field is currently obtaining an unprecedented level of understanding of the biology, molecular basis, and therapeutic vulnerabilities of metastasis. PMID:20598638

  1. [Lymph node metastasis of osteosarcomas].

    PubMed

    Vasil'ev, N V

    2016-01-01

    Lymph node metastasis of osteosarcomas is a rather rare phenomenon; according to different authors, the incidence of lymph node metastasis is 4 to 11%. The detection of lymph node metastases in osteosarcoma is associated with a significant reduction in the 5-year survival of patients and allows its classification as clinical stage IV tumor. The risk factors for lymph node metastases in patients with bone sarcomas are age (≥64 years), gender (female), nosological entity (undifferentiated pleomorphic sarcoma, osteosarcoma, chondrosarcoma), tumor depth (muscle, bone), and the size of primary tumor (>5 сm). The mechanism of lymph node metastasis of osteosarcomas seems to be related to mesenchymal-to-epithelial transition. PMID:27600784

  2. [Cerebral metastasis as the form of presentation of a basaloid carcinoma of the esophagus].

    PubMed

    Carvalho, I R; Lima, R M; Serafim, A; Lemos, M M; Cristas, J; Machado, J; Oliveira, H

    1995-09-01

    A case of oesophageal basaloid carcinoma is reported. The disease was revealed as a brain metastasis and was found ad initium to be in an advanced stage, with evidence of brain, lung and liver metastasis. The treatment performed was palliative subtotal oesophagectomy followed by roentgen therapy. A year and a half later, the patient is still alive and in home care follow up. The authors end stressing this uncommon presentation for an oesophageal neoplasm and the rarity of its histologic type. They also stress the role of surgery, although palliative, in long survival, very unlike the rapid evolution of the few published cases.

  3. FL V1.3

    2009-08-03

    A library of utility classes for computer vision. Contains implementations of various well-known image processing techniques, such as interest point operators and region descriptors. Includes interfaces to various libraries for image and video I/O, as well as an interface to LAPACK/BLAS. FL was developed at the University of Illinois, Urbana-Champaign (UIUC) and released under an open source license. Version 1.2 was a maintenance release provided by SNL under the LGPL license. Version 1.3 is amore » maintenance release, containing the following changes: - Improved image format handling. Now handles strided and planar memory layouts and a wider range of pixel formats. - Improved image file I/O, including better support for metadata, a wider range of stored pixel types, and a couple of new file formats. - Improvements to DOG and SIFT, and efficiency improvements in low-level convolution. - Improvements to networking, including a generic TCP listener. - Various improvements to numerical processing. The HISTORY file included in the distribution contains a more detailed description of the changes.« less

  4. FL V1.3

    SciTech Connect

    Rothganger, Frederick

    2009-08-03

    A library of utility classes for computer vision. Contains implementations of various well-known image processing techniques, such as interest point operators and region descriptors. Includes interfaces to various libraries for image and video I/O, as well as an interface to LAPACK/BLAS. FL was developed at the University of Illinois, Urbana-Champaign (UIUC) and released under an open source license. Version 1.2 was a maintenance release provided by SNL under the LGPL license. Version 1.3 is a maintenance release, containing the following changes: - Improved image format handling. Now handles strided and planar memory layouts and a wider range of pixel formats. - Improved image file I/O, including better support for metadata, a wider range of stored pixel types, and a couple of new file formats. - Improvements to DOG and SIFT, and efficiency improvements in low-level convolution. - Improvements to networking, including a generic TCP listener. - Various improvements to numerical processing. The HISTORY file included in the distribution contains a more detailed description of the changes.

  5. Metastasis genetics, epigenetics, and the tumor microenvironment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    KISS1 is a member of a family of genes known as metastasis suppressors, defined by their ability to block metastasis without blocking primary tumor development and growth. KISS1 re-expression in multiple metastatic cell lines of diverse cellular origin suppresses metastasis; yet, still allows comple...

  6. Intramedullary conus medullaris metastasis of periurethral adenocarcinoma.

    PubMed

    Ramakonar, H H; Thomas, A; Lind, C R P

    2011-04-01

    Intramedullary spinal cord metastasis to the conus medullaris is very rare. We report a 44-year-old woman with an intra-axial conus medullaris metastasis from periurethral adenocarcinoma. To our knowledge, this is the first report in the literature. We also discuss the clinical features, possible pathophysiological mechanisms and treatment options for intramedullary spinal cord metastasis to the conus medullaris.

  7. THE MRI FINDINGS OF IRIS METASTASIS IN PATIENTS WITH BREAST CANCER

    PubMed Central

    Mutlu, Hasan; Akça, Zeki; Büyükçelik, Abdullah; Öztürk, Mustafa; Taşdemir, Mustafa; Kubilay Yazıcıoğlu, Alper; Kaplan, Bünyamin; Uçar, Kadir

    2012-01-01

    Breast cancer and lung cancer are the most common tumors that metastasize to iris. The metastasis of iris was generally diagnosed on ophthalmologic examination. In this case, we reported iris metastasis of patients with adenocarcinoma of breast cancer and MRI findings. We report a case of a 51-year-old. She was diagnosed breast cancer two years ago. After adjuvant chemotherapy, radiotherapy and trastuzumab, she was admitted to hospital with the complaints of headache on February 2012. The magnetic resonance imaging (MRI ) revealed multiple brain metastasis. Whole brain radiotherapy and palliative chemotherapy were applied to the patients. In follow-up, on ophthalmological examination, there was a solid lesion on iris. The orbital MRI was performed and it revealed the thickness on iris of left eye. After diagnostic procedure final pathological rewiev reported that invasive ductal carcinom metastasis. Iris metastasis may be considered by MRI findings following: The thickness on iris and contrast enhanced lesion. This reason may be resulted that the fine niddle aspiration biopsy for diagnosis of iris metastasis is not need. PMID:23378695

  8. Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model

    PubMed Central

    Chen, Xiaoyun; Wang, Jian; Cao, Ziquan; Hosaka, Kayoko; Jensen, Lasse; Yang, Huasheng; Sun, Yuping; Zhuang, Rujie; Liu, Yizhi; Cao, Yihai

    2015-01-01

    Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses. PMID:26169357

  9. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer.

    PubMed

    Cai, Ling; Zhu, Jian-fei; Zhang, Xue-wen; Lin, Su-xia; Su, Xiao-dong; Lin, Peng; Chen, Kai; Zhang, Lan-jun

    2014-11-01

    We proposed to identify the efficacy of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) using whole brain radiotherapy (WBRT)/stereotactic radiosurgery (SRS)/surgery in brain metastases from patients with non-small cell lung cancer (NSCLC) and clarify the association between treatment outcome and EGFR gene mutation status. A total of 282 patients with NSCLC brain metastases who underwent WBRT/SRS/surgery alone or in combination with TKI were enrolled in our study from 2003-2013. Amplification mutation refractory system technology was used to determine the EGFR mutation status in 109 tissue samples. EGFR mutation detection was performed in 109 patients with tumor tissues. The EGFR positive rate was 50 % (55/109), including 26 exon 19 deletions and 24 L858R mutations. The median follow-up time was 28 months. The median overall survival, median progression-free survival of intracranial disease, and median progression-free survival of extracranial disease was significantly longer for patients with TKI treatment (31.9 vs 17.0 months, P < 0.0001; 19.8 vs 12.0 months, P < 0.0001; and 19.6 vs 12.3 months, P < 0.0001; respectively). In subgroup analysis within the TKI group, patients harboring EGFR mutations had better extracranial disease control (20.4 vs 14.1 months, P = 0.032). Administration of TKI agents with conventional therapy compared with conventional therapy alone might be beneficial for overall survival, progression-free survival of intracranial disease and progression-free survival of extracranial disease in patients with brain metastases from NSCLC independent of EGFR mutations.

  10. Hand1 overexpression inhibits medulloblastoma metastasis.

    PubMed

    Asuthkar, Swapna; Guda, Maheedhara R; Martin, Sarah E; Antony, Reuben; Fernandez, Karen; Lin, Julian; Tsung, Andrew J; Velpula, Kiran K

    2016-08-19

    Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor. Current treatment includes surgery, radiation and chemotherapy. However, ongoing treatment in patients is further classified according to the presence or absence of metastasis. Since metastatic medulloblastoma are refractory to current treatments, there is need to identify novel biomarkers that could be used to reduce metastatic potential, and more importantly be targeted therapeutically. Previously, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. We further demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand1. Among the histological subtypes classical and desmoplastic subtypes account for the majority while large cell/anaplastic variant is most commonly associated with metastatic disease. In this present study using immunohistochemical approach and patient data mining for the first time, we demonstrated that Hand1 expression is observed to be downregulated in all the subtypes of medulloblastoma. Previously we showed that Hand1 overexpression regulated medulloblastoma angiogenesis and here we investigated the role of Hand1 in the context of Epithelial-Mesenchymal Transition (EMT). Moreover, UW228 and D283 cells overexpressing Hand1 demonstrated decreased-expression of mesenchymal markers (N-cadherin, β-catenin and SOX2); metastatic marker (SMA); and increased expression of epithelial marker (E-cadherin). Strikingly, human pluripotent stem cell antibody array showed that Hand1 overexpression resulted in substantial decrease in pluripotency markers (Nanog, Oct3/4, Otx2, Flk1) suggesting that Hand1 expression may be essential to attenuate the EMT and our findings underscore a novel role for Hand1 in medulloblastoma metastasis.

  11. Vasculogenic mimicry and tumor metastasis.

    PubMed

    Zhang, Jingxin; Qiao, Lili; Liang, Ning; Xie, Jian; Luo, Hui; Deng, Guodong; Zhang, Jiandong

    2016-01-01

    Vasculogenic mimicry (VM), a microvascular channel made up of nonendothelial cells, has been accepted as a new model of neovascularization in aggressive tumors, owning to the specific capacity of malignant cells to form vessel-like networks which provide sufficient blood supply for tumor growth. Multiple molecular mechanisms, especially vascular endothelial (VE)-cadherin, erythropoietin-producing hepatocellular receptor A2 (EphA2), phosphatidyl inositol 3-kinase (PI3K), matrix metalloproteinases (MMPs), vascular endothelial growth factor receptor (VEGFR1), and hypoxia inducible factor (HIF)-1a, have been reported to participate in VM formation which is associated with tumor migration and invasion. In addition, hypoxia, cancer stem cells (CSCs) and epithelial-mesenehymal transition (EMT) are regarded as significant factors in VM formation and tumor metastasis. Due to the important effects of VM on tumor progression, a review was carried out in the present study, to synthetically analyze the relationship between VM and tumor metastasis. PMID:27569069

  12. Animal Models of Bone Metastasis.

    PubMed

    Simmons, J K; Hildreth, B E; Supsavhad, W; Elshafae, S M; Hassan, B B; Dirksen, W P; Toribio, R E; Rosol, T J

    2015-09-01

    Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone.

  13. Animal Models of Bone Metastasis

    PubMed Central

    Simmons, J. K.; Hildreth, B. E.; Supsavhad, W.; Elshafae, S. M.; Hassan, B. B.; Dirksen, W. P.; Toribio, R. E.; Rosol, T. J.

    2015-01-01

    Bone is one of the most common sites of cancer metastasis in humans and is a significant source of morbidity and mortality. Bone metastases are considered incurable and result in pain, pathologic fracture, and decreased quality of life. Animal models of skeletal metastases are essential to improve the understanding of the molecular pathways of cancer metastasis and growth in bone and to develop new therapies to inhibit and prevent bone metastases. The ideal animal model should be clinically relevant, reproducible, and representative of human disease. Currently, an ideal model does not exist; however, understanding the strengths and weaknesses of the available models will lead to proper study design and successful cancer research. This review provides an overview of the current in vivo animal models used in the study of skeletal metastases or local tumor invasion into bone and focuses on mammary and prostate cancer, lymphoma, multiple myeloma, head and neck squamous cell carcinoma, and miscellaneous tumors that metastasize to bone. PMID:26021553

  14. The Role of Glycosylation in Breast Cancer Metastasis and Cancer Control

    PubMed Central

    Kölbl, Alexandra C.; Andergassen, Ulrich; Jeschke, Udo

    2015-01-01

    Glycosylation and its correlation to the formation of remote metastasis in breast cancer had been an important scientific topic in the last 25 years. With the development of new analytical techniques, new insights were gained on the mechanisms underlying metastasis formation and the role of aberrant glycosylation within. Mucin-1 and Galectin were recognized as key players in glycosylation. Interestingly, aberrant carbohydrate structures seem to support the development of brain metastasis in breast cancer patients, as changes in glycosylation structures facilitate an overcoming of blood–brain barrier. Changes in the gene expression of glycosyltransferases are the leading cause for a modification of carbohydrate chains, so that also altered gene expression plays a role for glycosylation. In consequence, glycosylation and changes within can be useful for cancer diagnosis, determination of tumor stage, and prognosis, but can as well be targets for therapeutic strategies. Thus, further research on this topic would worthwhile for cancer combating. PMID:26528431

  15. Raman spectroscopy of bone metastasis

    NASA Astrophysics Data System (ADS)

    Esmonde-White, Karen A.; Sottnik, Joseph; Morris, Michael; Keller, Evan

    2012-02-01

    Raman spectroscopy of bone has been used to characterize chemical changes occurring in diseases such as osteoporosis, osteoarthritis and osteomyelitis. Metastasis of cancer into bone causes changes to bone quality that are similar to those observed in osteoporosis, such as decreased bone strength, but with an accelerated timeframe. In particular, osteolytic (bone degrading) lesions in bone metastasis have a marked effect on patient quality of life because of increased risk of fractures, pain, and hypercalcemia. We use Raman spectroscopy to examine bone from two different mouse models of osteolytic bone metastasis. Raman spectroscopy measures physicochemical information which cannot be obtained through standard biochemical and histological measurements. This study was reviewed and approved by the University of Michigan University Committee on the Care and Use of Animals. Two mouse models of prostate cancer bone metastasis, RM1 (n=3) and PC3-luc (n=4) were examined. Tibiae were injected with RM1 or PC3-luc cancer cells, while the contralateral tibiae received a placebo injection for use as controls. After 2 weeks of incubation, the mice were sacrificed and the tibiae were examined by Raman microspectroscopy (λ=785 nm). Spectroscopic markers corresponding to mineral stoichiometry, bone mineralization, and mineral crystallinity were compared in spectra from the cancerous and control tibiae. X-ray imaging of the tibia confirmed extensive osteolysis in the RM1 mice, with tumor invasion into adjoining soft tissue and moderate osteolysis in the PC3-luc mice. Raman spectroscopic markers indicate that osteolytic lesions are less mineralized than normal bone tissue, with an altered mineral stoichiometry and crystallinity.

  16. Colorectal hepatic metastasis: Evolving therapies

    PubMed Central

    Macedo, Francisco Igor B; Makarawo, Tafadzwa

    2014-01-01

    The approach for colorectal hepatic metastasis has advanced tremendously over the past decade. Multidrug chemotherapy regimens have been successfully introduced with improved outcomes. Concurrently, adjunct multimodal therapies have improved survival rates, and increased the number of patients eligible for curative liver resection. Herein, we described major advancements of surgical and oncologic management of such lesions, thereby discussing modern chemotherapeutic regimens, adjunct therapies and surgical aspects of liver resection. PMID:25067997

  17. The biology of cancer metastasis.

    PubMed

    Price, J E

    1990-01-01

    The formation of a metastasis entails a complex sequence of events with the end result dependent on the interaction of malignant cells with host factors. Intrinsic properties of the metastatic tumor cells, including production of proteolytic enzymes, cell surface properties, adhesiveness, and the ability to grow in a distant organ environment, act in concert to influence the tumor cells' interactions with host cells in forming metastases. Life-threatening metastases are formed only by those tumor cells that have survived all steps in a process that has been shown in many experimental studies to be a highly selective event. The results of studies on the distribution of radiolabelled mouse melanoma cells injected into syngeneic mice support the concept that the fate of tumor cells released into the bloodstream is determined by sequential and selective events, and introduces a third regulatory factor. Cells endowed with metastatic properties, isolated by cloning a heterogeneous tumor or selected from a metastasis, have a higher probability of forming metastases than cells not so endowed, yet this probability is not 100%. Metastasis should thus be considered as a selective, sequential and stochastic process. Interruption of the process at any stage will prevent the formation of metastatic disease. Hence, a better understanding of the metastatic process will provide the basis for rational approaches for the prevention or destruction of this most fatal aspect of cancer.

  18. Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain.

    PubMed

    Avraham, Hava Karsenty; Jiang, Shuxian; Fu, Yigong; Nakshatri, Harikrishna; Ovadia, Haim; Avraham, Shalom

    2014-02-01

    Although the incidence of breast cancer metastasis (BCM) in brain has increased significantly in triple-negative breast cancer (TNBC), the mechanisms remain elusive. Using in vivo mouse models for BCM in brain, we observed that TNBC cells crossed the blood-brain barrier (BBB), lodged in the brain microvasculature and remained adjacent to brain microvascular endothelial cells (BMECs). Breaching of the BBB in vivo by TNBCs resulted in increased BBB permeability and changes in ZO-1 and claudin-5 tight junction (TJ) protein structures. Angiopoietin-2 expression was elevated in BMECs and was correlated with BBB disruption. Secreted Ang-2 impaired TJ structures and increased BBB permeability. Treatment of mice with the neutralizing Ang-2 peptibody trebananib prevented changes in the BBB integrity and BMEC destabilization, resulting in inhibition of TNBC colonization in brain. Thus, Ang-2 is involved in initial steps of brain metastasis cascade, and inhibitors for Ang-2 may serve as potential therapeutics for brain metastasis.

  19. Extracranial oral cavity metastasis from glioblastoma multiforme: A case report

    PubMed Central

    Kup, Philipp Günther; Nieder, Carsten; Winnekendonk, Guido; Adamietz, Irenäus Anton; Fakhrian, Khashayar

    2016-01-01

    Glioblastoma multiforme is the most common primary malignant brain tumor. The clinical outcome following diagnosis remains extremely poor. The treatment of choice is wide surgical resection of the visible tumor, frequently followed by adjuvant combined radiochemotherapy (RCTx) with temozolomide as the chemotherapeutic agent. Extracranial metastases are extremely rare, with <200 cases of extracranial metastases from glioblastoma multiforme reported in the literature to date. We herein present a case of a patient suffering from a fast-growing metastasis to the oral cavity, completely filling the buccal cavity within 2 weeks, as the only manifestation of recurrent glioblastoma multiforme following initial surgical resection and adjuvant RCTx.

  20. Brain metastases from gestational trophoblastic neoplasia: review of pertinent literature.

    PubMed

    Piura, E; Piura, B

    2014-01-01

    Brain metastasis from gestational trophoblastic neoplasia (GTN) is rare with about 222 cases documented in the literature and an incidence of about 11% in living GTN patients. Brain metastasis from GTN was part of a disseminated disease in 90% of patients, single metastases in the brain - 80% and located in the cerebrum - 90%. Brain metastasis was the only manifestation of metastatic GTN in 11.3% of patients, appeared synchronously with metastatic GTN in other sites of the body - 30.6% and was diagnosed from 0.3 to 60 months after diagnosis of metastatic GTN in other sites (most often in the lung) - 58.1%. Overall, 83.9% of patients with brain metastases from GTN had also lung metastases from GTN. Brain metastases from GTN showed a greater tendency to be hemorrhagic compared to brain metastases from other primaries. In patients with brain metastases from GTN, the best outcome was achieved with multimodal therapy including craniotomy, whole brain radiotherapy, and EP-EMA or EMA-CO chemotherapy. Nonetheless, brain metastasis from GTN is a grave disease with a median survival time from diagnosis of brain metastasis of about 12 months.

  1. Metastatic brain tumor from urothelial carcinoma of the prostatic urethra

    PubMed Central

    Morita, Kohei; Oda, Masashi; Koyanagi, Masaomi; Saiki, Masaaki

    2016-01-01

    Background: Urothelial carcinoma occurs in the bladder, upper urinary tract, and lower urinary tract, including prostatic urethra. A majority of the reported cases of intracranial metastasis from urothelial carcinoma originates from the bladder and upper urinary tract. Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. Case Description: A 72-year-old male presented with a metastatic brain tumor and a 3-year history of urothelial carcinoma of the prostatic urethra treated with cystourethrectomy and chemotherapy with gemcitabine-cisplatin. Pathological diagnosis for tumor removal was compatible with metastatic brain tumor from urothelial carcinoma. Conclusion: Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. It is an extremely rare case, however, we should be careful of brain metastasis during follow-up for urothelial carcinoma in the lower urinary tract. PMID:27512612

  2. A Case of Pleuroparenchymal Metastasis: Rare Aetiology

    PubMed Central

    Sharma, Radhika; Narasimhan, Meenakshi; Shanmuganathan, Aruna; Rajendran, Adhithyan

    2016-01-01

    A phyllodes tumour is a malignancy of both mesenchymal and epithelial origin affecting the breast. The malignant course of this breast tumour causing lung metastasis is rare. Here we report a treated case of borderline phyllodes tumour that presented with pleuroparenchymal metastasis. Our case highlights the possibility of recurrence of borderline phyllodes tumour as pleuroparenchymal metastasis even after a long disease free interval. PMID:27190865

  3. Integrin activation controls metastasis in human breast cancer

    NASA Astrophysics Data System (ADS)

    Felding-Habermann, Brunhilde; O'Toole, Timothy E.; Smith, Jeffrey W.; Fransvea, Emilia; Ruggeri, Zaverio M.; Ginsberg, Mark H.; Hughes, Paul E.; Pampori, Nisar; Shattil, Sanford J.; Saven, Alan; Mueller, Barbara M.

    2001-02-01

    Metastasis is the primary cause of death in human breast cancer. Metastasis to bone, lungs, liver, and brain involves dissemination of breast cancer cells via the bloodstream and requires adhesion within the vasculature. Blood cell adhesion within the vasculature depends on integrins, a family of transmembrane adhesion receptors, and is regulated by integrin activation. Here we show that integrin v3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin v3 was found in two distinct functional states in human breast cancer cells. The activated, but not the nonactivated, state supported tumor cell arrest during blood flow through interaction with platelets. Importantly, activated αvβ3 was expressed by freshly isolated metastatic human breast cancer cells and variants of the MDA-MB 435 human breast cancer cell line, derived from mammary fat pad tumors or distant metastases in severe combined immunodeficient mice. Expression of constitutively activated mutant αvβ3D723R, but not αvβ3WT, in MDA-MB 435 cells strongly promoted metastasis in the mouse model. Thus breast cancer cells can exhibit a platelet-interactive and metastatic phenotype that is controlled by the activation of integrin αvβ3. Consequently, alterations within tumors that lead to the aberrant control of integrin activation are expected to adversely affect the course of human breast cancer.

  4. Neurotrophin receptor TrkB promotes lung adenocarcinoma metastasis.

    PubMed

    Sinkevicius, Kerstin W; Kriegel, Christina; Bellaria, Kelly J; Lee, Jaewon; Lau, Allison N; Leeman, Kristen T; Zhou, Pengcheng; Beede, Alexander M; Fillmore, Christine M; Caswell, Deborah; Barrios, Juliana; Wong, Kwok-Kin; Sholl, Lynette M; Schlaeger, Thorsten M; Bronson, Roderick T; Chirieac, Lucian R; Winslow, Monte M; Haigis, Marcia C; Kim, Carla F

    2014-07-15

    Lung cancer is notorious for its ability to metastasize, but the pathways regulating lung cancer metastasis are largely unknown. An in vitro system designed to discover factors critical for lung cancer cell migration identified brain-derived neurotrophic factor, which stimulates cell migration through activation of tropomyosin-related kinase B (TrkB; also called NTRK2). Knockdown of TrkB in human lung cancer cell lines significantly decreased their migratory and metastatic ability in vitro and in vivo. In an autochthonous lung adenocarcinoma model driven by activated oncogenic Kras and p53 loss, TrkB deficiency significantly reduced metastasis. Hypoxia-inducible factor-1 directly regulated TrkB expression, and, in turn, TrkB activated Akt signaling in metastatic lung cancer cells. Finally, TrkB expression was correlated with metastasis in patient samples, and TrkB was detected more often in tumors that did not have Kras or epidermal growth factor receptor mutations. These studies demonstrate that TrkB is an important therapeutic target in metastatic lung adenocarcinoma. PMID:24982195

  5. [A case of malignant melanoma metastasis to the mammary gland].

    PubMed

    Tanaka, Ryota; Kashiwagi, Shinichiro; Ishihara, Sae; Asano, Yuka; Noda, Satoru; Kawajiri, Hidemi; Takashima, Tsutomu; Onoda, Naoyoshi; Ohsawa, Masahiko; Hirakawa, Kosei

    2014-11-01

    Herein, we report a rare case of malignant melanoma metastasis to the mammary gland. A 76-year-old woman had a tumor resection performed for primary malignant melanoma of the epipharynx. The patient subsequently underwent local and lymph node recurrence, for which she received heavy ion radiotherapy and lymph node dissection, respectively. The patient was referred to our hospital for a problem with her right breast. Computed tomography and magnetic resonance imaging showed a mammary tumor and multiple subcutaneous tumors. A biopsy was performed, which proved positive for S100 and Melan A staining, and the diagnosis of malignant melanoma was confirmed. Partial mastectomy was performed; and S100, HMB45, and Melan A positivity was confirmed based on immunohistological findings. The diagnosis was malignant melanoma metastasis to the mammary gland. Malignant melanoma commonly metastasizes to the liver, mediastinum, mediastinal glands, lung, and brain; and metastasis to the mammary gland is rare. To our knowledge, only 2 cases have previously been reported in the Japanese literature.

  6. Protocadherin-7 induces bone metastasis of breast cancer

    SciTech Connect

    Li, Ai-Min; Tian, Ai-Xian; Zhang, Rui-Xue; Ge, Jie; Sun, Xuan; Cao, Xu-Chen

    2013-07-05

    Highlights: •PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. •PCDH7 is up-regulation in bone metastatic breast cancer tissues. •Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. •PCDH7 induces breast cancer bone metastasis in vivo. -- Abstract: Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer.

  7. [Jawbone metastasis masquerading as dental pain].

    PubMed

    Goldman, Y; Yarom, N

    2016-01-01

    Metastases to the oral cavity are rare. However, in 25% of cases, oral symptoms will be the first sign of metastatic disease. The incidence of jaws metastases is twice as high as the incidence of metastases to the soft tissues of the oral cavity. In some cases, jaws metastases can mimic dental or periodontal pain. We report a case of a 67 year old female who was referred to our clinic because of severe pain on her left posterior mandible which was not relieved by endodontic treatment of the first and second molar. She was diagnosed with breast cancer in 2005 and had been treated with surgery, chemotherapy and radiotherapy. Seven years later, lung metastases were found and she was treated with chemotherapy. Later on, brain metastases developed which had been treated with radiotherapy. On presentation, she complained of pain on the posterior left mandible which was accompanied by a burning sensation of the lower left lip and chin. CT scan revealed a soft tissue mass perforating the lingual and buccal plates of the posterior left mandible, which was compatible with a diagnosis of metastasis. Radiotherapy rapidly relieved the pain. Unfortunately, the patient passed away one month later. Dentists should be able to recognize the signs and symptoms associated with metastases to the jaws and should include it in the differential diagnosis, especially in patients with oncologic background. PMID:27295929

  8. 16 CFR 1.3 - Advice.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Advice. 1.3 Section 1.3 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE GENERAL PROCEDURES Industry Guidance Advisory Opinions § 1.3 Advice. (a) On the basis of the materials submitted, as well as any...

  9. 43 CFR 8365.1-3 - Vehicles.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 2 2011-10-01 2011-10-01 false Vehicles. 8365.1-3 Section 8365.1-3 Public... OF THE INTERIOR RECREATION PROGRAMS VISITOR SERVICES Rules of Conduct § 8365.1-3 Vehicles. (a) When operating a vehicle on the public lands, no person shall exceed posted speed limits, willfully...

  10. 50 CFR 1.3 - Service.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Service. 1.3 Section 1.3 Wildlife and Fisheries UNITED STATES FISH AND WILDLIFE SERVICE, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS DEFINITIONS § 1.3 Service. Service means the United States Fish and Wildlife Service, Department of the Interior....

  11. 5 CFR 1.3 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Definitions. 1.3 Section 1.3 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE RULES COVERAGE AND DEFINITIONS (RULE I) § 1.3 Definitions. As used in the rules in this subchapter: (a) Competitive service shall have the...

  12. 45 CFR 1216.1-3 - Policy.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 4 2012-10-01 2012-10-01 false Policy. 1216.1-3 Section 1216.1-3 Public Welfare Regulations Relating to Public Welfare (Continued) CORPORATION FOR NATIONAL AND COMMUNITY SERVICE NONDISPLACEMENT OF EMPLOYED WORKERS AND NONIMPAIRMENT OF CONTRACTS FOR SERVICE § 1216.1-3 Policy. (a)...

  13. 45 CFR 1216.1-3 - Policy.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 4 2013-10-01 2013-10-01 false Policy. 1216.1-3 Section 1216.1-3 Public Welfare Regulations Relating to Public Welfare (Continued) CORPORATION FOR NATIONAL AND COMMUNITY SERVICE NONDISPLACEMENT OF EMPLOYED WORKERS AND NONIMPAIRMENT OF CONTRACTS FOR SERVICE § 1216.1-3 Policy. (a)...

  14. Blocking the Adhesion Cascade at the Premetastatic Niche for Prevention of Breast Cancer Metastasis

    PubMed Central

    Kang, Shin-Ae; Hasan, Nafis; Mann, Aman P; Zheng, Wei; Zhao, Lichao; Morris, Lynsie; Zhu, Weizhu; Zhao, Yan D; Suh, K Stephen; Dooley, William C; Volk, David; Gorenstein, David G; Cristofanilli, Massimo; Rui, Hallgeir; Tanaka, Takemi

    2015-01-01

    Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)–/CD44+ hormone-independent breast cancer cells, but not of the ER+/CD44-/low hormone-dependent breast cancer cells. Coincidentally, CD44+ breast cancer cells were abundant in metastatic lung and brain lesions in ER– breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER–/CD44+ breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44+ cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER–/CD44+ breast cancer. PMID:25815697

  15. NSG Mice Provide a Better Spontaneous Model of Breast Cancer Metastasis than Athymic (Nude) Mice

    PubMed Central

    Puchalapalli, Madhavi; Zeng, Xianke; Mu, Liang; Anderson, Aubree; Hix Glickman, Laura; Zhang, Ming; Sayyad, Megan R.; Mosticone Wangensteen, Sierra; Clevenger, Charles V.; Koblinski, Jennifer E.

    2016-01-01

    Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice. In addition, a pattern of metastasis similar to that observed in human breast cancer patients (metastases to the lungs, liver, bones, brain, and lymph nodes) was found in NSG mice. Furthermore, there was an increase in the metastatic burden in NSG compared to nude mice that were injected with MDA-MB-231 breast cancer cells in an intracardiac experimental metastasis model. This data demonstrates that NSG mice provide a better model for studying human breast cancer metastasis compared to the current nude mouse model. PMID:27662655

  16. PARP1 enhances lung adenocarcinoma metastasis by novel mechanisms independent of DNA repair.

    PubMed

    Choi, E-B; Yang, A-Y; Kim, S C; Lee, J; Choi, J K; Choi, C; Kim, M-Y

    2016-09-01

    The role of poly (ADP-ribose) polymerase 1 (PARP1) in cancer has been extensively studied in the context of DNA repair, leading to clinical trials of PARP1 inhibitors in cancers defective in homologous recombination. However, the DNA repair-independent roles of PARP1 in carcinogenesis and metastasis, particularly in lung cancer metastasis, remain largely uncharacterized. Here, we report that PARP1 promotes lung adenocarcinoma relapse to the brain and bones by regulating several steps of the metastatic process in a DNA repair-independent manner. We find that PARP1 expression is associated with overall and distant metastasis-free survival in lung adenocarcinoma patients. Consistent with this, genetic knockdown and pharmacological inhibition of PARP1 significantly attenuated the metastatic potential of lung adenocarcinoma cells. Further investigation revealed that PARP1 potentiates lung adenocarcinoma metastasis by promoting invasion, anoikis resistance, extravasation and self-renewal of lung adenocarcinoma cells and also by modifying the brain microenvironment. Finally, we identified S100A4 and CLDN7 as novel transcriptional targets and clinically relevant effectors of PARP1. Collectively, our study not only revealed previously unknown functions of PARP1 in lung adenocarcinoma metastasis but also delineated the molecular mechanisms underlying the pro-metastatic function of PARP1. Furthermore, these findings provide a foundation for the potential use of PARP1 inhibitors as a new treatment option for lung adenocarcinoma patients with elevated PARP1 expression. PMID:26898760

  17. Endocannabinoids as Guardians of Metastasis

    PubMed Central

    Tegeder, Irmgard

    2016-01-01

    Endocannabinoids including anandamide and 2-arachidonoylglycerol are involved in cancer pathophysiology in several ways, including tumor growth and progression, peritumoral inflammation, nausea and cancer pain. Recently we showed that the endocannabinoid profiles are deranged during cancer to an extent that this manifests in alterations of plasma endocannabinoids in cancer patients, which was mimicked by similar changes in rodent models of local and metastatic cancer. The present topical review summarizes the complexity of endocannabinoid signaling in the context of tumor growth and metastasis. PMID:26875980

  18. A review of penile metastasis

    PubMed Central

    Mearini, Luigi; Colella, Renato; Zucchi, Alessandro; Nunzi, Elisabetta; Porrozzi, Carlo; Porena, Massimo

    2012-01-01

    Penile cancer as primary disease is relatively rare in developed countries. The penis is a rare site of metastases in spite of its rich vascularization. Approximately 500 cases have been reported in the literature; almost 70% of primary lesions are of pelvic origin (from genitourinary or recto-sigmoid primary tumors). We describe a case of penile metastasis from lung cancer. The rarity of the event prompted us to also explore related reviews and discuss the incidence, physiopathology, diagnosis and therapy of penile secondary cancer. PMID:25992200

  19. Metastasis

    MedlinePlus

    ... Trials Pain Management Nutrition and Exercise Holistic Care Pathology Intraductal Papillary Mucinous Neoplasms Islet Cell Tumors & Endocrine ... 410-933-7262 Site Map Policies & Credits News Pathology Home Goldman Center © 2016 Johns Hopkins University

  20. Postoperative recurrence of papillary thyroid carcinoma with lymph node metastasis

    PubMed Central

    Liu, Feng‐Hsuan; Kuo, Sheng‐Fong; Hsueh, Chuen; Chao, Tzu‐Chieh

    2015-01-01

    Background and Objectives : The purpose of this study was to retrospectively analyze the features of patients with papillary thyroid carcinoma (PTC) presenting with neck lymph node (LN) metastasis. Methods : The study enrolled 909 patients with PTC who had undergone total thyroidectomy. After a median follow‐up of 14.6 years, 73 (8.0%) patients died of thyroid cancer. A total of 536 patients had the tumor confined to the thyroid (intra‐thyroid), 111 had lymph node (LN) metastasis, 225 showed soft tissue invasion, and 37 had distant metastasis. Results : Compared with the intra‐thyroid group, the group with LN metastases showed larger tumor size, higher postoperative thyroglobulin levels, advanced TNM stage, higher recurrence rates (5.2% vs. 31.5%), and higher disease‐specific mortality (1.3% vs. 12.6%). Of the 111 patients with PTC and LN metastases, 35 (31.5%) were diagnosed with recurrence during a mean follow‐up period of 16.9 ± 0.6 years. Among the 35 patients with recurrent PTC, 14 (40.0%) died of thyroid cancer. The mortality group was characterized by older, mostly male patients who presented with larger initial tumor size compared with survivors. Conclusions : In patients with PTC, the rates of recurrence and cancer mortality were higher in the group with LN metastasis than that in the intra‐thyroid tumor group. J. Surg. Oncol. 2015 111:149–154. © 2015 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc. PMID:26175314

  1. Breast metastasis from vaginal cancer.

    PubMed

    Chandrasekaran, Neeraja; Scharifker, Daniel; Varsegi, George; Almeida, Zoyla

    2016-07-21

    Vaginal cancer is a rare malignancy accounting for 1-2% of all pelvic neoplasms. Dissemination usually occurs through local invasion and rarely metastasises to distal locations. Metastasis of vaginal cancer to the breast is extremely infrequent and unique. A 66-year-old Asian woman presented with vaginal bleeding and was found to have a vaginal mass and a left breast mass. Pathological assessment of the biopsies revealed identical squamous cell characteristics of both masses. We describe a very rare and novel case of a distally located vaginal carcinoma with metastasis to the breast Federation of Gynecology and Obstetrics (FIGO) stage IV (FIGO IVB). Robot-assisted extrafascial total hysterectomy with local vaginal mass excision and partial mastectomy of the left breast were performed. After surgery, the patient underwent adjuvant chemotherapy followed by breast and pelvic radiotherapy, with maintained complete remission after 3 years of follow-up. This combination of findings and treatment is very distinct with a unique and favourable response.

  2. Breast metastasis from vaginal cancer.

    PubMed

    Chandrasekaran, Neeraja; Scharifker, Daniel; Varsegi, George; Almeida, Zoyla

    2016-01-01

    Vaginal cancer is a rare malignancy accounting for 1-2% of all pelvic neoplasms. Dissemination usually occurs through local invasion and rarely metastasises to distal locations. Metastasis of vaginal cancer to the breast is extremely infrequent and unique. A 66-year-old Asian woman presented with vaginal bleeding and was found to have a vaginal mass and a left breast mass. Pathological assessment of the biopsies revealed identical squamous cell characteristics of both masses. We describe a very rare and novel case of a distally located vaginal carcinoma with metastasis to the breast Federation of Gynecology and Obstetrics (FIGO) stage IV (FIGO IVB). Robot-assisted extrafascial total hysterectomy with local vaginal mass excision and partial mastectomy of the left breast were performed. After surgery, the patient underwent adjuvant chemotherapy followed by breast and pelvic radiotherapy, with maintained complete remission after 3 years of follow-up. This combination of findings and treatment is very distinct with a unique and favourable response. PMID:27444140

  3. MicroRNA and Metastasis.

    PubMed

    Ma, L

    2016-01-01

    Noncoding RNAs are important regulatory molecules of cellular processes. MicroRNAs (miRNAs) are small noncoding RNAs that bind to complementary sequences in the 3' untranslated region of target mRNAs, leading to degradation of the target mRNAs and/or inhibition of their translation. Some miRNAs are essential for normal animal development; however, many other miRNAs are dispensable for development but play a critical role in pathological conditions, including tumorigenesis and metastasis. miRNA genes often reside at fragile chromosome sites and are deregulated in cancer. Some miRNAs function as oncogenes or tumor suppressors, collectively termed "oncomirs." Specific metastasis-regulating miRNAs, collectively termed "metastamirs," govern molecular processes and pathways in malignant progression in either a tumor cell-autonomous or a cell-nonautonomous manner. Recently, exosome-transferred miRNAs have emerged as mediators of the tumor-stroma cross talk. In this chapter, we focus on the functions, mechanisms of action, and therapeutic potential of miRNAs, particularly oncomirs and metastamirs. PMID:27613133

  4. Supratentorial metastasis of medulloblastoma in adults

    PubMed Central

    Kumar, Sushil; Handa, Amit; Jha, Deepak K.; Choudhary, Ajay

    2016-01-01

    Two adults, 31 and 20 years of age, developed supratentorial metastasis 3½ years and 11 months, respectively, after gross total removal of their posterior fossa medulloblastoma. The first case developed spinal metastasis as well. Both had undergone craniospinal irradiation. Case 1 underwent laminectomy and case 2 underwent craniotomy because their presenting symptoms required so. PMID:27366282

  5. The vasculature: a vessel for bone metastasis

    PubMed Central

    Raymaekers, Koen; Stegen, Steve; van Gastel, Nick; Carmeliet, Geert

    2015-01-01

    Emerging evidence indicates that the interactions between tumor cells and the bone microenvironment have a crucial role in the pathogenesis of bone metastasis and that they can influence tumor cell dissemination, quiescence and tumor growth in the bone. The vasculature is known to be critical for primary tumor growth, and anti-angiogenesis drugs are approved for the treatment of certain tumor types. The role of the vasculature in bone metastasis is less well known, but recent evidence shows that blood vessels in the bone are a key component of the local microenvironment for the tumor cells and contribute to the different consecutive phases of bone metastasis. A better insight in the importance of the vasculature for bone metastasis may help develop novel treatment modalities that either slow down tumor growth or, preferably, prevent or cure bone metastasis. PMID:27217954

  6. Isolated pancreatic metastasis from melanoma. Case report.

    PubMed

    Portale, T R; Di Benedetto, V; Mosca, F; Trovato, M A; Scuderi, M G; Puleo, S

    2011-03-01

    Pancreas is frequently site of isolated metastasis, approximately in the 40% of cases in patient with previous history of malignant neoplasia, more frequently from renal cell carcinoma. The melanoma metastasis can also interest the pancreas in case of disseminated disease (50% of the cases); more rarely the pancreas is site of isolated metastases from melanoma. The treatment of the pancreatic metastases from melanoma is controversial: the therapeutic choices are few and the role of surgery is not well defined. If the metastasis are confined to the pancreas, the surgical treatment can be useful for better long time survival. We report a rare case of melanoma with pancreatic isolated metastasi in a patient with a previous melanotic metastasis to the inguinal lymph nodes without evidence of primitive tumor.

  7. Subchronic toxicity studies on 1,3,5-trinitrobenzene, 1,3-dinitrobenzene and tetryl in rats. Final report

    SciTech Connect

    Reddy, T.V.; Daniel, F.B.

    1994-09-01

    Toxic effects of 1,3-Dinitrobenzene (1,3-DNB) in male and female F344 rats were evaluated by feeding powdered certified laboratory chow diet supplemented with varied concentrations of 1,3-DNB (0, 2.5, 10, 25, 75 and 150 mg/kg diet) for fourteen days. The average daily 1 ,3-DNB doses consumed were 0.21, 0.87, 2.02, 6.28 and 11.82 mg/kg b.w. for females and 0.21, 0.80, 1.98, 5.77 and 10.56 for males. Food consumption was significantly decreased in high dose animals of both sexes. Final body weights were not altered but relative organ weights were significantly changed in the 150 and 75 mg dose groups involving the spleen (males and females) and testes (males). Hematology and clinical chemistry studies indicated significantly increased values in both sexes relating to reticulocytes and methemoglobin in the 150 and 75 mg/kg dose groups while the red blood cell count, hemoglobin level and % hematocrit were decreased in these same groups. In addition, the levels of bilirubin, protein and albumin were increased in high dose males, Histopathological evaluations suggested that the susceptible organs for 1,3-DNB toxicity were kidneys (hyaline droplets), spleen (erythroid cell hyperplasia), brain (malacia and microgliosis), testes (seminiferous tubular degeneration). These changes were noted mainly in the 150 and 75 mg/kg dose groups except those changes involving the brain (150 mg/kg group only).

  8. Orthopaedic perspective on bone metastasis

    PubMed Central

    Molloy, Alan P; O’Toole, Gary C

    2013-01-01

    The incidence of cancer is increasing worldwide, with the advent of a myriad of new treatment options, so is the overall survival of these patients. However, from an orthopaedic perspective, there comes the challenge of treating more patients with a variety of metastatic bone lesions. The consequences of such lesions can be significant to the patient, from pain and abnormal blood results, including hypercalcemia, to pathological fracture. Given the multiple options available, the treatment of bone metastasis should be based on a patient-by patient manner, as is the case with primary bone lesions. It is imperative, given the various lesion types and locations, treatment of bone metastasis should be performed in an individualised manner. We should consider the nature of the lesion, the effect of treatment on the patient and the overall outcome of our decisions. The dissemination of primary lesions to distant sites is a complex pathway involving numerous cytokines within the tumour itself and the surrounding microenvironment. To date, it is not fully understood and we still base a large section of our knowledge on Pagets historic “seed and soil” theory. As we gain further understanding of this pathway it will allow us develop more medical based treatments. The treatment of primary cancers has long been provided in a multi-disciplinary setting to achieve the best patient outcomes. This should also be true for the treatment of bone metastases. Orthopaedic surgeons should be involved in the multidisciplinary treatment of such patients given that there are a variety of both surgical fixation methods and non-operative methods at our disposal. PMID:23878778

  9. Rectus abdominalis muscle metastasis from uterine leiomyosarcoma: An unusual case and review of the literature

    PubMed Central

    Güngör, Tayfun; Akbay, Serap; Aksüt, Hayri; Yılmaz, Bülent

    2014-01-01

    Uterine leiomyosarcoma is an aggressive malignancy. Spread to the lung, thyroid, liver, brain, pancreas, heart, duodenum, breast, vagina, submandibular gland, and bone has been reported. We describe a case of metastatic uterine leiomyosarcoma to the rectus abdominalis muscle as the first case in the literature. A 39-year-old nulligravid woman presented with a history of pelvic pain. Physical examination discovered about a 6-cm mass in the suprapubic region. She had previously undergone a hysterectomy for uterine leiomyosarcoma. Operative findings had revealed a mass measuring 4×5×6 cm located in the rectus abdominalis muscle. Abnormal mitotic figures and necrosis were evident, and uterine leiomyosarcoma was diagnosed. Uterine leiomyosarcomas are malignancies of the smooth muscle arising from the myometrium. Skeletal muscle is an uncommon site of metastasis by hematogenous spread. In conclusion, we have described a case of skeletal muscle metastasis (first case of rectus abdominalis muscle metastasis) secondary to uterine leiomyosarcoma. PMID:24976779

  10. 41 CFR 60-1.3 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 41 Public Contracts and Property Management 1 2013-07-01 2013-07-01 false Definitions. 60-1.3 Section 60-1.3 Public Contracts and Property Management Other Provisions Relating to Public Contracts...-OBLIGATIONS OF CONTRACTORS AND SUBCONTRACTORS Preliminary Matters; Equal Opportunity Clause;...

  11. 41 CFR 60-1.3 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 41 Public Contracts and Property Management 1 2012-07-01 2009-07-01 true Definitions. 60-1.3 Section 60-1.3 Public Contracts and Property Management Other Provisions Relating to Public Contracts...-OBLIGATIONS OF CONTRACTORS AND SUBCONTRACTORS Preliminary Matters; Equal Opportunity Clause;...

  12. 41 CFR 60-1.3 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 41 Public Contracts and Property Management 1 2014-07-01 2014-07-01 false Definitions. 60-1.3 Section 60-1.3 Public Contracts and Property Management Other Provisions Relating to Public Contracts...-OBLIGATIONS OF CONTRACTORS AND SUBCONTRACTORS Preliminary Matters; Equal Opportunity Clause;...

  13. 36 CFR 1.3 - Penalties.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 36 Parks, Forests, and Public Property 1 2010-07-01 2010-07-01 false Penalties. 1.3 Section 1.3 Parks, Forests, and Public Property NATIONAL PARK SERVICE, DEPARTMENT OF THE INTERIOR GENERAL PROVISIONS... 1 through 7, 12 and 13 of this chapter, within a park area not covered in paragraphs (b) or (c)...

  14. Brain metastases of breast cancer.

    PubMed

    Palmieri, Diane; Smith, Quentin R; Lockman, Paul R; Bronder, Julie; Gril, Brunilde; Chambers, Ann F; Weil, Robert J; Steeg, Patricia S

    Central nervous system or brain metastases traditionally occur in 10-16% of metastatic breast cancer patients and are associated with a dismal prognosis. The development of brain metastases has been associated with young age, and tumors that are estrogen receptor negative, Her-2+ or of the basal phenotype. Treatment typically includes whole brain irradiation, or either stereotactic radiosurgery or surgery with whole brain radiation, resulting in an approximately 20% one year survival. The blood-brain barrier is a formidable obstacle to the delivery of chemotherapeutics to the brain. Mouse experimental metastasis model systems have been developed for brain metastasis using selected sublines of human MDA-MB-231 breast carcinoma cells. Using micron sized iron particles and MRI imaging, the fate of MDA-MB-231BR cells has been mapped: Approximately 2% of injected cells form larger macroscopic metastases, while 5% of cells remain as dormant cells in the brain. New therapies with permeability for the blood-brain barrier are needed to counteract both types of tumor cells. PMID:17473372

  15. Synthesis of 1,3,3-trinitroazetidine

    DOEpatents

    Hiskey, Michael A.; Coburn, Michael D.

    1994-01-01

    A process of preparing 1,3,3-trinitroazetidine including forming a 5-hydroxymethyl-5-nitro-1-alkyltetrahydro-1,3-oxazine, e.g., reacting a 1,3,5-trialkyl hexahydrotriazine and tris(hydroxymethyl)nitromethane, ring opening said 5-hydroxymethyl-5-nitro-1-alkyltetrahydro-1,3-oxazine to form a 3-alkylamino-2-hydroxymethyl-2-nitro-1-propanol salt, ring closing said 3-alkylamino-2-hydroxymethyl-2-nitro-1-propanol salt to form a 3-hydroxymethyl-3-nitro-1-alkylazetidine salt, nitrating said 3-hydroxymethyl-3-nitro-1-alkylazetidine salt to form a 1-alkyl-3,3-dinitroazetidine, and converting said 1-alkyl-3,3-dinitroazetidine into 1,3,3-trinitroazetidine is disclosed.

  16. Synthesis of 1,3,3-trinitroazetidine

    DOEpatents

    Hiskey, M.A.; Coburn, M.D.

    1994-08-09

    A process of preparing 1,3,3-trinitroazetidine includes forming a 5-hydroxymethyl-5-nitro-1-alkyltetrahydro-1,3-oxazine, e.g., reacting a 1,3,5-trialkyl hexahydrotriazine and tris(hydroxymethyl)nitromethane, ring opening said 5-hydroxymethyl-5-nitro-1-alkyltetrahydro-1,3-oxazine to form a 3-alkylamino-2-hydroxymethyl-2-nitro-1-propanol salt, ring closing said 3-alkylamino-2-hydroxymethyl-2-nitro-1-propanol salt to form a 3-hydroxymethyl-3-nitro-1-alkylazetidine salt, nitrating said 3-hydroxymethyl-3-nitro-1-alkylazetidine salt to form a 1-alkyl-3,3-dinitroazetidine, and converting said 1-alkyl-3,3-dinitroazetidine into 1,3,3-trinitroazetidine is disclosed. 1 fig.

  17. The Current and Future Treatment of Brain Metastases

    PubMed Central

    Hardesty, Douglas A.; Nakaji, Peter

    2016-01-01

    Brain metastases are the most common intracranial malignancy, accounting for significant morbidity and mortality in oncology patients. The current treatment paradigm for brain metastasis depends on the patient’s overall health status, the primary tumor pathology, and the number and location of brain lesions. Herein, we review the modern management options for these tumors, including surgical resection, radiotherapy, and chemotherapy. Recent operative advances, such as fluorescence, confocal microscopy, and brachytherapy, are highlighted. With an increased understanding of the pathophysiology of brain metastasis come increased future therapeutic options. Therapy targeted to specific tumor molecular pathways, such as those involved in blood–brain barrier transgression, cell–cell adhesion, and angiogenesis, are also reviewed. A personalized plan for each patient, based on molecular characterizations of the tumor that are used to better target radiotherapy and chemotherapy, is undoubtedly the future of brain metastasis treatment. PMID:27252942

  18. Nearly Complete Response of Brain Metastases from HER2 Overexpressing Breast Cancer with Lapatinib and Capecitabine after Whole Brain Irradiation

    PubMed Central

    Oktay, Esin; Yersal, Özlem; Meydan, Nezih; Sağıroğlu, Mehmet; Uyanık, Ömer; Barutca, Sabri

    2013-01-01

    Trastuzumab treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in HER2 overexpressing breast cancer patients. Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of HER2-positive breast cancer. We report a patient with breast cancer overexpressing HER-2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine. PMID:24191208

  19. Imaging of bone metastasis: An update.

    PubMed

    O'Sullivan, Gerard J; Carty, Fiona L; Cronin, Carmel G

    2015-08-28

    Early detection of skeletal metastasis is critical for accurate staging and optimal treatment. This paper briefly reviews our current understanding of the biological mechanisms through which tumours metastasise to bone and describes the available imaging methods to diagnose bone metastasis and monitor response to treatment. Among the various imaging modalities currently available for imaging skeletal metastasis, hybrid techniques which fuse morphological and functional data are the most sensitive and specific, and positron emission tomography (PET)/computed tomography and PET/magnetic resonance imaging will almost certainly continue to evolve and become increasingly important in this regard.

  20. Paeoniflorin inhibits macrophage-mediated lung cancer metastasis.

    PubMed

    Wu, Qi; Chen, Gang-Ling; Li, Ya-Juan; Chen, Yang; Lin, Fang-Zhen

    2015-12-01

    Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pallas, can inhibit tumor growth and lung metastases of Lewis lung tumor-bearing mice. This study tried to investigate whether paeoniflorin inhibited lung cancer metastasis by inhibiting the alternative activation of macrophages (M2 macrophage). Using a viability assay, the cytotoxicity of paeoniflorin on Lewis lung cancer cells and peritoneal macrophages were investigated. In vitro scratch wound and in vivo lung metastasis experiments were used to test the ability to inhibit the migration of paeoniflorin and the function of M2 macrophages. Flow cytometry was performed to test the cell cycle of Lewis lung cancer cells, and to test the M2 macrophages in peritoneal macrophages and subcutaneous transplantable tumor. It was found that paeoniflorin showed no inhibitory effect on the growth of Lewis lung cancer cells and peritoneal macrophages of mouse in vitro. Paeoniflorin could attenuate the migration of LLC stimulated by alternatively activated macrophages (stimulated for 24 h and 48 h, paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 or P < 0.05 vs control group). Paeoniflorin could decrease the cell populations at S phases (paeoniflorin 10, 30, 100 μmol·L(-1), P < 0.05 vs control group) and increase the cell populations at G0-G1 phases of Lewis lung cancer cells (paeoniflorin 100 μmol·L(-1), P < 0.05 vs control group) and reduce the numbers of M2 macrophages in peritoneal macrophages induced by IL-4 (paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 vs Control group). Paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft and decrease the numbers of M2 macrophages in subcutaneous xenograft tumour in vivo (paeoniflorin 20, 40 mg·kg(-1), P < 0.01 vs control group). These results suggest that paeoniflorin could reduce

  1. Paeoniflorin inhibits macrophage-mediated lung cancer metastasis.

    PubMed

    Wu, Qi; Chen, Gang-Ling; Li, Ya-Juan; Chen, Yang; Lin, Fang-Zhen

    2015-12-01

    Alternatively activated macrophages are more frequently involved in tumor growth, angiogenesis, and immunosuppression. A previous study showed that paeoniflorin, the major active constituent of Paeonia lactiflora Pallas, can inhibit tumor growth and lung metastases of Lewis lung tumor-bearing mice. This study tried to investigate whether paeoniflorin inhibited lung cancer metastasis by inhibiting the alternative activation of macrophages (M2 macrophage). Using a viability assay, the cytotoxicity of paeoniflorin on Lewis lung cancer cells and peritoneal macrophages were investigated. In vitro scratch wound and in vivo lung metastasis experiments were used to test the ability to inhibit the migration of paeoniflorin and the function of M2 macrophages. Flow cytometry was performed to test the cell cycle of Lewis lung cancer cells, and to test the M2 macrophages in peritoneal macrophages and subcutaneous transplantable tumor. It was found that paeoniflorin showed no inhibitory effect on the growth of Lewis lung cancer cells and peritoneal macrophages of mouse in vitro. Paeoniflorin could attenuate the migration of LLC stimulated by alternatively activated macrophages (stimulated for 24 h and 48 h, paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 or P < 0.05 vs control group). Paeoniflorin could decrease the cell populations at S phases (paeoniflorin 10, 30, 100 μmol·L(-1), P < 0.05 vs control group) and increase the cell populations at G0-G1 phases of Lewis lung cancer cells (paeoniflorin 100 μmol·L(-1), P < 0.05 vs control group) and reduce the numbers of M2 macrophages in peritoneal macrophages induced by IL-4 (paeoniflorin 1, 3, 10, 30, 100 μmol·L(-1), P < 0.01 vs Control group). Paeoniflorin could reduce lung metastasis of Lewis lung cancer cells xenograft and decrease the numbers of M2 macrophages in subcutaneous xenograft tumour in vivo (paeoniflorin 20, 40 mg·kg(-1), P < 0.01 vs control group). These results suggest that paeoniflorin could reduce

  2. Evaluation of Lung Metastasis in Mouse Mammary Tumor Models by Quantitative Real-time PCR

    PubMed Central

    Abt, Melissa A.; Grek, Christina L.; Ghatnekar, Gautam S.; Yeh, Elizabeth S.

    2016-01-01

    Metastatic disease is the spread of malignant tumor cells from the primary cancer site to a distant organ and is the primary cause of cancer associated death 1. Common sites of metastatic spread include lung, lymph node, brain, and bone 2. Mechanisms that drive metastasis are intense areas of cancer research. Consequently, effective assays to measure metastatic burden in distant sites of metastasis are instrumental for cancer research. Evaluation of lung metastases in mammary tumor models is generally performed by gross qualitative observation of lung tissue following dissection. Quantitative methods of evaluating metastasis are currently limited to ex vivo and in vivo imaging based techniques that require user defined parameters. Many of these techniques are at the whole organism level rather than the cellular level 3–6. Although newer imaging methods utilizing multi-photon microscopy are able to evaluate metastasis at the cellular level 7, these highly elegant procedures are more suited to evaluating mechanisms of dissemination rather than quantitative assessment of metastatic burden. Here, a simple in vitro method to quantitatively assess metastasis is presented. Using quantitative Real-time PCR (QRT-PCR), tumor cell specific mRNA can be detected within the mouse lung tissue. PMID:26862835

  3. 1,3-Diferrocenyl-1,3-alkadienes in diene synthesis reactions

    SciTech Connect

    Pushin, A.N.; Klimova, E.I.; Sazanova, V.A.

    1987-11-10

    Stable 1,3-diferrocenyl-1,3-alkadienes, which form Diels-Alder adducts with N-substituted maleimides, have been prepared. Methyldiferrocenylbutadien participates in a cycloaddition reaction less readily than 1,3-diferrocenyl-1,3-butadiene. Adducts of 1,3-diferrocenyl-1,3-butadiene with N-substituted maleimides are dehydrogenated on Al/sub 2/O/sub 3/ or SiO/sub 2/ with subsequent formation of cyclohexadiene and benzene derivatives; protonation-deprotonation induces isomerization with transposition of the double bond.

  4. Molecular determinants of lung cancer metastasis to the central nervous system

    PubMed Central

    Whitsett, Timothy G.; Inge, Landon J.; Dhruv, Harshil D.; Cheung, Philip Y.; Weiss, Glen J.; Bremner, Ross M.; Winkles, Jeffrey A.

    2013-01-01

    Lung cancer remains the leading cause of cancer-related mortality worldwide. The propensity for metastasis to the central nervous system (CNS) is a major clinical hurdle contributing to the low five-year survival rate of advanced disease. CNS metastases significantly outnumber primary brain tumors and carry a dismal prognosis in part due to the inability of therapeutic agents to cross the blood brain barrier. Standard treatment using radiation has been largely ineffective in improving mortality, suggesting the need for new agents targeting the critical metastatic drivers. The genetic and molecular events governing CNS metastasis from the lung are poorly understood at this time. This review highlights genetic events associated with CNS dissemination from the lung and molecular mechanisms associated with CNS metastasis. In vivo model systems that faithfully recapitulate escape from the lung and colonization of the CNS are described as tools for understanding the metastatic phenotype and for testing new therapeutic agents. A deeper understanding of the mechanisms of lung cancer metastasis to the CNS is needed to elucidate novel therapeutic avenues towards the improvement of the mortality associated with advanced stage lung cancer. PMID:25806243

  5. 21 CFR 1.3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... REGULATIONS General Provisions § 1.3 Definitions. (a) Labeling includes all written, printed, or graphic... graphic matter on the immediate container of any article, or any such matter affixed to any...

  6. 21 CFR 1.3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... REGULATIONS § 1.3 Definitions. (a) Labeling includes all written, printed, or graphic matter accompanying an... delivery in interstate commerce. (b) Label means any display of written, printed, or graphic matter on...

  7. HANSF 1.3 user's manual

    SciTech Connect

    PLYS, M.G.

    1999-05-21

    The HANSF analysis tool is an integrated model considering phenomena inside a multi-canister overpack (MCO) spent nuclear fuel container such as fuel oxidation, convective and radiative heat transfer, and the potential for fission product release. It may be used for all phases of spent fuel disposition including cold vacuum drying, transportation, and storage. This manual reflects HANSF version 1.3, a revised version of version 1.2a. HANSF 1.3 was written to add new models for axial nodalization, add new features for ease of usage, and correct errors. HANSF 1.3 is intended for use on personal computers such as IBM-compatible machines with Intel processors running under a DOS-type operating system. HANSF 1.3 is known to compile under Lahey TI and Digital Visual FORTRAN, Version 6.0, but this does not preclude operation in other environments.

  8. Isolated Malignant Melanoma Metastasis to the Pancreas

    PubMed Central

    Krag, Christen; Geertsen, Poul; Jakobsen, Linda P.

    2013-01-01

    Summary: Malignant melanomas rarely develop isolated pancreatic metastases. We describe a unique patient who is still alive 22 years following an isolated pancreatic melanoma metastasis, and we review the sparse literature in the field. PMID:25289269

  9. Biology of cancer invasion and metastasis.

    PubMed

    Mareel, M M; Crombez, R

    1992-01-01

    Current concepts of invasion eventually leading to metastasis are discussed and exemplified by cancers of the head and neck mucosa. Invasion occurs at a number of steps, each step making an ecosystem comprising not only the neoplastic cells but also their normal counterparts, a variety of host cells and the extracellular matrix. The ecosystem concept may explain aspects of metastasis such as site-dependence and organ-specificity of cancer metastasis as well as invasiveness of normal leucocytes. Genes implicated in invasion and metastasis are actively searched for. Recently, the epithelial cell-cell adhesion molecule E-cadherin has been identified as an i- (invasion suppressor) gene product, i.e. a molecule the expression of which counterbalances i+ (invasion promotor) gene activity. Downregulation of E-cadherin in human head and neck cancers may account for their invasive and metastatic behaviour.

  10. Accessory spleen hypertrophy mimicking colon cancer metastasis.

    PubMed

    Ates, I; Yazici, O; Yazilitas, D; Ozdemir, N; Zengin, N

    2016-09-01

    Accessory spleen is a congenital form of an ectopic splenic tissue. In this report, we present a case of a patient who was followed with the diagnosis of rectal and sigmoid colon cancer and an accessory spleen hypertrophy, which was thought to be colon cancer metastasis in the left hypochondriac region. After colectomy and splenectomy, accessory spleen that mimics cancer metastasis was diffrentially diagnosed using scintigraphy. PMID:27685531

  11. Parotid gland metastasis originating from malignant meningioma.

    PubMed

    Dmytriw, Adam A; Gullane, Patrick; Bartlett, Eric; Perez-Ordonez, Bayardo; Yu, Eugene

    2013-01-01

    A case of malignant meningioma with metastasis to the parotid gland is reported. A 60-year-old woman with right-sided neurological symptoms secondary to malignant meningioma developed bilateral parotid masses with identical histology to the primary lesion. The primary lesion was differentiated from a benign oligodendroma with MRI, and the radiological features of this extraordinarily rare metastasis are chronicled with MRI and computed tomography.

  12. Cancer invasion and metastasis: changing views.

    PubMed

    Duffy, M J; McGowan, P M; Gallagher, W M

    2008-02-01

    The formation of distant metastasis is the main cause of morbidity and mortality in patients with cancer. The aim of this article is to review recent advances in molecular and clinical aspects of metastasis. Traditionally, genes encoding extracellular matrix (ECM) processing proteases, adhesion proteins, and motility factors were thought to be amongst the main mediators of metastasis. Recently, however, genes activated during the early stages of tumourigenesis were implicated in the process. Conversely, genes thought to be primarily involved in metastasis such as urokinase plasminogen (uPA) and certain matrix metalloproteases (MMPs) are now known to also play a role in the early steps of tumour progression, perhaps by stimulating cell proliferation and/or promoting angiogenesis. Paradoxically, certain endogenous protease inhibitors such as PAI-1 and TIMP-1 appear to promote cancer metastasis rather than inhibiting the process. These recent advances in our understanding should lead to the development of new molecular markers for predicting the likely formation of metastasis as well as the identification of new targets for anti-metastatic therapies.

  13. Detection of cancer before distant metastasis

    PubMed Central

    2013-01-01

    Background To establish a distant metastasis (DM) cells must disseminate from the primary tumor and overcome a series of obstacles, the metastatic cascade. In this study we develop a mathematical model for this cascade to estimate the tumor size and the circulating tumor cell (CTC) load before the first metastasis has formed from a primary breast cancer tumor. Methods The metastatic cascade is described in discrete steps: 1. local tumor growth; 2. dissemination into circulation; 3. survival in circulation; 4. extravasation into tissue; and 5. growth into a metastasis. The model was built using data and relationships described in the literature to predict the relationship between tumor size and probability of distant metastasis for 38715 patients with surgically removed TXNXM0 primary breast cancer from the Netherlands Cancer Registry. The model was calibrated using primary tumor size, probability of distant metastasis and time to distant metastasis for 1489 patients with stage T1BNXM0 (25% of total patients with T1BNXM0). Validation of the model was done with data for all patients. Results From the time to distant metastasis of these 38715 breast cancer patients, we determined a tumor doubling time of 1.7 ± 0.9 months. Fitting the data for 25% of T1B patients estimates a metastatic efficiency of 1 metastasis formed per 60 million disseminated tumor cells. Validation of the model to data of patients in all T-stages shows good agreement between model and epidemiological data. To reduce the 5-year risk of distant metastasis for TXNXM0 from 9.2% to 1.0%, the primary tumor needs to be detected and removed before it reaches a diameter of 2.7 ± 1.6 mm. At this size, the model predicts that there will be 9 ± 6 CTC/L blood. Conclusions To reduce the rate of distant metastasis in surgically treated TXNXM0 breast cancer to 1%, imaging technology will need to be able to detect lesions of 2.7 mm in diameter or smaller. Before CTC detection can be applied in

  14. Practical azidation of 1,3-dicarbonyls.

    PubMed

    Harschneck, Tobias; Hummel, Sara; Kirsch, Stefan F; Klahn, Philipp

    2012-01-23

    An operationally simple, direct azidation of 1,3-dicarbonyl compounds has been developed. The reaction proceeds readily under ambient conditions using sodium azide and an iodine-based oxidant such as I(2) or 2-iodoxybenzoic acid (IBX)-SO(3)K/NaI. In particular, the latter method, as a new and well-balanced oxidizing agent, shows excellent functional group tolerance and substrate scope and thus allows access to a variety of tertiary 2-azido and 2,2-bisazido 1,3-dicarbonyl compounds that would be more difficult to access by using traditional methods. Because the azide-containing products easily undergo 1,3-dipolar cycloaddition with alkynes, our report represents a novel route to analogues of sensitive complex molecules.

  15. Carcinogenicity of 1,3-butadiene.

    PubMed Central

    Melnick, R L; Shackelford, C C; Huff, J

    1993-01-01

    1,3-Butadiene, a high-production volume chemical used largely in the manufacture of synthetic rubber, is a multiple organ carcinogen in rats and mice. In inhalation studies conducted in mice by the National Toxicology Program, high rates of early lethal lymphomas occurring at exposure levels of 625 ppm or higher reduced the development and expression of later developing tumors at other sites. Use of survival-adjusted tumor rates to account for competing risk factors provided a clearer indication of the dose responses for 1,3-butadiene-induced neoplasms. An increase in lung tumors in female mice was observed at exposure concentrations as low as 6.25 ppm, the lowest concentration ever used in a long-term carcinogenicity study of this gas. Human exposures to 1,3-butadiene by workers employed at facilities that produce this chemical and at facilities that produce styrene-butadiene rubber have been measured at levels higher than those that cause cancer in animals. Furthermore, epidemiology studies have consistently revealed associations between occupational exposure to 1,3-butadiene and excess mortality due to lymphatic and hematopoietic cancers. In response to the carcinogenicity findings for 1,3-butadiene in animals and in humans, the Occupational Safety and Health Administration has proposed lowering the occupational exposure standard for this chemical from 1000 ppm to 2 ppm. Future work is needed to understand the mechanisms of tumor induction by 1,3-butadiene; however, the pursuit of this research should not delay the reduction of human exposure to this chemical. PMID:8354171

  16. Invasive cancer cells and metastasis

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2013-12-01

    The physics of cancer is a relatively new emerging field of cancer research. In the last decade it has become a focus of biophysical research as well as becoming a novel focus for classical cancer research. This special section of Physical Biology focusing on invasive cancer cells and metastasis (physical oncology) will give greater insight into the different subfields where physical approaches are being applied to cancer research. This focus on the physical aspects of cancer is necessary because novel approaches in the field of genomics and proteomics have not altered the field of cancer research dramatically, due to the fact that few breakthroughs have been made. It is still not understood why some primary tumors metastasize and thus have a worse outcome compared to others that do not metastasize. As biophysicists, we and others suggest that the mechanical properties of the cancer cells, which possess the ability to transmigrate, are quite different compared to non-metastatic and non-invasive cancer cells. Furthermore, we hypothesize that these cancer cells undergo a selection process within the primary tumor that enables them to weaken their cell-cell adhesions and to alter their cell-matrix adhesions in order to be able to cross the outermost boundary of the primary tumor, as well as the surrounding basement membrane, and to invade the connective tissue. This prerequisite may also help the cancer cells to enter blood or lymph vessels, get transported with the vessel flow and form secondary tumors either within the vessel, directly on the endothelium, or in a different organ after crossing the endothelial lining a second time. This special section begins with a paper by Mark F Coughlin and Jeffrey J Fredberg on the changes in cytoskeletal dynamics and nonlinear rheology due to the metastatic capability of cancer cells from different cancer tissue types such as skin, bladder, prostate and kidney [1]. The hypothesis was that the metastatic outcome is impacted by

  17. Sigma and opioid receptors in human brain tumors

    SciTech Connect

    Thomas, G.E.; Szuecs, M.; Mamone, J.Y.; Bem, W.T.; Rush, M.D.; Johnson, F.E.; Coscia, C.J. )

    1990-01-01

    Human brain tumors and nude mouse-borne human neuroblastomas and gliomas were analyzed for sigma and opioid receptor content. Sigma binding was assessed using ({sup 3}H) 1, 3-di-o-tolylguanidine (DTG), whereas opioid receptor subtypes were measured with tritiated forms of the following: {mu}, (D-ala{sup 2}, mePhe{sup 4}, gly-ol{sup 5}) enkephalin (DAMGE); {kappa}, ethylketocyclazocine (EKC) or U69,593; {delta}, (D-pen{sup 2}, D-pen{sup 5}) enkephalin (DPDPE) or (D-ala{sup 2}, D-leu{sup 5}) enkephalin (DADLE) with {mu} suppressor present. Binding parameters were estimated by homologous displacement assays followed by analysis using the LIGAND program. Sigma binding was detected in 15 of 16 tumors examined with very high levels found in a brain metastasis from an adenocarcinoma of lung and a human neuroblastoma (SK-N-MC) passaged in nude mice. {kappa} opioid receptor binding was detected in 4 of 4 glioblastoma multiforme specimens and 2 of 2 human astrocytoma cell lines tested but not in the other brain tumors analyzed.

  18. An evidence-based knowledgebase of metastasis suppressors to identify key pathways relevant to cancer metastasis

    PubMed Central

    Zhao, Min; Li, Zhe; Qu, Hong

    2015-01-01

    Metastasis suppressor genes (MS genes) are genes that play important roles in inhibiting the process of cancer metastasis without preventing growth of the primary tumor. Identification of these genes and understanding their functions are critical for investigation of cancer metastasis. Recent studies on cancer metastasis have identified many new susceptibility MS genes. However, the comprehensive illustration of diverse cellular processes regulated by metastasis suppressors during the metastasis cascade is lacking. Thus, the relationship between MS genes and cancer risk is still unclear. To unveil the cellular complexity of MS genes, we have constructed MSGene (http://MSGene.bioinfo-minzhao.org/), the first literature-based gene resource for exploring human MS genes. In total, we manually curated 194 experimentally verified MS genes and mapped to 1448 homologous genes from 17 model species. Follow-up functional analyses associated 194 human MS genes with epithelium/tissue morphogenesis and epithelia cell proliferation. In addition, pathway analysis highlights the prominent role of MS genes in activation of platelets and coagulation system in tumor metastatic cascade. Moreover, global mutation pattern of MS genes across multiple cancers may reveal common cancer metastasis mechanisms. All these results illustrate the importance of MSGene to our understanding on cell development and cancer metastasis. PMID:26486520

  19. First description of cervical intradural thymoma metastasis

    PubMed Central

    Marotta, Nicola; Mancarella, Cristina; Colistra, Davide; Landi, Alessandro; Dugoni, Demo Eugenio; Delfini, Roberto

    2015-01-01

    Thymoma and thymic carcinoma are rare epithelial tumors, which originate from the thymus gland. According to the World Health Organization there are “organotypic” (types A, AB, B1, B2, and B3) and “non-organotypic” (thymic carcinomas) thymomas. Type B3 thymomas are aggressive tumors, which can metastasize. Due to the rarity of these lesions, only 7 cases of extradural metastasis are described in the literature. We report the first and unique case of a man with cervical intradural B3 thymoma metastasis. A 46-year-old man underwent thymoma surgical removal. The year after the procedure he was treated for a parietal pleura metastasis. In 2006 he underwent cervical-dorsal extradural metastasis removal and C5-Th1 stabilization. Seven years after he came to our observation complaining left cervicobrachialgia and a reduction of strength of the left arm. He underwent a cervical spine magnetic resonance imaging, which showed a new lesion at the C5-C7 level. The patient underwent a surgery for the intradural B3 thymoma metastasis. Neurological symptoms improved although the removal was subtotal. He went through postoperative radiation therapy with further mass reduction. Spinal metastases are extremely rare. To date, only 7 cases of spinal extradural metastasis have been described in the literature. This is the first case of spinal intradural metastasis. Early individuation of these tumors and surgical treatment improve neurological outcome in patients with spinal cord compression. A multimodal treatment including neoadjuvant chemotherapy, surgery and postoperative radiation therapy seems to improve survival in patients with metastatic thymoma. PMID:26601098

  20. First description of cervical intradural thymoma metastasis.

    PubMed

    Marotta, Nicola; Mancarella, Cristina; Colistra, Davide; Landi, Alessandro; Dugoni, Demo Eugenio; Delfini, Roberto

    2015-11-16

    Thymoma and thymic carcinoma are rare epithelial tumors, which originate from the thymus gland. According to the World Health Organization there are "organotypic" (types A, AB, B1, B2, and B3) and "non-organotypic" (thymic carcinomas) thymomas. Type B3 thymomas are aggressive tumors, which can metastasize. Due to the rarity of these lesions, only 7 cases of extradural metastasis are described in the literature. We report the first and unique case of a man with cervical intradural B3 thymoma metastasis. A 46-year-old man underwent thymoma surgical removal. The year after the procedure he was treated for a parietal pleura metastasis. In 2006 he underwent cervical-dorsal extradural metastasis removal and C5-Th1 stabilization. Seven years after he came to our observation complaining left cervicobrachialgia and a reduction of strength of the left arm. He underwent a cervical spine magnetic resonance imaging, which showed a new lesion at the C5-C7 level. The patient underwent a surgery for the intradural B3 thymoma metastasis. Neurological symptoms improved although the removal was subtotal. He went through postoperative radiation therapy with further mass reduction. Spinal metastases are extremely rare. To date, only 7 cases of spinal extradural metastasis have been described in the literature. This is the first case of spinal intradural metastasis. Early individuation of these tumors and surgical treatment improve neurological outcome in patients with spinal cord compression. A multimodal treatment including neoadjuvant chemotherapy, surgery and postoperative radiation therapy seems to improve survival in patients with metastatic thymoma. PMID:26601098

  1. First description of cervical intradural thymoma metastasis.

    PubMed

    Marotta, Nicola; Mancarella, Cristina; Colistra, Davide; Landi, Alessandro; Dugoni, Demo Eugenio; Delfini, Roberto

    2015-11-16

    Thymoma and thymic carcinoma are rare epithelial tumors, which originate from the thymus gland. According to the World Health Organization there are "organotypic" (types A, AB, B1, B2, and B3) and "non-organotypic" (thymic carcinomas) thymomas. Type B3 thymomas are aggressive tumors, which can metastasize. Due to the rarity of these lesions, only 7 cases of extradural metastasis are described in the literature. We report the first and unique case of a man with cervical intradural B3 thymoma metastasis. A 46-year-old man underwent thymoma surgical removal. The year after the procedure he was treated for a parietal pleura metastasis. In 2006 he underwent cervical-dorsal extradural metastasis removal and C5-Th1 stabilization. Seven years after he came to our observation complaining left cervicobrachialgia and a reduction of strength of the left arm. He underwent a cervical spine magnetic resonance imaging, which showed a new lesion at the C5-C7 level. The patient underwent a surgery for the intradural B3 thymoma metastasis. Neurological symptoms improved although the removal was subtotal. He went through postoperative radiation therapy with further mass reduction. Spinal metastases are extremely rare. To date, only 7 cases of spinal extradural metastasis have been described in the literature. This is the first case of spinal intradural metastasis. Early individuation of these tumors and surgical treatment improve neurological outcome in patients with spinal cord compression. A multimodal treatment including neoadjuvant chemotherapy, surgery and postoperative radiation therapy seems to improve survival in patients with metastatic thymoma.

  2. Neuroendocrine Tumors of the Large Intestine: Clinicopathological Features and Predictive Factors of Lymph Node Metastasis.

    PubMed

    Kojima, Motohiro; Ikeda, Koji; Saito, Norio; Sakuyama, Naoki; Koushi, Kenichi; Kawano, Shingo; Watanabe, Toshiaki; Sugihara, Kenichi; Ito, Masaaki; Ochiai, Atsushi

    2016-01-01

    A new histological classification of neuroendocrine tumors (NETs) was established in WHO 2010. ENET and NCCN proposed treatment algorithms for colorectal NET. Retrospective study of NET of the large intestine (colorectal and appendiceal NET) was performed among institutions allied with the Japanese Society for Cancer of the Colon and Rectum, and 760 neuroendocrine tumors from 2001 to 2011 were re-assessed using WHO 2010 criteria to elucidate the clinicopathological features of NET in the large intestine. Next, the clinicopathological relationship with lymph node metastasis was analyzed to predict lymph node metastasis in locally resected rectal NET. The primary site was rectum in 718/760 cases (94.5%), colon in 30/760 cases (3.9%), and appendix in 12/760 cases (1.6%). Patients were predominantly men (61.6%) with a mean age of 58.7 years. Tumor size was <10 mm in 65.4% of cases. Proportions of NET G1, G2, G3, and mixed adeno-neuroendocrine carcinoma (MANEC) were 88.4, 6.3, 3.9, and 1.3%, respectively. Of the 760 tumors, 468 were locally resected, and 292 were surgically resected with lymph node dissection. Rectal NET showed a higher proportion of NET G1, and colonic and appendiceal NET was more commonly G3 and MANEC. Of the 292 surgically resected cases, 233 NET G1 and G2 located in the rectum were used for the prediction of lymph node metastasis. Lymphatic and blood vessel invasion were independent predictive factors of lymph node metastasis. NET G2 cases showed more frequent lymph node metastasis than that seen in NET G1 cases, but this was not an independent predictor of lymph node metastasis. Of the 98 surgically resected cases <10 mm in size, we found 9 cases with lymph node metastasis (9.2%). All cases were NET G1, and eight of the nine cases were positive either for lymphatic invasion or blood vessel invasion. Using the WHO classification, we found NET in the large intestine showed a tumor-site-dependent variety of histological and clinicopathological

  3. Neuroendocrine Tumors of the Large Intestine: Clinicopathological Features and Predictive Factors of Lymph Node Metastasis.

    PubMed

    Kojima, Motohiro; Ikeda, Koji; Saito, Norio; Sakuyama, Naoki; Koushi, Kenichi; Kawano, Shingo; Watanabe, Toshiaki; Sugihara, Kenichi; Ito, Masaaki; Ochiai, Atsushi

    2016-01-01

    A new histological classification of neuroendocrine tumors (NETs) was established in WHO 2010. ENET and NCCN proposed treatment algorithms for colorectal NET. Retrospective study of NET of the large intestine (colorectal and appendiceal NET) was performed among institutions allied with the Japanese Society for Cancer of the Colon and Rectum, and 760 neuroendocrine tumors from 2001 to 2011 were re-assessed using WHO 2010 criteria to elucidate the clinicopathological features of NET in the large intestine. Next, the clinicopathological relationship with lymph node metastasis was analyzed to predict lymph node metastasis in locally resected rectal NET. The primary site was rectum in 718/760 cases (94.5%), colon in 30/760 cases (3.9%), and appendix in 12/760 cases (1.6%). Patients were predominantly men (61.6%) with a mean age of 58.7 years. Tumor size was <10 mm in 65.4% of cases. Proportions of NET G1, G2, G3, and mixed adeno-neuroendocrine carcinoma (MANEC) were 88.4, 6.3, 3.9, and 1.3%, respectively. Of the 760 tumors, 468 were locally resected, and 292 were surgically resected with lymph node dissection. Rectal NET showed a higher proportion of NET G1, and colonic and appendiceal NET was more commonly G3 and MANEC. Of the 292 surgically resected cases, 233 NET G1 and G2 located in the rectum were used for the prediction of lymph node metastasis. Lymphatic and blood vessel invasion were independent predictive factors of lymph node metastasis. NET G2 cases showed more frequent lymph node metastasis than that seen in NET G1 cases, but this was not an independent predictor of lymph node metastasis. Of the 98 surgically resected cases <10 mm in size, we found 9 cases with lymph node metastasis (9.2%). All cases were NET G1, and eight of the nine cases were positive either for lymphatic invasion or blood vessel invasion. Using the WHO classification, we found NET in the large intestine showed a tumor-site-dependent variety of histological and clinicopathological

  4. Adaptive hypofractionated gamma knife radiosurgery for a large brainstem metastasis

    PubMed Central

    Sinclair, Georges; Bartek, Jiri; Martin, Heather; Barsoum, Pierre; Dodoo, Ernest

    2016-01-01

    Background: To demonstrate how adaptive hypofractionated radiosurgery by gamma knife (GK) can be successfully utilized to treat a large brainstem metastasis - a novel approach to a challenging clinical situation. Case Description: A 42-year-old woman, diagnosed with metastatic nonsmall cell lung cancer in July 2011, initially treated with chemotherapy and tyrosine kinase inhibitors, developed multiple brain metastases March 2013, with subsequent whole brain radiotherapy, after which a magnetic resonance imaging (MRI) showed a significant volume regression of all brain metastases. A follow-up MRI in October 2013 revealed a growing brainstem lesion of 26 mm. Linear accelerator-based radiotherapy and microsurgery were judged contraindicated, why the decision was made to treat the patient with three separate radiosurgical sessions during the course of 1 week, with an 18% tumor volume reduction demonstrated after the last treatment. Follow-up MRI 2.5 months after her radiosurgical treatment showed a tumor volume reduction of 67% compared to the 1st day of treatment. Later on, the patient developed a radiation-induced perilesional edema although without major clinical implications. An MRI at 12 months and 18-fluoro-deoxyglucose positron emission tomography of the brain at 13 months showed decreased edema with no signs of tumor recurrence. Despite disease progression during the last months of her life, the patient's condition remained overall acceptable. Conclusion: GK-based stereotactic adaptive hypofractionation proved to be effective to achieve tumor control while limiting local adverse reactions. This surgical modality should be considered when managing larger brain lesions in critical areas. PMID:26958430

  5. 45 CFR 1211.1-3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... VOLUNTEER GRIEVANCE PROCEDURES § 1211.1-3 Definitions. (a) Volunteer means a person enrolled and currently serving as a full-time volunteer under part A of title I of the Domestic Volunteer Service Act of 1973. For the purpose of this part, a volunteer whose service has terminated shall be deemed to be...

  6. 45 CFR 1211.1-3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... VOLUNTEER GRIEVANCE PROCEDURES § 1211.1-3 Definitions. (a) Volunteer means a person enrolled and currently serving as a full-time volunteer under part A of title I of the Domestic Volunteer Service Act of 1973. For the purpose of this part, a volunteer whose service has terminated shall be deemed to be...

  7. 45 CFR 1211.1-3 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... conditions of service resulting in the denial or infringement of a right or benefit to the grieving volunteer... VOLUNTEER GRIEVANCE PROCEDURES § 1211.1-3 Definitions. (a) Volunteer means a person enrolled and currently serving as a full-time volunteer under part A of title I of the Domestic Volunteer Service Act of...

  8. 45 CFR 1211.1-3 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... conditions of service resulting in the denial or infringement of a right or benefit to the grieving volunteer... VOLUNTEER GRIEVANCE PROCEDURES § 1211.1-3 Definitions. (a) Volunteer means a person enrolled and currently serving as a full-time volunteer under part A of title I of the Domestic Volunteer Service Act of...

  9. 45 CFR 1211.1-3 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... conditions of service resulting in the denial or infringement of a right or benefit to the grieving volunteer... VOLUNTEER GRIEVANCE PROCEDURES § 1211.1-3 Definitions. (a) Volunteer means a person enrolled and currently serving as a full-time volunteer under part A of title I of the Domestic Volunteer Service Act of...

  10. A Dogrib History. Grade 1-3.

    ERIC Educational Resources Information Center

    Fraser, Tara

    A publication on the history and traditional lifestyle of the Dogrib Tribe of Canada's Northwest Territories is intended for use in grades 1-3. Text is printed in large, clear letters and accompanied by many drawings. Some subjects covered are cooking, food, canoes, clothes, homes, and games. Sections are devoted to beavers and caribou and their…

  11. 45 CFR 1210.1-3 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... VISTA TRAINEE DESELECTION AND VOLUNTEER EARLY TERMINATION PROCEDURES General § 1210.1-3 Definitions. (a... of supporting VISTA Volunteers on a national or multi-regional basis. VISTA Volunteers may be... affiliate of a national grantee to which VISTA Volunteers are assigned under the VISTA National...

  12. Natural 1,3-Dipolar Cycloadditions.

    PubMed

    Baunach, Martin; Hertweck, Christian

    2015-10-19

    [3+2] in the wild: Biomimetic natural product syntheses and theoretical considerations have indicated that 1,3-dipolar cycloadditions take place in nature. Now, the structure, biosynthesis, and function of a heavily modified prenylated flavin cofactor have been elucidated. In the azomethine ylide form, it undergoes [3+2] cycloadditions with aromatic acids and promotes their decarboxylation. PMID:26465651

  13. On the Origin of Cancer Metastasis

    PubMed Central

    Seyfried, Thomas N.; Huysentruyt, Leanne C.

    2013-01-01

    Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis. These involve an epithelial mesenchymal transition, an accumulation of mutations in stem cells, a macrophage facilitation process, and a macrophage origin involving either transformation or fusion hybridization with neoplastic cells. Many of the properties of metastatic cancer cells are also seen in normal macrophages. A macrophage origin of metastasis can also explain the long-standing “seed and soil” hypothesis and the absence of metastasis in plant cancers. The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management. PMID:23237552

  14. The protein C pathway in cancer metastasis.

    PubMed

    Spek, C Arnold; Arruda, Valder R

    2012-04-01

    Cancer is frequently associated with activation of blood coagulation, which in turn has been suggested to promote tumor growth and metastasis. Indeed, low molecular weight heparin treatment significantly prolongs the survival of a wide variety of patients with cancer. Based on this notion that anticoagulant treatment seems to benefit cancer patients, recent experiments aimed to elucidate the importance of the natural anticoagulant protein C pathways in cancer progression. Interestingly, these experiments showed that the repeated administration of exogenous activated protein C limits cancer cell extravasation in experimental animal models. In line, reducing endogenous activated protein C activity dramatically increased the number of experimental metastasis. These data thus strongly suggest that exogenous activated protein C administration may be a novel therapeutic avenue to limit cancer metastasis thereby prolonging overall survival of cancer patients. The current review provides an overview of recent data on the role of the protein C pathway in cancer metastasis. It discusses the potential of activated protein C as a novel target to reduce cancer progression, it points to several limitations of activated protein C administration in the setting of cancer cell metastasis and it suggest zymogen protein C as an attractive alternative. PMID:22682140

  15. Brain angiogenesis: Mechanism and Therapeutic Intervention in Brain Tumors

    PubMed Central

    Kim, Woo-Young; Lee, Ho-Young

    2010-01-01

    Summary Formation of new blood vessels is required for growth and metastasis of all solid tumors. New blood vessels are established in tumors mainly through angiogenesis. Brain tumors in particular are highly angiogenic. Therefore, interventions designed to prevent angiogenesis may be effective at controlling brain tumors. Indeed, many recent findings from preclinical and clinical studies of antiangiogenic therapy for brain tumors showed that it is a promising approach to managing this deadly disease, especially when combined with other cytotoxic treatments. In this review, we summarize the basic characteristics of brain tumor angiogenesis and role of known angiogenic factors in regulating this angiogenesis, which can be targets of antiangiogenic therapy. We also discuss the current status of antiangiogenic therapy for brain tumors, the suggested mechanisms of this therapy, and the limitations of this strategy. PMID:19664069

  16. Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking

    PubMed Central

    Barthel, Steven R.; Wiese, Georg K.; Cho, Jaehyung; Opperman, Matthew J.; Hays, Danielle L.; Siddiqui, Javed; Pienta, Kenneth J.; Furie, Bruce; Dimitroff, Charles J.

    2009-01-01

    How cancer cells bind to vascular surfaces and extravasate into target organs is an underappreciated, yet essential step in metastasis. We postulate that the metastatic process involves discrete adhesive interactions between circulating cancer cells and microvascular endothelial cells. Sialyl Lewis X (sLeX) on prostate cancer (PCa) cells is thought to promote metastasis by mediating PCa cell binding to microvascular endothelial (E)-selectin. Yet, regulation of sLeX and related E-selectin ligand expression in PCa cells is a poorly understood factor in PCa metastasis. Here, we describe a glycobiological mechanism regulating E-selectin-mediated adhesion and metastatic potential of PCa cells. We demonstrate that α1,3 fucosyltransferases (FT) 3, 6, and 7 are markedly elevated in bone- and liver-metastatic PCa and dictate synthesis of sLeX and E-selectin ligands on metastatic PCa cells. Upregulated FT3, FT6, or FT7 expression induced robust PCa PC-3 cell adhesion to bone marrow (BM) endothelium and to inflamed postcapillary venules in an E-selectin-dependent manner. Membrane proteins, CD44, carcinoembryonic antigen (CEA), podocalyxin-like protein (PCLP), and melanoma cell adhesion molecule (MCAM) were major scaffolds presenting E-selectin-binding determinants on FT-upregulated PC-3 cells. Furthermore, elevated FT7 expression promoted PC-3 cell trafficking to and retention in BM through an E-selectin dependent event. These results indicate that α1,3 FTs could enhance metastatic efficiency of PCa by triggering an E-selectin-dependent trafficking mechanism. PMID:19889975

  17. Solitary metachronous splenic metastasis from cutaneous melanoma

    PubMed Central

    Gavriilidis, Paschalis; Goupou, Eleni

    2012-01-01

    Melanoma has been found to metastasise to the spleen, usually in cases of disseminated disease. Solitary splenic metastasis from cutaneous melanoma is very rare. Herein we report the case of a 43-year-old man who developed solitary splenic metastasis from cutaneous melanoma. The patient was operated for T4b N1a Mo superficial spreading melanoma of the anterior thoracic wall. He subsequently underwent left axillary lymph node dissection due to a positive sentinel lymph node. The 33 retrieved lymph nodes were negative for metastasis. The patient received adjuvant therapy with high-dose interferon α-2b. After 27 months and during the follow-up visit an increasing lactate dehydrogenase serum level was observed. Furthermore, CT of the whole body revealed a solitary hypodense tumour of the spleen 9 cm×6 cm. Curative splenectomy was performed and the histopathological report confirmed metastatic melanoma to the spleen. PMID:23104633

  18. Micromanaging of tumor metastasis by extracellular vesicles.

    PubMed

    Tominaga, Naoomi; Katsuda, Takeshi; Ochiya, Takahiro

    2015-04-01

    Extracellular vesicles (EVs) are nanometer-sized membranous vesicles that are released by a variety of cell types into the extracellular space. In the past two decades, EVs have emerged as novel mediators of cancer biology. Many reports have demonstrated the contribution of EVs to cancer metastasis. Metastasis is a multistep process that is responsible for the majority of deaths in cancer patients. This process includes proliferation, angiogenesis, immune modulation, extravasation, intravasation, and colonization. EVs from cancer cells impact these steps through modulation of the host immune system, angiogenesis, and pre-/pro-metastatic niche formation. In this review, we summarize the function of EVs in cancer metastasis. In addition, we also discuss the hurdles to be overcome for further developing this research field. PMID:25746922

  19. Hematogenous Gastric Metastasis of Pancreatic Cancer

    PubMed Central

    Sasajima, Junpei; Okamoto, Kotaro; Taniguchi, Masato

    2016-01-01

    While the gastric involvement of pancreatic cancer is occasionally observed as the result of direct invasion, hematogenous gastric metastasis is rare. A 72-year-old Japanese male presented with general fatigue, pollakiuria, and thirst. Computed tomography revealed a 4.6-cm solid mass in the pancreatic tail and a 4.2-cm multilocular cystic mass in the pancreatic head with multiple liver and lymphatic metastasis. Notably, two solid masses were detected in the gastric wall of the upper body and the antrum; both were separated from the primary pancreatic cancer and seemed to be located in the submucosal layer. Esophagogastroduodenoscopy revealed a submucosal tumor with a normal mucosa in the posterior wall of the upper body of the stomach, suggesting the gastric hematogenous metastasis of pancreatic cancer. The suspected diagnosis was unresectable pancreatic cancer with multiple metastases that was concomitant with the intraductal papillary mucinous neoplasm of the pancreas. PMID:27403106

  20. Hematogenous Gastric Metastasis of Pancreatic Cancer.

    PubMed

    Sasajima, Junpei; Okamoto, Kotaro; Taniguchi, Masato

    2016-01-01

    While the gastric involvement of pancreatic cancer is occasionally observed as the result of direct invasion, hematogenous gastric metastasis is rare. A 72-year-old Japanese male presented with general fatigue, pollakiuria, and thirst. Computed tomography revealed a 4.6-cm solid mass in the pancreatic tail and a 4.2-cm multilocular cystic mass in the pancreatic head with multiple liver and lymphatic metastasis. Notably, two solid masses were detected in the gastric wall of the upper body and the antrum; both were separated from the primary pancreatic cancer and seemed to be located in the submucosal layer. Esophagogastroduodenoscopy revealed a submucosal tumor with a normal mucosa in the posterior wall of the upper body of the stomach, suggesting the gastric hematogenous metastasis of pancreatic cancer. The suspected diagnosis was unresectable pancreatic cancer with multiple metastases that was concomitant with the intraductal papillary mucinous neoplasm of the pancreas. PMID:27403106

  1. [Sacral metastasis simulating aneurysmal bone cyst].

    PubMed

    Sanromán-Álvarez, Pablo; Simal-Julián, Juan Antonio; Miranda-Lloret, Pablo; Pérez-Borredá, Pedro; Botella-Asunción, Carlos

    2014-01-01

    Cystic spinal lesions with characteristic patterns, such as the presence of haematic fluid-fluid levels (H-FFL), have been associated with many tumoral lineages, more frequently with aneurysmal bone cyst (ABC) and exceptionally with metastasis. We present the case of a 60-year-old man with the finding of a sacral cystic bone lesion with H-FFL, with initial suspicion of ABC and confirmed diagnosis of metastasis. The case presented is, to our knowledge, the second case published of spinal cystic bone metastasis with H-FFL pattern with unknown primary tumour at the time of diagnosis and the only one that received resective surgical treatment, achieving pulmonary and metastatic disease control with good quality of life after 1 year of follow up.

  2. Breast cancer metastasis suppressor 1 coordinately regulates metastasis-associated microRNA expression

    PubMed Central

    Edmonds, Mick D.; Hurst, Douglas R.; Vaidya, Kedar S.; Stafford, Lewis J.; Chen, Dongquan; Welch, Danny R.

    2009-01-01

    Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis of multiple tumor types without blocking tumorigenesis. BRMS1 forms complexes with SIN3, histone deacetylases and selected transcription factors that modify metastasis-associated gene expression (e.g., EGFR, OPN, PI4P5K1A, PLAU). microRNA (miRNA) are a recently discovered class of regulatory, noncoding RNA, some of which are involved in neoplastic progression. Based on these data, we hypothesized that BRMS1 may also exert some of its antimetastatic effects by regulating miRNA expression. Micro-RNA arrays were done comparing small RNAs that were purified from metastatic MDA-MB-231 and MDA-MB-435 and their non-metastatic BRMS1-transfected counterparts. miRNA expression changed by BRMS1 were validated using SYBR Green RT-PCR. BRMS1 decreased metastasis-promoting (miR-10b, -373 and -520c) miRNA, with corresponding reduction of their downstream targets (e.g., RhoC which is downstream of miR-10b). Concurrently, BRMS1 increased expression of metastasis suppressing miRNA (miR-146a, -146b and -335). Collectively, these data show that BRMS1 coordinately regulates expression of multiple metastasis-associated miRNA and suggests that recruitment of BRMS1-containing SIN3:HDAC complexes to, as yet undefined, miRNA promoters might be involved in the regulation of cancer metastasis. PMID:19585508

  3. Bio-luminescent imaging and characterization of organ-specific metastasis of human cancer in NOD/SCID mice

    NASA Astrophysics Data System (ADS)

    Chun, Nicole A. L.; Murakami, Takashi

    2010-02-01

    Many clinical evidences demonstrate that the sites of distant metastasis are not random and certain malignant tumors show a tendency to develop metastases in specific organs (e.g., brain, liver, and lungs). However, an appropriate animal model to characterize the metastatic nature of transplantable human cancer cell lines has not been reported well. Recent advances in bio-luminescent imaging (BLI) technologies have facilitated the quantitative analysis of various cellular processes in vivo. To visualize the fate of tumor progression in the living mice, we are constructing a luciferaseexpressing human cancer cell library (including melanoma, colon, breast, and prostate cancer). Herein we demonstrate that the BLI technology in couple with a fine ultrasonic guidance realizes cancer cell-type dependent metastasis to the specific organs. For example, some melanoma cell lines showed frequent metastasis to brain, lungs, and lymph nodes in the mouse model. Notably, reflecting the clinical features of melanoma, breast, and prostate cancer, some of the cell lines showed preferential metastasis to the brain. Moreover, these cellular resources for BLI allow a high throughput screening for potential anti-cancer drugs. Thus, this BLI-mediated additional strategy with the luciferase-expressing cancer cell resources should promote many translational studies for human cancer therapy.

  4. Cranial computed tomographic abnormalities in leptomeningeal metastasis

    SciTech Connect

    Lee, Y.Y.; Glass, J.P.; Geoffray, A.; Wallace, S.

    1984-11-01

    Sixty-four (57.6%) of 111 cancer patients with cerebrospinal fluid cytology positive for malignant cells had cranial computed tomographic (CT) scans within 2 weeks before or after a lumbar puncture. Twenty-two (34.3%) of the 64 had abnormal CT findings indicative of leptomeningeal metastasis. Thirteen (59.6%) of these 22 patients had associated parenchymal metastases. Recognition of leptomeningeal disease may alter the management of patients with parenchymal metastases. Communicating hydrocephalus in cancer patients should be considered to be related to leptomeningeal metastasis until proven otherwise.

  5. Hand metastasis from a sacral chordoma

    PubMed Central

    Kaya, M; Sugita, S; Soma, T; Sasaki, M; Yamashita, T

    2014-01-01

    Chordomas are rare, low grade, malignant tumours derived from the ectopic remnants of the notochord that line the axial skeleton. They are characterised by their slow growth, long disease course and propensity for local relapse. Furthermore, up to 40% of non-cranial chordomas metastasise. We describe the first reported case of a hand metastasis arising from a conventional sacral chordoma after carbon ion radiotherapy. The common occurrence of distant metastasis with chordomas makes it important to perform a systemic examination, in part because their resection might improve patient prognosis. PMID:25350167

  6. Crossing the endothelial barrier during metastasis.

    PubMed

    Reymond, Nicolas; d'Água, Bárbara Borda; Ridley, Anne J

    2013-12-01

    During metastasis, cancer cells disseminate to other parts of the body by entering the bloodstream in a process that is called intravasation. They then extravasate at metastatic sites by attaching to endothelial cells that line blood vessels and crossing the vessel walls of tissues or organs. This Review describes how cancer cells cross the endothelial barrier during extravasation and how different receptors, signalling pathways and circulating cells such as leukocytes and platelets contribute to this process. Identification of the mechanisms that underlie cancer cell extravasation could lead to the development of new therapies to reduce metastasis.

  7. Surviving at a distance: organ specific metastasis

    PubMed Central

    Obenauf, Anna C.; Massagué, Joan

    2015-01-01

    The clinical manifestation of metastasis in a vital organ is the final stage of cancer progression and the main culprit of cancer related mortality. Once established, metastasis is devastating, yet only a small proportion of the cancer cells that leave a tumor succeed at infiltrating, surviving, and ultimately overtaking a distant organ. The bottlenecks that challenge cancer cells in newly invaded microenvironments are organ specific and consequently demand distinct mechanisms for metastatic colonization. Here we review the metastatic traits that allow cancer cells to colonize distinct organ sites. PMID:26693180

  8. Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

    Integrated Risk Information System (IRIS)

    Hexahydro - 1,3,5 - trinitro - 1,3,5 - triazine ( RDX ) ; CASRN 121 - 82 - 4 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health

  9. Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX)

    Integrated Risk Information System (IRIS)

    Octahydro - 1,3,5,7 - tetranitro - 1,3,5,7 - tetr . . . ( HMX ) ; CASRN 2691 - 41 - 0 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I

  10. Potassium Channel Kv1.3 Is Highly Expressed by Microglia in Human Alzheimer’s Disease

    PubMed Central

    Rangaraju, Srikant; Gearing, Marla; Jin, Lee-Way; Levey, Allan

    2015-01-01

    Recent genetic studies suggest a central role for innate immunity in Alzheimer’s disease (AD) pathogenesis, wherein microglia orchestrate neuroinflammation. Kv1.3, a voltage-gated potassium channel of therapeutic relevance in autoimmunity, is upregulated by activated microglia and mediates amyloid-mediated microglial priming and reactive oxygen species production in vitro. We hypothesized that Kv1.3 channel expression is increased in human AD brain tissue. In a blinded postmortem immunohistochemical semi-quantitative analysis performed on ten AD patients and ten non-disease controls, we observed a significantly higher Kv1.3 staining intensity (p = 0.03) and Kv1.3-positive cell density (p = 0.03) in the frontal cortex of AD brains, compared to controls. This paralleled an increased number of Iba1-positive microglia in AD brains. Kv1.3-positive cells had microglial morphology and were associated with amyloid-β plaques. In immunofluorescence studies, Kv1.3 channels co-localized primarily with Iba1 but not with astrocyte marker GFAP, confirming that elevated Kv1.3 expression is limited to microglia. Higher Kv1.3 expression in AD brains was also confirmed by western blot analysis. Our findings support that Kv1.3 channels are biologically relevant and microglia-specific targets in human AD. PMID:25362031

  11. The EMT-activator ZEB1 induces bone metastasis associated genes including BMP-inhibitors

    PubMed Central

    Mock, Kerstin; Preca, Bogdan-Tiberius; Brummer, Tilman; Brabletz, Simone; Stemmler, Marc P.; Brabletz, Thomas

    2015-01-01

    Tumor cell invasion, dissemination and metastasis is triggered by an aberrant activation of epithelial-to-mesenchymal transition (EMT), often mediated by the transcription factor ZEB1. Disseminating tumor cells must acquire specific features that allow them to colonize at different organ sites. Here we identify a set of genes that is highly expressed in breast cancer bone metastasis and activated by ZEB1. This gene set includes various secreted factors, e.g. the BMP-inhibitor FST, that are described to reorganize the bone microenvironment. By inactivating BMP-signaling, BMP-inhibitors are well-known to induce osteolysis in development and disease. We here demonstrate that the expression of ZEB1 and BMP-inhibitors is correlated with bone metastasis, but not with brain or lung metastasis of breast cancer patients. In addition, we show that this correlated expression pattern is causally linked, as ZEB1 induces the expression of the BMP-inhibitors NOG, FST and CHRDL1 both by directly increasing their gene transcription, as well as by indirectly suppressing their reduction via miR-200 family members. Consequently, ZEB1 stimulates BMP-inhibitor mediated osteoclast differentiation. These findings suggest that ZEB1 is not only driving EMT, but also contributes to the formation of osteolytic bone metastases in breast cancer. PMID:25973542

  12. Invasive cancer cells and metastasis

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2013-12-01

    The physics of cancer is a relatively new emerging field of cancer research. In the last decade it has become a focus of biophysical research as well as becoming a novel focus for classical cancer research. This special section of Physical Biology focusing on invasive cancer cells and metastasis (physical oncology) will give greater insight into the different subfields where physical approaches are being applied to cancer research. This focus on the physical aspects of cancer is necessary because novel approaches in the field of genomics and proteomics have not altered the field of cancer research dramatically, due to the fact that few breakthroughs have been made. It is still not understood why some primary tumors metastasize and thus have a worse outcome compared to others that do not metastasize. As biophysicists, we and others suggest that the mechanical properties of the cancer cells, which possess the ability to transmigrate, are quite different compared to non-metastatic and non-invasive cancer cells. Furthermore, we hypothesize that these cancer cells undergo a selection process within the primary tumor that enables them to weaken their cell-cell adhesions and to alter their cell-matrix adhesions in order to be able to cross the outermost boundary of the primary tumor, as well as the surrounding basement membrane, and to invade the connective tissue. This prerequisite may also help the cancer cells to enter blood or lymph vessels, get transported with the vessel flow and form secondary tumors either within the vessel, directly on the endothelium, or in a different organ after crossing the endothelial lining a second time. This special section begins with a paper by Mark F Coughlin and Jeffrey J Fredberg on the changes in cytoskeletal dynamics and nonlinear rheology due to the metastatic capability of cancer cells from different cancer tissue types such as skin, bladder, prostate and kidney [1]. The hypothesis was that the metastatic outcome is impacted by

  13. Malignant potential of cells isolated from lymph node or brain metastases of melanoma patients and implications for prognosis.

    PubMed

    Zhang, R D; Price, J E; Schackert, G; Itoh, K; Fidler, I J

    1991-04-15

    We studied the correlation between the formation of brain metastasis and the malignant growth potential of seven human melanoma cell lines, isolated from lymph node metastases (A375-SM, TXM-1, DM-4) or from brain metastases (TXM-13, TXM-18, TXM-34, TXM-40), and the potential of three variants of the mouse K-1735 melanoma. Growth rates in different concentrations of fetal bovine serum and colony-forming efficiency in semisolid agarose were measured, and the tumorigenicity and metastatic ability were determined in nude mice (for the human melanoma cell lines) or in C3H/HeN mice (for the K-1735 variants). The ability to form brain metastasis was tested by injection of cells into the carotid artery. A high colony-forming efficiency in agarose, especially at concentrations of agarose greater than 0.6%, corresponded with high tumor take rates, rapid tumor growth rates, and metastatic colonization of the lungs of the recipient mice. For the human melanomas, the lymph node metastasis-derived cells were more tumorigenic and metastatic than the brain metastasis-derived cells. In the K-1735 mouse melanoma, the tumorigenic and metastatic behavior of the cells after i.v. and s.c. injection corresponded with growth in agarose cultures. However, for growth in the brain after intracarotid injection, the different melanoma cell lines showed similar frequencies of tumor take, regardless of tumorigenicity in other sites of the recipient mice, although mice given injections of brain metastasis-derived cells survived longer than mice given injections of lymph node metastasis (human melanoma) or lung metastasis (K-1735 M-2)-derived cell lines. The results from the human and mouse melanoma cell lines show that the brain metastasis-derived cell lines were not more malignant than the lymph node or lung metastasis-derived cells. These data imply that the production of brain metastasis is not always the final stage of a metastatic cascade. PMID:1826230

  14. Biodegradation of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine

    PubMed Central

    McCormick, N. G.; Cornell, J. H.; Kaplan, A. M.

    1981-01-01

    Biodegradation of the explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) occurs under anaerobic conditions, yielding a number of products, including: hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine, hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine, hexahydro-1,3,5-trinitroso-1,3,5-triazine, hydrazine, 1,1-dimethyl-hydrazine, 1,2-dimethylhydrazine, formaldehyde, and methanol. A scheme for the biodegradation of RDX is proposed which proceeds via successive reduction of the nitro groups to a point where destabilization and fragmentation of the ring occurs. The noncyclic degradation products arise via subsequent reduction and rearrangement reactions of the fragments. The scheme suggests the presence of several additional compounds, not yet identified. Several of the products are mutagenic or carcinogenic or both. Anaerobic treatment of RDX wastewaters, which also contain high nitrate levels, would permit the denitrification to occur, with concurrent degradation of RDX ultimately to a mixture of hydrazines and methanol. The feasibility of using an aerobic mode in the further degradation of these products is discussed. PMID:16345884

  15. Powering Tumor Metastasis with Recycled Fuel.

    PubMed

    Hung, Mien-Chie; Yang, Riyao; Sun, Yutong

    2016-09-12

    Receptor tyrosine kinase (RTK) recycling is of critical importance for RTK signaling and cancer, yet the process is poorly understood. In this issue, Ye et al. identify GOLM1 as a cargo adaptor that drives hepatocellular carcinoma metastasis by promoting EGFR recycling and provide insights into how this process is regulated. PMID:27622330

  16. Bone metastasis and the metastatic niche.

    PubMed

    Ren, Guangwen; Esposito, Mark; Kang, Yibin

    2015-11-01

    The bone marrow has been long known to host a unique environment amenable to colonization by metastasizing tumor cells. Yet, the underlying molecular interactions within this specialized microenvironment which give rise to the high incidence of bone metastasis in breast and prostate cancer patients have long remained uncharacterized. With the recent description of the bone metastatic "niche," considerable focus has been placed on understanding how the bone stroma contributes to each step of metastasis. Discoveries within this field have demonstrated that when cancer cells home to the niche in which hematopoietic and mesenchymal stem/progenitor cells normally reside, a bidirectional crosstalk emerges between the tumor cells and the bone metastatic stroma. This communication modulates every step of cancer cell metastasis to the bone, including the initial homing and seeding, formation of micrometastases, outgrowth of macrometastases, and the maintenance of long-term dormancy of disseminated tumor cells in the bone. In clinical practice, targeting the bone metastatic niche is evolving into a promising avenue for the prevention of bone metastatic relapse, therapeutic resistance, and other aspects of cancer progression. Here, we review the current knowledge concerning the role of the bone metastatic niche in bone metastasis.

  17. Altered Tumor-Cell Glycosylation Promotes Metastasis

    PubMed Central

    Häuselmann, Irina; Borsig, Lubor

    2014-01-01

    Malignant transformation of cells is associated with aberrant glycosylation presented on the cell-surface. Commonly observed changes in glycan structures during malignancy encompass aberrant expression and glycosylation of mucins; abnormal branching of N-glycans; and increased presence of sialic acid on proteins and glycolipids. Accumulating evidence supports the notion that the presence of certain glycan structures correlates with cancer progression by affecting tumor-cell invasiveness, ability to disseminate through the blood circulation and to metastasize in distant organs. During metastasis tumor-cell-derived glycans enable binding to cells in their microenvironment including endothelium and blood constituents through glycan-binding receptors – lectins. In this review, we will discuss current concepts how tumor-cell-derived glycans contribute to metastasis with the focus on three types of lectins: siglecs, galectins, and selectins. Siglecs are present on virtually all hematopoietic cells and usually negatively regulate immune responses. Galectins are mostly expressed by tumor cells and support tumor-cell survival. Selectins are vascular adhesion receptors that promote tumor-cell dissemination. All lectins facilitate interactions within the tumor microenvironment and thereby promote cancer progression. The identification of mechanisms how tumor glycans contribute to metastasis may help to improve diagnosis, prognosis, and aid to develop clinical strategies to prevent metastasis. PMID:24592356

  18. Targeting tumor cell motility to prevent metastasis

    PubMed Central

    Palmer, Trenis D.; Ashby, William J.; Lewis, John D.; Zijlstra, Andries

    2011-01-01

    Mortality and morbidity in patients with solid tumors invariably results from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities. PMID:21664937

  19. An Integrative Platform for Three-dimensional Quantitative Analysis of Spatially Heterogeneous Metastasis Landscapes

    NASA Astrophysics Data System (ADS)

    Guldner, Ian H.; Yang, Lin; Cowdrick, Kyle R.; Wang, Qingfei; Alvarez Barrios, Wendy V.; Zellmer, Victoria R.; Zhang, Yizhe; Host, Misha; Liu, Fang; Chen, Danny Z.; Zhang, Siyuan

    2016-04-01

    Metastatic microenvironments are spatially and compositionally heterogeneous. This seemingly stochastic heterogeneity provides researchers great challenges in elucidating factors that determine metastatic outgrowth. Herein, we develop and implement an integrative platform that will enable researchers to obtain novel insights from intricate metastatic landscapes. Our two-segment platform begins with whole tissue clearing, staining, and imaging to globally delineate metastatic landscape heterogeneity with spatial and molecular resolution. The second segment of our platform applies our custom-developed SMART 3D (Spatial filtering-based background removal and Multi-chAnnel forest classifiers-based 3D ReconsTruction), a multi-faceted image analysis pipeline, permitting quantitative interrogation of functional implications of heterogeneous metastatic landscape constituents, from subcellular features to multicellular structures, within our large three-dimensional (3D) image datasets. Coupling whole tissue imaging of brain metastasis animal models with SMART 3D, we demonstrate the capability of our integrative pipeline to reveal and quantify volumetric and spatial aspects of brain metastasis landscapes, including diverse tumor morphology, heterogeneous proliferative indices, metastasis-associated astrogliosis, and vasculature spatial distribution. Collectively, our study demonstrates the utility of our novel integrative platform to reveal and quantify the global spatial and volumetric characteristics of the 3D metastatic landscape with unparalleled accuracy, opening new opportunities for unbiased investigation of novel biological phenomena in situ.

  20. An Integrative Platform for Three-dimensional Quantitative Analysis of Spatially Heterogeneous Metastasis Landscapes

    PubMed Central

    Guldner, Ian H.; Yang, Lin; Cowdrick, Kyle R.; Wang, Qingfei; Alvarez Barrios, Wendy V.; Zellmer, Victoria R.; Zhang, Yizhe; Host, Misha; Liu, Fang; Chen, Danny Z.; Zhang, Siyuan

    2016-01-01

    Metastatic microenvironments are spatially and compositionally heterogeneous. This seemingly stochastic heterogeneity provides researchers great challenges in elucidating factors that determine metastatic outgrowth. Herein, we develop and implement an integrative platform that will enable researchers to obtain novel insights from intricate metastatic landscapes. Our two-segment platform begins with whole tissue clearing, staining, and imaging to globally delineate metastatic landscape heterogeneity with spatial and molecular resolution. The second segment of our platform applies our custom-developed SMART 3D (Spatial filtering-based background removal and Multi-chAnnel forest classifiers-based 3D ReconsTruction), a multi-faceted image analysis pipeline, permitting quantitative interrogation of functional implications of heterogeneous metastatic landscape constituents, from subcellular features to multicellular structures, within our large three-dimensional (3D) image datasets. Coupling whole tissue imaging of brain metastasis animal models with SMART 3D, we demonstrate the capability of our integrative pipeline to reveal and quantify volumetric and spatial aspects of brain metastasis landscapes, including diverse tumor morphology, heterogeneous proliferative indices, metastasis-associated astrogliosis, and vasculature spatial distribution. Collectively, our study demonstrates the utility of our novel integrative platform to reveal and quantify the global spatial and volumetric characteristics of the 3D metastatic landscape with unparalleled accuracy, opening new opportunities for unbiased investigation of novel biological phenomena in situ. PMID:27068335

  1. Cutaneous metastasis: a rare herald of a silent cancer.

    PubMed

    Hussain, Jonathan; Westerveld, Donevan; Sattari, Maryam

    2016-01-01

    A 59-year-old previously healthy man with a 50-pack-year smoking history presented with rib pain 1 month after a mechanical fall. Physical examination revealed a 1.5 cm right cervical lymph node and a 0.9 × 0.9 cm scalp nodule. The patient had only noticed the scalp lesion a month prior to presentation. Chest X-ray revealed a 5.8 × 5.0 cm left infrahilar mass. CT angiography demonstrated extensive metastatic mediastinal and right hilar adenopathy as well as hepatic, right adrenal and brain lesions. Pathology from fine-needle aspiration of cervical lymph nodes and punch biopsy of the scalp lesion were consistent with non-small cell lung cancer (NSCLC) metastasis. The patient underwent brain stereotactic radiosurgery and palliative radiation therapy. Unfortunately, he passed away 4 months after diagnosis. Malignancy (primary or secondary) should be considered by clinicians in the work up of patients with new skin lesions, particularly in those at high risk of cancer. PMID:26783009

  2. Bilateral Choroidal Metastasis from Non-Small Cell Lung Cancer

    PubMed Central

    Namad, Tariq; Wang, Jiang; Tilton, Annemarie; Abdel Karim, Nagla

    2014-01-01

    Breast and lung cancers are the most common primary neoplasms to manifest with choroidal metastases. The incidence of choroidal metastases from metastatic lung cancer was reported to be 2–6.7%. We report a case of bilateral choroidal metastasis from non-small cell lung cancer. A 59-year-old Caucasian female patient, never a smoker, was diagnosed with stage IV lung adenocarcinoma metastatic to the pleura, bones, and the brain. Her initial scan of the chest showed innumerable soft tissue nodules and mediastinal adenopathy compatible with metastatic disease. Her initial brain MRI showed numerous small enhancing lesions consistent with extensive disease. Unfortunately, during her follow-up visits, she presented with bulge on her left eye. Simultaneously, her follow-up chest scan showed increase in the size of the lung nodules. She continued to have a reasonable performance status at that time, except for mild increase in her dyspnea. The choroidal metastases require a multidisciplinary care and should be among the differential patients with malignancy who present with ocular symptoms. PMID:25295203

  3. S100A4 in Cancer Metastasis: Wnt Signaling-Driven Interventions for Metastasis Restriction

    PubMed Central

    Dahlmann, Mathias; Kobelt, Dennis; Walther, Wolfgang; Mudduluru, Giridhar; Stein, Ulrike

    2016-01-01

    The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of β-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success. PMID:27331819

  4. Significance of galectins-1, -3, -4 and -7 in the progression of squamous cell carcinoma of the tongue.

    PubMed

    Alves, Pollianna M; Godoy, Gustavo P; Gomes, Daliana Q; Medeiros, Ana Miryam C; de Souza, Lélia B; da Silveira, Ericka J D; Vasconcelos, Marcelo G; Queiroz, Lélia M G

    2011-04-15

    The aim of this study was to analyze the immunohistochemical expression of galectins-1, -3, -4, and -7 in 65 cases of squamous cell carcinoma of the tongue and to correlate this expression with clinical (disease outcome, metastasis, and clinical stage) and morphological parameters (histological grade of malignancy). Clinical data were obtained from the patient records. The histological grading system of malignancy proposed by Bryne (1998) [9] was used for the analysis of morphological parameters. The results were analyzed statistically by χ(2) test (p < 0.05). Galectin-1 expression was observed in 87.7% of cases and was significantly correlated with metastasis (p = 0.033) and clinical stage (p = 0.016). Immunoexpression of galectin-3 was observed in 87.7% of cases and was correlated with the presence of metastasis (p = 0.033) and histological grade of malignancy (p = 0.031). Galectin-4 showed no significant correlation with any of the parameters studied. Expression of galectin-7 was observed in 73.8% of cases and was significantly correlated with the histological grade of malignancy (p = 0.005). In conclusion, the intense immunoexpression of galectins-1, -3, and -7 suggests the participation of these proteins in oral carcinogenesis and their use as markers of biological behavior and tumor progression in squamous cell carcinoma of the tongue. PMID:21397408

  5. Silyl- and disilanyl-1,3-butadiyne polymers from hexachloro-1,3-butadiene

    DOEpatents

    Barton, Thomas J.; Ijadi-Maghsoodi, Sina

    1990-10-23

    Organosilane polymers having recurring silylene-1,3-butadiyne and/or disilylene-1,3-butadiyne units are prepared in a one-pot synthesis from hexachlorobutadiene. Depending on the organic substituents (R and R'), these polymers have useful film-forming properties, and are converted to the ceramic, silicon carbide upon heating a very uniform high char yields. They can also be pulled into fibers. The polymers are thermally crosslinked above 100.degree. C.

  6. Silyl- and disilanyl-1,3-butadiyne polymers from hexachloro-1,3-butadiene

    DOEpatents

    Barton, T.J.; Ijadi-Maghsoodi, S.

    1990-10-23

    Organosilane polymers having recurring silylene-1,3-butadiyne and/or disilylene-1,3-butadiyne units are prepared in a one-pot synthesis from hexachlorobutadiene. Depending on the organic substituents (R and R[prime]), these polymers have useful film-forming properties, and are converted to the ceramic, silicon carbide upon heating a very uniform high char yields. They can also be pulled into fibers. The polymers are thermally crosslinked above 100 C.

  7. On the non-planarity of 1,3-dioxole and 1,3-dioxolane

    NASA Astrophysics Data System (ADS)

    Vila, Antonio; Mosquera, Ricardo A.

    2010-03-01

    The conformational preferences of 1,3-dioxole and 1,3-dioxolane are explained on the basis of the QTAIM electron density analysis of B3LYP/6-311++G(2d,2p) electron distributions, supporting the interpretation of the anomeric effect previously proposed by Vila and Mosquera [14]. Thus, distances from methylenic hydrogens to oxygen lone pairs and H-C-O- lp dihedral angles sufficiently explain the atomic population and energy variations, thereby explaining the ring puckering preference.

  8. Hearing loss due to metastasis of gastric cancer to temporal bone: A case report

    PubMed Central

    CAO, XIANGMING; CUI, FANGBO; WEI, JIA; WANG, QING; DENG, LI CHUN; LIU, BAO RUI; SHEN, WEI SHENG

    2016-01-01

    Metastatic temporal bone tumors are rare, and tend to be asymptomatic. The clinical symptoms consist of aural discharge, bleeding, hearing loss and facial nerve paresis. The most common origin of the metastasis is breast cancer, and other sites of the primary tumor include the thyroid gland, brain, lungs, prostate and blood. Clinical reports of hearing loss due to gastric cancer metastatic to temporal bone are rare. In the present study, a case of gastric cancer metastasis to temporal bone without other organ involvement is described. The patient presented with the symptom of hearing loss, and the metastatic tumor was diagnosed by radiological imaging, including magnetic resonance imaging, computed tomography and bone scan. PMID:26893735

  9. P62: An emerging oncotarget for osteolytic metastasis

    PubMed Central

    Zhang, Jing; Yang, Zuozhang; Dong, Jian

    2016-01-01

    Bone metastasis occurs in the majority of late-stage tumors with poor prognosis. It is mainly classified as osteoblastic metastasis and osteolytic metastasis. The pathogenesis of osteolytic metastasis is a “vicious cycle” between tumor cells and bone cells (primarily the osteoclasts), which is mediated by secretory factors. The P62 adapter protein is a versatile multitasker between tumor cells and bone cells. The overexpression of P62 has been detected among a variety of tumors, playing positive roles in both tumorigenesis and metastasis. Moreover, P62 is an important modulator of the osteoclastogenesis pathway. Therefore, the ability of P62 to modulate tumors and osteoclasts suggests that it may be a feasible oncotarget for bone metastasis, especially for osteolytic metastasis. Recent research has shown that a P62 DNA vaccine triggered effective anti-tumor, anti-metastatic and anti-osteoporotic activities. Growing lines of evidence point to P62 as an emerging oncotarget for osteolytic metastasis. In this review, we outline the different roles of P62 in tumor cells and osteoclasts, focusing on the P62-related signaling pathway in key steps of osteolytic metastasis, including tumorigenesis, metastasis and osteoclastogenesis. Finally, we discuss the newest observations on P62 as an oncotarget for osteolytic metastasis treatment. PMID:26998424

  10. Hysteretic Behavior of Proprotein Convertase 1/3 (PC1/3)

    PubMed Central

    Icimoto, Marcelo Y.; Barros, Nilana M.; Ferreira, Juliana C.; Marcondes, Marcelo F.; Andrade, Douglas; Machado, Mauricio F.; Juliano, Maria A.; Júdice, Wagner A.; Juliano, Luiz; Oliveira, Vitor

    2011-01-01

    The proprotein convertases (PCs) are calcium-dependent proteases responsible for processing precursor proteins into their active forms in eukariotes. The PC1/3 is a pivotal enzyme of this family that participates in the proteolytic maturation of prohormones and neuropeptides inside the regulated secretory pathway. In this paper we demonstrate that mouse proprotein convertase 1/3 (mPC1/3) has a lag phase of activation by substrates that can be interpreted as a hysteretic behavior of the enzyme for their hydrolysis. This is an unprecedented observation in peptidases, but is frequent in regulatory enzymes with physiological relevance. The lag phase of mPC1/3 is dependent on substrate, calcium concentration and pH. This hysteretic behavior may have implications in the physiological processes in which PC1/3 participates and could be considered an additional control step in the peptide hormone maturation processes as for instance in the transformation of proinsulin to insulin. PMID:21935423

  11. Brain herniation

    MedlinePlus

    ... herniation; Uncal herniation; Subfalcine herniation; Tonsillar herniation; Herniation - brain ... Brain herniation occurs when something inside the skull produces pressure that moves brain tissues. This is most ...

  12. Microenvironmental regulation of tumor progression and metastasis.

    PubMed

    Quail, Daniela F; Joyce, Johanna A

    2013-11-01

    Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

  13. Roadblocks to translational advances on metastasis research.

    PubMed

    Brabletz, Thomas; Lyden, David; Steeg, Patricia S; Werb, Zena

    2013-09-01

    Promising advances in cancer therapy stemming from an increasing understanding of the molecular and genetic underpinnings of the tumorigenic process have been fueled by a strong, determined scientific community, influential patient advocacy groups and committed funding bodies. Despite these efforts, the development of effective drugs to prevent systemic dissemination of cancer cells or to eliminate overt metastasis in secondary organs remains a challenge to both researchers and physicians. In an attempt to tackle the most relevant and timely translational issues, a meeting held in 2012 as a result of a successful partnership between the Volkswagen Foundation and Nature Medicine brought together a group of metastasis research experts to identify the most important hurdles and help create a framework for potential clinical and translational strategies. PMID:24013756

  14. Progression and metastasis of lung cancer.

    PubMed

    Popper, Helmut H

    2016-03-01

    Metastasis in lung cancer is a multifaceted process. In this review, we will dissect the process in several isolated steps such as angiogenesis, hypoxia, circulation, and establishment of a metastatic focus. In reality, several of these processes overlap and occur even simultaneously, but such a presentation would be unreadable. Metastasis requires cell migration toward higher oxygen tension, which is based on changing the structure of the cell (epithelial-mesenchymal transition), orientation within the stroma and stroma interaction, and communication with the immune system to avoid attack. Once in the blood stream, cells have to survive trapping by the coagulation system, to survive shear stress in small blood vessels, and to find the right location for extravasation. Once outside in the metastatic locus, tumor cells have to learn the communication with the "foreign" stroma cells to establish vascular supply and again express molecules, which induce immune tolerance.

  15. Distinctive properties of metastasis-initiating cells

    PubMed Central

    Celià-Terrassa, Toni; Kang, Yibin

    2016-01-01

    Primary tumors are known to constantly shed a large number of cancer cells into systemic dissemination, yet only a tiny fraction of these cells is capable of forming overt metastases. The tremendous rate of attrition during the process of metastasis implicates the existence of a rare and unique population of metastasis-initiating cells (MICs). MICs possess advantageous traits that may originate in the primary tumor but continue to evolve during dissemination and colonization, including cellular plasticity, metabolic reprogramming, the ability to enter and exit dormancy, resistance to apoptosis, immune evasion, and co-option of other tumor and stromal cells. Better understanding of the molecular and cellular hallmarks of MICs will facilitate the development and deployment of novel therapeutic strategies. PMID:27083997

  16. MRI of metastasis-permissive microenvironments

    PubMed Central

    Penet, Marie-France; Chen, Zhihang; Bhujwalla, Zaver M

    2011-01-01

    One of the earliest documented observations of the importance of the microenvironment in metastasis was made by Stephen Paget in 1889. More than a century later, the metastatic cascade remains a major cause of mortality from cancer. Cancer meets the criterion of a successful organization that is able to survive by adapting to changing environments. In fact, the tumor microenvironment and stroma are co-opted and shaped by cancer cells to derive a survival advantage. Cohesive strategies integrating advances in molecular biology and chemistry, with noninvasive multimodality imaging, provide new insights into the role of the tumor microenvironment in promoting metastasis from primary tumors as well as insights into environments that attract and permit cancer cells to establish colonies in distant organs. This article provides an overview of molecular and functional imaging characterization of microenvironments that can promote or permit cancer cells to metastasize and the microenvironmental characteristics of distant metastases. PMID:22044202

  17. Hexahydro-1,3,5-trinitro-1,3,5-triazine translocation in poplar trees

    SciTech Connect

    Thompson, P.L.; Ramer, L.A.; Schnoor, J.L.

    1999-02-01

    This article evaluates the translocation of the explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in hybrid poplar trees (Populus deltoides x nigra, DN34) grown in hydroponic solutions. Mass balances with [U-{sup 14}C]RDX were used to assess RDX translocation. Up to 60% of the RDX uptaken by the tree accumulated in leaf tissues. Analysis of plant extracts by high-performance liquid chromatography equipped with radiochemical detection indicated that RDX was not significantly transformed during exposure periods of up to 7 d. The bioaccumulation of RDX may be an important concern for phytoremediation efforts.

  18. 1,3-Dinitrobenzene neurotoxicity - Passage effect in immortalized astrocytes.

    PubMed

    Maurer, Laura L; Latham, Jackelyn D; Landis, Rory W; Song, Dong Hoon; Epstein, Tamir; Philbert, Martin A

    2016-03-01

    Age-related disturbances in astrocytic mitochondrial function are linked to loss of neuroprotection and decrements in neurological function. The immortalized rat neocortical astrocyte-derived cell line, DI-TNC1, provides a convenient model for the examination of cellular aging processes that are difficult to study in primary cell isolates from aged brain. Successive passages in culture may serve as a surrogate of aging in which time-dependent adaptation to culture conditions may result in altered responses to xenobiotic challenge. To investigate the hypothesis that astrocytic mitochondrial homeostatic function is decreased with time in culture, low passage DI-TNC1 astrocytes (LP; #2-8) and high passage DI-TNC1 astrocytes (HP; #17-28) were exposed to the mitochondrial neurotoxicant 1,3-dinitrobenzene (DNB). Cells were exposed in either monoculture or in co-culture with primary cortical neurons. Astrocyte mitochondrial membrane potential, morphology, ATP production and proliferation were monitored in monoculture, and the ability of DI-TNC1 cells to buffer K(+)-induced neuronal depolarization was examined in co-cultures. In HP DI-TNC1 cells, DNB exposure decreased proliferation, reduced mitochondrial membrane potential and significantly decreased mitochondrial form factor. Low passage DI-TNC1 cells effectively attenuated K(+)-induced neuronal depolarization in the presence of DNB whereas HP counterparts were unable to buffer K(+) in DNB challenge. Following DNB challenge, LP DI-TNC1 cells exhibited greater viability in co-culture than HP. The data provide compelling evidence that there is an abrupt phenotypic change in DI-TNC1 cells between passage #9-16 that significantly diminishes the ability of DI-TNC1 cells to compensate for neurotoxic challenge and provide neuroprotective spatial buffering. Whether or not these functional changes have an in vivo analog in aging brain remains to be determined. PMID:26769196

  19. Mandibular metastasis of cholangiocarcinoma: A case report

    PubMed Central

    You, Tae Min; Kim, Kee-Deog; Jeong, Ho-Gul

    2015-01-01

    Tumors metastasizing from distant regions to the oral and maxillofacial region are uncommon, comprising only 1%-2% of all malignancies. Cholangiocarcinoma is a malignancy that arises from cholangiocytes, which are epithelial cells that line the bile ducts. These cancers are difficult to diagnose and have a poor prognosis. In this paper, we report a rare case of mandibular metastasis of cholangiocarcinoma diagnosed at the primary site and discuss the radiographic findings observed in this case. PMID:26730373

  20. Pathobiology of cancer metastasis: a short account.

    PubMed

    Feller, Liviu; Kramer, Beverley; Lemmer, Johan

    2012-01-01

    Cancer-initiating cells display aberrant functional and phenotypic characteristics of normal stem cells from which they evolved by accumulation of multiple cytogenetic and/or epigenetic alterations. Signal transduction pathways which are essential for normal stem cell function are abnormally expressed by cancer cells, with a cancer cell phenotype playing an essential role in cancerization and metastasis.Local tumour progression, metastasis and metastatic tumour growth are mediated by direct cell-to-cell and paracrine reciprocal interactions between cancer cells and various stromal cells including fibroblasts, macrophages, bone marrow derived stem cells and progenitor cells. These interactions mediate breakdown of basement membrane barriers and angiogenesis both locally at the invasive front of the primary tumour and at the distant metastatic site; attract primary tumour cells to the candidate metastatic site; and promote proliferation, survival and growth of primary tumour cells and of metastatic cells at their distant site.It is the purpose of this article to highlight the analogies between some of the genetic programs of normal stem cells, and of cancer cells participating in the process of metastasis. PMID:22676510

  1. Bone Metastasis from Renal Cell Carcinoma.

    PubMed

    Chen, Szu-Chia; Kuo, Po-Lin

    2016-01-01

    About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The "vicious cycle" hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden. PMID:27338367

  2. Bone Metastasis from Renal Cell Carcinoma

    PubMed Central

    Chen, Szu-Chia; Kuo, Po-Lin

    2016-01-01

    About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The “vicious cycle” hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden. PMID:27338367

  3. Metastasis of Prostate Adenocarcinoma to the Testis

    PubMed Central

    Campara, Zoran; Simic, Dejan; Aleksic, Predrag; Spasic, Aleksandar; Milicevic, Snjezana

    2016-01-01

    Introduction: Prostate carcinoma is the most frequently diagnosed carcinoma in the male population. The most typical places of the metastases are pelvic lymphatic glands, bones and lungs, and very rarely it metastasizes into a testis. The prognostic importance of testicular metastasis of prostate cancer is not yet well-known, due to a very few published cases. According to the known facts, it is certain that a metastasis of the prostate carcinoma into a testis is a sign of an advanced disease. Case report: This work presents a 48-year-old patient, to whom an adenocarcinoma of the prostate has been proven by the pathohistological finding of transrectal biopsy, performed due to the elevated level of prostate-specific antigen (PSA). Nine years after the initial diagnosis, due to a gradual rise of PSA and tumorous enlargement of the left testis, left inguinal orchectomy and right orchectomy were performed. Metastatic dissemination of prostate adenocarcinoma into a testis was determined by a pathohistological analysis of the left testis. Conclusion: The metastasis of the prostate carcinoma into a testis, as a rare localization of the metastatic dissemination, after additionally performed orchectomy along with further oncological therapy, can provide a continuation of a good life quality as well as a control of the disease in a longer time period. PMID:27703299

  4. micrOMEGAs: Version 1.3

    NASA Astrophysics Data System (ADS)

    Bélanger, G.; Boudjema, F.; Pukhov, A.; Semenov, A.

    2006-04-01

    We present the latest version of micrOMEGAs, a code that calculates the relic density of the lightest supersymmetric particle (LSP) in the minimal supersymmetric standard model (MSSM). All tree-level processes for the annihilation of the LSP are included as well as all possible coannihilation processes with neutralinos, charginos, sleptons, squarks and gluinos. The cross-sections extracted from CalcHEP are calculated exactly using loop-corrected masses and mixings as specified in the SUSY Les Houches Accord. Relativistic formulae for the thermal average are used and care is taken to handle poles and thresholds by adopting specific integration routines. The input parameters can be either the soft SUSY parameters in a general MSSM or the parameters of a SUGRA model specified at the GUT scale. In the latter case, a link with Suspect, SOFTSUSY, Spheno and Isajet allows one to calculate the supersymmetric spectrum, Higgs masses, as well as mixing matrices. Higher-order corrections to Higgs couplings to quark pairs including QCD as well as some SUSY corrections ( Δm) are implemented. Routines calculating (, b→sγ and B→μμ are also included. In particular the b→sγ routine includes an improved NLO for the SM and the charged Higgs while the SUSY large tanβ effects beyond leading-order are included. This new version also provides cross-sections for any 2→2 process as well as partial decay widths for two-body final states in the MSSM allowing for easy simulation at colliders. Program summaryProgram title:micrOMEGAs1.3 Catalogue identifier:ADQR_v1_3 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADQR_v1_3 Program obtainable from: CPC Program Library, Queen's University of Belfast, N. Ireland Licensing provisions:none Computer:PC, Alpha, Silicon graphics, Sun Programming language:C and Fortran Operating system:UNIX (Linux, OSF1, IRIX64, SunOS) RAM:20 MB depending on the number of processes required No of lines in distributed program, including test data, etc

  5. Surgical Brain Metastases: Management and Outcome Related to Prognostic Indexes: A Critical Review of a Ten-Year Series

    PubMed Central

    Caroli, Manuela; Di Cristofori, Andrea; Lucarella, Francesca; Raneri, Fabio Angelo; Portaluri, Francesco; Gaini, Sergio Maria

    2011-01-01

    Brain metastasis are the most common neoplastic lesions of the nervous system. Many cancer patients are diagnosed on the basis of a first clinical presentation of cancer on the basis of a single or multiple brain lesions. Brain metastases are manifestations of primary disease progression and often determine a poor prognosis. Not all patients with a brain metastases undergo surgery: many are submitted to alternative or palliative treatments. Management of patients with brain metastases is still controversial, and many studies have been developed to determine which is the best therapy. Furthermore, management of patients operated for a brain metastasis is often difficult. Chemotherapy, stereotactic radiosurgery, panencephalic radiation therapy, and surgery, in combination or alone, are the means most commonly used. We report our experience in the management of a ten-year series of surgical brain metastasis and discuss our results in the preoperative and postoperative management of this complex condition. PMID:22084749

  6. The voltage-dependent K+ channels Kv1.3 and Kv1.5 in human cancer

    PubMed Central

    Comes, Núria; Bielanska, Joanna; Vallejo-Gracia, Albert; Serrano-Albarrás, Antonio; Marruecos, Laura; Gómez, Diana; Soler, Concepció; Condom, Enric; Ramón y Cajal, Santiago; Hernández-Losa, Javier; Ferreres, Joan C.; Felipe, Antonio

    2013-01-01

    Voltage-dependent K+ channels (Kv) are involved in a number of physiological processes, including immunomodulation, cell volume regulation, apoptosis as well as differentiation. Some Kv channels participate in the proliferation and migration of normal and tumor cells, contributing to metastasis. Altered expression of Kv1.3 and Kv1.5 channels has been found in several types of tumors and cancer cells. In general, while the expression of Kv1.3 apparently exhibits no clear pattern, Kv1.5 is induced in many of the analyzed metastatic tissues. Interestingly, evidence indicates that Kv1.5 channel shows inversed correlation with malignancy in some gliomas and non-Hodgkin's lymphomas. However, Kv1.3 and Kv1.5 are similarly remodeled in some cancers. For instance, expression of Kv1.3 and Kv1.5 correlates with a certain grade of tumorigenicity in muscle sarcomas. Differential remodeling of Kv1.3 and Kv1.5 expression in human cancers may indicate their role in tumor growth and their importance as potential tumor markers. However, despite of this increasing body of information, which considers Kv1.3 and Kv1.5 as emerging tumoral markers, further research must be performed to reach any conclusion. In this review, we summarize what it has been lately documented about Kv1.3 and Kv1.5 channels in human cancer. PMID:24133455

  7. CCR5 receptor antagonists block metastasis to bone of v-Src-oncogene-transformed metastatic prostate cancer cell lines

    PubMed Central

    Sicoli, Daniela; Jiao, Xuanmao; Ju, Xiaoming; Velasco-Velazquez, Marco; Ertel, Adam; Addya, Sankar; Li, Zhiping; Ando, Sebastiano; Fatatis, Alessandro; Paudyal, Bishnuhari; Cristofanilli, Massimo; Thakur, Mathew L.; Lisanti, Michael P; Pestell, Richard G.

    2014-01-01

    Src family kinases (SFKs) integrate signal transduction for multiple receptors, regulating cellular proliferation invasion and metastasis in human cancer. Although Src is rarely mutated in human prostate cancer, SFK activity is increased in the majority of human prostate cancers. In order to determine the molecular mechanisms governing prostate cancer bone metastasis, FVB murine prostate epithelium was transduced with oncogenic v-Src. The prostate cancer cell lines metastasized in FVB mice to brain and bone. Gene expression profiling of the tumors identified activation of a CCR5 signaling module when the prostate epithelial cells (PEC) lines were grown in vivo vs. tissue cultures. The whole body, bone and brain metastatic prostate cancer burden was reduced by oral CCR5 antagonist. Clinical trials of CCR5 inhibitors may warrant consideration in patients with CCR5 activation in their tumors. PMID:25452256

  8. Study of the surface modification of LiNi1/3Co1/3Mn1/3O2 cathode material for lithium ion battery

    NASA Astrophysics Data System (ADS)

    Hashem, A. M. A.; Abdel-Ghany, A. E.; Eid, A. E.; Trottier, J.; Zaghib, K.; Mauger, A.; Julien, C. M.

    2011-10-01

    The surface of LiNi1/3Co1/3Mn1/3O2 (LNMCO) particles has been studied for material synthesized at 900 °C by a two-step process from a mixture of LiOH·H2O and metal oxalate [(Ni1/3Co1/3Mn1/3)C2O4] obtained by co-precipitation. Samples have been characterized by X-ray diffraction (XRD), high-resolution transmission electron microscope (HRTEM), Raman scattering (RS) spectroscopy, and magnetic measurements. We have investigated the effect of the heat treatment of particles at 600 °C with organic substances such as sucrose and starch. HRTEM images and RS spectra indicate that the surface of particles has been modified. The annealing does not lead to any carbon coating but it leads to the crystallization of the thin disordered layer on the surface of LiNi1/3Co1/3Mn1/3O2. The beneficial effect has been tested on the electrochemical properties of the LiNi1/3Co1/3Mn1/3O2 cathode materials. The capacity at 10C-rate is enhanced by 20% for post-treated LNMCO particles at 600 °C for half-an-hour.

  9. Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

    PubMed

    Chakrabarti, Mrinmay; Ray, Swapan K

    2016-03-01

    Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo. PMID:26573275

  10. Pulmonary metastasis of giant cell tumor of bones.

    PubMed

    Muheremu, Aikeremujiang; Niu, Xiaohui

    2014-08-20

    Giant cell tumor of bone (GCTB) accounts for 5% of primary skeletal tumors. Although it is considered to be a benign lesion, there are still incidences of pulmonary metastasis. Pulmonary metastasis of GCTB may be affected by tumor grading and localization as well as the age, gender and overall health status of the patient. Patients with local recurrence are more likely to develop pulmonary metastasis of GCTB. High expression of some genes, cytokines and chemokines may also be closely related to the metastatic potential and prognosis of GCTB. The treatment of the primary GCTB is key to the final outcome of the disease, as intralesional curettage has a significantly higher local recurrence and pulmonary metastasis rate than wide resection. However, even patients with pulmonary metastasis seem to have a good prognosis after timely and appropriate surgical resection. It is hoped that with the development of novel surgical methods and drugs, pulmonary metastasis of GCTB can be prevented and treated more effectively.

  11. Visfatin Mediates SCLC Cells Migration across Brain Endothelial Cells through Upregulation of CCL2.

    PubMed

    Liu, Tingting; Miao, Ziwei; Jiang, Jiusheng; Yuan, Shuai; Fang, Wengang; Li, Bo; Chen, Yuhua

    2015-05-18

    Small-cell lung cancer (SCLC) is characterized as an aggressive tumor with brain metastasis. Although preventing SCLC metastasis to the brain is immensely important for survival, the molecular mechanisms of SCLC cells penetrating the blood-brain barrier (BBB) are largely unknown. Recently, visfatin has been considered as a novel pro-inflammatory adipocytokine involved in various cancers. Herein, we present evidence that elevated levels of visfatin in the serum of SCLC patients were associated with brain metastasis, and visfain was increased in NCI-H446 cells, a SCLC cell line, during interacting with human brain microvascular endothelial cells (HBMEC). Using in vitro BBB model, we found that visfatin could promote NCI-H446 cells migration across HBMEC monolayer, while the effect was inhibited by knockdown of visfatin. Furthermore, our findings indicated that CC chemokine ligand 2 (CCL2) was involved in visfatin-mediated NCI-H446 cells transendothelial migtation. Results also showed that the upregulation of CCL2 in the co-culture system was reversed by blockade of visfatin. In particular, visfatin-induced CCL2 was attenuated by specific inhibitor of PI3K/Akt signaling in NCI-H446 cells. Taken together, we demonstrated that visfatin was a prospective target for SCLC metastasis to brain, and understanding the molecular mediators would lead to effective strategies for inhibition of SCLC brain metastasis.

  12. Pituitary metastasis of lung neuroendocrine carcinoma: case report and literature review.

    PubMed

    Siqueira, Pedro Freire de; Mathez, Andréia Latanza Gomes; Pedretti, Denize Borges; Abucham, Julio

    2015-12-01

    Metastasis to the pituitary gland is an unusual situation in clinical practice, but the frequency thereof is increasing due to the increased survival of cancer patients, and greater availability of imaging. In most cases, they are found between the sixth and seventh decades of life, as determined in image examination of patients with known malignant neoplasm, but, generally, asymptomatic with respect to pituitary involvement. The most common primary sites are breast in women and lung in men. We present the case of a 64-year-old patient with clinical visual changes, polyuria, polydipsia, and decreased level of consciousness whose tests showed pan-hypopituitarism, hypernatremia and low urine specific gravity, and extensive mass in sellar region. Diabetes insipidus was confirmed and treated, corticotrophic and thyroid deficits were corrected and then the patient underwent resection by transsphenoidal surgery. The histopathological and immunohistochemistry analysis revealed pituitary metastasis of lung neuroendocrine tumor. Subsequently, a chest CT scan showed pulmonary mass consistent with primary neoplasm. Despite the water and electrolyte correction and intravenous glucocorticoid replacement, the patient continued to show decreased level of consciousness due to compression of the brain stem by the pituitary mass, evolving to death. The purpose is to call attention to the differential diagnosis of invasive lesions of the sellar region, mainly in individuals over 50 years and/or when associated with diabetes insipidus, as it may be a case of metastasis, although there is no known primary neoplasm. PMID:26677090

  13. Skeletal metastasis: treatments, mouse models, and the Wnt signaling

    PubMed Central

    Valkenburg, Kenneth C.; Steensma, Matthew R.; Williams, Bart O.; Zhong, Zhendong

    2013-01-01

    Skeletal metastases result in significant morbidity and mortality. This is particularly true of cancers with a strong predilection for the bone, such as breast, prostate, and lung cancers. There is currently no reliable cure for skeletal metastasis, and palliative therapy options are limited. The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target. Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments. In this review, we discuss pathologic process of bone metastasis, the roles of the Wnt signaling, and the available experimental models and treatments. PMID:23327798

  14. [Research progress on mechanisms of modern medicine in cancer metastasis].

    PubMed

    Chen, Hui; Qu, Jing-Lian; Gong, Jie-Ning

    2014-08-01

    Cancer metastasis is the most dangerous stage of tumorigenesis and evolution, the primary cause of death in cancer patients. Clinically, more than 60% of cancer patients have found metastasis at the time of examination. Modern medicine has made significant progress on the mechanisms of cancer metastasis in recent years, from the simple "anatomy and machinery" theory forward to the "seed and soil" theory, then to the "microenvironmental" theory and the "cancer stem cell" theory. The emerging "cancer stem cell" theory successfully explains phenomenon such as tumor genetic heterogeneity, anoikis resistance, tumor dormancy, providing more new targets and ideas for the diagnosis and treatment of cancer metastasis.

  15. The molecular biology of pulmonary metastasis.

    PubMed

    Krishnan, Kartik; Khanna, Chand; Helman, Lee J

    2006-05-01

    Curing cancer requires the treatment of metastatic disease. Whether this is a patient with advanced disease and clinically apparent metastases, or if the patient with localized disease is at risk for development of dissemination, failure to control metastasis will result in a poor outcome. Here, we have presented a molecular guide to our current understanding of the processes underlying metastasis. Experimental clinical trials designed to further the understanding of metastasis are often limited by selection of patients with advanced disease. Therefore, our understanding of the processes involved in the metastatic cascade is limited by the availability of comprehensive experimental model systems. The study of metastasis relies most heavily on xenografts, tumors using human cell lines, or tumor tissue that can grow in mice. These models present a limited recapitulation of the patients. Xenograft models require some degree of immunosuppression on the part of the host, because mice with native immune systems will reject transplanted human tumors, preventing their growth. As a result, mice with immune defects ranging from depleted T cells (nude mice) to absent T, B, and NK cells (SCID-Beige) are used as hosts. As the evasion of the immune system is a key function demonstrated by the metastatic cancer cell, xenograft models, by necessity, subvert this step. Furthermore, recent studies have established that angiogenesis in transplanted tumors is different than in native tumors, further highlighting the limitations of these models. With these limitations, studies of metastasis may require development of models of autochthonous tumors, that is, tumors originating in the study animals. A number of cell lines of autochthonous murine tumors have been established that generate metastatic disease after implantation into mice. Moreover, some transgenic animals spontaneously develop metastatic tumors that, although occurring in genetically engineered animals, may represent the

  16. Breast metastasis from lung cancer: a report of two cases and literature review

    PubMed Central

    Wang, Li; Wang, Shu-Ling; Shen, Hong-Hong; Niu, Feng-Ting; Niu, Yun

    2014-01-01

    Breast metastasis from extra-mammary malignancy is rare. An incidence of 0.4% to 1.3% has been reported in literature. The primary malignancies that most commonly metastasize to the breast are leukemia, lymphoma, and malignant melanoma. In this report, two cases of pulmonary metastasis to the breast were presented. A 40-year-old female manifested a right breast mass of 2-month duration. After physical examination was performed, a poorly defined mass was noted in the upper outer quadrant of the right breast. Another 49-year-old female manifested right breast mass of 5-day duration. A poorly defined mass was noted in the lower inner quadrant of the right breast. Mammography results also revealed breast cancer. The patients underwent local excision. After histological and immunohistochemical analyses were conducted, a primary lung carcinoma that metastasized to the breast was diagnosed. An accurate differentiation of metastasis to the breast from primary breast cancer is very important because the treatment and prognosis of the two differ significantly. PMID:25364582

  17. Ovarian metastasis of clear cell renal cell carcinoma: A case report.

    PubMed

    Bauerová, Lenka; Dundr, Pavel; Fischerová, Daniela; Pešl, Michael; Zikán, Michal; Burgetová, Andrea

    2014-01-01

    We report on a 61-year-old woman with a history of right-sided nephrectomy for clear cell renal cell carcinoma (RCC) occurring 21 years ago; she currently presented with a bilateral ovarian tumour. Histologically, the tumour of both ovaries was clear cell carcinoma. Immunohistochemically, the tumour cells were positive for vimentin, RCC marker, epithelial membrane antigen, cytokeratin AE1/3 and CD10. Cytokeratin 7, CA125, HMWCK, estrogen and progesterone receptors were all negative. Based on the morphology and immunophenotype of the tumour, we established a diagnosis of late metastasis of RCC in the ovaries. A postoperative abdominal computed tomography scan, however, revealed a tumour mass solely in the left kidney, which had not been visible in the preoperative ultrasound. The patient underwent nephron-sparing surgery and a biopsy showed the tumour to be clear cell RCC. Metastasis of RCC to the ovaries is rare, and to the best of our knowledge, only 24 cases have been reported to date. However, due to the different treatments and prognosis, the distinction between a primary ovarian tumour and metastasis of RCC is important. PMID:24678363

  18. Contemporary approaches for imaging skeletal metastasis

    PubMed Central

    Ulmert, David; Solnes, Lilja; Thorek, Daniel LJ

    2015-01-01

    The skeleton is a common site of cancer metastasis. Notably high incidences of bone lesions are found for breast, prostate, and renal carcinoma. Malignant bone tumors result in significant patient morbidity. Identification of these lesions is a critical step to accurately stratify patients, guide treatment course, monitor disease progression, and evaluate response to therapy. Diagnosis of cancer in the skeleton typically relies on indirect bone-targeted radiotracer uptake at sites of active bone remodeling. In this manuscript, we discuss established and emerging tools and techniques for detection of bone lesions, quantification of skeletal tumor burden, and current clinical challenges. PMID:26273541

  19. Fully Regressive Melanoma: A Case Without Metastasis.

    PubMed

    Ehrsam, Eric; Kallini, Joseph R; Lebas, Damien; Khachemoune, Amor; Modiano, Philippe; Cotten, Hervé

    2016-08-01

    Fully regressive melanoma is a phenomenon in which the primary cutaneous melanoma becomes completely replaced by fibrotic components as a result of host immune response. Although 10 to 35 percent of cases of cutaneous melanomas may partially regress, fully regressive melanoma is very rare; only 47 cases have been reported in the literature to date. AH of the cases of fully regressive melanoma reported in the literature were diagnosed in conjunction with metastasis on a patient. The authors describe a case of fully regressive melanoma without any metastases at the time of its diagnosis. Characteristic findings on dermoscopy, as well as the absence of melanoma on final biopsy, confirmed the diagnosis. PMID:27672418

  20. Monoclonal Antibody Testing for Cancer Metastasis

    NASA Technical Reports Server (NTRS)

    1993-01-01

    Malignant cells are characterized by the ability to invade surrounding normal tissues. Tumor invasion is abetted by proteolytic enzymes that have been correlated with recurrent disease and metastasis. These enzymes are involved in a cascade of proteolytic interactions with other enzymes and inhibitors which allow cancer cells to dissolve surrounding extracellular matrix, thereby enabling the cells to rapidly invade adjacent tissues and migrate to metastatic sites distant from the primary tumor. Among these proteases are the plasminogen activators (PA), collagenase IV, faminase, and in some cases cathepsin D, which together mediate key steps in the invasion process of metastasis. Cells which have the selective advantage for invasion and metastasis are those capable of regulating their proteolytic activity and proliferation. Cells in the process of invasion would be probably down-regulated for proliferation, but subsequent to attachment and adhesion at a distant site, would then be in a proliferative mode, up-regulating DNA replication. Urokinase (uPA) can be present in the tissues in several molecular forms. The inactive proenzyme is a single chain protein (scuPA) that is cleaved at Lys. 158 to form the double chain, high molecular weight active form (HMW-uPA) of 54 kD. A low molecular weight form (LMW-uPA) can also be produced by cleavage of the HMW-U PA at Lys. 135 - Lys. 136 giving a 35 kD active enzyme. Recently, it has been shown that the HMW active form of urokinase, bound to the tumor cell membrane, is responsible for the local lysis of the extracellular matrix, hence the tissue invasion mechanism for metastasis (Andreasen et al, 19861. Receptor- (membrane) bound uPA is twice as efficient (catalytically) as free fluid-phase uPA. Tho unbound uPA and the LMW form is not responsible for most of the local dissolution of extracellular matrix in the immediate vicinity of the metastatic tumor cell. High levels of urokinase (greater than 3.49 ng/mg of total protein

  1. Orbital Metastasis of Multiple Myeloma: Case Report

    PubMed Central

    Vatansever, Mustafa; Bozkurt, Fatma Merve; Dinç, Erdem; Yılmaz, Eda Bengi; Nayir, Erdinç; Sarı, Ayşe Ayça; Yıldırım, Özlem; Kara, Tuba

    2016-01-01

    A 68-year-old woman with a history of multiple myeloma presented to the clinic with pain and vision loss in her right eye. Proptosis was observed in her right eye and eye movements were restricted in all directions. Best corrected visual acuity was 3/10 in her right eye. On biomicroscopic examination, hyperemia and subconjunctival hemorrhage were present. Fundus examination of the right eye revealed optic disc edema and choroidal folds. In magnetic resonance imaging two orbital masses were detected. Based on the patient’s history and ocular examination, we evaluated the masses as orbital metastasis of multiple myeloma. Palliative radiotherapy was recommended. PMID:27800278

  2. Is inositol (1,3,4,5)-tetrakisphosphate a new second messenger

    SciTech Connect

    Hansen, C.A.; Williamson, J.R.

    1986-05-01

    Hormone-stimulated hydrolysis of inositol (Ins) lipids results in the rapid formation of Ins(1,4,5)P/sub 3/, the second messenger for intracellular Ca/sup 2 +/ mobilization. Recently, a more polar inositol phosphate, Ins(1,3,4,5)P/sub 4/ as well as its probable hydrolysis product Ins(1,3,4)P/sub 3/ have been reported to accumulate in carbachol-stimulated brain slices. Vasopressin addition to hepatocytes prelabeled with (/sup 3/H)-Ins also showed a rapid increase of Ins(1,3,4,5)P/sub 4/, which was similar to that of Ins(1,4,5)P/sub 3/, while the accumulation of Ins(1,3,4)P/sub 3/ was slower. In order to examine whether Ins(1,3,4,5)P/sub 4/ has any functional effects on Ca/sup 2 +/ homeostasis, it was synthesized enzymatically from (/sup 3/H)-Ins(1,4,5)P/sub 3/ using a partially purified phosphoinositol kinase activity from rat brain cortex. (/sup 3/H)-labeled inositol phosphates were separated by anion exchange chromatography and analyzed by HPLC using ammonium formate/phosphoric acid gradient elution. Preliminary experiments indicate that Ins(1,3,4,5)P/sub 4/ up to 10 ..mu..M does not release Ca/sup 2 +/ from vesicular pools in saponin-permeabilized hepatocytes. It has a slight inhibitory effect on Ins(1,4,5)P/sub 3/-induced Ca/sup 2 +/ release. The effect of Ins(1,3,4,5)P/sub 4/ on plasma membrane Ca/sup 2 +/ fluxes are presently being investigated.

  3. Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling.

    PubMed

    Kawamura, Kazuhiro; Kawamura, Nanami; Okamoto, Naoki; Manabe, Motomu

    2013-12-01

    Brain-derived neurotrophic factor (BDNF) acts through its cognate receptor tyrosine kinase-B (TrkB) to regulate diverse physiological functions in reproductive and other tissues. In normal and malignant trophoblastic cells, the BDNF/TrkB signaling promotes cell growth. Due to the highly malignant nature of choriocarcinoma, we investigated possible involvement of this system in choriocarcinoma cell invasion and metastasis. We demonstrated that treatment of cultured choriocarcinoma cells, known to express both BDNF and TrkB, with a soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cell invasion accompanied with decreased expression of matrix metalloproteinase-2, a cell invasion marker. In vivo studies using a tumor xenograft model in athymic nude mice further showed inhibition of cell invasion from tumors to surrounding tissues following the suppression of endogenous TrkB signaling. For an in vivo model of choriocarcinoma metastasis, we performed intravenous injections of JAR cells expressing firefly luciferase into severe combined immunodeficiency (SCID) mice. Treatment with K252a inhibited metastasis of tumors to distant organs. In vivo K252a treatment also suppressed metastatic tumor growth as reflected by decreased cell proliferation and increased apoptosis and caspases-3/7 activities, together with reduced tissue levels of a tumor marker, human chorionic gonadotropin-β. In vivo suppression of TrkB signaling also led to decreased expression of angiogenic markers in metastatic tumor, including cluster of differentiation 31 and vascular endothelial growth factor A. Our findings suggested essential autocrine/paracrine roles of the BDNF/TrkB signaling system in choriocarcinoma invasion and metastasis. Inhibition of this signaling could serve as the basis to develop a novel therapy for patients with choriocarcinoma.

  4. Thyroid gland metastasis arising from primary liver cholangiocarcinoma: The first case report involving surgical operation

    PubMed Central

    Park, Min Ho; Cho, Jin Seong; Lee, Ji Shin; Kim, Hee Kyung; Yoon, Jung Han

    2011-01-01

    Introduction A primary cancer causing thyroid metastasis is extremely rare. In western countries, the most common primary tumors causing thyroid metastases include kidney, lung, breast, and gastrointestinal cancers. In contrast, breast is the most common primary site, followed by kidney, colon, and lung cancers in Korea. To the best of our knowledge, surgically confirmed thyroid metastasis from cholangiocarcinoma has not been reported. Herein, we report the first case of thyroid metastasis secondary to cholangiocarcinoma on which surgery was performed. Presentation of case A 55-year-old man was diagnosed with hepatic malignancy in December 2008. He subsequently received 2 cycles of transarterial chemoembolization and 4 cycles of radio-frequency ablation between 2008 and 2010. At follow-up in January 2011, brain metastasis was identified in the right parietal area secondary to cholangiocarcinoma. In April 2011, the patient was found to have palpable masses on the left thyroid and lateral neck. The patient subsequently underwent total thyroidectomy followed by left radical neck dissection. Intraoperatively, an ill-defined mass measuring 6.0 cm was found infiltrating the subcutaneous tissue into the prevertebral fascia. Microscopic and immunohistochemical findings confirmed that the thyroid masses and lymph nodes were metastatic cholangiocarcinoma. Discussion Positive immunohistochemical staining for cytokeratin 7, cytokeratin 19, and AFP and negative results for TG, TTF-1, and cytokeratin 20 can be definitely helpful in arriving at a correct diagnosis. Conclusion To the best of our knowledge, this is the first case report on surgically resected thyroid and lateral neck metastases secondary to cholangiocarcinoma. PMID:22288052

  5. Expression of TYMS in lymph node metastasis from low-grade glioma

    PubMed Central

    DING, BINGQIAN; GAO, MING; LI, ZHENJIANG; XU, CHENYANG; FAN, SHAOKANG; HE, WEIYA

    2015-01-01

    The aim of the present study was to investigate the expression of thymidylate synthase (TYMS) in the primary foci and metastatic lymph nodes of low-grade glioma, and to analyze the function of TYMS in the lymph node metastases from low-grade glioma. The study included 93 cases of surgically resected and pathologically confirmed low-grade glioma, form patients treated at Huaihe Hospital of Henan University (Kaifeng, China). The following clinical data was obtained from each patient: Gender, age, subjective symptoms (dizziness, headache, a feeling of pressure in the head, etc.), site of disease, tumor type, pathological stage, degree of differentiation and lymph node involvement. The surgically resected gliomas and dissected cervical lymph nodes were immunohistochemically stained, and DNA was extracted from the tumor and lymph node tissues samples for polymerase chain reaction sequencing and amplification. The expression of TYMS in the primary foci and metastatic lymph nodes of low-grade glioma was examined. Additionally, the association between pathological features and the postoperative survival rate of the patients was analyzed. The primary lesions of all 93 cases exhibited positive TYMS expression and 43/157 (27.39%) lymph nodes exhibited positive TYMS expression. Factors that significantly influenced the postoperative survival rate of the patients, included the metastasis of the cervical lymph nodes (P<0.01), the number of dissected cervical lymph nodes (P<0.01) and the degree of differentiation (P<0.05). The metastasis of the cervical lymph nodes was the only independent risk factor affecting postoperative disease-free survival. The risk of recurrence in patients with metastasis of the cervical lymph nodes was 6.3-fold higher than in those without metastasis (P<0.01). Thus, the results of the present study provide a theoretical basis for accurately predicting the prognosis of patients with low-grade malignant brain glioma, reducing the conjecture involved in

  6. Preparation, characterization of LiNi{sub 1/3}Mn{sub 1/3}Co{sub 1/3}O{sub 2} film cathode.

    SciTech Connect

    Kang, S. H.; Abraham, D. P.; Chemical Engineering

    2006-01-01

    Positive electrodes based on the LiNi{sub 1/3}Mn{sub 1/3}Co{sub 1/3}O{sub 2} material are being evaluated in high-power lithium-ion cells for hybrid-electric vehicle applications. To determine performance degradation mechanisms that are associated with the active material, we prepared carbon- and binder-free LiNi{sub 1/3}Mn{sub 1/3}Co{sub 1/3}O{sub 2} film cathode on a Pt substrate using a sol-gel spin coating technique. The material was characterized by X-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy. Initial data from cyclic voltammetry, galvanostatic cycling, and electrochemical impedance spectroscopy measurements conducted on the electrodes are reported.

  7. Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis.

    PubMed

    Okugawa, Yoshinaga; Toiyama, Yuji; Hur, Keun; Toden, Shusuke; Saigusa, Susumu; Tanaka, Koji; Inoue, Yasuhiro; Mohri, Yasuhiko; Kusunoki, Masato; Boland, C Richard; Goel, Ajay

    2014-12-01

    The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs-Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)-by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia.

  8. Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis

    PubMed Central

    Okugawa, Yoshinaga; Toiyama, Yuji; Hur, Keun; Toden, Shusuke; Saigusa, Susumu; Tanaka, Koji; Inoue, Yasuhiro; Mohri, Yasuhiko; Kusunoki, Masato; Boland, C.Richard; Goel, Ajay

    2014-01-01

    The prognosis of gastric cancer (GC) patients with peritoneal dissemination remains poor, and a better understanding of the underlying mechanisms is critical for the development of new treatments that will improve survival in these patients. This study aimed to clarify the clinical and biological role of two key metastasis-associated long non-coding RNAs (lncRNAs) in GC. We analyzed the expression levels of two lncRNAs—Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and HOX-Antisense Intergenic RNA (HOTAIR)—by real-time reverse transcription PCR in 300 gastric tissues (150 GC and 150 adjacent normal mucosa), and in seven GC cell lines. Functional characterization for the role of HOTAIR in GC was performed by small interfering RNA (siRNA) knockdown, followed by series of in-vitro and in-vivo experiments. Expression of both lncRNAs was significantly higher in cancerous tissues than in corresponding normal mucosa, and higher expression of these lncRNAs significantly correlated with peritoneal metastasis in GC patients. In addition, elevated HOTAIR expression emerged both as an independent prognostic and risk factor for peritoneal dissemination. SiRNA knockdown of HOTAIR in GC cells significantly inhibited cell proliferation, migration and invasion, but concurrently enhanced the anoikis rate in transfected cells. In an in vivo assay, HOTAIR siRNA-transfected MKN45 cells injected into nude mice inhibited the growth of xenograft tumors and peritoneal metastasis compared with controls. Our data provide novel evidence for the biological and clinical significance of HOTAIR expression as a potential biomarker for identifying patients with peritoneal metastasis, and as a novel therapeutic target in patients with gastric neoplasia. PMID:25280565

  9. Short and general procedure for synthesizing cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives.

    PubMed

    Castilla, Javier; Marín, Irene; Matheu, M Isabel; Díaz, Yolanda; Castillón, Sergio

    2010-01-15

    Novel cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives have been prepared by treatment of the corresponding 1,2-anhydrosugars with potassium thiocyanate, potassium selenocyanate, and sodium cyanamide, respectively. The procedure is compatible with several protecting groups such as acyl, benzyl, and silyl and also with sugars of different configurations.

  10. Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis

    PubMed Central

    Pavlovic, Milica; Arnal-Estapé, Anna; Rojo, Federico; Bellmunt, Anna; Tarragona, Maria; Guiu, Marc; Planet, Evarist; Garcia-Albéniz, Xabier; Morales, Mónica; Urosevic, Jelena; Gawrzak, Sylwia; Rovira, Ana; Prat, Aleix; Nonell, Lara; Lluch, Ana; Jean-Mairet, Joël; Coleman, Robert; Albanell, Joan

    2015-01-01

    Background: There are currently no biomarkers for early breast cancer patient populations at risk of bone metastasis. Identification of mediators of bone metastasis could be of clinical interest. Methods: A de novo unbiased screening approach based on selection of highly bone metastatic breast cancer cells in vivo was used to determine copy number aberrations (CNAs) associated with bone metastasis. The CNAs associated with bone metastasis were examined in independent primary breast cancer datasets with annotated clinical follow-up. The MAF gene encoded within the CNA associated with bone metastasis was subjected to gain and loss of function validation in breast cancer cells (MCF7, T47D, ZR-75, and 4T1), its downstream mechanism validated, and tested in clinical samples. A multivariable Cox cause-specific hazard model with competing events (death) was used to test the association between 16q23 or MAF and bone metastasis. All statistical tests were two-sided. Results: 16q23 gain CNA encoding the transcription factor MAF mediates breast cancer bone metastasis through the control of PTHrP. 16q23 gain (hazard ratio (HR) for bone metastasis = 14.5, 95% confidence interval (CI) = 6.4 to 32.9, P < .001) as well as MAF overexpression (HR for bone metastasis = 2.5, 95% CI = 1.7 to 3.8, P < .001) in primary breast tumors were specifically associated with risk of metastasis to bone but not to other organs. Conclusions: These results suggest that MAF is a mediator of breast cancer bone metastasis. 16q23 gain or MAF protein overexpression in tumors may help to select patients at risk of bone relapse. PMID:26376684

  11. Expression of annexin A7 and its clinical significance in differentiation and metastasis of gastric carcinoma

    PubMed Central

    Yuan, Hu-Fang; Li, Yong; Zhao, Qun; Fan, Li-Qiao; Tan, Bi-Bo; Ye, Wei-Hua

    2014-01-01

    Objective: To investigate the expression and clinical significance of annexin A7 in the differentiation and lymphatic metastasis of gastric cancer (GC). Methods: The clinical and pathological data were recorded for analysis. Immunohistochemical staining and Western blot were performed to analyze the expression of ANXA 7 in primary GC tissues. Logistic regression analyses were conducted to evaluate the associations between annexin A7 expression levels and differentiations of GC. Analyses of the ROC were conducted to determine the cut-off value of the ratio of pixel density of annexin A7 for predicting lymphatic metastasis of GC. Results: A total of 162 GC patients were enrolled in this study, and expression rate of annexin A7 was 65.4% in GC. The survival rate of patients with positive expression of annexin A7 was lower than that in patients with negative expression (P=0.000). The results of COX regression showed that the positive expression of annexin A7, submucosal confinement and pathological stage of GC were associated with poor clinical outcomes. The ratio of pixel density value of primary GC tissues with PN 1-3 lymphatic spread was significantly higher than those in tissues with PN 0 lymphatic spread (0.56±0.09 vs. 0.42±0.07, P < 0.05). ROC analysis showed a high area under the curve for the ratio of pixel density value of annexin A7 in primary GC tissues. At a cut-off level of > 0.505, the ratio of pixel density value of annexin A7 exhibited 76.7% sensitivity and 88.3% specificity for detecting lymphatic metastasis of GC. Conclusion: High annexin A7 expression is associated with poor differentiation in GC patients, and it may be a predictor for lymphatic metastasis of GC. PMID:25400735

  12. Brain Tumors

    MedlinePlus

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  13. Water quality criteria for hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX).

    PubMed

    Etnier, E L

    1989-04-01

    The occurrence of the munitions compound hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in groundwater surrounding Army ammunition plants may result in contamination of local drinking water supplies. RDX exerts its primary toxic effect in humans on the central nervous system, but also involves gastrointestinal and renal effects. Symptomatic effects following acute exposure include hyperirritability, nausea, vomiting, generalized epileptiform seizures, and prolonged postictal confusion and amnesia. Health effects data were analyzed for RDX, and although no controlled human studies exist concerning the acute or chronic toxic effects of exposure to RDX, sufficient animal toxicity data are available to derive an ambient water quality criterion for the protection of human health. This paper summarizes the available literature on metabolism of RDX and human and animal toxicity. Based on noncarcinogenic mammalian toxicity data, and following the methodologies of the U.S. Environmental Protection Agency, an ambient water quality criterion for the protection of human health of 103 micrograms/liter is proposed for ingestion of drinking water and aquatic foodstuffs. A criterion of 105 micrograms/liter is proposed for ingestion of drinking water alone.

  14. Water quality criteria for hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

    SciTech Connect

    Etnier, E.L.

    1989-04-01

    The occurrence of the munitions compound hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in groundwater surrounding Army ammunition plants may result in contamination of local drinking water supplies. RDX exerts its primary toxic effect in humans on the central nervous system, but also involves gastrointestinal and renal effects. Symptomatic effects following acute exposure include hyperirritability, nausea, vomiting, generalized epileptiform seizures, and prolonged postictal confusion and amnesia. Health effects data were analyzed for RDX, and although no controlled human studies exist concerning the acute or chronic toxic effects of exposure to RDX, sufficient animal toxicity data are available to derive an ambient water quality criterion for the protection of human health. This paper summarizes the available literature on metabolism of RDX and human and animal toxicity. Based on noncarcinogenic mammalian toxicity data, and following the methodologies of the U.S. Environmental Protection Agency, an ambient water quality criterion for the protection of human health of 103 micrograms/liter is proposed for ingestion of drinking water and aquatic foodstuffs. A criterion of 105 micrograms/liter is proposed for ingestion of drinking water alone.54 references.

  15. Solitary Spinal Epidural Metastasis from Gastric Cancer

    PubMed Central

    Sako, Taisei; Iida, Yasuaki; Yokoyama, Yuichirou; Tsuge, Shintaro; Hasegawa, Keiji; Wada, Akihito; Mikami, Tetsuo

    2016-01-01

    Solitary epidural space metastasis of a malignant tumor is rare. We encountered a 79-year-old male patient with solitary metastatic epidural tumor who developed paraplegia and dysuria. The patient had undergone total gastrectomy for gastric cancer followed by chemotherapy 8 months priorly. The whole body was examined for suspected metastatic spinal tumor, but no metastases of the spine or important organs were observed, and a solitary mass was present in the thoracic spinal epidural space. The mass was excised for diagnosis and treatment and was histopathologically diagnosed as metastasis from gastric cancer. No solitary metastatic epidural tumor from gastric cancer has been reported in English. Among the Japanese, 3 cases have been reported, in which the outcome was poor in all cases and no definite diagnosis could be made before surgery in any case. Our patient developed concomitant pneumonia after surgery and died shortly after the surgery. When a patient has a past medical history of malignant tumor, the possibility of a solitary metastatic tumor in the epidural space should be considered. PMID:27703825

  16. Disseminated Skeletal Muscle and Cardiac Metastasis from Squamous Cell Carcinoma of the Lung Detected with FDG and FLT PET/CT

    PubMed Central

    Jain, Tarun Kumar; Rayamajhi, Sampanna Jung; Basher, Rajender Kumar; Gupta, Dheeraj; Maturu, Venkata Nagarjuna; Mittal, Bhagwant Rai

    2016-01-01

    Lung cancer is one of the leading cancers all over the world. Positron emission tomography (PET) using 18F fluorodeoxyglucose (18F FDG) is useful for staging of the disease and decide the appropriate management. 3’-deoxy-3’-18 F-fluorothymidine (18F FLT) is a tracer being extensively evaluated currently and is said to represent tumor proliferation. Common sites of metastases from lung cancer include adrenal glands, bone, and brain. Muscle metastasis and cardiac metastasis are uncommon findings. We report a case of squamous cell carcinoma of the lung with metastases to multiple skeletal muscles and myocardium detected with both FDG and FLT PET/computed tomography (CT).

  17. Disseminated Skeletal Muscle and Cardiac Metastasis from Squamous Cell Carcinoma of the Lung Detected with FDG and FLT PET/CT.

    PubMed

    Jain, Tarun Kumar; Rayamajhi, Sampanna Jung; Basher, Rajender Kumar; Gupta, Dheeraj; Maturu, Venkata Nagarjuna; Mittal, Bhagwant Rai

    2016-09-01

    Lung cancer is one of the leading cancers all over the world. Positron emission tomography (PET) using 18F fluorodeoxyglucose (18F FDG) is useful for staging of the disease and decide the appropriate management. 3'-deoxy-3'-18 F-fluorothymidine (18F FLT) is a tracer being extensively evaluated currently and is said to represent tumor proliferation. Common sites of metastases from lung cancer include adrenal glands, bone, and brain. Muscle metastasis and cardiac metastasis are uncommon findings. We report a case of squamous cell carcinoma of the lung with metastases to multiple skeletal muscles and myocardium detected with both FDG and FLT PET/computed tomography (CT). PMID:27651747

  18. The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis

    PubMed Central

    Gumireddy, Kiranmai; Li, Anping; Kossenkov, Andrew V.; Sakurai, Masayuki; Yan, Jinchun; Li, Yan; Xu, Hua; Wang, Jian; Zhang, Paul J.; Zhang, Lin; Showe, Louise C.; Nishikura, Kazuko; Huang, Qihong

    2016-01-01

    Metastasis is a critical event affecting breast cancer patient survival. To identify molecules contributing to the metastatic process, we analysed The Cancer Genome Atlas (TCGA) breast cancer data and identified 41 genes whose expression is inversely correlated with survival. Here we show that GABAA receptor alpha3 (Gabra3), normally exclusively expressed in adult brain, is also expressed in breast cancer, with high expression of Gabra3 being inversely correlated with breast cancer survival. We demonstrate that Gabra3 activates the AKT pathway to promote breast cancer cell migration, invasion and metastasis. Importantly, we find an A-to-I RNA-edited form of Gabra3 only in non-invasive breast cancers and show that edited Gabra3 suppresses breast cancer cell invasion and metastasis. A-to-I-edited Gabra3 has reduced cell surface expression and suppresses the activation of AKT required for cell migration and invasion. Our study demonstrates a significant role for mRNA-edited Gabra3 in breast cancer metastasis. PMID:26869349

  19. Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-β pathways.

    PubMed

    Liu, Jiao; Chen, Sheng; Wang, Wei; Ning, Bei-Fang; Chen, Fei; Shen, Weifeng; Ding, Jin; Chen, Wansheng; Xie, Wei-Fen; Zhang, Xin

    2016-08-28

    Fibroblasts are rich in the surrounding microenvironment of hepatocellular carcinoma (HCC) because most HCCs occur in fibrotic or cirrhotic livers. However, the role of cancer-associated fibroblasts (CAFs) in HCC metastasis remains obscure. Here, we reported that CAFs promote the migration and invasion of HCC cells in vitro and facilitate the HCC metastasis to the bone, brain and lung in NOD/SCID mice. The RayBio human chemokine antibody array revealed that CAFs secret higher levels of CCL2, CCL5, CCL7 and CXCL16 than peri-tumor fibroblasts. CCL2 and CCL5 increase the migration but not the invasion of HCC cells, while CCL7 and CXCL16 promote both migration and invasion of HCC cells. Moreover, CCL2 and CCL5 stimulate the activation of the hedgehog (Hh) pathway, while CCL7 and CXCL16 enhance the activity of the transforming growth factor-β (TGF-β) pathway in HCC cells. The neutralizing antibodies of chemokines notably attenuate the effect of CAFs on HCC metastasis and compromised the activation of Hh and TGF-β pathways in HCC cells. In summary, CAF-secreted CCL2, CCL5, CCL7 and CXCL16 promote HCC metastasis through the coordinate activation of Hh and TGF-β pathways in HCC cells. PMID:27216982

  20. [Bilateral testicular metastasis of cancer of the prostate].

    PubMed

    el Moussaoui, A; Sarf, I; Dakir, M; Zamiati, S; Benjelloun, S

    1997-01-01

    Testicular metastasis of prostate cancer rarely occurs. Bilateral localization is exceptional. We report a new case of prostate adenocarcinoma with bilateral testicular metastasis. The diagnosis was made on clinical and ultrasonic arguments, and confirmed on the pathological specimen. Treatment consisted in a bilateral orchidectomy, associated with nonsteroid androgens.

  1. AACR centennial series: the biology of cancer metastasis: historical perspective.

    PubMed

    Talmadge, James E; Fidler, Isaiah J

    2010-07-15

    Metastasis resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His "seed and soil" hypothesis was substantiated a century later with experimental studies, and numerous reports have confirmed these seminal observations. An improved understanding of the metastatic process and the attributes of the cells selected by this process is critical for the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, so metastasis prevention may not be relevant. Treating systemic disease and identifying patients with early disease should be our goal. Revitalized research in the past three decades has focused on new discoveries in the biology of metastasis. Even though our understanding of molecular events that regulate metastasis has improved, the contributions and timing of molecular lesion(s) involved in metastasis pathogenesis remain unclear. Review of the history of pioneering observations and discussion of current controversies should increase understanding of the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and should lead to the design of successful therapy.

  2. Brain surgery

    MedlinePlus

    Craniotomy; Surgery - brain; Neurosurgery; Craniectomy; Stereotactic craniotomy; Stereotactic brain biopsy; Endoscopic craniotomy ... cut depends on where the problem in the brain is located. The surgeon creates a hole in ...

  3. Brain Malformations

    MedlinePlus

    Most brain malformations begin long before a baby is born. Something damages the developing nervous system or causes it ... medicines, infections, or radiation during pregnancy interferes with brain development. Parts of the brain may be missing, ...

  4. Bioavailability of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) to the Praire Vole (Microtus ochrogaster).

    SciTech Connect

    Fellows, Robert J.; Driver, Crystal J.; Cataldo, Dominic A.; Harvey, Scott D.

    2006-07-01

    Estimating risk to wildlife requires that measures of exposure be equivalent to that of the laboratory studies from which toxic responses were observed. Exposure measures are often based on modeled estimates of uptake through the food web. These modeled estimates use largely untested assumptions that can lead to inaccurate, uncertain, and unreliable estimates of exposure. Recently, concerns have been raised over the potential bioavailability and biotransfer of munitions or energetics materials such as hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). RDX is more recalcitrant in the soil, may remain as the parent compound for extended periods of time, and is rapidly taken up by the roots of higher plants and partitioned predominantly into the above ground, herbivore-accessible tissues. This study assessed plant incorporated [14C]-RDX and plant derived [14C]-RDX-metabolites ingestion by a representative hindgut herbivore, the prairie vole (Microtus ochrogaster). The animals were fed the labeled chow (≤10 g/ day max) for five or seven days followed by a six or four day chase period with the control chow prior to final weighing and sacrifice. Animal excreta including feces, urine, and respired CO2 were collected and measured. Greater than 95% of all label presented to the voles was recovered in the summed excreta. Seventy-four percent of the label in the total excreta was found in the fecal non-absorbed bulk. This means that greater than 20% of the presented 14C-RDX and plant-derived 14C-RDX-metabolites were absorbed by the animal’s digestive tracts over the time course of the experiment and modified prior to release. These materials were either metabolized to 14CO2 (8 to 10% of the total label) or removed as nitrogenous waste through the kidneys (10 to 14%). The feeding regimes were followed by a rapid, 2 to 3 day, clearing of label from the bulk feces with the cessation of exposure. Both 14C-urine and 14CO2 excretion continued after the feces cleared indicating

  5. 21 CFR 573.225 - 1,3-Butylene glycol.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.225 1,3-Butylene glycol. The food additive 1,3-butylene glycol (1,3-butanediol) may... 21 Food and Drugs 6 2011-04-01 2011-04-01 false 1,3-Butylene glycol. 573.225 Section 573.225...

  6. 21 CFR 573.225 - 1,3-Butylene glycol.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.225 1,3-Butylene glycol. The food additive 1,3-butylene glycol (1,3-butanediol) may... 21 Food and Drugs 6 2013-04-01 2013-04-01 false 1,3-Butylene glycol. 573.225 Section 573.225...

  7. 21 CFR 573.225 - 1,3-Butylene glycol.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.225 1,3-Butylene glycol. The food additive 1,3-butylene glycol (1,3-butanediol) may... 21 Food and Drugs 6 2010-04-01 2010-04-01 false 1,3-Butylene glycol. 573.225 Section 573.225...

  8. 21 CFR 573.225 - 1,3-Butylene glycol.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.225 1,3-Butylene glycol. The food additive 1,3-butylene glycol (1,3-butanediol) may... 21 Food and Drugs 6 2014-04-01 2014-04-01 false 1,3-Butylene glycol. 573.225 Section 573.225...

  9. 21 CFR 573.225 - 1,3-Butylene glycol.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.225 1,3-Butylene glycol. The food additive 1,3-butylene glycol (1,3-butanediol) may... 21 Food and Drugs 6 2012-04-01 2012-04-01 false 1,3-Butylene glycol. 573.225 Section 573.225...

  10. Lung cancer metastasis presenting as a solitary skull mass

    PubMed Central

    Turner, Ryan C.; Lucke-Wold, Brandon P.; Hwang, Roy; Underwood, Bill D.

    2016-01-01

    Lung cancer has been well documented to spread to bone and the axial skeleton after metastasis to adjacent organs. Bony metastasis is not, however, the typical presenting manifestation. The differential diagnosis for a tissue mass on the skull should warrant a workup for metastatic disease. Bony metastasis plays an important role in treatment and disease management. We report an exceptionally rare case of stage IV lung adenocarcinoma that presented with a solitary skull metastasis and a significant soft-tissue component. The lesion was treated by excision via craniotomy and subsequent medical management of the adenocarcinoma. This case illustrates a very rare presentation of lung adenocarcinoma and also represents what the authors believe to be the first report of a solitary skull mass originating from a lung primary. We also present a review of the literature surrounding bony metastasis to the skull and implications for patient care. PMID:27340229

  11. Lung cancer metastasis presenting as a solitary skull mass.

    PubMed

    Turner, Ryan C; Lucke-Wold, Brandon P; Hwang, Roy; Underwood, Bill D

    2016-01-01

    Lung cancer has been well documented to spread to bone and the axial skeleton after metastasis to adjacent organs. Bony metastasis is not, however, the typical presenting manifestation. The differential diagnosis for a tissue mass on the skull should warrant a workup for metastatic disease. Bony metastasis plays an important role in treatment and disease management. We report an exceptionally rare case of stage IV lung adenocarcinoma that presented with a solitary skull metastasis and a significant soft-tissue component. The lesion was treated by excision via craniotomy and subsequent medical management of the adenocarcinoma. This case illustrates a very rare presentation of lung adenocarcinoma and also represents what the authors believe to be the first report of a solitary skull mass originating from a lung primary. We also present a review of the literature surrounding bony metastasis to the skull and implications for patient care. PMID:27340229

  12. Endometrial metastasis of colorectal cancer with coincident endometrial adenocarcinoma

    PubMed Central

    Colling, Richard; Lopes, Tito; Das, Nagiindra; Mathew, Joe

    2010-01-01

    Metastasis to the uterine corpus is uncommon and secondary colorectal tumours of the endometrium are rare. We describe a uterine tumour with components of both primary endometrial and metastatic colorectal carcinomata. In this case, a 72-year-old obese woman presented with a 2-week history of postmenopausal bleeding per vaginum and weight loss. She had an abdominoperineal resection 3 years previously for a Dukes stage B rectal carcinoma. A transvaginal ultrasonography showed a thickened endometrium. Histology immunophenotyping showed a CK7+, CK20+, CA125− and CEA+ colorectal metastasis (a profile consistent with her previous cancer) associated with a primary CK7+, CK20−, CA125+ and CEA− endometroid endometrial adenocarcinoma. We conclude this represents endometrial metastasis of colorectal carcinoma with coincident primary endometrial adenocarcinoma. We speculate as to whether the endometrial carcinoma arose de novo or was induced by the colorectal metastasis, or whether the primary endometrial tumour provided a fertile site for the colorectal metastasis. PMID:22791861

  13. Choroid Melanoma Metastasis to Spine: A Rare Case Report

    PubMed Central

    Mandaliya, Hiren; Singh, Nandini; George, Sanila; George, Mathew

    2016-01-01

    Metastatic choroid melanoma is a highly malignant disease with a limited life expectancy. The liver is the most common site for metastasis of uveal melanoma followed by lung, bone, skin, and subcutaneous tissue. Metastasis from choroidal melanoma usually occurs within the first five years of treatment for primary tumours. Metastatic choroid melanoma to the spine/vertebrae is extremely rare. We report the first case of spinal metastasis from choroid melanoma in a 61-year-old man who had been treated for primary ocular melanoma three years earlier with radioactive plaque brachytherapy. Synchronously, at the time of metastasis, he was also diagnosed as having a new primary lung adenocarcinoma as well. The only other case reported on vertebral metastasis from malignant melanoma of choroid in literature in which primary choroid melanoma was enucleated. PMID:26989537

  14. Bone marrow metastasis presenting as bicytopenia originating from hepatocellular carcinoma

    PubMed Central

    Hong, Young Mi; Yoon, Ki Tae; Cho, Mong; Kang, Dae Hwan; Kim, Hyung Wook; Choi, Cheol Woong; Park, Su Bum; Heo, Jeong; Woo, Hyun Young; Lim, Won; Bakhtiar UI Islam, SM

    2016-01-01

    The bone is a common site for metastasis in hepatocellular carcinoma (HCC). However, bone marrow metastasis from HCC is rarely reported, and its frequency is unclear. Here we report a rare case of bone marrow metastasis that presented as bicytopenia originating from HCC without bone metastasis. A 58-year-old man was admitted for investigation of a liver mass with extensive lymph node enlargement that was detected when examining his general weakness and weight loss. Laboratory findings revealed anemia, thrombocytopenia, mild elevated liver enzymes, normal prothrombin time percentage and high levels of tumor markers (α-fetoprotein and des-γ-carboxyprothrombin). Abdominal computed tomography showed multiple enhanced masses in the liver and multiple enlarged lymph nodes in the abdomen. A bone marrow biopsy revealed only a few normal hematopoietic cells and abundant tumor cells. Despite its rarity, bone marrow metastasis should always be suspected in HCC patients even if accompanied by cirrhosis. PMID:27184470

  15. 14 CFR 1.3 - Rules of construction.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 1 2014-01-01 2014-01-01 false Rules of construction. 1.3 Section 1.3 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION DEFINITIONS DEFINITIONS AND ABBREVIATIONS § 1.3 Rules of construction. (a) In Subchapters A through K of this chapter,...

  16. 10 CFR 960.3-1-3 - Regionality.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Regionality. 960.3-1-3 Section 960.3-1-3 Energy DEPARTMENT OF ENERGY GENERAL GUIDELINES FOR THE PRELIMINARY SCREENING OF POTENTIAL SITES FOR A NUCLEAR WASTE REPOSITORY Implementation Guidelines § 960.3-1-3 Regionality. In making site recommendations for...

  17. Production of α1,3-Galactosyltransferase–Deficient Pigs

    PubMed Central

    Phelps, Carol J.; Koike, Chihiro; Vaught, Todd D.; Boone, Jeremy; Wells, Kevin D.; Chen, Shu-Hung; Ball, Suyapa; Specht, Susan M.; Polejaeva, Irina A.; Monahan, Jeff A.; Jobst, Pete M.; Sharma, Sugandha B.; Lamborn, Ashley E.; Garst, Amy S.; Moore, Marilyn; Demetris, Anthony J.; Rudert, William A.; Bottino, Rita; Bertera, Suzanne; Trucco, Massimo; Starzl, Thomas E.; Dai, Yifan; Ayares, David L.

    2011-01-01

    The enzyme α1,3-galactosyltransferase (α1,3GT or GCTA1) synthesizes α1,3-galactose (α1,3Gal) epitopes (Galα1,3Galβ1,4GlcNAc-R), which are the major xenoantigens causing hyperacute rejection in pig-to-human xenotransplantation. Complete removal of α1,3Gal from pig organs is the critical step toward the success of xenotransplantation. We reported earlier the targeted disruption of one allele of the α1,3GT gene in cloned pigs. A selection procedure based on a bacterial toxin was used to select for cells in which the second allele of the gene was knocked out. Sequencing analysis demonstrated that knockout of the second allele of the α1,3GT gene was caused by a T-to-G single point mutation at the second base of exon 9, which resulted in inactivation of the α1,3GT protein. Four healthy α1,3GT double-knockout female piglets were produced by three consecutive rounds of cloning. The piglets carrying a point mutation in the α1,3GT gene hold significant value, as they would allow production of α1,3Gal-deficient pigs free of antibiotic-resistance genes and thus have the potential to make a safer product for human use. PMID:12493821

  18. 7 CFR 1.3 - Agency implementing regulations.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Agency implementing regulations. 1.3 Section 1.3 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Official Records § 1.3 Agency implementing regulations. Each agency of the Department shall promulgate regulations setting forth...

  19. 49 CFR 1.3 - Exercise of authority.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 1 2014-10-01 2014-10-01 false Exercise of authority. 1.3 Section 1.3... § 1.3 Exercise of authority. (a) In exercising powers and performing duties delegated by this part or..., the Assistant Secretaries, the Inspector General, and the Administrators exercise the powers...

  20. 49 CFR 1.3 - Exercise of authority.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 1 2012-10-01 2012-10-01 false Exercise of authority. 1.3 Section 1.3... § 1.3 Exercise of authority. (a) In exercising powers and performing duties delegated by this part or..., the Assistant Secretaries, the Inspector General, and the Administrators exercise the powers...

  1. 49 CFR 1.3 - Exercise of authority.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 1 2013-10-01 2013-10-01 false Exercise of authority. 1.3 Section 1.3... § 1.3 Exercise of authority. (a) In exercising powers and performing duties delegated by this part or..., the Assistant Secretaries, the Inspector General, and the Administrators exercise the powers...

  2. 49 CFR 1.3 - Organization of the Department.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false Organization of the Department. 1.3 Section 1.3 Transportation Office of the Secretary of Transportation ORGANIZATION AND DELEGATION OF POWERS AND DUTIES General § 1.3 Organization of the Department. (a) The Secretary of Transportation is the head of the Department. (b) The Department is...

  3. 7 CFR 1.3 - Agency implementing regulations.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 1 2013-01-01 2013-01-01 false Agency implementing regulations. 1.3 Section 1.3 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Official Records § 1.3 Agency implementing regulations. Each agency of the Department shall promulgate regulations setting forth...

  4. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier.

    PubMed

    Tominaga, Naoomi; Kosaka, Nobuyoshi; Ono, Makiko; Katsuda, Takeshi; Yoshioka, Yusuke; Tamura, Kenji; Lötvall, Jan; Nakagama, Hitoshi; Ochiya, Takahiro

    2015-04-01

    Brain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through blood-brain barrier (BBB). However, the molecular mechanism behind the passage through this natural barrier remains unclear. Here we show that cancer-derived extracellular vesicles (EVs), mediators of cell-cell communication via delivery of proteins and microRNAs (miRNAs), trigger the breakdown of BBB. Importantly, miR-181c promotes the destruction of BBB through the abnormal localization of actin via the downregulation of its target gene, PDPK1. PDPK1 degradation by miR-181c leads to the downregulation of phosphorylated cofilin and the resultant activated cofilin-induced modulation of actin dynamics. Furthermore, we demonstrate that systemic injection of brain metastatic cancer cell-derived EVs promoted brain metastasis of breast cancer cell lines and are preferentially incorporated into the brain in vivo. Taken together, these results indicate a novel mechanism of brain metastasis mediated by EVs that triggers the destruction of BBB.

  5. Novel 1,3-dioxanes from apple juice and cider.

    PubMed

    Kavvadias, D; Beuerle, T; Wein, M; Boss, B; König, T; Schwab, W

    1999-12-01

    Extracts obtained by XAD solid-phase extraction of apple juice and cider were separated by liquid chromatography on silica gel. Several new 1,3-dioxanes including the known 2-methyl-4-pentyl-1,3-dioxane and 2-methyl-4-[2'(Z)-pentenyl]-1,3-dioxane, were identified in the nonpolar fractions by GC/MS analysis and confirmed by chemical synthesis. The enantioselective synthesis of the stereoisomers of the 1,3-dioxanes was performed using (R)- and (R,S)-octane-1,3-diol and (R)- and (R,S)-5(Z)-octene-1,3-diol as starting material. Comparison with the isolated products indicated that the natural products consisted of a mixture of (2S,4R) and (2R,4R) stereoisomers in the ratio of approximately 10:1, except for 1,3-dioxanes generated from acetone and 2-butanone. It is assumed that the 1, 3-dioxanes are chemically formed in the apples and cider from the natural apple ingredients (R)-octane-1,3-diol, (R)-5(Z)-octene-1, 3-diol, (3R,7R)- and (3R,7S)-octane-1,3,7-triol, and the appropriate aldehydes and ketones, which are produced either by the apples or by yeast during fermentation of the apple juice.

  6. [Thyroid metastasis due to right colonic carcinoma].

    PubMed

    Rauber, E; Pancrazio, F; Spivach, A; Stanta, G

    1998-12-01

    Clinical evident metastases to the thyroid gland are rarely found antemortem. A case of a 62 year-old man with a history of right colonic carcinoma, who presented a mass in the right lobe of his thyroid gland one year after the removal of a metachronous metastasis in his right lung, is presented. The tumour of the thyroid was found to be metastatic adenocarcinoma from his previous colonic cancer. The clinical finding of metastases to the thyroid gland is rare, particularly from a colorectal primary neoplasm. However, the possibility of a tumour of the thyroid gland representing a secondary malignancy is to be considered in any patient with a prior history of cancer.

  7. Bone metastasis: mechanisms and therapeutic opportunities

    PubMed Central

    Suva, Larry J.; Washam, Charity; Nicholas, Richard W.; Griffin, Robert J.

    2011-01-01

    The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy. PMID:21200394

  8. Exercise, natural immunity, and tumor metastasis.

    PubMed

    Hoffman-Goetz, L

    1994-02-01

    Exercise has been shown to reduce the growth of primary tumors and to enhance certain aspects of host natural immunity. The question of whether these are independent phenomena or are casually related has not been systematically evaluated. This paper presents information concerning the methodological difficulties in studying proposed relationships between exercise and cancer, focusing specifically on tumor metastasis, the process by which malignant cells disseminate to distant organs and establish new colonies. This paper also focuses on how natural immune processes and tumor cells exert bidirectional influences on each other. It is suggested that the direction of the impact of exercise on the control of metastatic spread of neoplastic cells will reflect, in part, the sensitivity of the specific tumor to cytolysis by natural immune mechanisms, the route of dissemination, the timing of exercise relative to tumor exposure, and whether exercise acts as a distress or eustress state.

  9. Pinworm infection masquerading as colorectal liver metastasis

    PubMed Central

    Roberts, KJ; Hubscher, S; Mangat, K; Sutcliffe, R; Marudanayagam, R

    2012-01-01

    Enterobius vermicularis is responsible for a variety of diseases but rarely affects the liver. Accurate characterisation of suspected liver metastases is essential to avoid unnecessary surgery. In the presented case, following a diagnosis of rectal cancer, a solitary liver nodule was diagnosed as a liver metastasis due to typical radiological features and subsequently resected. At pathological assessment, however, a necrotic nodule containing E vermicularis was identified. Solitary necrotic nodules of the liver are usually benign but misdiagnosed frequently as malignant due to radiological features. It is standard practice to diagnose colorectal liver metastases solely on radiological evidence. Without obtaining tissue prior to liver resection, misdiagnosis of solitary necrotic nodules of the liver will continue to occur. PMID:22943320

  10. Advances in cancer pain from bone metastasis

    PubMed Central

    Zhu, Xiao-Cui; Zhang, Jia-Li; Ge, Chen-Tao; Yu, Yuan-Yang; Wang, Pan; Yuan, Ti-Fei; Fu, Cai-Yun

    2015-01-01

    With the technological advances in cancer diagnosis and treatment, the survival rates for patients with cancer are prolonged. The issue of figuring out how to improve the life quality of patients with cancer has become increasingly prominent. Pain, especially bone pain, is the most common symptom in malignancy patients, which seriously affects the life quality of patients with cancer. The research of cancer pain has a breakthrough due to the development of the animal models of cancer pain in recent years, such as the animal models of mouse femur, humerus, calcaneus, and rat tibia. The establishment of several kinds of animal models related to cancer pain provides a new platform in vivo to investigate the molecular mechanisms of cancer pain. In this review, we focus on the advances of cancer pain from bone metastasis, the mechanisms involved in cancer pain, and the drug treatment of cancer pain in the animal models. PMID:26316696

  11. Adrenal Metastasis from Uterine Papillary Serous Carcinoma

    PubMed Central

    Lubana, Sandeep Singh; Singh, Navdeep; Tuli, Sandeep S.; Seligman, Barbara

    2016-01-01

    Patient: Female, 60 Final Diagnosis: UPSC with adrenal metastasis Symptoms: Post menopausal bleeding Medication: — Clinical Procedure: Adrenalectomy Specialty: Oncology Objective: Rare disease Background: Uterine papillary serous carcinoma (UPSC) is a highly malignant form of endometrial cancer with a high propensity for metastases and recurrences even when there is minimal or no myometrial invasion. It usually metastasizes to the pelvis, retroperitoneal lymph nodes, upper abdomen, and peritoneum. However, adrenal metastases from UPSC is extremely rare. Here, we present a case of UPSC with adrenal metastasis that occurred 6 years after the initial diagnosis. Case Report: A 60-year-old woman previously diagnosed with uterine papillary serous carcinoma at an outside facility presented in September of 2006 with postmenopausal bleeding. She underwent comprehensive surgical staging with FIGO (International Federation of Gynecology and Obstetrics) stage 2. Post-operatively, the patient was treated with radiation and chemotherapy. The treatment was completed in April of 2007. The patient had no evidence of disease until July 2009 when she was found to have a mass highly suspicious for malignancy. Subsequently, she underwent right upper lobectomy. The morphology of the carcinoma was consistent with UPSC. She refused chemotherapy due to a previous history of chemotherapy-induced neuropathy. The patient was followed up with regular computed tomography (CT) scans. In October 2012 a new right adrenal nodule was seen on CT, which showed intense metabolic uptake on positron emission tomography (PET)/CT scan. The patient underwent right adrenalectomy. Pathology of the surgical specimen was consistent with UPSC. Conclusions: UPSC is an aggressive variant of endometrial cancer associated with high recurrence rate and poor prognoses. Long-term follow-up is needed because there is a possibility of late metastases, as in this case. PMID:27117594

  12. Anaplastic extramedullary cervical ependymoma with leptomeningeal metastasis.

    PubMed

    Pomeraniec, I J; Dallapiazza, R F; Sumner, H M; Lopes, M B; Shaffrey, C I; Smith, J S

    2015-12-01

    We present a rare extramedullary ependymoma with diffuse spinal metastatic disease, and review the previous reports of extramedullary spinal ependymomas. Ependymomas are the most common intramedullary spinal cord tumor in adults. These tumors rarely present as extramedullary masses. We treated a 23-year-old man with a history of progressive neck, shoulder and arm pain, with sensory and motor symptoms in the C7 dermatome. MRI of the cervical spine demonstrated a ventral contrast-enhancing lesion with evidence of enhancement along the dura and spinal cord of the upper cervical spine, thoracic spine, and cauda equina. He underwent a tumor debulking procedure without complications. Following surgery, he received craniospinal radiation to treat the remaining tumor and diffuse leptomeningeal disease. The final pathology of the tumor revealed that is was a World Health Organization Grade III anaplastic ependymoma. At the 1 year follow-up, the patient had stable imaging and had returned to his preoperative functional status. Of the 19 reported patients with primary intradural, extramedullary spinal ependymomas, two had extradural components and seven had anaplastic grades. Only one tumor with an anaplastic grade resulted in metastatic disease, but without spinal recurrence. To our knowledge, this is the first report of an intradural, extramedullary spinal ependymoma with an anaplastic grade, presenting with concomitant diffuse, nodular leptomeningeal metastasis involving the upper cervical spine, thoracic spine, conus medullaris, and cauda equina. Similar to the treatment of intramedullary ependymomas with metastasis, this patient underwent an aggressive debulking procedure followed by radiation therapy to the entire neuroaxis. PMID:26601808

  13. Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis.

    PubMed

    Wu, Zhen-Zhen; Chen, Li-Shan; Zhou, Rui; Bin, Jian-Ping; Liao, Yu-Lin; Liao, Wang-Jun

    2016-08-01

    Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer (GC), MACC1 has been shown to be involved in oncogenesis and tumor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelial-to-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry (VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment. PMID:27547006

  14. Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis

    PubMed Central

    Wu, Zhen-Zhen; Chen, Li-Shan; Zhou, Rui; Bin, Jian-Ping; Liao, Yu-Lin; Liao, Wang-Jun

    2016-01-01

    Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer (GC), MACC1 has been shown to be involved in oncogenesis and tumor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelial-to-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry (VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment. PMID:27547006

  15. A case of long-term survival after multimodal local treatments of intramedullary spinal cord metastasis of squamous cell lung cancer.

    PubMed

    Minomo, Shojiro; Tokoro, Akihiro; Utsumi, Tomoki; Ishihara, Masahiro; Akira, Masanori; Atagi, Shinji

    2016-08-01

    Intramedullary spinal cord metastasis of non-small cell lung cancer is rare, and it has a short prognosis. We report a 53-year-old man diagnosed with cT4N0M0, stage IIIA squamous cell lung cancer. Ten months after left pneumonectomy (pT4N0M0), an intramedullary spinal cord tumor developed at the axis level. The intramedullary spinal cord tumor was resected, and he was diagnosed with metastatic squamous cell lung cancer. Radiotherapies and another tumor resection were conducted, as he had a good performance status and the discrete lesion was associated with the risk of brain stem compression. Multimodal local treatments for intramedullary spinal cord metastasis caused the tumor to shrink, and he lived for 25 months after the spinal metastasis occurred. PMID:27621899

  16. A case of long-term survival after multimodal local treatments of intramedullary spinal cord metastasis of squamous cell lung cancer

    PubMed Central

    Tokoro, Akihiro; Utsumi, Tomoki; Ishihara, Masahiro; Akira, Masanori; Atagi, Shinji

    2016-01-01

    Intramedullary spinal cord metastasis of non-small cell lung cancer is rare, and it has a short prognosis. We report a 53-year-old man diagnosed with cT4N0M0, stage IIIA squamous cell lung cancer. Ten months after left pneumonectomy (pT4N0M0), an intramedullary spinal cord tumor developed at the axis level. The intramedullary spinal cord tumor was resected, and he was diagnosed with metastatic squamous cell lung cancer. Radiotherapies and another tumor resection were conducted, as he had a good performance status and the discrete lesion was associated with the risk of brain stem compression. Multimodal local treatments for intramedullary spinal cord metastasis caused the tumor to shrink, and he lived for 25 months after the spinal metastasis occurred. PMID:27621899

  17. Serpine2, a potential novel target for combating melanoma metastasis

    PubMed Central

    Wu, Qi Wei

    2016-01-01

    Early stages of melanoma can be treated by surgical resection of tumor, but there is still no effective treatment once it is progressed to metastatic phases. Although growing family of both metastasis promoting and metastasis suppressor genes have been reported, the molecular mechanisms governing melanoma metastatic cascade are still not completely understood. Therefore, defining the molecules that govern melanoma metastasis may aid the development of more effective therapeutic strategies for combating cancer. In the present study, we found that Serpin Peptidase Inhibitor 2, Serpine2 was involved in the metastasis of melanoma cells. The requirement of Serpine2 in the migration of melanoma cells was confirmed by gene silencing and over-expression in vitro. Moreover, down-regulation of Serpine2 expression strikingly inhibited melanoma cellular metastasis in vivo. Finally, we found that Serpine2 promotes melanoma metastasis through the glycogen synthesis kinase 3β, GSK-3β signaling pathway. To conclude, our findings suggested a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma. PMID:27347308

  18. A proposed classification system for liver metastasis from colorectal carcinoma.

    PubMed

    Petrelli, N J; Bonnheim, D C; Herrera, L O; Mittelman, A

    1984-04-01

    A proposed classification system for liver metastasis from colorectal carcinoma is presented. This proposed system utilizes the prognostic factors of the extent of hepatic involvement by metastasis at the time of laparotomy, performance status, preoperative serum alkaline phosphatase level, and the presence or absence of extrahepatic intraabdominal disease at the time of laparotomy. Because of the several different modes of treatment for liver metastasis from colorectal carcinoma, it is necessary that a liver classification system be adopted so that different treatment groups will be comparable. The proposed system utilizes the extent of hepatic involvement by metastasis at laparotomy with a division into three subsets of patients described by a Roman numeral. Roman numeral I represents less than or equal to 25 per cent involvement of the liver by metastasis; Roman numeral II represents greater than 25 per cent but less than or equal to 50 per cent involvement by liver metastasis, and Roman numeral III represents greater than 50 per cent involvement by liver metastasis. An Arabic subscript number is used to describe the patients' performance status. Alkaline phosphatase levels are described by a subscript letter with a representing less than two times normal alkaline phosphatase, b representing greater than two times, but less than four times normal levels, and c representing greater than four times normal levels. At the time of laparotomy extrahepatic intra-abdominal disease is represented by the superscript letter E. PMID:6714032

  19. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

    PubMed

    Wang, Hui; Liu, Xiufei; Long, Min; Huang, Yi; Zhang, Linlin; Zhang, Rui; Zheng, Yi; Liao, Xiaoyu; Wang, Yuren; Liao, Qian; Li, Wenjie; Tang, Zili; Tong, Qiang; Wang, Xiaocui; Fang, Fang; Rojo de la Vega, Montserrat; Ouyang, Qin; Zhang, Donna D; Yu, Shicang; Zheng, Hongting

    2016-04-13

    Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis. PMID:27075625

  20. A cell–ECM screening method to predict breast cancer metastasis

    PubMed Central

    Barney, L.E.; Dandley, E.C.; Jansen, L.E.; Reich, N.G.; Mercurio, A.M.

    2015-01-01

    Breast cancer preferentially spreads to the bone, brain, liver, and lung. The clinical patterns of this tissue-specific spread (tropism) cannot be explained by blood flow alone, yet our understanding of what mediates tropism to these physically and chemically diverse tissues is limited. While the microenvironment has been recognized as a critical factor in governing metastatic colonization, the role of the extracellular matrix (ECM) in mediating tropism has not been thoroughly explored. We created a simple biomaterial platform with systematic control over the ECM protein density and composition to determine if integrin binding governs how metastatic cells differentiate between secondary tissue sites. Instead of examining individual behaviors, we compiled large patterns of phenotypes associated with adhesion to and migration on these controlled ECMs. In combining this novel analysis with a simple biomaterial platform, we created an in vitro fingerprint that is predictive of in vivo metastasis. This rapid biomaterial screen also provided information on how β1, α2, and α6 integrins might mediate metastasis in patients, providing insights beyond a purely genetic analysis. We propose that this approach of screening many cell–ECM interactions, across many different heterogeneous cell lines, is predictive of in vivo behavior, and is much simpler, faster, and more economical than complex 3D environments or mouse models. We also propose that when specifically applied toward the question of tissue tropism in breast cancer, it can be used to provide insight into certain integrin subunits as therapeutic targets. Insight, innovation, integration We developed a high-throughput method to rapidly screen cell adhesion, motility, and growth factor responses on biomaterial surfaces. This approach is analogous to systems biology, relying on cell phenotypes in lieu of genetics. We used this technique to reveal patterns of phenotypes associated with breast cancer metastasis to

  1. Cigarette Smoking and Risk of Lung Metastasis from Esophageal Cancer

    PubMed Central

    Abrams, Julian A.; Lee, Paul C.; Port, Jeffrey L.; Altorki, Nasser K.; Neugut, Alfred I.

    2008-01-01

    Background While extensive research has explored the impact of environmental factors on the etiology of specific cancers, the influence of exposures such as smoking on risk of site-specific metastasis is unknown. We investigated the association of cigarette smoking with lung metastasis in esophageal cancer. Methods We performed a case-control study of esophageal cancer patients from two centers, comparing cases with lung metastases to controls without lung metastases. Information was gathered from medical records on smoking history, imaging results, site(s) of metastasis, and other patient and tumor characteristics. We used logistic regression to assess association. Results We identified 354 esophageal cancer cases; smoking status was known in 289 (82%). Among patients with lung metastases, 73.6% (39/53) were ever smokers, versus 47.8% (144/301) of patients without lung metastases (p=0.001) (summary OR 2.52, 95%CI 1.17-5.45; stratified by histology). Smoking was associated with a nonsignificant increased adjusted odds of lung metastasis (OR 1.89, 95%CI 0.80-4.46). Upper esophageal subsite (OR 4.71, 95%CI 1.20-18.5) but not histology (squamous OR 0.65,95%CI 0.27-1.60) was associated with lung metastasis. Compared to the combined never/unknown smoking status group, smoking was associated with a significantly increased odds of lung metastasis (OR 2.35, 95%CI 1.11-4.97). There was no association between liver metastasis and smoking (OR 0.88, 95%CI 0.42-1.83) Conclusions Smoking is associated with increased odds of lung metastasis from esophageal cancer, and this relationship appears to be site-specific. Future studies are needed to determine whether smoking affects the tumor cell or the site of metastasis, and whether this changes the survival outcome. PMID:18843013

  2. Capacity improvement by deficit of transition metals in inverse spinel LiNi1/3Co1/3Mn1/3VO4 cathodes

    NASA Astrophysics Data System (ADS)

    Kitajou, Ayuko; Yoshida, Jun; Nakanishi, Shinji; Matsuda, Yasuaki; Kanno, Ryoji; Okajima, Toshihiro; Okada, Shigeto

    2016-01-01

    Although inverse spinel materials have attracted attention because of their unusually high voltage characteristics, their rechargeable capacities are generally less than 50 mAh g-1, as a result of the coexistence of Li and transition metal ions at 16d octahedral sites. This work attempted to improve cathode functioning by optimizing the quantities of Li and transition metal ions residing at the 16d sites of LiNi1/3Co1/3Mn1/3VO4. The rechargeable capacity of the LiNi0.28Co0.28Mn0.26V0.80O4 synthesized in the present study was found to be above 120 mAh g-1, representing the largest capacity reported to date for an inverse spinel material. The results of in-situ XANES analysis demonstrated that the charge-discharge reactions of LiNi1/3Co1/3Mn1/3VO4 corresponds to the Mn2+/Mn4+ and Co2+/Co3+ redox couples, mainly.

  3. Synthesis of high performance LiNi1/3Mn1/3Co1/3O2 from lithium ion battery recovery stream

    NASA Astrophysics Data System (ADS)

    Sa, Qina; Gratz, Eric; He, Meinan; Lu, Wenquan; Apelian, Diran; Wang, Yan

    2015-05-01

    Spent lithium ion batteries that contain valuable metal elements such as Co, Ni, Mn, Cu are being landfilled in many countries and raising resources depletion and human toxicity potentials. Low cost and high efficiency recovery process is highly desired. In this work we confirmed that high performance Ni1/3Mn1/3Co1/3(OH)2 precursor and LiNi1/3Mn1/3Co1/3O2 cathode material can be synthesized from leaching solution of a lithium ion battery recovery stream. The precursor was synthesized from a typical co-precipitation process with carefully controlling the reaction parameters. Electrochemical properties including rate capacity and cycle life were tested to evaluate the final product. The results show that the cathode material synthesized from spent lithium ion battery recovery stream is performing a discharge capacity of 158 mAh/g at first cycle of 0.1C and 139 mAh/g at first cycle of 0.5C cycle life test. After 100 and 200 cycles, still over 80% and 65% of capacity is remained, respectively. The materials are also evaluated independently at Argonne National Laboratory.

  4. Elevation of serum acid phosphatase in cancers with bone metastasis

    SciTech Connect

    Tavassoli, M.; Rizo, M.; Yam, L.T.

    1980-05-01

    In patients with nonprostatic cancer, serum acid phosphatase activity is usually elevated when bone metastasis is present but not when bone metastasis is absent. The fraction responsible for serum enzyme elevation is a normal component of serum; it appears in gel electrophoresis as band 5; and is tartrate-resistant. It is suggested that the origin of acid phosphatase elevation is bone osteoclasts rather than cancer tissue, as is the case with prostatic carcinoma. Determination of serum acid phosphatase activity may be useful in the detection of bone metastasis.

  5. The cofilin pathway in breast cancer invasion and metastasis

    PubMed Central

    Wang, Weigang; Eddy, Robert; Condeelis, John

    2014-01-01

    Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis. PMID:17522712

  6. Inter- and intra-tumor profiling of multi-regional colon cancer and metastasis.

    PubMed

    Kogita, Akihiro; Yoshioka, Yasumasa; Sakai, Kazuko; Togashi, Yosuke; Sogabe, Shunsuke; Nakai, Takuya; Okuno, Kiyotaka; Nishio, Kazuto

    2015-02-27

    Intra- and inter-tumor heterogeneity may hinder personalized molecular-target treatment that depends on the somatic mutation profiles. We performed mutation profiling of formalin-fixed paraffin embedded tumors of multi-regional colon cancer and characterized the consequences of intra- and inter-tumor heterogeneity and metastasis using targeted re-sequencing. We performed targeted re-sequencing on multiple spatially separated samples obtained from multi-regional primary colon carcinoma and associated metastatic sites in two patients using next-generation sequencing. In Patient 1 with four primary tumors (P1-1, P1-2, P1-3, and P1-4) and one liver metastasis (H1), mutually exclusive pattern of mutations was observed in four primary tumors. Mutations in primary tumors were identified in three regions; KARS (G13D) and APC (R876*) in P1-2, TP53 (A161S) in P1-3, and KRAS (G12D), PIK3CA (Q546R), and ERBB4 (T272A) in P1-4. Similar combinatorial mutations were observed between P1-4 and H1. The ERBB4 (T272A) mutation observed in P1-4, however, disappeared in H1. In Patient 2 with two primary tumors (P2-1 and P2-2) and one liver metastasis (H2), mutually exclusive pattern of mutations were observed in two primary tumors. We identified mutations; KRAS (G12V), SMAD4 (N129K, R445*, and G508D), TP53 (R175H), and FGFR3 (R805W) in P2-1, and NRAS (Q61K) and FBXW7 (R425C) in P2-2. Similar combinatorial mutations were observed between P2-1 and H2. The SMAD4 (N129K and G508D) mutations observed in P2-1, however, were nor detected in H2. These results suggested that different clones existed in primary tumors and metastatic tumor in Patient 1 and 2 likely originated from P1-4 and P2-1, respectively. In conclusion, we detected the muti-clonalities between intra- and inter-tumors based on mutational profiling in multi-regional colon cancer using next-generation sequencing. Primary region from which metastasis originated could be speculated by mutation profile. Characterization of inter- and

  7. Kv1.3 channels regulate synaptic transmission in the nucleus of solitary tract.

    PubMed

    Ramirez-Navarro, Angelina; Glazebrook, Patricia A; Kane-Sutton, Michelle; Padro, Caroline; Kline, David D; Kunze, Diana L

    2011-06-01

    The voltage-gated K(+) channel Kv1.3 has been reported to regulate transmitter release in select central and peripheral neurons. In this study, we evaluated its role at the synapse between visceral sensory afferents and secondary neurons in the nucleus of the solitary tract (NTS). We identified mRNA and protein for Kv1.3 in rat nodose ganglia using RT-PCR and Western blot analysis. In immunohistochemical experiments, anti-Kv1.3 immunoreactivity was very strong in internal organelles in the soma of nodose neurons with a weaker distribution near the plasma membrane. Anti-Kv1.3 was also identified in the axonal branches that project centrally, including their presynaptic terminals in the medial and commissural NTS. In current-clamp experiments, margatoxin (MgTx), a high-affinity blocker of Kv1.3, produced an increase in action potential duration in C-type but not A- or Ah-type neurons. To evaluate the role of Kv1.3 at the presynaptic terminal, we examined the effect of MgTx on tract evoked monosynaptic excitatory postsynaptic currents (EPSCs) in brain slices of the NTS. MgTx increased the amplitude of evoked EPSCs in a subset of neurons, with the major increase occurring during the first stimuli in a 20-Hz train. These data, together with the results from somal recordings, support the hypothesis that Kv1.3 regulates the duration of the action potential in the presynaptic terminal of C fibers, limiting transmitter release to the postsynaptic cell. PMID:21430270

  8. Parotid gland metastasis in Merkel cell carcinoma of the head and neck: A series of 14 cases.

    PubMed

    Day, Kristine E; Carroll, William R; Rosenthal, Eben L

    2016-09-01

    Merkel cell carcinoma (MCC) is a rare cutaneous cancer of neuroendocrine cell origin that occurs frequently on the head and neck. With a high incidence of local recurrence and regional and distant metastasis, it carries a poor prognosis. We performed a retrospective study to determine the prognostic implications of parotid gland metastasis in MCC of the head and neck. Our study population was made up of 14 patients-13 men and 1 woman, aged 62 to 87 years (mean: 75.9)-who underwent a parotidectomy for the diagnosis of MCC over a period of 10 years and 9 months. Ten patients had a primary skin lesion of the head and neck and 4 presented with a parotid mass and an unknown primary. In all, 13 of the 14 patients were found to have parotid involvement-either a direct extension of MCC into the gland or a positive intraparotid lymph node; some patients had both. All patients underwent tumor excision, and 10 underwent neck dissection. Eleven patients received adjuvant radiotherapy; none received adjuvant chemotherapy. Of the 10 patients who underwent a neck dissection, 6 were found to have a cervical lymph node metastasis on pathologic examination. Follow-up ranged from 1.3 to 39.2 months (mean: 12.4). Three patients were lost to follow-up shortly after surgery, although some information was available on 2 of them. At the final follow-up, mortality data were available on 12 patients; of these, 11 had died. The lone survivor was the patient without a parotid metastasis. Among those known to have died, survival ranged from 1.6 to 49.2 months (mean: 16.0). We conclude that parotid metastasis in patients with MCC of the head and neck is associated with a dismal survival rate that is even worse than the poor survival associated with cervical node involvement. PMID:27657318

  9. Preoperative navigated transcranial magnetic stimulation in patients with motor eloquent lesions with emphasis on metastasis.

    PubMed

    Hendrix, Philipp; Senger, Sebastian; Griessenauer, Christoph J; Simgen, Andreas; Schwerdtfeger, Karsten; Oertel, Joachim

    2016-10-01

    Navigated transcranial magnetic stimulation (nTMS) is a frequently used, non-invasive method to map the motor cortex. It is of great value in the preoperative workup of patients that suffer from motor eloquent brain lesions. Here, we present a single-center experience using preoperative nTMS in cortical motor eloquent lesions with emphasis on metastasis. All patients that underwent preoperative nTMS between June 2013 and January 2016 were evaluated. A total of 61 patients underwent nTMS before undergoing surgery for a motor eloquent brain lesion. Patients suffered from cerebral metastasis (23), glioblastoma (16), high grade glioma WHO III (4), low grade glioma WHO II (4), lymphoma (2), meningioma (8), cavernous hemangioma (3), or arteriovenous malformation (1). Thirty patients (49.2%) presented with a preoperative motor deficit. One week after surgery, paresis had resolved or improved in 56.7% of the patients. Out of the patients with postoperative paresis, 89.5% experienced an improvement of motor status at follow-up. All metastatic lesions were completely resected compared to 78.9% of non-metastatic lesions (P = 0.02). Only 4.3% of patients with a metastatic lesion, but 26.3% of patients with a non-metastatic lesion experienced deterioration of motor function after surgery (P = 0.04). Preoperative nTMS is suitable for mapping of a variety of motor eloquent brain lesions resulting in favorable neurological outcome. Particularly in metastatic motor eloquent lesion, motor function appears to be preserved after surgery. Clin. Anat. 29:925-931, 2016. © 2016 Wiley Periodicals, Inc.

  10. Preoperative navigated transcranial magnetic stimulation in patients with motor eloquent lesions with emphasis on metastasis.

    PubMed

    Hendrix, Philipp; Senger, Sebastian; Griessenauer, Christoph J; Simgen, Andreas; Schwerdtfeger, Karsten; Oertel, Joachim

    2016-10-01

    Navigated transcranial magnetic stimulation (nTMS) is a frequently used, non-invasive method to map the motor cortex. It is of great value in the preoperative workup of patients that suffer from motor eloquent brain lesions. Here, we present a single-center experience using preoperative nTMS in cortical motor eloquent lesions with emphasis on metastasis. All patients that underwent preoperative nTMS between June 2013 and January 2016 were evaluated. A total of 61 patients underwent nTMS before undergoing surgery for a motor eloquent brain lesion. Patients suffered from cerebral metastasis (23), glioblastoma (16), high grade glioma WHO III (4), low grade glioma WHO II (4), lymphoma (2), meningioma (8), cavernous hemangioma (3), or arteriovenous malformation (1). Thirty patients (49.2%) presented with a preoperative motor deficit. One week after surgery, paresis had resolved or improved in 56.7% of the patients. Out of the patients with postoperative paresis, 89.5% experienced an improvement of motor status at follow-up. All metastatic lesions were completely resected compared to 78.9% of non-metastatic lesions (P = 0.02). Only 4.3% of patients with a metastatic lesion, but 26.3% of patients with a non-metastatic lesion experienced deterioration of motor function after surgery (P = 0.04). Preoperative nTMS is suitable for mapping of a variety of motor eloquent brain lesions resulting in favorable neurological outcome. Particularly in metastatic motor eloquent lesion, motor function appears to be preserved after surgery. Clin. Anat. 29:925-931, 2016. © 2016 Wiley Periodicals, Inc. PMID:27501333

  11. Role of the neural niche in brain metastatic cancer.

    PubMed

    Termini, John; Neman, Josh; Jandial, Rahul

    2014-08-01

    Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically, brain metastases were rarely investigated because patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts, the brain. The central nervous system is the most complex biologic system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us toward new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of bidirectional interactions between the brain milieu and metastatic cancer.

  12. Expression and Prognostic Value of Aquaporin 1, 3 in Cervical Carcinoma in Women of Uygur Ethnicity from Xinjiang, China

    PubMed Central

    Chen, Rui; Shi, Yonghua; Amiduo, Reshalaity; Tuokan, Talaf; Suzuk, Lalai

    2014-01-01

    Background Overexpression of several aquaporins has been reported in different types of human cancer but the role of aquaporins in carcinogenesis has not yet been clearly defined. There is few report concerning role of aquaporins in human cervical carcinogenesis so far. Here, we determined the expression and prognostic value of aquaporin 1, 3 in cervical carcinoma in Chinese women of Uygur ethnicity. Methods and Results Real-time PCR analyses demonstrated aquaporin 1, 3 mRNA were differentially expressed in cervical carcinoma, CIN 2-3 and mild cervicitis. Immunofluorescent and immunohistochemical analyses demonstrated aquaporin 1 was predominantly localized to stromal endothelial cells in cervical lesions. Aquaporin 3 was localized to the membrane of normal squamous epithelium, CIN and carcinoma cells. Aquaporin 1 and 3 were upregulated in cervical cancer compared to mild cervicitis and CIN2-3 (P<0.05); Tumor expression of aquaporin 1, 3 significantly increased in advanced stage disease, and patients with deeper tumor infiltration, lymph node metastases or larger tumor volume (P<0.05). Multivariate analysis demonstrated that aquaporin 1, 3 were not independent prognostic factors in cervical carcinoma. Conclusion Aquaporins may participate in the initiation and progression of cervical carcinoma by promoting tumor growth, invasion or lymph node metastasis. Further study is required to determine whether aquaporins have potential as prognostic factors in cervical cancer. PMID:24918928

  13. Peanut agglutinin appearance in the blood circulation after peanut ingestion mimics the action of endogenous galectin-3 to promote metastasis by interaction with cancer-associated MUC1.

    PubMed

    Zhao, Qicheng; Duckworth, Carrie A; Wang, Weikun; Guo, Xiuli; Barrow, Hannah; Pritchard, D Mark; Rhodes, Jonathan M; Yu, Lu-Gang

    2014-12-01

    Peanut agglutinin (PNA), which accounts for ~0.15% of the weight of the common peanut, is a carbohydrate-binding protein that binds the oncofoetal Thomsen-Friedenreich (TF) disaccharide (galactoseβ1,3N-acetylgalactosamineα-) that is overexpressed by ~90% of human cancers. Previous studies have shown that PNA is highly resistant to cooking and digestion and rapidly enters the human blood circulation after peanut ingestion. This study investigates the hypothesis that PNA appearance in the circulation after peanut ingestion may mimic the actions of endogenous TF-binding human galectin-3 in metastasis promotion. It shows that PNA at concentrations similar to those found in blood circulation after peanut ingestion increases cancer cell heterotypic adhesion to the blood vascular endothelium and enhances the formation of tumour cell homotypic aggregates, two important steps in the metastasis cascade, and enhances metastasis in a mouse metastasis model. These effects of PNA are shown to result from its interaction with the cancer-associated TF disaccharide on the transmembrane mucin protein MUC1, causing MUC1 cell surface polarization that reveals underlying cell surface adhesion molecules. Thus, PNA appearance in the blood circulation after peanut ingestion mimics the actions of endogenous galectin-3 and promotes cancer cell metastatic spread by interaction with cancer-associated TF/MUC1. As metastasis accounts for the majority of cancer-associated fatality, regular consumption of peanuts by cancer patients would therefore be expected to have an adverse effect on cancer survival.

  14. Kisspeptin Signaling in the Brain

    PubMed Central

    Oakley, Amy E.; Clifton, Donald K.; Steiner, Robert A.

    2009-01-01

    Kisspeptin (a product of the Kiss1 gene) and its receptor (GPR54 or Kiss1r) have emerged as key players in the regulation of reproduction. Mutations in humans or genetically targeted deletions in mice of either Kiss1 or Kiss1r cause profound hypogonadotropic hypogonadism. Neurons that express Kiss1/kisspeptin are found in discrete nuclei in the hypothalamus, as well as other brain regions in many vertebrates, and their distribution, regulation, and function varies widely across species. Kisspeptin neurons directly innervate and stimulate GnRH neurons, which are the final common pathway through which the brain regulates reproduction. Kisspeptin neurons are sexually differentiated with respect to cell number and transcriptional activity in certain brain nuclei, and some kisspeptin neurons express other cotransmitters, including dynorphin and neurokinin B (whose physiological significance is unknown). Kisspeptin neurons express the estrogen receptor and the androgen receptor, and these cells are direct targets for the action of gonadal steroids in both male and female animals. Kisspeptin signaling in the brain has been implicated in mediating the negative feedback action of sex steroids on gonadotropin secretion, generating the preovulatory GnRH/LH surge, triggering and guiding the tempo of sexual maturation at puberty, controlling seasonal reproduction, and restraining reproductive activity during lactation. Kisspeptin signaling may also serve diverse functions outside of the classical realm of reproductive neuroendocrinology, including the regulation of metastasis in certain cancers, vascular dynamics, placental physiology, and perhaps even higher-order brain function. PMID:19770291

  15. Development of Individualized Anti-Metastasis Strategies by Engineering Nanomedicines

    PubMed Central

    He, Qianjun; Guo, Shengrong; Qian, Zhiyong; Chen, Xiaoyuan

    2015-01-01

    Metastasis is deadly and also tough to treat as it is much more complicated than the primary tumour. Anti-metastasis approaches available so far are far from being optimal. A variety of nanomedicine formulas provide a plethora of opportunities for developing new strategies and means for tackling metastasis. It should be noted that individualized anti-metastatic nanomedicines are different from common anti-cancer nanomedicines as they specifically target different populations of malignant cells. This review briefly introduces the features of the metastatic cascade, and proposes a series of nanomedicine-based anti-metastasis strategies aiming to block each metastatic step. Moreover, we also concisely introduce the advantages of several promising nanoparticle platforms and their potential for constructing state-of-the-art individualized anti-metastatic nanomedicines. PMID:26056688

  16. Gastric Metastasis of Breast Cancer: A Case Series

    PubMed Central

    dos Santos Fernandes, Gustavo; Batista Bugiato Faria, Luiza D.; de Assis Pereira, Isadora; Neves, Natália C. Moreira; Vieira, Yasmine Oliveira; Leal, Alessandro I. Cavalcanti

    2016-01-01

    Gastric metastasis is rare but it can be the initial symptom of cancer. The second leading cause of this type of metastasis is breast cancer. A lack of clinical signs and nonspecific side effects of the treatment of primary tumors can lead to the misdiagnosis of metastatic gastric cancer. Upper gastrointestinal endoscopy with biopsy and immunohistochemistry should be used for diagnosis. Treatment is palliative; it includes chemo, endocrine, and radiation therapies. Four patients with breast cancer and gastric metastasis were identified. All the patients tested positive for estrogen and progesterone receptors, and received chemotherapy and hormone therapy. One patient underwent surgery and two received radiation therapy. Patients with breast cancer and gastrointestinal symptoms should be investigated for gastric metastasis, given its morbidity and negative impact on quality of life. PMID:27746881

  17. Copper Impurity Effects on LiNi(1/3)Mn(1/3)Co(1/3)O2 Cathode Material.

    PubMed

    Sa, Qina; Heelan, Joseph A; Lu, Yuan; Apelian, Diran; Wang, Yan

    2015-09-23

    The crystal structure and electrochemical properties of LiNi1/3Mn1/3Co1/3O2 (NMC) synthesized from a lithium ion battery recovery stream have been studied previously. In this report, we study the Cu impurity effects on NMC in detail. The difference in crystal structures and electrochemical properties were examined for pure and copper impurity included products. Scanning electron microscopy figures show that the precursor particles of NMC are slightly bigger than that of NMC with copper impurity. After undergoing 150 cycles at 2C, X-ray diffraction refinements results show that the lattice parameters for impurity containing NMC and pure NMC change to different extents. Furthermore, due to the minor change of lattice parameters, copper-containing NMC offers a more stable capacity retention compared to pure NMC.

  18. Solitary Spinal Epidural Metastasis from Prostatic Small Cell Carcinoma

    PubMed Central

    Maeng, Young Hee

    2016-01-01

    Solitary, spinal epidural metastasis (SEM) that is not related to vertebral metastasis is very rare. And solitary SEM from prostatic cancer is rarely found in previously published reports. However, it is clinically significant due to the possibility of neurologic dysfunction, and it can be assessed by MRI. In this report, we show a case of solitary SEM arising from prostatic small cell carcinoma detected by MRI. PMID:27413569

  19. An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis.

    PubMed

    Paschall, Amy V; Liu, Kebin

    2016-01-01

    Metastasis is the primary cause of mortality of breast cancer patients. The mechanism underlying cancer cell metastasis, including breast cancer metastasis, is largely unknown and is a focus in cancer research. Various breast cancer spontaneous metastasis mouse models have been established. Here, we report a simplified procedure to establish orthotopic transplanted breast cancer primary tumor and resultant spontaneous metastasis that mimic human breast cancer metastasis. Combined with the bioluminescence live tumor imaging, this mouse model allows tumor growth and progression kinetics to be monitored and quantified. In this model, a low dose (1 x 10(4) cells) of 4T1-Luc breast cancer cells was injected into BALB/c mouse mammary fat pad using a tuberculin syringe. Mice were injected with luciferin and imaged at various time points using a bioluminescent imaging system. When the primary tumors grew to the size limit as in the IACUC-approved protocol (approximately 30 days), mice were anesthetized under constant flow of 2% isoflurane and oxygen. The tumor area was sterilized with 70% ethanol. The mouse skin around the tumor was excised to expose the tumor which was removed with a pair of sterile scissors. Removal of the primary tumor extends the survival of the 4T-1 tumor-bearing mice for one month. The mice were then repeatedly imaged for metastatic tumor spreading to distant organs. Therapeutic agents can be administered to suppress tumor metastasis at this point. This model is simple and yet sensitive in quantifying breast cancer cell growth in the primary site and progression kinetics to distant organs, and thus is an excellent model for studying breast cancer growth and progression, and for testing anti-metastasis therapeutic and immunotherapeutic agents in vivo. PMID:27584043

  20. ["Clown nose"--skin metastasis of breast cancer].

    PubMed

    Soyer, H P; Cerroni, L; Smolle, J; Kerl, H

    1990-10-01

    We report on a 74-year-old woman showing a reddish infiltration of the tip of the nose, which had appeared 3 months ago. Clinically, we considered the following differential diagnoses: sarcoidosis, rosacea, pseudolymphoma, and metastasis. Histological and immunohistological investigation proved a cutaneous metastasis of carcinoma of the breast. Our case report gives evidence of the fact that cutaneous metastases of systemic malignancies are frequently located in acral regions of the skin. PMID:2291293

  1. ["Clown nose"--skin metastasis of breast cancer].

    PubMed

    Soyer, H P; Cerroni, L; Smolle, J; Kerl, H

    1990-10-01

    We report on a 74-year-old woman showing a reddish infiltration of the tip of the nose, which had appeared 3 months ago. Clinically, we considered the following differential diagnoses: sarcoidosis, rosacea, pseudolymphoma, and metastasis. Histological and immunohistological investigation proved a cutaneous metastasis of carcinoma of the breast. Our case report gives evidence of the fact that cutaneous metastases of systemic malignancies are frequently located in acral regions of the skin.

  2. Brain metastases from breast cancer during pregnancy

    PubMed Central

    Sharma, Ashish; Nguyen, Ha Son; Lozen, Andrew; Sharma, Abhishiek; Mueller, Wade

    2016-01-01

    Background: Brain metastasis during pregnancy is a rare occurrence. In particular, there have only been three prior cases regarding breast cancer metastasis. We report a patient with breast cancer metastasis to the brain during pregnancy and review the literature. Case Description: The patient was a 35-year-old female with a history of breast cancer (estrogen receptor/progesterone receptor negative, human epidermal growth factor receptor 2/neu positive, status post-neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab therapy, status post-bilateral mastectomies), and prior right frontal brain metastases (status post-resection, capecitabine/lapatinib/temozolomide therapy, and cyberknife treatment). Patient was found to be pregnant at 9 weeks’ gestation while on chemotherapy; the patient elected to continue with the pregnancy and chemotherapy was discontinued. At 14 weeks’ gestation, she returned with recurrent right frontal disease. She was taken for a craniotomy at 16 weeks’ gestation, which confirmed metastases. Six weeks later, patient returned with worsening headaches and fatigue, with more recurrent right frontal disease. She was started on decadron and chemotherapy (5-fluorouracil, adriamycin, and cyclophosphamide). Serial magnetic resonance imaging (MRI) demonstrated enlarging right frontal lesions. She underwent a craniotomy at 27 weeks’ gestation, and chemotherapy was discontinued promptly. Starting at 30 weeks’ gestation, she received whole brain radiation for 2 weeks. Subsequently, she delivered a baby girl via cesarean section at 32 weeks’ gestation. At 6 weeks follow-up, an MRI brain demonstrated no new intracranial disease, with stable postoperative findings. Conclusion: There is a lack of guidelines and clinical consensus on medical and surgical treatment for breast cancer metastases in pregnant patients. Treatment usually varies based upon underlying tumor burden, location, gestational age of the fetus, and patient's preference and

  3. Evidence for the Presence of 1,3-Dimethylamylamine (1,3-DMAA) in Geranium Plant Materials.

    PubMed

    Gauthier, Thomas D

    2013-01-01

    1,3-Dimethylamylamine (1,3-DMAA) is an aliphatic amine with stimulant properties that are reportedly found naturally only in geranium plants (Pelargonium graveolens). The presence of 1,3-DMAA in geranium plants was first reported in a paper published in 1996, but some have questioned the identification of 1,3-DMAA in that study. Since then, a number of additional studies have been published, largely reporting the absence of 1,3-DMAA in geranium plants and commercial geranium oils. However, in two recent studies, 1,3-DMAA was detected in geranium plant tissues and a geranium oil sample using a simplified extraction approach on tissues and oil sourced from China. Whether or not 1,3-DMAA is found naturally in plants has significant implications as to how commercial products containing 1,3-DMAA are regulated by the US Food and Drug Administration. In this paper, differences in source materials, extraction procedures, and analytical approaches are reviewed in an attempt to rationalize the apparently conflicting evidence for the presence of 1,3-DMAA in geranium plant materials. PMID:23843687

  4. Evidence for the Presence of 1,3-Dimethylamylamine (1,3-DMAA) in Geranium Plant Materials

    PubMed Central

    Gauthier, Thomas D.

    2013-01-01

    1,3-Dimethylamylamine (1,3-DMAA) is an aliphatic amine with stimulant properties that are reportedly found naturally only in geranium plants (Pelargonium graveolens). The presence of 1,3-DMAA in geranium plants was first reported in a paper published in 1996, but some have questioned the identification of 1,3-DMAA in that study. Since then, a number of additional studies have been published, largely reporting the absence of 1,3-DMAA in geranium plants and commercial geranium oils. However, in two recent studies, 1,3-DMAA was detected in geranium plant tissues and a geranium oil sample using a simplified extraction approach on tissues and oil sourced from China. Whether or not 1,3-DMAA is found naturally in plants has significant implications as to how commercial products containing 1,3-DMAA are regulated by the US Food and Drug Administration. In this paper, differences in source materials, extraction procedures, and analytical approaches are reviewed in an attempt to rationalize the apparently conflicting evidence for the presence of 1,3-DMAA in geranium plant materials. PMID:23843687

  5. 43 CFR 9185.1-3 - Mining claims.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 2 2011-10-01 2011-10-01 false Mining claims. 9185.1-3 Section 9185.1-3 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT... Mining claims. (a) Application for survey. Application for the survey of a mining claim should be...

  6. 43 CFR 9185.1-3 - Mining claims.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 2 2012-10-01 2012-10-01 false Mining claims. 9185.1-3 Section 9185.1-3 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT... Mining claims. (a) Application for survey. Application for the survey of a mining claim should be...

  7. 43 CFR 9185.1-3 - Mining claims.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 2 2014-10-01 2014-10-01 false Mining claims. 9185.1-3 Section 9185.1-3 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT... Mining claims. (a) Application for survey. Application for the survey of a mining claim should be...

  8. 43 CFR 9185.1-3 - Mining claims.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 2 2013-10-01 2013-10-01 false Mining claims. 9185.1-3 Section 9185.1-3 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT... Mining claims. (a) Application for survey. Application for the survey of a mining claim should be...

  9. 10 CFR 960.3-1-3 - Regionality.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Regionality. 960.3-1-3 Section 960.3-1-3 Energy DEPARTMENT OF ENERGY GENERAL GUIDELINES FOR THE PRELIMINARY SCREENING OF POTENTIAL SITES FOR A NUCLEAR WASTE... repositories. Such consideration shall take into account the proximity of sites to locations at which waste...

  10. 10 CFR 960.3-1-3 - Regionality.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Regionality. 960.3-1-3 Section 960.3-1-3 Energy DEPARTMENT OF ENERGY GENERAL GUIDELINES FOR THE PRELIMINARY SCREENING OF POTENTIAL SITES FOR A NUCLEAR WASTE... repositories. Such consideration shall take into account the proximity of sites to locations at which waste...

  11. 10 CFR 960.3-1-3 - Regionality.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Regionality. 960.3-1-3 Section 960.3-1-3 Energy DEPARTMENT OF ENERGY GENERAL GUIDELINES FOR THE PRELIMINARY SCREENING OF POTENTIAL SITES FOR A NUCLEAR WASTE... repositories. Such consideration shall take into account the proximity of sites to locations at which waste...

  12. 10 CFR 960.3-1-3 - Regionality.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Regionality. 960.3-1-3 Section 960.3-1-3 Energy DEPARTMENT OF ENERGY GENERAL GUIDELINES FOR THE PRELIMINARY SCREENING OF POTENTIAL SITES FOR A NUCLEAR WASTE... repositories. Such consideration shall take into account the proximity of sites to locations at which waste...

  13. 43 CFR 2201.1-3 - Assumption of costs.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 2 2014-10-01 2014-10-01 false Assumption of costs. 2201.1-3 Section 2201... Exchanges-Specific Requirements § 2201.1-3 Assumption of costs. (a) Generally, parties to an exchange will...-Federal party; and (5) There are no other practicable means available to the authorized officer of...

  14. Colon cancer metastasis to mediastinal lymph nodes without liver or lung involvement: A case report.

    PubMed

    El-Halabi, Mustapha M; Chaaban, Said A; Meouchy, Joseph; Page, Seth; Salyers, William J

    2014-11-01

    Colon cancer is the second most common type of cancer in females and the third in males, worldwide. The most common sites of colon cancer metastasis are the regional lymph nodes, liver, lung, bone and brain. In this study, an extremely rare case of colon adenocarcinoma with extensive metastasis to the mediastinal lymph nodes without any other organ involvement is presented. A 44-year-old Caucasian male presented with abdominal pain, a change in bowel habits, melena and weight loss. Colonoscopy revealed a large friable, ulcerated, circumferential mass in the ascending colon. Biopsies were consistent with the diagnosis of invasive moderately differentiated adenocarcinoma. Subsequently, right colon resection was performed, and pathological analysis revealed moderately differentiated adenocarcinoma of the right colon with extensive regional lymph node involvement. Computed tomography (CT) scans of the chest, abdomen and pelvis were performed preoperatively as part of routine staging for colon cancer. No liver or lung pathology was identified; however, multiple pathologically enlarged mediastinal lymph nodes were observed. Endoscopic ultrasound with fine needle aspiration of the largest mediastinal lymph node, which measured 5.2×3.5 cm on CT scans, was performed. The pathology was again consistent with the diagnosis of metastatic colorectal primary adenocarcinoma. At present, no optimum treatment has been identified for metastatic colon cancer to the mediastinal lymph nodes. The patient in the current case received chemotherapy with folinic acid, fluorouracil and oxaliplatin (FOLFOX), as well as with bevacizumab. Initial follow-up CT scans of the chest revealed a positive response to treatment. Physicians, in particular, radiologists, must consider the mediastinum during the first evaluation and further follow-up of patients with colorectal carcinoma even in the absence of metastasis. PMID:25289100

  15. Skeletal metastasis: the effect on immature skeleton

    SciTech Connect

    Ogden, J.A.; Ogden, D.A.

    1982-12-01

    The unique opportunity to study the entire appendicular skeleton of a child who died from metastatic angiosarcoma allowed detailed assessment of radiographically evident involvement. Virtually every portion of the appendicular skeleton had evidence of metastatic disease. However, the extent of involvement was extremely variable, especially when contralateral regions were assessed. The most likely region of metastasis, the metaphysis, is normally a fenestrated cortex of woven bone in the young child, rather than a well demarcated cortex formed by osteon (lamellar) bone, as it is in the adult. The pattern of destruction is such that less extensive areas may be involved before becoming radiographically evident, and trabecular bone involvement may be evident even without cortical damage. The metaphyseal metastatic spread supports the concept of arterial hematogeneous dissemination, comparable to osteomyelitis in the child. Pathologic metaphyseal fractures involved both proximal humeri; the fracture also extended along a portion of the methaphyseal-physeal interface in one humerus. In one distal femur the physis readily separated from the metaphysis; this was a nondisplaced type 1 growth mechanism injury.

  16. Odontogenic ghost cell carcinoma with pulmonary metastasis

    PubMed Central

    Sukumaran, Renu; Somanathan, Thara; Kattoor, Jayasree

    2015-01-01

    Odontogenic ghost cell carcinoma (OGCC) is an exceptionally rare malignant odontogenic epithelial tumor. It is characterized by ameloblastic-like islands of epithelial cells with aberrant keratinization in the form of ghost cells with varying amounts of dysplastic dentin. Malignant histological characteristics include infiltration, cellular pleomorphism, numerous mitosis and necrosis. Its biological behavior varies from slow-growing locally invasive lesions to rapidly growing highly aggressive tumors. OGCC metastasizing to distant sites is extremely rare. Only three cases of metastasis have been reported in literature. We are reporting the case of a 54-year-old male patient who presented with tender swelling in the malar region. Histopathological examination revealed OGCC and he received postoperative radiotherapy. Two years later, he presented with a lung mass. Biopsy from the lung lesion showed the same morphology as that of maxillary tumor with scattered ghost cells. This case points to the aggressive behavior of OGCC and its metastatic potential. It also highlights the need for long-term follow-up of these patients. PMID:26980967

  17. Degradation of 1,3-dichloropropene in aerobic soils

    SciTech Connect

    Batzer, F.; Balcer, J.L.; Wolt, J.D.

    1995-12-31

    The degradation of the soil fumigant, 1,3-dichloropropene (1,3-D), was investigated to determine its rate of degradation and the identify of metabolites in aerobic soils. Studies were conducted in the dark at 25{degrees}C with uniformly {sup 14}C-labeled 1,3-D at a concentration of approximately 100 ug/g on three soils: Wahiawa silty clay, Catlin silt loam and Fuquay loamy sand. Aerobic soil half-lives for 1,3-D were 1.8, 11.5 and 52.5 days on the Wahiawa silty clay, Catlin silt loam, and Fuquay loamy sand, respectively. Degradation of 1,3-D resulted in the formation of cis- and trans-3-chloroallyl alcohol, cis- and trans-3-chloroacrylic acid, numerous minor carboxylic acid metabolites, and carbon dioxide. In addition, there was also extensive incorporation of {sup 14}C labeled material into the soil organic matter of both soils.

  18. Preferentially Expressed Antigen of Melanoma Prevents Lung Cancer Metastasis

    PubMed Central

    Sun, Zhengwang; Li, Lei; Lin, Zaijun; Xu, Wei; Han, Shuai; Cao, Wenjiao; Xu, Yunfei; Song, Dianwen; Yang, Xinghai; Xiao, Jianru

    2016-01-01

    Lung cancer is the most common cause of cancer death worldwide. The poor survival rate is largely due to the extensive local invasion and metastasis. However, the mechanisms underlying the invasion and metastasis of lung cancer cells remain largely elusive. In this study, we examined the role of preferentially expressed antigen of melanoma (PRAME) in lung cancer metastasis. Our results show that PRAME is downregulated in lung adenocarcinoma and lung bone metastasis compared with normal human lung. Knockdown of PRAME decreases the expression of E-Cadherin and promotes the proliferation, invasion, and metastasis of lung cancer cells by regulating multiple critical genes, most of which are related to cell migration, including MMP1, CCL2, CTGF, and PLAU. Clinical data analysis reveals that the expression of MMP1 correlates with the clinical features and outcome of lung adenocarcinoma. Taken together, our data demonstrate that PRAME plays a role in preventing the invasion and metastasis of lung adenocarcinoma and novel diagnostic or therapeutic strategies can be developed by targeting PRAME. PMID:27391090

  19. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis.

    PubMed

    You, Yiwen; Shan, Ying; Chen, Jing; Yue, Huijun; You, Bo; Shi, Si; Li, Xingyu; Cao, Xiaolei

    2015-12-01

    Nasopharyngeal cancer (NPC) is an endemic type of head and neck cancer with a high rate of cervical lymph node metastasis. Metastasis is the major cause of death in NPC patients. Increasing evidence indicates that exosomes play a pivotal role in promoting cancer metastasis by enhancing angiogenesis and ECM degradation. Matrix metalloproteinase 13 is an important kind of matrix proteinase that is often overexpressed in various tumors and increases the risk of metastasis. However, little is known about the potential role of MMP13-containing exosomes in NPC. In this study, we found that MMP13 was overexpressed in NPC cells and exosomes purified from conditioned medium (CM) as well as NPC patients' plasma. Transwell analysis revealed that MMP13-containing exosomes facilitated the metastasis of NPC cells. Furthermore, siRNA inhibited the effect of MMP13-containing exosomes on tumor cells metastasis as well as angiogenesis. The current findings provided novel insight into the vital role of MMP13-containing exosomes in NPC progression which might offer unique insights for potential therapeutic strategies for NPC progressions. PMID:26362844

  20. Severe pulmonary metastasis in obese and diabetic mice.

    PubMed

    Mori, Akinori; Sakurai, Hiroaki; Choo, Min-Kyung; Obi, Ryosuke; Koizumi, Keiichi; Yoshida, Chiho; Shimada, Yutaka; Saiki, Ikuo

    2006-12-15

    Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. PMID:16998795

  1. Effects of vascular targeting photodynamic therapy on lymphatic tumor metastasis

    NASA Astrophysics Data System (ADS)

    Fateye, B.; He, C.; Chen, B.

    2009-06-01

    Vascular targeting photodynamic therapy (vPDT) is currently in clinical trial for prostate cancer (PCa) treatment. In order to study the effect of vPDT on tumor metastasis, GFP-PC3 or PC-3 xenografts were treated with verteporfin (BPD) PDT. Vascular function was assessed by ultrasound imaging; lymph node and lung metastasis were assessed by fluorescence imaging. vPDT significantly reduced tumor blood flow within 30minutes to 2 hours of treatment. Sub-curative treatment resulted in re-perfusion within 2 weeks of treatment and increased lymph node metastasis. With curative doses, no metastasis was observed. In order to identify cellular or matrix factors and cytokines implicated, conditioned medium from BPD PDTtreated endothelial cells was incubated with PC3 cells in vitro. Tumor cell proliferation and migration was assessed. By immunoblotting, we evaluated the change in mediators of intracellular signaling or that may determine changes in tumor phenotype. Low sub-curative dose (200ng/ml BPD) of endothelial cells was associated with ~15% greater migration in PC3 cells when compared with control. This dose was also associated with sustained activation of Akt at Ser 473, an upstream effector in the Akt/ mTOR pathway that has been correlated with Gleason scores in PCa and with survival and metastasis in vitro and in vivo. In conclusion, the study implicates efficacy of PDT of endothelial cells as an important determinant of its consequences on adjacent tumor proliferation and metastasis.

  2. Dequalinium blocks macrophage-induced metastasis following local radiation.

    PubMed

    Timaner, Michael; Bril, Rotem; Kaidar-Person, Orit; Rachman-Tzemah, Chen; Alishekevitz, Dror; Kotsofruk, Ruslana; Miller, Valeria; Nevelsky, Alexander; Daniel, Shahar; Raviv, Ziv; Rotenberg, Susan A; Shaked, Yuval

    2015-09-29

    A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis. PMID:26348470

  3. Dequalinium blocks macrophage-induced metastasis following local radiation

    PubMed Central

    Kaidar-Person, Orit; Rachman-Tzemah, Chen; Alishekevitz, Dror; Kotsofruk, Ruslana; Miller, Valeria; Nevelsky, Alexander; Daniel, Shahar; Raviv, Ziv; Rotenberg, Susan A.; Shaked, Yuval

    2015-01-01

    A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis. PMID:26348470

  4. Emerging molecular basis of hematogenous metastasis in gastric cancer

    PubMed Central

    Zhong, Jing; Chen, Yan; Wang, Liang-Jing

    2016-01-01

    Lymphatic metastasis is commonly observed in gastric cancer (GC), but hematogenous metastasis is more likely responsible for the cancer-related mortality. Since Stephen Paget first introduced the “seed and soil hypothesis” a century ago, growing evidence recognizes that numerous essential secreted factors and signaling pathway effectors participate in the pre-metastatic niche formation and distant organ metastasis. The cross-talk between GC cells and surrounding microenvironment may consist of a series of interrelated steps, including epithelial mesenchymal transition, intravasation into blood vessels, circulating tumor cell translocation, and secondary organ metastasis. Secreted factors including vascular endothelial growth factor (VEGF), matrix metalloproteinases and cancer-derived extracellular vesicles, especially exosomes, are essential in formation of premetastatic niche. Circulating tumor cells and microRNAs represent as ‘‘metastatic intermediates’’ between primary tumors and sites of dissemination. Many biomarkers have been identified as novel metastatic markers and prognostic effectors. In addition, molecular therapy has been designed to target biomarkers such as growth factors (human epidermal growth factor receptor 2, VEGF) and chemokines, although they have not clearly proven to be effective in inhibiting GC metastasis in clinical trials. In this review, we will systematically discuss the emerging molecules and their microenvironment in hematogenous metastasis of GC, which may help us to find new therapeutic strategies in the future. PMID:26937132

  5. FRZB up-regulated in hepatocellular carcinoma bone metastasis

    PubMed Central

    Huang, Jia; Hu, Wenhao; Lin, Xiangjin; Wang, Xuanwei; Jin, Ketao

    2015-01-01

    The clinical relevance of frizzled-related protein (FRZB) in hepatocellular carcinoma (HCC) bone metastasis remains uncertain. The aim of this study was to assess the clinical relationship of FRZB in patients with HCC bone metastasis after surgical resection. FRZB expression was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) HCC and paired bone metastasis tissues from 13 patients that underwent surgical resection. The clinical characteristics of 13 HCC patients with synchronous or metachronous bone metastasis received surgery were retrospectively reviewed. We found that FRZB was positive in 9 HCC tissues (69.2%) and in 11 paired bone metastatic tissues (84.6%) among these 13 paired samples. The expression of FRZB in the bone metastases was noticeably higher than that in the paired HCC tissues. The expression of FRZB was up-regulated in 10 (76.9%) paired bone metastases tissues. FRZB expression was up-regulated in HCC bone metastasis tissue, which suggested that FRZB might play a key role in the HCC bone metastasis. PMID:26722540

  6. Remodeling of the Methylation Landscape in Breast Cancer Metastasis

    PubMed Central

    Reyngold, Marsha; Turcan, Sevin; Giri, Dilip; Kannan, Kasthuri; Walsh, Logan A.; Viale, Agnes; Drobnjak, Marija; Vahdat, Linda T.; Lee, William; Chan, Timothy A.

    2014-01-01

    The development of breast cancer metastasis is accompanied by dynamic transcriptome changes and dramatic alterations in nuclear and chromatin structure. The basis of these changes is incompletely understood. The DNA methylome of primary breast cancers contribute to transcriptomic heterogeneity and different metastatic behavior. Therefore we sought to characterize methylome remodeling during regional metastasis. We profiled the DNA methylome and transcriptome of 44 matched primary breast tumors and regional metastases. Striking subtype-specific patterns of metastasis-associated methylome remodeling were observed, which reflected the molecular heterogeneity of breast cancers. These divergent changes occurred primarily in CpG island (CGI)-poor areas. Regions of methylome reorganization shared by the subtypes were also observed, and we were able to identify a metastasis-specific methylation signature that was present across the breast cancer subclasses. These alterations also occurred outside of CGIs and promoters, including sequences flanking CGIs and intergenic sequences. Integrated analysis of methylation and gene expression identified genes whose expression correlated with metastasis-specific methylation. Together, these findings significantly enhance our understanding of the epigenetic reorganization that occurs during regional breast cancer metastasis across the major breast cancer subtypes and reveal the nature of methylome remodeling during this process. PMID:25083786

  7. Matrix metalloproteinase 13-containing exosomes promote nasopharyngeal carcinoma metastasis.

    PubMed

    You, Yiwen; Shan, Ying; Chen, Jing; Yue, Huijun; You, Bo; Shi, Si; Li, Xingyu; Cao, Xiaolei

    2015-12-01

    Nasopharyngeal cancer (NPC) is an endemic type of head and neck cancer with a high rate of cervical lymph node metastasis. Metastasis is the major cause of death in NPC patients. Increasing evidence indicates that exosomes play a pivotal role in promoting cancer metastasis by enhancing angiogenesis and ECM degradation. Matrix metalloproteinase 13 is an important kind of matrix proteinase that is often overexpressed in various tumors and increases the risk of metastasis. However, little is known about the potential role of MMP13-containing exosomes in NPC. In this study, we found that MMP13 was overexpressed in NPC cells and exosomes purified from conditioned medium (CM) as well as NPC patients' plasma. Transwell analysis revealed that MMP13-containing exosomes facilitated the metastasis of NPC cells. Furthermore, siRNA inhibited the effect of MMP13-containing exosomes on tumor cells metastasis as well as angiogenesis. The current findings provided novel insight into the vital role of MMP13-containing exosomes in NPC progression which might offer unique insights for potential therapeutic strategies for NPC progressions.

  8. AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective

    PubMed Central

    Talmadge, James E; Fidler, Isaiah J

    2014-01-01

    Metastases resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His “seed and soil” hypothesis was substantiated a century later with experimental studies and numerous reports have confirmed these seminal observations. Inarguably, an improved understanding of the metastatic process and the attributes of the cells selected by this process are critical to the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, such that metastasis prevention may not be relevant, and treatment of systemic disease, as well as the identity of patients with early disease, should be our goal. During the last three decades, revitalized research has focused on new discoveries in the biology of metastasis. While our understanding of the molecular events that regulate metastasis has improved; nonetheless, the relevant contributions and timing of molecular lesion(s) potentially involved in its pathogenesis remain unclear. The history of pioneering observations and discussion of current controversies should help investigators understand the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and allow for the design of successful therapy. PMID:20610625

  9. Brain Power.

    ERIC Educational Resources Information Center

    Albrecht, Karl

    2002-01-01

    Reviews significant findings of recent brain research, including the concept of five minds: automatic, subconscious, practical, creative, and spiritual. Suggests approaches to training the brain that are related to this hierarchy of thinking. (JOW)

  10. Brain Basics

    MedlinePlus

    ... have been linked to many mental disorders, including autism , obsessive compulsive disorder (OCD) , schizophrenia , and depression . Brain ... studies show that brain growth in children with autism appears to peak early. And as they grow ...

  11. Brain components

    MedlinePlus

    ... 3 major components of the brain are the cerebrum, cerebellum, and brain stem. The cerebrum is divided into left and right hemispheres, each ... gray matter) is the outside portion of the cerebrum and provides us with functions associated with conscious ...

  12. Brain Diseases

    MedlinePlus

    The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

  13. Brain abscess

    MedlinePlus

    Tunkel AR. Brain abscess. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice ... Philadelphia, PA: Elsevier Saunders; 2015:chap 92. Tunkel AR, Scheld WM. Brain abscess. In: Winn HR, ed. ...

  14. Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers.

    PubMed

    Rempe, Ralf G; Hartz, Anika Ms; Bauer, Björn

    2016-09-01

    Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood-brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.

  15. miR-128 and its target genes in tumorigenesis and metastasis

    SciTech Connect

    Li, Molin; Fu, Weiming; Wo, Lulu; Shu, Xiaohong; Liu, Fang; Li, Chuangang

    2013-12-10

    MicroRNAs (miRNAs) are a class of endogenous, non-coding, 18–24 nucleotide length single-strand RNAs that could modulate gene expression at post-transcriptional level. Previous studies have shown that miR-128 enriched in the brain plays an important role in the development of nervous system and the maintenance of normal physical functions. Aberrant expression of miR-128 has been detected in many types of human tumors and its validated target genes are involved in cancer-related biological processes such as cell proliferation, differentiation and apoptosis. In this review, we will summarize the roles of miR-128 and its target genes in tumorigenesis and metastasis. - Highlights: • Aberrant expression of miR-128 can be observed in many kinds of malignant tumors. • The molecular mechanisms regulating miR-128 expression are elucidated. • Roles of miR-128 and its target genes in tumorigenesis and metastasis are summarized.

  16. Identification of ovine ruminal microbes capable of biotransforming hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bioremediation is of great interest in the detoxification of soil contaminated with residues from explosives such as hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). Although there are numerous forms of in situ and ex situ bioremediation, ruminants would provide the option of an in situ bioreactor tha...

  17. Hexahydro-1,3,5-trinitro-1,3,5-triazine mineralization by zerovalent iron and mixed anaerobic cultures.

    PubMed

    Oh, B T; Just, C L; Alvarez, P J

    2001-11-01

    Soil microcosms were used to evaluate the potential benefits of an integrated microbial-Fe0 system to treat groundwater contamination by RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine). Microcosms amended with both Fe0 filings and municipal anaerobic sludge mineralized RDX faster and to a greater extent than separate treatments, with up to 51% 14CO2 recovery after 77 d. The nitroso byproducts 1,3-dinitro-5-nitroso-1,3,5-triazacyclohexane (MNX), 1,3-dinitroso-5-nitro-1,3,5-triazacyclohexane (DNX), and 1,3,5-trinitroso-1,3,5-triazacyclohexane (TNX) were detected in all microcosms, although these compounds never accumulated above 5% of the added RDX on a molar basis. A soluble intermediate that was tentatively identified as methylenedinitramine [(O2NNH)2CH2] was relatively persistent, although it accumulated to a much lower extent in combined-treatment reactors than in sets with Fe0 or sludge alone. Some of the radiolabel was bound to soil and Fe0 and could not be extracted with CH3CN. This fraction, which was recovered by combustion with a biological oxidizer, was also found at lower concentrations in combined-treatment reactors. This work suggests that permeable reactive Fe0 barriers might be an effective approach to intercept and degrade RDX plumes and that treatment efficiency might be enhanced by biogeochemical interactions through bioaugmentation.

  18. IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (Rdx) (Interagency Science Consultation Draft)

    EPA Science Inventory

    On March 10, 2016, the public comment draft Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine and the draft charge to external peer reviewers were released for public review and comment. The Toxicological Review and charge were reviewed internally by EPA and by othe...

  19. IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (Rdx) (Public Comment Draft)

    EPA Science Inventory

    EPA is developing an Integrated Risk Information System (IRIS) assessment of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and has released the draft assessment for public comment. When final, the assessment will appear on the IRIS database.

  20. IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (Rdx) (External Review Draft)

    EPA Science Inventory

    The IRIS Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) was released for external peer review in September 2016. The EPA’s Science Advisory Board’s (SAB) Chemical Assessment Advisory Committee (CAAC) will conduct a peer review of the scientific basis suppor...

  1. Bone marrow-derived stem cell therapy for metastatic brain cancers.

    PubMed

    Kaneko, Yuji; Tajiri, Naoki; Staples, Meaghan; Reyes, Stephanny; Lozano, Diego; Sanberg, Paul R; Freeman, Thomas B; van Loveren, Harry; Kim, Seung U; Borlongan, Cesar V

    2015-01-01

    We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood-brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumor-derived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases.

  2. Regulation of aldosterone secretion by Cav1.3.

    PubMed

    Xie, Catherine B; Shaikh, Lalarukh Haris; Garg, Sumedha; Tanriver, Gizem; Teo, Ada E D; Zhou, Junhua; Maniero, Carmela; Zhao, Wanfeng; Kang, Soosung; Silverman, Richard B; Azizan, Elena A B; Brown, Morris J

    2016-01-01

    Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) CaV1.3. Using a novel antagonist of CaV1.3, compound 8, we investigated the role of CaV1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, CaV1.2, over CaV1.3. In H295R cells transfected with wild-type or mutant CaV1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 μM of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 μM). Selective CaV1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of CaV1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of CaV1.3. PMID:27098837

  3. Regulation of aldosterone secretion by Cav1.3

    PubMed Central

    Xie, Catherine B.; Haris Shaikh, Lalarukh; Garg, Sumedha; Tanriver, Gizem; Teo, Ada E. D.; Zhou, Junhua; Maniero, Carmela; Zhao, Wanfeng; Kang, Soosung; Silverman, Richard B.; Azizan, Elena A. B.; Brown, Morris J.

    2016-01-01

    Aldosterone-producing adenomas (APAs) vary in phenotype and genotype. Zona glomerulosa (ZG)-like APAs frequently have mutations of an L-type calcium channel (LTCC) CaV1.3. Using a novel antagonist of CaV1.3, compound 8, we investigated the role of CaV1.3 on steroidogenesis in the human adrenocortical cell line, H295R, and in primary human adrenal cells. This investigational drug was compared with the common antihypertensive drug nifedipine, which has 4.5-fold selectivity for the vascular LTCC, CaV1.2, over CaV1.3. In H295R cells transfected with wild-type or mutant CaV1.3 channels, the latter produced more aldosterone than wild-type, which was ameliorated by 100 μM of compound 8. In primary adrenal and non-transfected H295R cells, compound 8 decreased aldosterone production similar to high concentration of nifedipine (100 μM). Selective CaV1.3 blockade may offer a novel way of treating primary hyperaldosteronism, which avoids the vascular side effects of CaV1.2-blockade, and provides targeted treatment for ZG-like APAs with mutations of CaV1.3. PMID:27098837

  4. Brain Aneurysm

    MedlinePlus

    A brain aneurysm is an abnormal bulge or "ballooning" in the wall of an artery in the brain. They are sometimes called berry aneurysms because they ... often the size of a small berry. Most brain aneurysms produce no symptoms until they become large, ...

  5. Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis.

    PubMed

    Yeung, Tsz-Lun; Leung, Cecilia S; Yip, Kay-Pong; Au Yeung, Chi Lam; Wong, Stephen T C; Mok, Samuel C

    2015-10-01

    Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-yr survival rate of <30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and the importance of the "seed-and-soil" hypothesis for ovarian cancer metastasis. In this review we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease.

  6. Brain metastases as site of first and isolated recurrence of breast cancer: the role of systemic therapy after local treatment.

    PubMed

    Niwińska, Anna

    2016-10-01

    The role of systemic treatment was assessed after local therapy for breast cancer patients who developed central nervous system (CNS) metastases as a first and isolated recurrence. Subjects were 128 breast cancer patients with brain metastases as the first and isolated site of recurrence that were selected from 673 consecutive breast cancer patients with brain metastases treated at the same institution. Median survival from brain metastases in patients with and without systemic treatment after local therapy was respectively 15 and 4 months (p < 0.001). In patients with a Karnofsky Performance Status ≥70 and those <70, survival was respectively 16 and 5.5 months (p < 0.001). The median survival from brain metastasis in patients with solitary brain metastasis, with and without systemic treatment after local therapy, was respectively 22 and 7 months (p = 0.003). Cox multivariate analysis demonstrated that good performance status, solitary brain metastasis and systemic therapy undertaken after local treatment were factors which prolonged survival. However patient survival was adversely affected by those having leptomeningeal metastasis associated with brain parenchymal lesions. Systemic therapy, undertaken after local treatment improved survival in those patients with breast cancer and brain metastases as the site of first and isolated recurrence. Further study is required in order to fully establish the role of systemic treatment for this patient group.

  7. Dielectric properties of multiatomic alcohols: 1,3-butanediol

    NASA Astrophysics Data System (ADS)

    Zhuravlev, V. I.

    2016-10-01

    The dielectric spectra of 1,3-butanediol in the temperature range of 298-423 K are analyzed using a variety of theoretical approaches. It is shown that the dielectric spectra of 1,3-butanediol are described by the Davidson-Cole equation. Conclusions as to possible mechanisms of dispersion are drawn using the Debye theory. The relaxation times of 1,3-butanediol, calculated in different ways, are compared. The dipole moments of clusters are calculated for the first time using the Dissado-Hill cluster model.

  8. Laparoscopic adrenalectomy for metachronous ipsilateral metastasis following nephrectomy for renal cell carcinoma

    PubMed Central

    Eret, Viktor; Ürge, Tomáš; Trávníček, Ivan; Chudáček, Zdeněk; Hes, Ondřej; Hora, Milan

    2013-01-01

    Introduction Although laparoscopic adrenalectomy (LA) is considered as a gold standard approach for adrenalectomy, there are minimal data describing options and outcomes of LA after previous ipsilateral nephrectomy (PIN). Aim To describe our results in a group of patients who underwent LA after PIN. Material and methods From August 2004 to October 2012 we performed at our institution 88 LA. Of this amount we performed 5 LA for metachronous metastasis of renal cell carcinoma (RCC) after PIN. This group was compared to a group without previous nephrectomy. Results The group comprised 4 men (80%) and 1 woman (20%); the mean age at the time of surgery was 66.8 ±8.5 (range: 60-77) years; the mean period between nephrectomy and adrenalectomy was 5.2 (range: 1.5-14) years; the operating time was longer in patients after PIN for 7 min; the mean blood loss was higher by 22 ml; duration of hospitalization was shorter by 1.3 days, paradoxically, compared with patients without PIN. There was no need for conversion to open surgery and we did not observe any other complications. Conclusions Laparoscopic adrenalectomy for metastasis of RCC after PIN is a technically feasible method in selected patients and it is associated with no significant differences in perioperative data in comparison with the group without prior nephrectomy. The patients benefit from minimally invasive surgery. The performance has required an experienced laparoscopic surgeon. PMID:24130636

  9. Prognostic Factors After Extraneural Metastasis of Medulloblastoma

    SciTech Connect

    Mazloom, Ali; Zangeneh, Azy H.; Paulino, Arnold C.

    2010-09-01

    Purpose: To review the existing literature regarding the characteristics, prognostic factors, treatment, and survival of patients with medulloblastoma, who develop extraneural metastasis (ENM). Methods and Materials: A PubMed search of English language articles from 1961 to 2007 was performed, yielding 47 articles reporting on 119 patients. Factors analyzed included age, time interval to development of ENM, ENM location, central nervous system (CNS) involvement, treatment, and outcome. Results: Sites of ENM included bone in 84% of patients, bone marrow in 27% of patients, lymph nodes in 15% of patients, lung in 6% of patients, and liver in 6% of patients. Median survival was 8 months after diagnosis of ENM. The 1-, 2-, and 5-year overall survival (OS) rates after diagnosis of ENM were 41.9%, 31.0%, and 26.0%, respectively. The 1-, 2-, and 5-year progression-free survival (PFS) rates after diagnosis of ENM were 34.5%, 23.2%, and 13.4%, respectively. For patients without CNS involvement at the time of ENM diagnosis, the 1-, 2-, and 5-year OS rates for those treated with and without radiotherapy (RT) were 82.4%, 64.8%, and 64.8% vs. 51.0%, 36.6%, and 30.5%, respectively (p = 0.03, log-rank test). RT did not significantly improve OS or PFS rates for those with CNS involvement. Concurrent CNS involvement, ENM in the lung or liver, a time interval of <18 months to development of ENM, and a patient age of <16 years at ENM diagnosis were found to be negative prognostic factors for both OS and PFS. Conclusions: Several prognostic factors were identified for patients with ENM from medulloblastoma. Patients without concurrent CNS involvement, who received RT after ENM diagnosis had an OS and PFS benefit compared to those who did not receive RT.

  10. Brain Basics: Know Your Brain

    MedlinePlus

    ... fact sheet is a basic introduction to the human brain. It may help you understand how the healthy ... largest and most highly developed part of the human brain: it consists primarily of the cerebrum ( 2 ) and ...

  11. Oligodendroglioma metastasis to the bone marrow mimicking multiple myeloma: A case report

    PubMed Central

    JIAN, YUAN; GAO, WEN; WU, YIN; LI, YANCHEN; ZHANG, YONG; YANG, GUANGZHONG; CHEN, WENMING

    2016-01-01

    The present study reports a case of a 59-year-old male suffering from oligodendroglioma that metastasized to the bone marrow (BM). The metastasis was detected 5 years after craniotomy was performed for the resection of the primary tumor; however, it manifested as multiple myeloma (MM)-like bone lesions, a small M component and myeloma cell-like morphology in the BM. A brain magnetic resonance imaging scan was performed; evidence from the previously performed oligodendroglioma resection was observed on the scan, but there were no significant findings, which made the diagnosis particularly challenging. The patient exhibited no response to the multiple combination therapies administered targeting MM and oligodendroglioma, and subsequently developed epilepsy and pneumonia, prior to succumbing to multiple organ failure. Among the various tumor types involving the central nervous system, oligodendroglioma is the least likely to metastasize; thus, distant metastases from brain oligodendrogliomas are extremely rare. To the best of our knowledge, this is the first case of metastatic oligodendroglioma presenting with typical MM-like symptoms and without any recurrence in the brain. PMID:27347150

  12. The Fragile X Protein binds mRNAs involved in cancer progression and modulates metastasis formation

    PubMed Central

    Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; Fata, Giorgio La; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

    2013-01-01

    The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

  13. The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.

    PubMed

    Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; La Fata, Giorgio; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

    2013-10-01

    The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

  14. Liver Metastasis of Gastrointestinal Neuroendocrine Tumors: A Single Center Experience

    PubMed Central

    Geramizadeh, Bita; Kashkooe, Ali; Malekhosseini, Seyed Ali

    2016-01-01

    Background Gastrointestinal neuroendocrine tumors (GI-NETs) are potentially malignant tumors, and their most common location of metastasis is the liver. Objectives In this report, we will describe our experience with some clinical and pathologic findings of hepatic metastasis in a group of cases of GI-NETs at the largest referral center of GI and liver diseases in south Iran. Materials and Methods In this four-year study (2011 - 2014), all GI and liver NETs were extracted from the pathology files of hospitals affiliated with Shiraz University of Medical Sciences. After classification based on the world health organization guidelines, the patients were evaluated according to their location, sex, age, and proliferative index. After studying the imaging and clinical charts of liver-NET cases with an unknown primary location, a complete panel of immunohistochemical markers (TTF-1, CDX-2, CK-7, CK-2, etc.) was used to find the primary GI location. Carcinoid tumors from other sites, such as the lung, were omitted from this study. Results The most common primary site of metastatic GI-NET to the liver in our center was the small intestine, which was also the most frequent location of GI-NET without liver metastasis. No cases of appendiceal-NET were found with liver metastasis. In 8 cases (11.6%) with liver-NETs, no primary location was identified. GI-NETs with liver metastasis had a significantly higher grade and proliferative index compared with NETs without liver metastasis. Conclusions Liver metastasis of neuroendocrine tumors in Iran presents in a very similar manner as that seen in western countries. In about 89% of cases with liver-NET, complete imaging, clinical, and pathological studies can help to identify the primary origin of the liver-NET, which is very important in the patient’s management. PMID:27330538

  15. Targeting type Iγ phosphatidylinositol phosphate kinase inhibits breast cancer metastasis.

    PubMed

    Chen, C; Wang, X; Xiong, X; Liu, Q; Huang, Y; Xu, Q; Hu, J; Ge, G; Ling, K

    2015-08-27

    Most deaths from breast cancer are caused by metastasis, a complex behavior of cancer cells involving migration, invasion, survival and microenvironment manipulation. Type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) regulates focal adhesion assembly and its phosphorylation at Y639 is critical for cell migration induced by EGF. However, the role of this lipid kinase in tumor metastasis remains unclear. Here we report that PIPKIγ is vital for breast cancer metastasis. Y639 of PIPKIγ can be phosphorylated by stimulation of EGF and hepatocyte growth factor (HGF), two promoting factors for breast cancer progression. Histological analysis revealed elevated Y639 phosphorylation of PIPKIγ in invasive ductal carcinoma lesions and suggested a positive correlation with tumor grade. Orthotopically transplanted PIPKIγ-depleted breast cancer cells showed substantially reduced growth and metastasis, as well as suppressed expression of multiple genes related to cell migration and microenvironment manipulation. Re-expression of wild-type PIPKIγ in PIPKIγ-depleted cells restored tumor growth and metastasis, reinforcing the importance of PIPKIγ in breast cancer progression. Y639-to-F or a kinase-dead mutant of PIPKIγ could not recover the diminished metastasis in PIPKIγ-depleted cancer cells, suggesting that Y639 phosphorylation and lipid kinase activity are both required for development of metastasis. Further analysis with in vitro assays indicated that depleting PIPKIγ inhibited cell proliferation, MMP9 secretion and cell migration and invasion, lending molecular mechanisms for the eliminated cancer progression. These results suggest that PIPKIγ, downstream of EGF and/or HGF receptor, participates in breast cancer progression from multiple aspects and deserves further studies to explore its potential as a therapeutic target.

  16. Denosumab and Bone Metastasis-Free Survival in Men With Castration-Resistant Prostate Cancer: Results of a Global Phase 3, Randomised, Placebo-Controlled Trial

    PubMed Central

    Smith, Matthew R; Saad, Fred; Coleman, Robert; Shore, Neal; Fizazi, Karim; Tombal, Bertrand; Miller, Kurt; Sieber, Paul; Karsh, Lawrence; Damião, Ronaldo; Tammela, Teuvo L; Egerdie, Blair; Van Poppel, Hendrik; Chin, Joseph; Morote, Juan; Gómez-Veiga, Francisco; Borkowski, Tomasz; Ye, Zhishen; Kupic, Amy; Dansey, Roger; Goessl, Carsten

    2013-01-01

    Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition may prevent bone metastases. This phase 3 study evaluated denosumab, a fully human anti-RANKL monoclonal antibody, to prevent bone metastasis or death from any cause in men with non-metastatic castration-resistant prostate cancer (CRPC). Methods Men with non-metastatic CRPC at high risk for bone metastasis (PSA ≥8.0 ng/mL and/or PSA doubling time ≤10.0 months) were enrolled in 319 centers from 30 countries. Patients were randomised 1:1 in blinded fashion using an interactive voice response system to receive monthly subcutaneous denosumab 120 mg or placebo. The primary endpoint was bone metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death. Results 1432 patients were randomised, 716 to receive denosumab and 716 to receive placebo. Denosumab significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (hazard ratio 0.85 [0.73–0.98]; P=0.028). Denosumab also significantly delayed time to first bone metastasis (hazard ratio 0.84 [0.71–0.98]; P=0.032). Overall survival was similar between groups (hazard ratio 1.01 [0.85–1.20]; P=0.91). Rates of adverse events (AEs) and serious AEs were generally similar between groups, except for osteonecrosis of jaw (ONJ) and hypocalcemia. Yearly cumulative incidence of ONJ for denosumab was: 1%, 3%, 4% in years 1, 2, 3, respectively; overall, less than 5% (n=33). Hypocalcemia occurred in under 2% (n=12) of denosumab and under 1% (n=2) of placebo patients. The blinded treatment phase has been completed. Conclusion In men with CRPC, denosumab significantly prolonged bone metastasis-free survival and delayed time to bone metastasis. This is the first large randomised study to demonstrate that targeting the bone microenvironment prevents bone metastasis in

  17. 1.3 GHz superconducting RF cavity program at Fermilab

    SciTech Connect

    Ginsburg, C.M.; Arkan, T.; Barbanotti, S.; Carter, H.; Champion, M.; Cooley, L.; Cooper, C.; Foley, M.; Ge, M.; Grimm, C.; Harms, E.; /Fermilab

    2011-03-01

    At Fermilab, 9-cell 1.3 GHz superconducting RF (SRF) cavities are prepared, qualified, and assembled into cryomodules (CMs) for Project X, an International Linear Collider (ILC), or other future projects. The 1.3 GHz SRF cavity program includes targeted R&D on 1-cell 1.3 GHz cavities for cavity performance improvement. Production cavity qualification includes cavity inspection, surface processing, clean assembly, and one or more cryogenic low-power CW qualification tests which typically include performance diagnostics. Qualified cavities are welded into helium vessels and are cryogenically tested with pulsed high-power. Well performing cavities are assembled into cryomodules for pulsed high-power testing in a cryomodule test facility, and possible installation into a beamline. The overall goals of the 1.3 GHz SRF cavity program, supporting facilities, and accomplishments are described.

  18. Waste form characteristics report, revision 1.3

    SciTech Connect

    Leider, H.R.; Stout, R.B.

    1998-07-01

    This Waste Form Characteristics Report (WFCR) update, Version 1.3, incorporates substantial additions and changes to following 10 sections of the WFCR: 2.1.3.1 Cladding Degradation; 2.1.3.2 UO2 Oxidation in Fuel; 2.1.3.5 Dissolution Release from UO{sub 2}; 2.2.1.5 Fracture /Fragmentation Studies of Glass; 2.2.2.2 Dissolution Radionuclide Release from Glass; 2.2.2.3 Soluble-Precipitated/Colloidal Species from Glass; 3.2.2 Spent-Fuel Oxidation Models; 3.4.2 Spent-Fuel Dissolution Models; 3.5.1 Glass Dissolution Experimental Parameters; and 3.5.2 Glass Dissolution Models.

  19. 1. 3/4 VIEW, LOOKING NE. Philadelphia & Reading Railroad, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. 3/4 VIEW, LOOKING NE. - Philadelphia & Reading Railroad, Pedestrian Suspension Bridge, Foot of Sixth Street at Schuylkill River (formerly spanned Philadelphia & Reading main line at Reading Depot), Reading, Berks County, PA

  20. Treating cancer stem cells and cancer metastasis using glucose-coated gold nanoparticles.

    PubMed

    Hu, Chenxia; Niestroj, Martin; Yuan, Daniel; Chang, Steven; Chen, Jie

    2015-01-01

    Cancer ranks among the leading causes of human mortality. Cancer becomes intractable when it spreads from the primary tumor site to various organs (such as bone, lung, liver, and then brain). Unlike solid tumor cells, cancer stem cells and metastatic cancer cells grow in a non-attached (suspension) form when moving from their source to other locations in the body. Due to the non-attached growth nature, metastasis is often first detected in the circulatory systems, for instance in a lymph node near the primary tumor. Cancer research over the past several decades has primarily focused on treating solid tumors, but targeted therapy to treat cancer stem cells and cancer metastasis has yet to be developed. Because cancers undergo faster metabolism and consume more glucose than normal cells, glucose was chosen in this study as a reagent to target cancer cells. In particular, by covalently binding gold nanoparticles (GNPs) with thio-PEG (polyethylene glycol) and thio-glucose, the resulting functionalized GNPs (Glu-GNPs) were created for targeted treatment of cancer metastasis and cancer stem cells. Suspension cancer cell THP-1 (human monocytic cell line derived from acute monocytic leukemia patients) was selected because it has properties similar to cancer stem cells and has been used as a metastatic cancer cell model for in vitro studies. To take advantage of cancer cells' elevated glucose consumption over normal cells, different starvation periods were screened in order to achieve optimal treatment effects. Cancer cells were then fed using Glu-GNPs followed by X-ray irradiation treatment. For comparison, solid tumor MCF-7 cells (breast cancer cell line) were studied as well. Our irradiation experimental results show that Glu-GNPs are better irradiation sensitizers to treat THP-1 cells than MCF-7 cells, or Glu-GNPs enhance the cancer killing of THP-1 cells 20% more than X-ray irradiation alone and GNP treatment alone. This finding can help oncologists to design

  1. Toxic effects of oral hexahydro-1,3,5-trinitro-1,3,5-triazine in the western fence lizard (Sceloporus occidentalis).

    PubMed

    McFarland, Craig A; Quinn, Michael J; Bazar, Matthew A; Talent, Larry G; Johnson, Mark S

    2009-05-01

    Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) has been widely used as an explosive in munition formulations, resulting in contamination of wildlife habitat on military installations. To estimate health effects for reptilian species, acute, subacute, and subchronic oral toxicity studies were conducted using the Western fence lizard (Sceloporus occidentalis). Estimated oral median lethal doses were 72 (95% confidence interval [CI], 49-106) mg/kg body weight (slope, 3.754) for males and 88 (95% CI, 65-119) mg/kg (slope, 4.525) for females. Toxicity from RDX suggested the neurological system as the critical target tissue. A 14-d subacute study followed with males dosed orally with RDX (corn oil) at 0, 10, 20, 25, 30, 45, and 60 mg/kg/d. Signs of toxicity frequently included a characteristic body posture. A significant dose-survival relationship was seen over the range of doses, with a significant decrease in survival at 20 mg/kg/d. Males in the 60-d subchronic study were dosed at 0, 1, 2.5, 5, 8, and 11 mg/kg/d, and signs of toxicity included lethargy, cachexia, and anorexia. Survival was decreased at 8 and 11 mg/kg/d. Reduced growth rate and food consumption occurred at 5 mg/kg/d. Brain tissue was assayed for RDX when seizures were observed at a residue concentration of at least 18 microg/g. No abnormalities were observed in the hematologic indices, whereas plasma proteins were reduced. Hepatic enlargement and decreased testes mass occurred at 8 and 11 mg/kg/d. Plasma testosterone concentrations, sperm counts, and motility measures were variable for all treatment levels. Based on survival, growth rate, food intake, and testes to brain weight ratios, these data suggest a lowest-observed-adverse effect level of 5 mg/kg/d and a no-observed-adverse effect level of 2.5 mg/kg/d. PMID:19102580

  2. Process to prepare 1,3-diamino-5-pentafluorosulfanylbenzene

    NASA Technical Reports Server (NTRS)

    St.clair, Terry L. (Inventor); St.clair, Anne K. (Inventor); Thrasher, Joseph S. (Inventor)

    1993-01-01

    A process was developed to prepare 1,3-diamino- 5-pentafluoro sulfanylbenzene. This process involved two steps: preparing the dinitro compound, 1,3-dinitro- 5-pentafluoro sulfanylbenzene, and reducing this compound to form the corresponding diamine. This diamine was reacted with various dianhydrides, diacidchlorides, and epoxy resins to form polyimides, polyamides, and cross linked epoxies. These polymers were used to prepare semi-permeable membranes, wire coatings, and films.

  3. Classification of glioblastoma and metastasis for neuropathology intraoperative diagnosis: a multi-resolution textural approach to model the background

    NASA Astrophysics Data System (ADS)

    Ahmad Fauzi, Mohammad Faizal; Gokozan, Hamza Numan; Elder, Brad; Puduvalli, Vinay K.; Otero, Jose J.; Gurcan, Metin N.

    2014-03-01

    Brain cancer surgery requires intraoperative consultation by neuropathology to guide surgical decisions regarding the extent to which the tumor undergoes gross total resection. In this context, the differential diagnosis between glioblastoma and metastatic cancer is challenging as the decision must be made during surgery in a short time-frame (typically 30 minutes). We propose a method to classify glioblastoma versus metastatic cancer based on extracting textural features from the non-nuclei region of cytologic preparations. For glioblastoma, these regions of interest are filled with glial processes between the nuclei, which appear as anisotropic thin linear structures. For metastasis, these regions correspond to a more homogeneous appearance, thus suitable texture features can be extracted from these regions to distinguish between the two tissue types. In our work, we use the Discrete Wavelet Frames to characterize the underlying texture due to its multi-resolution capability in modeling underlying texture. The textural characterization is carried out in primarily the non-nuclei regions after nuclei regions are segmented by adapting our visually meaningful decomposition segmentation algorithm to this problem. k-nearest neighbor method was then used to classify the features into glioblastoma or metastasis cancer class. Experiment on 53 images (29 glioblastomas and 24 metastases) resulted in average accuracy as high as 89.7% for glioblastoma, 87.5% for metastasis and 88.7% overall. Further studies are underway to incorporate nuclei region features into classification on an expanded dataset, as well as expanding the classification to more types of cancers.

  4. The Brains Behind the Brain.

    ERIC Educational Resources Information Center

    D'Arcangelo, Marcia

    1998-01-01

    Interviews with five neuroscientists--Martin Diamond, Pat Wolfe, Robert Sylwester, Geoffrey Caine, and Eric Jensen--disclose brain-research findings of practical interest to educators. Topics include brain physiology, environmental enrichment, memorization, windows of learning opportunity, brain learning capacity, attention span, student interest,…

  5. Metabolic engineering for the production of 1,3-propanediol

    SciTech Connect

    Cameron, D.C.; Tong, I.T., Skraly, F.A.

    1993-12-31

    Metabolic engineering involves the use of recombinant DNA techniques for the modification of intermediary metabolic pathways. Microorganisms have recently been engineered to produce compounds such as indigo, ethanol, fatty acids and polyhydroxyalkanoates. As a model system for research in metabolic engineering, the authors have constructed a strain of the bacterium Escherichia coli, that is able to produce 1,3-propanediol (1,3-PD) from glycerol. This strain contains the genes for the glycerol deydratase and the 1,3-PD oxidoreductase from Klebsiella pneumoniae. The authors have also investigated genetic and environmental strategies for improving the yield and productivity of 1,3-PD by the engineered organism. In addition to being a useful model system, 1,3-PD production is of current practical interest. First 1,3-PD (also known as trimethylene glycol) and 1,4-butanediol, the more readily available diols. Second, the volume of feedstock (glycerol) is expected to grow, as it is a by-product of the production of polyglycoside surfactants and biodiesel fluids.

  6. Key enzymes catalyzing glycerol to 1,3-propanediol.

    PubMed

    Jiang, Wei; Wang, Shizhen; Wang, Yuanpeng; Fang, Baishan

    2016-01-01

    Biodiesel can replace petroleum diesel as it is produced from animal fats and vegetable oils, and it produces about 10 % (w/w) glycerol, which is a promising new industrial microbial carbon, as a major by-product. One of the most potential applications of glycerol is its biotransformation to high value chemicals such as 1,3-propanediol (1,3-PD), dihydroxyacetone (DHA), succinic acid, etc., through microbial fermentation. Glycerol dehydratase, 1,3-propanediol dehydrogenase (1,3-propanediol-oxydoreductase), and glycerol dehydrogenase, which were encoded, respectively, by dhaB, dhaT, and dhaD and with DHA kinase are encompassed by the dha regulon, are the three key enzymes in glycerol bioconversion into 1,3-PD and DHA, and these are discussed in this review article. The summary of the main research direction of these three key enzyme and methods of glycerol bioconversion into 1,3-PD and DHA indicates their potential application in future enzymatic research and industrial production, especially in biodiesel industry. PMID:26966462

  7. Development of 1.3GHz HTc rf SQUID

    NASA Astrophysics Data System (ADS)

    Liu, Xin-Yuan; Xie, Fei-Xiang; Meng, Shu-Chao; Dai, Yuan-Dong; Li, Zhuang-Zhi; Ma, Ping; Yang, Tao; Nie, Rui-Juan; Wang, Fu-Ren

    2004-01-01

    A new HTc rf SQUID working at around 1.3GHz has been developed to avoid electromagnetic interference such as growing mobile communication jamming. This new system works in a frequency range from 1.23 to 1.42GHz (centred at 1.3GHz), which is not occupied by commercial communication. The sensor used in the 1.3GHz rf SQUID is made of a HTc coplanar superconducting resonator and a large-area HTc superconducting film concentrator. We have achieved in the 1.3GHz HTc rf SQUID system a minimal flux noise of 2.5×10-5Phi0/(Hz)1/2 and a magnetic field sensitivity of 38fT/(Hz)1/2 in white noise range, respectively. The effective area of the concentrator fabricated on a 15×15mm2 substrate is 1.35mm2. It is shown that the 1.3GHz rf SQUID system has a high field sensitivity. Design and implementation of 1.3GHz HTc rf SQUID offers a promising direction of rf SQUID development for higher working frequency ranges.

  8. Facile 1,3- and 1,5-Chlorine Migration.

    PubMed

    Koch, Rainer; Wong, Ming Wah; Wentrup, Curt

    1996-10-01

    High-level ab initio molecular orbital calculations, using the G2(MP2,SVP) theory (and semiempirical methods) have been used to examine several 1,3- and 1,5-chlorine migrations. It is found that the interaction of chlorine lone pair electrons with a low-lying LUMO accelerates the Cl shift dramatically (lone pair-LUMO-mediated pericyclic reaction). The activation barriers for the 1,3-migration in chloro oxo ketene 1 (Cl(C=O)CH=C=O) and the 1,5-migration in (2-(chlorocarbonyl)vinyl)ketene 2 (Cl(C=O)CH=CHCH=C=O) are only 53 and 61 kJ mol(-)(1), respectively, compared to the 216 and 173 kJ mol(-)(1) barriers for the corresponding unassisted 1,3- and 1,5-sigmatropic shifts of Cl in 3-chloro-1-propene and 5-chloro-1,3-pentadiene. The transition structures for 1 and 2 reveal that migration of the chlorine atoms takes place in the molecular planes. The 1,5-chlorine shift in 6-chlorocyclohexa-2,4-dienone (3) has a significantly higher barrier due to a lack of appropriate orbital interaction. The related 1,3-shift in the (chlorocarbonyl)imine-alpha-chloro isocyanate system is also dramatically accelerated compared with conventional pericyclic 1,3-Cl migration.

  9. Cryptands with 1,3,5-tris(1',3'-dioxan-2'-yl)-benzene units: synthesis and structural investigations.

    PubMed

    Cîrcu, Monica; Soran, Albert; Hădade, Niculina Daniela; Rednic, Monica; Terec, Anamaria; Grosu, Ion

    2013-09-01

    Various cryptands based on 1,3-dioxane decorated 1,3,5-trisubstituted-benzene building blocks, connected by different chains (exhibiting ester, ether, or triazol groups) to several units with C3 symmetry, are reported. The structure of the compounds was investigated by single crystal X-ray diffraction, NMR, and MS. The role of the 1,3-dioxane units was targeted to ensure the preorganization of the substrate for the macrocyclization reactions on one side, and for easier NMR assignment of the structure of the cryptands on the other side. PMID:23924384

  10. Electrolyte additive to improve performance of MCMB/LiNi 1/3Co 1/3Mn 1/3O 2 Li-ion cell

    NASA Astrophysics Data System (ADS)

    Qin, Yan; Chen, Zonghai; Lu, Wenquan; Amine, Khalil

    The electrolyte additive, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5,5] undecane (TOS), was investigated as a means to improve the life of mesocarbon microbead (MCMB)/Li 1.1[Ni 1/3Co 1/3Mn 1/3] 0.9O 2 (NCM) cells for high-power applications. With the addition of an appropriate amount of TOS (no more than 1 wt%) to MCMB/NCM cells, the capacity retention was significantly improved at 55 °C compared with cells containing pristine electrolyte. Aging tests at 55 °C indicated that the capacity retention of the negative electrode had benefited as a result of the formation of a stable passivation film at the surface of the carbon electrode due to TOS reduction. Electrochemical impedance spectroscopy showed that a TOS addition of more than 0.5 wt% increased the cell interfacial impedance. Differential scanning calorimetry showed that the thermal stability of lithiated MCMB was also improved with the TOS addition.

  11. Colony-stimulating factor 1 potentiates lung cancer bone metastasis.

    PubMed

    Hung, Jaclyn Y; Horn, Diane; Woodruff, Kathleen; Prihoda, Thomas; LeSaux, Claude; Peters, Jay; Tio, Fermin; Abboud-Werner, Sherry L

    2014-04-01

    Colony-stimulating factor 1 (CSF1) is essential for osteoclastogenesis that mediates osteolysis in metastatic tumors. Patients with lung cancer have increased CSF1 in serum and high levels are associated with poor survival. Adenocarcinomas metastasize rapidly and many patients suffer from bone metastasis. Lung cancer stem-like cells sustain tumor growth and potentiate metastasis. The purpose of this study was to determine the role of CSF1 in lung cancer bone metastasis and whether inhibition of CSF1 ameliorates the disease. Human lung adenocarcinoma A549 cells were examined in vitro for CSF1/CSF1R. A549-luc cells were injected intracardiac in NOD/SCID mice and metastasis was assessed. To determine the effect of CSF1 knockdown (KD) in A549 cells on bone metastasis, cells were stably transfected with a retroviral vector containing short-hairpin CSF1 (KD) or empty vector (CT). Results showed that A549 cells express CSF1/CSF1R; CSF1 increased their proliferation and invasion, whereas soluble CSF1R inhibited invasion. Mice injected with A549-luc cells showed osteolytic bone lesions 3.5 weeks after injection and lesions increased over 5 weeks. Tumors recapitulated adenocarcinoma morphology and showed osteoclasts along the tumor/bone interface, trabecular, and cortical bone loss. Analyses of KD cells showed decreased CSF1 protein levels, reduced colony formation in soft agar assay, and decreased fraction of stem-like cells. In CSF1KD mice, the incidence of tumor metastasis was similar to controls, although fewer CSF1KD mice had metastasis in both hind limbs. KD tumors showed reduced CSF1 expression, Ki-67+ cells, and osteoclasts. Importantly, there was a low incidence of large tumors >0.1 mm(2) in CSF1KD mice compared with control mice (10% vs 62.5%). This study established a lung osteolytic bone metastasis model that resembles human disease and suggests that CSF1 is a key determinant of cancer stem cell survival and tumor growth. Results may lead to novel strategies to

  12. N-glycans and metastasis in galectin-3 transgenic mice.

    PubMed

    More, Shyam K; Srinivasan, Nithya; Budnar, Srikanth; Bane, Sanjay M; Upadhya, Archana; Thorat, Rahul A; Ingle, Arvind D; Chiplunkar, Shubhada V; Kalraiya, Rajiv D

    2015-05-01

    Poly-N-acetyl-lactosamine (polyLacNAc) on N-glycans facilitate lung specific metastasis of melanoma cells by serving as high affinity ligands for galectin-3, expressed in highest amounts in the lungs, on almost all its tissue compartments including on the surface of vascular endothelium. PolyLacNAc not only aids in initial arrest on the organ endothelium but in all the events of extravasation. Inhibition of polyLacNAc synthesis, or competitive inhibition of its interaction with galectin-3 all inhibited these processes and experimental metastasis. Transgenic galectin-3 mice, viz., gal-3(+/+) (wild type), gal-3(+/-) (hemizygous) and gal-3(-/-) (null) have been used to prove that galectin-3/polyLacNAc interactions are indeed critical for lung specific metastasis. Gal-3(+/-) mice which showed <50% expression of galectin-3 on the lungs also showed proportionate decrease in the number of B16F10 melanoma metastatic colonies affirming that galectin-3 and polyLacNAc interactions are indeed key determinants of lung metastasis. However, surprisingly, the number and size of metastatic colonies in gal-3(-/-) mice was very similar as that seen in gal-3(+/+) mice. The levels of lactose binding lectins on the lungs and the transcripts of other galectins (galectin-1, -8 and -9) which are expressed on lungs and have similar sugar binding specificities as galectins-3, remain unchanged in gal-3(+/+) and gal-3(-/-) mice. Further, inhibition of N-glycosylation with Swainsonine (SW) which drastically reduces metastasis of B16F10 cells in gal-3(+/+) mice, did not affect lung metastasis when assessed in gal-3(-/-) mice. Together, these results rule out the possibility of some other galectin taking over the function of galectin-3 in gal-3(-/-) mice. Chimeric mice generated to assess if absence of any effect on metastasis is due to compromised tumor immunity by replacing bone marrow of gal-3(-/-) mice with that from gal-3(+/+) mice, also failed to impact melanoma metastasis. As galectin-3

  13. The molecular signature of breast cancer metastasis to bone.

    PubMed

    Bahrami, Tayyeb; Mokmeli, Sharareh; Hossieni, Hossien; Pourpaknia, Reza; Makani, Zahra; Salmaninejad, Arash; Estiar, Mehrdad A; Hossieni, Ali; Farshbaf, Alieh

    2016-10-01

    Distant metastasis during the advanced stage of malignant tumor progression can cause considerable morbidity in cancer patients. Bone is known to be one of the most common sites of distant metastasis in patients with breast cancer (BC). BC metastases in bone are associated with excessive skeletal complications. These complications can be fatal and reduce quality of life of patients. It is important to understand the metastatic process of BC to bone to improve quality of life and design new therapeutic methods. At present, the molecular mechanisms leading to the BC metastasis to bone are not fully understood. Studying the molecular basis of BC metastasis to bone might improve our insight into this complex process. In addition, it can provide novel approaches for designing advanced and effective targeted therapies. The present article aimed to review the published papers on the molecular basis of the metastatic process of BC to bone, focusing on involved genes and signaling networks. Furthermore, we propose potential therapeutic targets that may be more effective for the inhibition and treatment of BC metastasis to bone. PMID:27384592

  14. Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion

    PubMed Central

    Kenny, Hilary A.; Chiang, Chun-Yi; White, Erin A.; Schryver, Elizabeth M.; Habis, Mohammed; Romero, Iris L.; Ladanyi, Andras; Penicka, Carla V.; George, Joshy; Matlin, Karl; Montag, Anthony; Wroblewski, Kristen; Yamada, S. Diane; Mazar, Andrew P.; Bowtell, David; Lengyel, Ernst

    2014-01-01

    Ovarian cancer (OvCa) metastasizes to organs in the abdominal cavity, such as the omentum, which are covered by a single layer of mesothelial cells. Mesothelial cells are generally thought to be “bystanders” to the metastatic process and simply displaced by OvCa cells to access the submesothelial extracellular matrix. Here, using organotypic 3D cultures, we found that primary human mesothelial cells secrete fibronectin in the presence of OvCa cells. Moreover, we evaluated the tumor stroma of 108 human omental metastases and determined that fibronectin was consistently overexpressed in these patients. Blocking fibronectin production in primary mesothelial cells in vitro or in murine models, either genetically (fibronectin 1 floxed mouse model) or via siRNA, decreased adhesion, invasion, proliferation, and metastasis of OvCa cells. Using a coculture model, we determined that OvCa cells secrete TGF-β1, which in turn activates a TGF-β receptor/RAC1/SMAD-dependent signaling pathway in the mesothelial cells that promotes a mesenchymal phenotype and transcriptional upregulation of fibronectin. Additionally, blocking α5 or β1 integrin function with antibodies reduced metastasis in an orthotopic preclinical model of OvCa metastasis. These findings indicate that cancer-associated mesothelial cells promote colonization during the initial steps of OvCa metastasis and suggest that mesothelial cells actively contribute to metastasis. PMID:25202979

  15. Quantitation of Intra-peritoneal Ovarian Cancer Metastasis.

    PubMed

    Lewellen, Kyle A; Metzinger, Matthew N; Liu, Yueying; Stack, M Sharon

    2016-01-01

    Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Mortality is due to diagnosis of 75% of women with late stage disease, when metastasis is already present. EOC is characterized by diffuse and widely disseminated intra-peritoneal metastasis. Cells shed from the primary tumor anchor in the mesothelium that lines the peritoneal cavity as well as in the omentum, resulting in multi-focal metastasis, often in the presence of peritoneal ascites. Efforts in our laboratory are directed at a more detailed understanding of factors that regulate EOC metastatic success. However, quantifying metastatic tumor burden represents a significant technical challenge due to the large number, small size and broad distribution of lesions throughout the peritoneum. Herein we describe a method for analysis of EOC metastasis using cells labeled with red fluorescent protein (RFP) coupled with in vivo multispectral imaging. Following intra-peritoneal injection of RFP-labelled tumor cells, mice are imaged weekly until time of sacrifice. At this time, the peritoneal cavity is surgically exposed and organs are imaged in situ. Dissected organs are then placed on a labeled transparent template and imaged ex vivo. Removal of tissue auto-fluorescence during image processing using multispectral unmixing enables accurate quantitation of relative tumor burden. This method has utility in a variety of applications including therapeutic studies to evaluate compounds that may inhibit metastasis and thereby improve overall survival. PMID:27500635

  16. Dietary linoleate-enhanced metastasis of 4526 murine mammary tumors

    SciTech Connect

    Hubbard, N.E.

    1987-01-01

    The influence of quantitative differences in dietary linoleic acid (18:2) and of the cyclooxygenase inhibitor, indomethacin (IM), on the metastasis of line 4526 mammary tumors was investigated. All mice were fed high fat (20%, w/w), semipurified diets that were prepared using different mixtures of coconut (primarily saturated) and safflower (mostly 18:2) oil and thus contained either 1, 2, 4, 8, or 12% 18:2 (w/w). The spontaneous metastasis of 4526 tumor cells from primary sites, was increased 2-4 fold in mice that were fed diets containing higher levels of 18:2 (8 and 12%). Chronic treatment of mice with a relatively low dosage of IM reduced the growth rate of primary 4526 tumors, slightly reduced metastasis in mice fed 1 and 4% 18:2, and completely inhibited the increased metastasis observed in mice fed 12% 18:2. Treatment with a higher dosage of IM reduced metastasis even further compared to controls, but did not decrease growth rate compared to the low dosage of IM. The level of 18:2 in the diet did not appear to affect the incorporation of {sup 3}H-thymidine into tumor cells of metastatic lung nodules. The effect of 18:2 may be through a modulation of arachidonic acid metabolism. This modulation, in turn, may affect particular steps in the metastatic cascade such as lodgement and survival of tumor cells.

  17. ZBTB7A suppresses melanoma metastasis by transcriptionally repressing MCAM

    PubMed Central

    Liu, Xue-Song; Genet, Matthew D; Haines, Jenna E; Mehanna, Elie K; Wu, Shaowei; Chen, Hung-I Harry; Chen, Yidong; Qureshi, Abrar A; Han, Jiali; Chen, Xiang; Fisher, David E; Pandolfi, Pier Paolo; Yuan, Zhi-Min

    2015-01-01

    The excessive metastatic propensity of melanoma makes it the most deadly form of skin cancer, yet the underlying mechanism of metastasis remains elusive. Here, mining of cancer genome datasets discovered a frequent loss of chromosome 19p13.3 and associated down-regulation of the zinc finger transcription factor ZBTB7A in metastatic melanoma. Functional assessment of ZBTB7A-regulated genes identified MCAM, which encodes an adhesion protein key to melanoma metastasis. Using an integrated approach, it is demonstrated that ZBTB7A directly binds to the promoter and transcriptionally represses the expression of MCAM, establishing ZBTB7A as a bona fide transcriptional repressor of MCAM. Consistently, down-regulation of ZBTB7A results in marked upregulation of MCAM and enhanced melanoma cell invasion and metastasis. An inverse correlation of ZBTB7A and MCAM expression in association with melanoma metastasis is further validated with data from analysis of human melanoma specimens. Implications Together these results uncover a previously unrecognized role of ZBTB7A in negative regulation of melanoma metastasis and have important clinical implications. PMID:25995384

  18. Biology of colorectal pulmonary metastasis: implications for surgical resection.

    PubMed

    Poullis, Michael; Littler, John; Gosney, John

    2012-02-01

    In colorectal cancer, little high grade evidence for cure, life extension, disease modification or palliation achieved by pulmonary metastasectomy exists. This has prompted the pulmonary metastasectomy in colorectal cancer (PulMiCC) trial. Reappraisal of the biological facts on colorectal metastasis may, however, shed light on an alternative avenue of clinical management. Early onset of metastasis, short doubling time and a short disease-free interval are all associated with poor clinical outcomes. Selecting who will be cured (i.e. no occult metastasis) remains the holy grail for pulmonary metastasectomy surgery. Serial CT scans can be utilized to calculate the tumour doubling time by volumetric analysis. Knowing the doubling time and size of the largest metastasis, which by definition is the first cell that has successfully spread from the primary site, the time of initial metastasis can be predicted. More importantly, using the doubling time, calculating the time interval from the primary surgery to the point at which all pulmonary metastases are visible should be possible. Perhaps watchful waiting, with interval CT scanning, followed by pulmonary metastasectomy should be utilized, rather than clinical opinion or randomization in a trial based upon first presentation. PMID:22159245

  19. Oxidative stress inhibits distant metastasis by human melanoma cells

    PubMed Central

    Piskounova, Elena; Agathocleous, Michalis; Murphy, Malea M.; Hu, Zeping; Huddlestun, Sara E.; Zhao, Zhiyu; Leitch, A. Marilyn; Johnson, Timothy M.; DeBerardinis, Ralph J.; Morrison, Sean J.

    2015-01-01

    Solid cancer cells commonly enter the blood and disseminate systemically but are highly inefficient at forming distant metastases for poorly understood reasons. We studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NSG mice. All melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficient metastasizers. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence upon NADPH-generating enzymes in the folate pathway. Anti-oxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumors in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo. PMID:26466563

  20. Matricellular proteins as regulators of cancer metastasis to bone.

    PubMed

    Trotter, Timothy N; Yang, Yang

    2016-01-01

    Metastasis is the major cause of death in cancer patients, and a frequent site of metastasis for many cancers is the bone marrow. Therefore, understanding the mechanisms underlying the metastatic process is necessary for future prevention and treatment. The tumor microenvironment is now known to play a role in the metastatic cascade, both at the primary tumor and in metastatic sites, and includes both cellular and non-cellular components. The extracellular matrix (ECM) provides structural support and signaling cues to cells. One particular group of molecules associated with the ECM, known as matricellular proteins, modulate multiple aspects of tumor biology, including growth, migration, invasion, angiogenesis and metastasis. These proteins are also important for normal function in the bone by regulating bone formation and bone resorption. Recent studies have described a link between some of these proteins and metastasis of various tumors to the bone. The aim of this review is to summarize what is currently known about matricellular protein influence on bone metastasis. Particular attention to the contribution of both tumor cells and non-malignant cells in the bone has been given.