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Sample records for 1-3 brain metastasis

  1. Intracranial tuberculoma mimicking brain metastasis.

    PubMed

    Salaskar, Abhijit L; Hassaneen, Wael; Keenan, Cheryl H; Suki, Dima

    2015-01-01

    To our knowledge, this is the first report of an intracranial tuberculoma in an immunocompetent patient with a solid primary tumor outside the central nervous system. This case is important because the patient underwent treatment for a presumed brain metastasis, based on the knowledge that a solid extracranial primary tumor was present, but before the brain lesion pathology was determined.

  2. Heparanase Mechanisms in Melanoma Brain Metastasis

    DTIC Science & Technology

    2014-08-01

    Melanoma Brain Metastasis PRINCIPAL INVESTIGATOR: Dr. Dario Marchetti RECIPIENT: Baylor College of Medicine REPORT DATE...Annual 3. DATES COVERED 1 Aug 2013-31 Jul 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Heparanase Mechanisms in Melanoma Brain...brain. This emphasizes the potential for therapeutically targeting this enzyme in brain metastasis in general, brain-metastatic melanoma (BMM) in

  3. Heparanase Mechanisms in Melanoma Brain Metastasis

    DTIC Science & Technology

    2015-10-01

    recently reported the HPSE inhibition by microRNA 1258 which resulted in a suppression of brain metastasis in in xenograft models of breast cancer...AWARD NUMBER: W81XWH-12-1-0281 TITLE: Heparanase Mechanisms in Melanoma Brain Metastasis PRINCIPAL INVESTIGATOR: Dr. Dario Marchetti...Mechanisms in Melanoma Brain Metastasis 5b. GRANT NUMBER W81XWH-12-1-0281 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Dario Marchetti

  4. 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

  5. Treatment of brain metastasis from lung cancer.

    PubMed

    Kawabe, Takuya; Phi, Ji Hoon; Yamamoto, Masaaki; Kim, Dong Gyu; Barfod, Bierta E; Urakawa, Yoichi

    2012-01-01

    Brain metastasis from lung cancer occupies a significant portion of all brain metastases. About 15-20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis during the course of the disease. The prognosis of brain metastasis is poor with median survival of less than 1 year. Whole-brain radiation therapy (WBRT) is widely used for the treatment of brain metastasis. WBRT can also be used as adjuvant treatment along with surgery and stereotactic radiosurgery (SRS).Surgery provides a rapid relief of mass effects and may be the best choice for a large single metastasis. SRS confers local control rates comparable to those for surgery with minimal toxicities and versatility that makes it applicable to multiple lesions, deep-seated lesions, and to patients with poor medical conditions. Recursive partitioning analysis (RPA) classes are widely used for prognostic stratification. However, the validity of RPA classes, especially for NSCLC, has been questioned and other scoring systems are being developed. Synchronous presentation of primary NSCLC and brain metastases is a special situation in which surgery for the lung lesion and surgery or SRS for brain lesions are recommended if the thoracic disease is in early stages. Small cell lung cancer (SCLC) has a higher likelihood for brain metastasis than NSCLC and prophylactic cranial irradiation and subsequent WBRT are usually recommended. Recently, SRS for brain metastasis from SCLC has been tried, but requires further verification.

  6. Surgical treatment of brain metastasis: a review.

    PubMed

    Mut, Melike

    2012-01-01

    Brain metastasis is the most common intracranial tumor in adults. Currently, treatment of brain metastasis requires multidisciplinary approach tailored for each individual patient. Surgery has an indispensible role in relieving intracranial mass effect, improving neurological status and survival while providing or confirming neuropathological diagnosis with low mortality and morbidity rates. Besides the resection of a single brain metastasis in patients with accessible lesions, good functional status, and absent/controlled extracranial disease; surgery is proven to play a role in management of multiple metastases. Surgical technique has an impact on the outcome since piecemeal resection rather than en bloc resection and leaving infiltrative zone behind around resection cavity may have a negative influence on local control. Best local control of brain metastasis can be accomplished with optimal surgical resection involving current armamentarium of preoperative structural and functional imaging, intraoperative neuromonitoring, and advanced microneurosurgical techniques; followed by adjunct therapies like stereotactic radiosurgery, whole brain radiotherapy, or intracavitary therapies. Here, treatment options for brain metastasis are discussed with controversies about surgery.

  7. Stereotactic radiosurgery of brain metastasis from melanoma.

    PubMed

    Marchan, Edward M; Sheehan, Jason

    2012-01-01

    Brain metastasis represents the most common intracranial neoplasm in adult patients. Melanoma is the third most frequent cancer histology and consequently comprises a significant portion of brain metastasis patients. Unlike the more frequent lung and breast cancers, melanoma represents a particularly challenging entity because of its radioresistant nature. Stereotactic radiosurgery appears to overcome the inherent radioresistance of brain metastasis from melanoma and, thereby, affords a high rate of local tumor control. Reports from leading centers indicate a favorable benefit to risk profile for radiosurgery in melanoma patients. Local tumor control after radiosurgery generally exceeds 80%, and neurological complications as a result of radiosurgery are infrequent. A higher performance status and lower intracranial tumor burden in melanoma patients at the time of radiosurgery are associated with longer survival. Radiosurgery may be used in conjunction upfront with radiotherapy, resection, and chemotherapy or as a salvage therapy in selected melanoma patients. Careful radiological and neurological follow-up is required to assess local tumor control and distant intracranial disease progression. Further clinical studies will be required to better define the role of upfront and salvage radiosurgery in selected cohorts of patients with brain metastasis from melanoma. However, it appears likely that radiosurgery will play an expanded role in the overall management of these patients.

  8. [Diagnosis and treatment of brain metastasis].

    PubMed

    Sajama, Carlos; Lorenzoni, José; Tagle, Patricio

    2008-10-01

    Cerebral metastasis occur in 20 to 30 percent of patients with systemic cancer and are the most common type of intracranial tumor. The median survival of untreated patients is one month with a slightly longer survival in those treated with steroids. Patients treated with whole brain radiation therapy survive between 3 to 6 months. In selected cases survival can increase to 10 to 12 months with combination of surgery and radiotherapy or stereotactic radiosurgery alone or associated to radiotherapy. Most brain metastasis arise from lung, breast and melanomas. The most important criteria for selecting patients who will benefit from surgery or stereotactic radiosurgery are a Karnofsky score of 70 or more, systemic control of the cancer and absence of leptomeningeal involvement. Surgery is indicated in patients with a single lesion located in an accessible zone and stereotactic radiosurgery is indicated for lesions up to 3 cm of diameter, and in patients with up to 3 or 4 metastasis, no matter their location. The survival benefit of chemotherapy in brain metastasis has not been demonstrated.

  9. 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.

  10. Brain metastasis reirradiation in patients with advanced breast cancer

    PubMed Central

    Huang, Zhou; Sun, Bing; Shen, Ge; Cha, Lei; Meng, Xiangying; Wang, Junliang; Zhou, Zhenshan; Wu, Shikai

    2017-01-01

    The outcome of recurrent brain metastasis is dismal. This study aims to assess the clinical outcomes and toxicity of reirradiation as a salvage treatment for progressive brain metastasis in patients with advanced breast cancer. Between July 2005 and September 2014, the medical records of 56 patients with brain metastasis from breast cancer were retrospectively reviewed. Of these patients, 39 received whole-brain radiotherapy (WBRT) followed by stereotactic radiosurgery (SRS) reirradiation (Group 1), and 17 received SRS followed by WBRT reirradiation (Group 2). Overall survival (OS) and brain progression-free survival rates/times were calculated using the Kaplan–Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Change in neurologic function was also assessed. The median OS was 10.8 months (range, 1.3–56.8 months). In Group 1, the median PFS time (PFS-1) was 6.5 months and the OS time was 11.4 months. Multivariate analysis revealed that longer OS was significantly associated with a high Karnofsky performance score (KPS) (P = 0.004), controlled extracranial metastasis (P = 0.001) and a good response to reirradiation (P = 0.034). In Group 2, the median PFS time (PFS-2) after reirradiation was 8.5 months and the OS time was 10.8 months. Multivariate analysis revealed that longer OS was significantly associated with a high KPS (P = 0.018). The majority of the patients had improved or stable neurological function. Reirradiation is an effective and a safe treatment for patients with brain metastases from breast cancer. It might delay the progression of intracranial disease and improve neurological function. A suitable patient selection for reirradiation was suggested. PMID:27707842

  11. The Molecular Biology of Brain Metastasis

    PubMed Central

    Rahmathulla, Gazanfar; Toms, Steven A.; Weil, Robert J.

    2012-01-01

    Metastasis to the central nervous system (CNS) remains a major cause of morbidity and mortality in patients with systemic cancers. Various crucial interactions between the brain environment and tumor cells take place during the development of the cancer at its new location. The rapid expansion in molecular biology and genetics has advanced our knowledge of the underlying mechanisms involved, from invasion to final colonization of new organ tissues. Understanding the various events occurring at each stage should enable targeted drug delivery and individualized treatments for patients, with better outcomes and fewer side effects. This paper summarizes the principal molecular and genetic mechanisms that underlie the development of brain metastasis (BrM). PMID:22481931

  12. 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.

  13. Targeting Phosphatidylserince for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2014-10-01

    Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis 5b. GRANT NUMBER W81XWH-12-1-0316 5c. PROGRAM ELEMENT NUMBER 6...SUPPLEMENTARY NOTES 14. ABSTRACT Brain metastasis occurs in ~30% of metastatic breast cancer patients. The prognosis is extremely poor, with a...Introduction Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, with a median survival of 4-6 months even

  14. Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0214 TITLE: Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis PRINCIPAL INVESTIGATOR: Dario...5a. CONTRACT NUMBER Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis 5b. GRANT NUMBER W81XWH-14-1-0214 5c. PROGRAM ELEMENT NUMBER 6...SUPPLEMENTARY NOTES None 14. ABSTRACT Breast cancer brain metastasis (BCBM) is devastating and increasing in frequency, however, BCBM mechanisms are

  15. 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.

  16. γ knife radiosurgery of brain metastasis from breast cancer.

    PubMed

    Padovani, Laetitia; Muracciole, Xavier; Régis, Jean

    2012-01-01

    The incidence of brain metastasis in patients with metastatic breast cancer ranges from 14 to 16%.Age, number of metastatic sites, short disease-free survival and molecular subtypes are associated with the occurrence of brain metastasis. Patients classified in the triple-negative group more frequently presented brain metastasis as the first site (26%) than those in the human epidermal growth factor receptor 2 (HER2)-positive (6%) or luminal (12%) subtypes. Whole brain radiation therapy (WBRT) is still the standard treatment for breast cancer patients with brain metastasis. The 1- and 2-year survival rates of patients with brain metastasis were 25 and 10%, respectively, with a median survival of 6 months. In selected patients with single brain metastasis, majority of lung cancer, three randomized controlled trials underlined the significant survival benefit in adding local treatment such as surgery or stereotactic radio surgery to WBRT. Similarly, the upfront stereotactic radiosurgery (SRS) alone did not affect survival rate in three other randomized studies and represents an alternative treatment for patients with stage 1-4. Metastatic breast cancer patients with Karnofsky Performance Scale ≥70, single or oligometastatic brain metastases and well-controlled extracranial disease or favorable disease-specific graded prognostic assessment group presented a median overall survival of 16 months. Delaying WBRT could spare patients of neurocognitive toxicity due to full-dose whole brain irradiation. Nevertheless, the real WBRT neurocognitive impact is still unclear. These patients should be followed with serial magnetic resonance image every 3 months and treated with WBRT or additional SRS at recurrence to control brain disease.

  17. Pathogenesis and Blood-Brain Barrier Heterogeneity of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2005-07-01

    diagnosis and treatment and improve our understanding of the role of BBB in chemotherapy of brain tumors. 15. SUBJECT TERMS Breast Cancer, Brain...of the pathobiology of brain metastasis may lead to novel targeted treatment paradigms and a better prognosis for patients with brain metastatic...metastasis (Fenner and Possinger, 2002; Walsh, 1996) may be incorrect. The development of rational therapeutic strategies for the treatment of brain

  18. Genes that mediate breast cancer metastasis to the brain.

    PubMed

    Bos, Paula D; Zhang, Xiang H-F; Nadal, Cristina; Shu, Weiping; Gomis, Roger R; Nguyen, Don X; Minn, Andy J; van de Vijver, Marc J; Gerald, William L; Foekens, John A; Massagué, Joan

    2009-06-18

    The molecular basis for breast cancer metastasis to the brain is largely unknown. Brain relapse typically occurs years after the removal of a breast tumour, suggesting that disseminated cancer cells must acquire specialized functions to take over this organ. Here we show that breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization. We isolated cells that preferentially infiltrate the brain from patients with advanced disease. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the alpha2,6-sialyltransferase ST6GALNAC5 as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 were previously linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions.

  19. 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

  20. Brain tumor imaging: imaging brain metastasis using a brain-metastasizing breast adenocarcinoma.

    PubMed

    Madden, Kelley S; Zettel, Martha L; Majewska, Ania K; Brown, Edward B

    2013-03-01

    Brain metastases from primary or secondary breast tumors are difficult to model in the mouse. When metastatic breast cancer cell lines are injected directly into the arterial circulation, only a small fraction of cells enter the brain to form metastatic foci. To study the molecular and cellular mechanisms of brain metastasis, we have transfected MB-231BR, a brain-homing derivative of a human breast adenocarcinoma line MDA-MB-231, with the yellow fluorescent protein (YFP) variant Venus. MB-231BR selectively enters the brain after intracardiac injection into the arterial circulation, resulting in accumulation of fluorescent foci of cells in the brain that can be viewed by standard fluorescence imaging procedures. We describe how to perform the intracardiac injection and the parameters used to quantify brain metastasis in brain sections by standard one-photon fluorescence imaging. The disadvantage of this model is that the kinetics of growth over time cannot be determined in the same animal. In addition, the injection technique does not permit precise placement of tumor cells within the brain. This model is useful for determining the molecular determinants of brain tumor metastasis.

  1. Solitary brain metastasis from prostate cancer: a case report.

    PubMed

    Barakat, Tasneem; Agarwal, Arnav; McDonald, Rachel; Ganesh, Vithusha; Vuong, Sherlyn; Borean, Michael; Chow, Edward; Soliman, Hany

    2016-07-01

    Brain metastases arising from prostate cancer are exceedingly rare and typically occur late in the course of the disease. Most patients have widespread metastatic disease before developing brain metastases from prostate cancer. We report the case of a 67-year-old male with prostate cancer presenting with an isolated symptomatic brain metastasis. Aggressive treatment of the metastatic site included tumor resection and adjuvant stereotactic radiation treatment (RT) to the surgical bed, resulting in a favorable outcome.

  2. 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.

  3. Occurrence and clinical features of brain metastasis after chemoradiotherapy for esophageal carcinoma.

    PubMed

    Kanemoto, Ayae; Hashimoto, Takayuki; Harada, Hideyuki; Asakura, Hirofumi; Ogawa, Hirofumi; Furutani, Kazuhisa; Boku, Narikazu; Nakasu, Yoko; Nishimura, Tetsuo

    2011-01-01

    Brain metastasis from esophageal carcinoma has been considered rare and survival following esophageal carcinoma with distant metastasis is poor. The purpose of this report was to clarify cumulative incidence and risk factors for brain metastasis after chemoradiotherapy for esophageal carcinoma, and to consider recommended treatments for brain metastasis from esophageal carcinoma. We reviewed 391 patients treated with chemoradiotherapy. Median age was 65 years. Clinical stages were I, II, III, and IV in 32, 47, 150, and 162 patients, respectively. Brain imaging was performed usually when patients revealed neurological symptoms. The 3-year cumulative incidence of brain metastasis after chemoradiotherapy was 6.6%. There were 4 patients with single metastasis and 8 with multiple metastases. Initial clinical stages were II, III, and IV in 1, 2, and 9 patients, respectively. Histology included squamous cell carcinoma in 10 patients and others in 2 patients. Univariate analysis demonstrated M factor, distant lymph node relapse, and recurrent lung and liver metastasis as significant risk factors of brain metastasis (P < 0.05). Median survival time after diagnosis of brain metastasis was 2.1 months. Brain metastasis was not directly related to cause of mortality. The causes were extracranial tumor deterioration in 8 patients and infection in 4 patients. Brain metastasis may increase in the future with improving survival from esophageal carcinoma. However, considering the poor survival after diagnosis of brain metastasis, short-term palliative therapy for brain metastasis appears preferable to vigorous long-term therapy.

  4. The vascular basement membrane as "soil" in brain metastasis.

    PubMed

    Carbonell, W Shawn; Ansorge, Olaf; Sibson, Nicola; Muschel, Ruth

    2009-06-10

    Brain-specific homing and direct interactions with the neural substance are prominent hypotheses for brain metastasis formation and a modern manifestation of Paget's "seed and soil" concept. However, there is little direct evidence for this "neurotropic" growth in vivo. In contrast, many experimental studies have anecdotally noted the propensity of metastatic cells to grow along the exterior of pre-existing vessels of the CNS, a process termed vascular cooption. These observations suggest the "soil" for malignant cells in the CNS may well be vascular, rather than neuronal. We used in vivo experimental models of brain metastasis and analysis of human clinical specimens to test this hypothesis. Indeed, over 95% of early micrometastases examined demonstrated vascular cooption with little evidence for isolated neurotropic growth. This vessel interaction was adhesive in nature implicating the vascular basement membrane (VBM) as the active substrate for tumor cell growth in the brain. Accordingly, VBM promoted adhesion and invasion of malignant cells and was sufficient for tumor growth prior to any evidence of angiogenesis. Blockade or loss of the beta1 integrin subunit in tumor cells prevented adhesion to VBM and attenuated metastasis establishment and growth in vivo. Our data establishes a new understanding of CNS metastasis formation and identifies the neurovasculature as the critical partner for such growth. Further, we have elucidated the mechanism of vascular cooption for the first time. These findings may help inform the design of effective molecular therapies for patients with fatal CNS malignancies.

  5. 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

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

    PubMed

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

    2016-09-02

    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.

  7. 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.

  8. Integrated genomic and epigenomic analysis of breast cancer brain metastasis.

    PubMed

    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.

  9. Uptake of indium-111-labeled leukocytes by brain metastasis

    SciTech Connect

    Balachandran, S.; Husain, M.M.; Adametz, J.R.; Pallin, J.S.; Angtuaco, T.L.; Boyd, C.M.

    1987-04-01

    Uptake of indium-labeled leukocytes was seen in two cases of histologically proven brain metastasis. In one, this led to misdiagnosis of the lesion as an abscess. On histological evaluation, a large number of white blood cells or macrophages was seen at the neoplastic sites. Reasons for leukocyte accumulation around metastatic brain neoplasms are discussed. In contrast to the current reports that indium-labeled leukocyte scans can differentiate intracranial infection from tumor, these cases demonstrate their lack of specificity in the detection of brain abscess.

  10. Gastrointestinal cancer and brain metastasis: a rare and ominous sign.

    PubMed

    Go, Pauline H; Klaassen, Zachary; Meadows, Michael C; Chamberlain, Ronald S

    2011-08-15

    Metastatic brain tumors represent 20% to 40% of all intracranial neoplasms and are found most frequently in association with lung cancer (50%) and breast cancer (12%). Although brain metastases occur in <4% of all tumors of the gastrointestinal (GI) tract, the incidence of GI brain metastasis is rising in part due to more effective systemic treatments and prolonged survival of patients with GI cancer. Data were collected from 25 studies (11 colorectal, 7 esophageal, 2 gastric, 1 pancreatic, 1 intestinal, 3 all-inclusive GI tract cancer) and 13 case reports (4 pancreatic, 4 gallbladder, and 5 small bowel cancer). Brain metastases are found in 1% of colorectal cancer, 1.2% of esophageal cancer, 0.62% of gastric cancer, and 0.33% of pancreatic cancer cases. Surgical resection with whole brain radiation therapy (WBRT) has been associated with the longest median survival (38.4-262 weeks) compared with surgery alone (16.4-70.8 weeks), stereotactic radiosurgery (20-38 weeks), WBRT alone (7.2-16 weeks), or steroids (4-7 weeks). Survival in patients with brain metastasis from GI cancer was found to be diminished compared with metastases arising from the breast, lung, or kidney. Prolonged survival and improvement in clinical symptoms has been found to be best achieved with surgical resection and WBRT. Although early treatment has been linked to prolonged survival and improved quality of life, brain metastases represent a late manifestation of GI cancers and remain an ominous sign.

  11. Brain metastasis: analysis of patients without known cancer

    SciTech Connect

    Dhopesh, V.P.; Yagnik, P.M.

    1985-02-01

    A retrospective review of the charts of patients receiving radiation therapy for brain metastasis revealed that one third presented neurologic symptoms without prior diagnosis of cancer. Lung cancer was detected in two thirds of this group, and in one third, the primary site remained unknown. There was good clinical and CT correlation. CT scans with and without contrast injection were evaluated in the study. 6 references, 4 tables.

  12. EGFR and HER2 signaling in breast cancer brain metastasis

    PubMed Central

    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. PMID:26709660

  13. Frequency of brain metastasis in adenocarcinoma and large cell carcinoma of the lung: correlation with survival

    SciTech Connect

    Komaki, R.; Cox, J.D.; Stark, R.

    1983-10-01

    From January 1970 through December 1981, 469 patients with histologically or cytologically proven adenocarcinoma (AC) (349) and large cell carcinoma (LC) (120) of the lung were seen at the Department of Radiation Oncology, Medical College of Wisconsin Affiliated Hospitals. One quarter (126/469) of these patients had brain metastasis: 48 patients presented with brain metastasis and 78 patients subsequently developed brain metastasis. Brain was the dominant site of metastasis in 82 patients who received only cranial + thoracic irradiation; 37 patients (17 simultaneous, 20 metachronous) also required irradiation of other sites of metastasis. All 17 patients with LC, and 47/61 (77%) with AC who developed metachronous brain metastasis did so within one year. The cumulative probability of brain metastasis increased with survival to the levels predicted by autopsy studies. Therapeutic brain irradiation may result in long-term survival in patients with single organ brain metastasis. Since patients with AC and LC so frequently develop brain metastasis and the brain may be the only site of metastasis, prophylactic cranial irradiation may significantly reduce morbidity and mortality from these diseases.

  14. Comparing available criteria for measuring brain metastasis response to immunotherapy.

    PubMed

    Qian, Jack M; Mahajan, Amit; Yu, James B; Tsiouris, A John; Goldberg, Sarah B; Kluger, Harriet M; Chiang, Veronica L S

    2017-03-08

    The response assessment in neuro-oncology (RANO) working group recently proposed standardized response criteria for brain metastases (RANO-BM). We sought to compare RANO-BM to other criteria in an ongoing brain metastasis trial. The first 36 patients enrolled on NCT02085070, an ongoing trial of pembrolizumab for patients with untreated brain metastases, were included in this analysis. As RANO-BM had not been proposed when the protocol was written, response on trial was assessed using an institutional modification of RECIST 1.1 (mRECIST), wherein minimum target brain lesion size was 5 mm in longest diameter and up to five target brain lesions were followed. We here additionally assessed response using standard RECIST 1.1, RANO high-grade glioma (RANO-HGG), and RANO-BM. Comparison between the four criteria sets using cases eligible across the board revealed excellent concordance (kappa statistic > 0.8), with only one discordant case. However, compared to RECIST 1.1 or RANO-BM, using a 5 mm threshold for target brain lesions in mRECIST allowed enrollment of 13 additional patients, five of whom had durable responses. Compared to RANO-HGG, 19 additional patients were enrolled using mRECIST, eight of whom had durable responses. Consequently, this resulted in response rates ranging from 12% with RANO-HGG to 28% with mRECIST. This study supports using a 5 mm threshold for target brain lesions when using high resolution MRI with ≤2 mm slices to facilitate accrual to similar clinical trials and provide earlier access to novel therapies for brain metastasis patients. Concordance among the four criteria studied was otherwise very high.

  15. Differential Reactions of Microglia to Brain Metastasis of Lung Cancer

    PubMed Central

    He, Bei Ping; Wang, Jian Jun; Zhang, Xian; Wu, Yan; Wang, Miao; Bay, Boon-Huat; Chang, Alex Yuang-Chi

    2006-01-01

    The brain is a common metastatic site for various types of cancers, especially lung cancer. Patients with brain metastases have a poor prognosis in spite of radiotherapy and/or chemotherapy. It is postulated that immune cells in the brain may play a major role in cancer metastasis, dormancy, and relapse. Although microglia may serve as a major component in the brain immune system, the interaction between metastatic cancer cells and microglia is still largely unknown and remains to be elucidated. In this study, we have investigated microglial reactions in brain tissues with metastatic lung cancer cells and evaluated the cytotoxic effects of lipopolysaccharide (LPS)-activated microglia on metastatic lung cancer cells in vitro. In the vicinity of metastatic lung cancer mass in the brain, microglia showed signs of significant activation. There was an obvious increase in the number of microglia labeled with ionized calcium binding adaptor molecule 1 (Iba-1) antibody, a specific marker of microglia. The microglia were observed to form a clear boundary between the tumor mass and normal brain tissue. In the region where the tumor mass was situated, only a few microglia expressed inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α), indicating differential activation in those microglia. The supernatant from LPS-activated microglia induced apoptosis of metastatic lung cancer cells in vitro in a dose- and time-dependent manner. However, at lower concentrations of activated microglial supernatant, trophic effects on cancer cells were observed, some lung cancer cells being insensitive to microglial cytotoxicity. Together with the observation that TNF-α alone induced proliferation of the tumor cells, the findings provide possible clues to the mechanism involved in metastasis of lung cancer cells to the brain. PMID:17088948

  16. [Brain metastasis: clinical and cognitive assessments].

    PubMed

    Ramirez, Carole; Blonski, Marie; Belin, Catherine; Carpentier, Antoine; Taillia, Hervé

    2013-01-01

    The incidence of brain metastases (BM) has increased due to the improvement of therapeutics and diagnostic imaging, but also to an aging population. The initial symptoms may develop suddenly or insidiously over weeks or months. The symptoms depend on the location of the BM and related complications (hydrocephalus, tumor hemorrhage, cerebral herniation). Headaches are the most frequent symptoms (50%); they are related to intracranial hypertension. Cognitive deficits are commonly described at diagnosis (67 to 90.5%). Cognitive assessment is essential because of its impact on patients' prognosis and quality of life. Nevertheless, these deficits remain underestimated. The Karnofsky Perfomance Scale and the Mini Mental State Examination (MMSE) seem inadequate. A short battery was proposed and internationally validated, assessing seven domains: attention (Digit Symbol Test WAIS-III), episodic memory (Hopkins Verbal Learning Test [HVLT]), working memory (Digit Span Test WAIS-III), verbal fluency (Controlled Oral Word Association Test [COWA]), fine motor dexterity (Grooved Pegboard Test), information processing speed (Trail Making Test [TMT] A) and executive functions (TMT B). This battery is relevant, feasible and associated with a good compliance. These cognitive tests are currently recommended to assess cognitive functions in patients with BM.

  17. 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

  18. Characteristics and Treatments of Large Cystic Brain Metastasis: Radiosurgery and Stereotactic Aspiration

    PubMed Central

    Kim, Moinay; Cheok, Stephanie; Chung, Lawrance K.; Ung, Nolan; Thill, Kimberly; Voth, Brittany; Kwon, Do Hoon; Kim, Jeong Hoon; Kim, Chang Jin; Tenn, Stephen; Lee, Percy

    2015-01-01

    Brain metastasis represents one of the most common causes of intracranial tumors in adults, and the incidence of brain metastasis continues to rise due to the increasing survival of cancer patients. Yet, the development of cystic brain metastasis remains a relatively rare occurrence. In this review, we describe the characteristics of cystic brain metastasis and evaluate the combined use of stereotactic aspiration and radiosurgery in treating large cystic brain metastasis. The results of several studies show that stereotactic radiosurgery produces comparable local tumor control and survival rates as other surgery protocols. When the size of the tumor interferes with radiosurgery, stereotactic aspiration of the metastasis should be considered to reduce the target volume as well as decreasing the chance of radiation induced necrosis and providing symptomatic relief from mass effect. The combined use of stereotactic aspiration and radiosurgery has strong implications in improving patient outcomes. PMID:25977901

  19. Leptomeningeal metastasis from gynecologic cancers diagnosed by brain MRI.

    PubMed

    Toyoshima, Masafumi; Tsuji, Keita; Shigeta, Shogo; Tokunaga, Hideki; Ito, Kiyoshi; Watanabe, Yoh; Yoshinaga, Kosuke; Otsuki, Takeo; Niikura, Hitoshi; Yaegashi, Nobuo

    Leptomeningeal metastasis (LM) is rarely observed in gynecologic cancers. As gadolinium-enhanced magnetic resonance imaging (Gd-MRI) is highly effective for diagnosing LM, the aim of this study is to describe the clinical behaviors and outcomes of LM patients who were diagnosed by Gd-MRI. After securing institutional review board approvals, we retrospectively reviewed patient records. Eight patients were found to have LM from gynecological malignancies. Primary tumors included three ovarian cancers, one tubal cancer, one peritoneal cancer, two endometrial cancers, and one cervical cancer. Gd-MRI of the brain and the spine is indicated as the high-priority inspection for the diagnosis of this devastating complication.

  20. 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.

  1. Scalp Seeding Post Craniotomy and Radiosurgery for Solitary Brain Metastasis: A Case Report and Systematic Review

    PubMed Central

    Mulroy, Liam; Weeks, Adrienne; Mansoor, Samina; Pahil, Rajbir; Islam, Muhammad U

    2017-01-01

    Background   Radiosurgery is being increasingly used post craniotomy for brain metastasis, instead of whole-brain radiation. We report a case of scalp metastasis following craniotomy and radiosurgery, along with a systematic review of the literature. Methods         Our patient was a 70-year-old male who presented with a scalp metastasis, two years after craniotomy and radiosurgery, for a solitary brain metastasis from esophageal carcinoma. Using Medline® (United States National Library of Medicine, Bethesda, MD), we performed a systematic review of the literature to identify cases of isolated scalp metastases following craniotomy for brain lesions. Results           The scalp metastasis was in close proximity to the craniotomy site. Workup did not show any other site of active disease. Biopsy confirmed it to be a metastasis from esophageal carcinoma. The literature review did not yield any case of isolated scalp metastasis following craniotomy and whole-brain radiotherapy or radiosurgery. However, it yielded six cases of isolated scalp metastases following craniotomy for primary brain tumors. Conclusion     Isolated scalp metastasis has not been reported following craniotomy and whole-brain radiotherapy for brain metastases. Our patient likely had surgical seeding during craniotomy. These surgically implanted cells could not be ablated because the radiosurgery treatment volume does not cover the surgical tract. Further research is needed to identify risk factors for surgical seeding.

  2. The Biology of Brain Metastasis: Challenges for Therapy.

    PubMed

    Fidler, Isaiah J

    2015-01-01

    Many patients with lung cancer, breast cancer, and melanoma develop brain metastases that are resistant to conventional therapy. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with surgery, radiotherapy, and chemotherapy. The outcome of metastasis depends on multiple interactions of unique metastatic cells with host homeostatic mechanisms which the tumor cells exploit for their survival and proliferation. The blood-brain barrier is leaky in metastases that are larger than 0.5-mm diameter because of production of vascular endothelial growth factor by metastatic cells. Brain metastases are surrounded and infiltrated by microglia and activated astrocytes. The interaction with astrocytes leads to up-regulation of multiple genes in the metastatic cells, including several survival genes that are responsible for the increased resistance of tumor cells to cytotoxic drugs. These findings substantiate the importance of the "seed and soil" hypothesis and that successful treatment of brain metastases must include targeting of the organ microenvironment.

  3. Cognition in patients with newly diagnosed brain metastasis: profiles and implications.

    PubMed

    Gerstenecker, Adam; Nabors, Louis B; Meneses, Karen; Fiveash, John B; Marson, Daniel C; Cutter, Gary; Martin, Roy C; Meyers, Christina A; Triebel, Kristen L

    2014-10-01

    Cognitive impairment is a common symptom in patients with brain metastasis, and significant cognitive dysfunction is prevalent in a majority of patients who are still able to engage in basic self-care activities. In the current study, the neurocognitive performance of 32 patients with brain metastasis and 32 demographically-matched controls was examined using a battery of standardized neuropsychological tests, with the goal of comprehensively examining the cognitive functioning of newly diagnosed brain metastasis patients. The cognition of all patients was assessed within 1 week of beginning treatment for brain metastasis. Results indicated impairments in verbal memory, attention, executive functioning, and language in relation to healthy controls. Performance in relation to appropriate normative groups was also examined. Overall, cognitive deficits were prevalent and memory was the most common impairment. Given that cognitive dysfunction was present in this cohort of patients with largely minimal functional impairment, these results have implications for patients, caregivers and health care providers treating patients with brain metastasis.

  4. 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.

  5. 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.

  6. Incidence of brain metastasis at initial presentation of lung cancer

    PubMed Central

    Villano, J. Lee; Durbin, Eric B.; Normandeau, Chris; Thakkar, Jigisha P.; Moirangthem, Valentina; Davis, Faith G.

    2015-01-01

    Background No reliable estimates are available on the incidence of brain metastasis (BM) in cancer patients. This information is valuable for planning patient care and developing measures that may prevent or decrease the likelihood of metastatic brain disease. Methods We report the first population-based analysis on BM incidence at cancer diagnosis using the Kentucky Cancer Registry (KCR) and Alberta Cancer Registry (ACR). All cancer cases with BM were identified from KCR and ACR, with subsequent focus on metastases from lung primaries; the annual number of BMs at initial presentation was derived. Comparisons were made between Kentucky and Alberta for the stage and site of organ involvement of lung cancer. Results Low incidence of BM was observed in the United States until mandatory reporting began in 2010. Both the KCR and ACR recorded the highest incidence of BM from lung cancer, with total BM cases at initial presentation occurring at 88% and 77%, respectively. For lung cancer, stage IV was the most common stage at presentation for both registries and ranged from 45.9% to 57.2%. When BM from lung was identified, the most common synchronous organ site of metastasis was osseous, occurring at 28.4%. Conclusion Our analysis from the Kentucky and Alberta cancer registries similarly demonstrated the aggressive nature of lung cancer and its propensity for BM at initial presentation. Besides widespread organ involvement, no synchronous organ site predicted BM in lung cancer. BM is a common and important clinical outcome, and use of registry data is becoming more available. PMID:24891450

  7. Brain metastasis in two patients with stage IA papillary serous carcinoma of the uterus

    PubMed Central

    Narasimhulu, Deepa M.; Khulpateea, Neekianund; Meritz, Keith; Xu, Yiquing

    2015-01-01

    We report two cases of brain metastasis in patients initially diagnosed with extremely early stage UPSC after extensive staging surgery. They did not receive either adjuvant chemotherapy or adjuvant pelvic or vaginal cuff radiation. At the same time that these patients were diagnosed with systemic metastasis, they both had a local “drop” metastasis in the vulva or the vaginal cuff. After the initial response to palliative chemotherapy, they both developed brain metastasis. The pattern of recurrence with the lack of adjuvant treatment underscores the urgent need in further evaluation of the potential benefits of adjuvant treatment, including chemotherapy and possibly in combination with radiation in this highly aggressive disease. PMID:26425708

  8. Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer.

    PubMed

    Shen, Liqin; Chen, Lei; Wang, Yongsheng; Jiang, Xiaochun; Xia, Hongping; Zhuang, Zhixiang

    2015-01-01

    Brain metastasis often has a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Therefore, it is urgent to identify factors associated with lung cancer brain metastasis. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) also known as noncoding nuclear-enriched abundant transcript 2 is a long noncoding RNA, which is highly conserved amongst mammals. It has been shown to be increased in a variety of tumors including NSCLC and regulate the expression of metastasis-associated genes. However, the role of MALAT1 in lung cancer brain metastasis has not been investigated. In this study, we examined the level of MALAT1 in 78 cases of NSCLC samples with 19 brain metastasis and 59 non-brain metastasis by qRT-PCR. We observed that the level of MALAT1 was significantly higher in brain metastasis than that of non brain metastasis samples (P < 0.001). The level of MALAT1 was associated with patients' survival. To investigate the role of MALAT1 in brain metastasis, we established a highly invasive and metastatic cell subline using the brain metastasis lung cancer cell H1915. We found that MALAT1 is increased in highly invasive subline of brain metastasis lung cancer cells. Further functional studies indicate that silencing MALAT1 inhibits highly invasive subline of brain metastasis lung cancer cell migration and metastasis by inducing epithelial-mesenchymal transition (EMT). Therefore, increased level of long noncoding RNA MALAT1 promotes lung cancer brain metastasis by inducing EMT, which may be a promising prognosis factor and therapeutic target to treat lung cancer brain metastasis in future.

  9. Metastasis

    MedlinePlus

    ... Trials Database Supporting Research Raising Awareness Our Blog Patient Education Pancreas News Basics of Pancreatic Cancer FAQs The ... Detection- Goggins Lab Sol Goldman Center Discussion Board Patient Education / Diagnosis Metastasis A major concern when diagnosing a ...

  10. Pazopanib reveals a role for tumor cell B-Raf in the prevention of HER2+ breast cancer brain metastasis

    PubMed Central

    Gril, Brunilde; Palmieri, Diane; Qian, Yong; Smart, DeeDee; Ileva, Lilia; Liewehr, David J.; Steinberg, Seth M.; Steeg, Patricia S.

    2010-01-01

    Purpose Brain metastases of breast cancer contribute significantly to patient morbidity and mortality. We have tested pazopanib, a recently approved anti-angiogenic drug that targets VEGFR1-3, PDGFRβ, PDGFRα and c-kit, for prevention of experimental brain metastases and mechanism of action. Experimental Design In vitro assays included B-Raf enzymatic assays, western blots and angiogenesis assays. For in vivo assays, HER2 transfectants of the brain seeking sublines of MDA-MB-231 cells (231-BR-HER2) and MCF7 cells (MCF7-HER2-BR3, derived herein) were injected into the left cardiac ventricle of mice and treated with vehicle or pazopanib beginning on day 3 post-injection. Brain metastases were counted histologically, imaged and immunostained. Results Treatment with 100 mg/kg pazopanib resulted in a 73% decline in large 231-BR-HER2 metastases (p<0.0001) and 39% decline in micrometastases (p=0.004). In vitro, pazopanib was directly anti-proliferative to 231-BR-HER2 breast cancer cells and inhibited MEK and ERK activation in vitro despite B-Raf and Ras mutations. Enzymatic assays demonstrated that pazopanib directly inhibited the wild type and exon 11 oncogenic mutant, but not the V600E mutant forms of B-Raf. Activation of the B-Raf targets pERK1/2 and pMEK1/2 was decreased in pazopanib treated brain metastases while blood vessel density was unaltered. In the MCF7-HER2-BR3 experimental brain metastasis model, pazopanib reduced overall brain metastasis volume upon MRI imaging by 55% (p=0.067), without affecting brain metastasis vascular density. Conclusions The data identify a new activity for pazopanib directly on tumor cells as a pan-Raf inhibitor, and suggest its potential for prevention of brain metastatic colonization of HER2+ breast cancer. PMID:21081656

  11. The relevance of serum carcinoembryonic antigen as an indicator of brain metastasis detection in advanced non-small cell lung cancer.

    PubMed

    Lee, Dong-Soo; Kim, Yeon-Sil; Jung, So-Lyoung; Lee, Kyo-Young; Kang, Jin-Hyoung; Park, Sarah; Kim, Young-Kyoon; Yoo, Ie-Ryung; Choi, Byung-Ock; Jang, Hong-Seok; Yoon, Sei-Chul

    2012-08-01

    Although many biomarkers have emerged in non-small cell lung cancer (NSCLC), the predictive value of site-specific spread is not fully defined. We designed this study to determine if there is an association between serum biomarkers and brain metastasis in advanced NSCLC. We evaluated 227 eligible advanced NSCLC patients between May 2005 and March 2010. Patients who had been newly diagnosed with stage IV NSCLC but had not received treatment previously, and had available information on at least one of the following pretreatment serum biomarkers were enrolled: carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA 21-1), cancer antigen 125 (CA 125), cancer antigen 19-9, and squamous cancer cell antigen. Whole body imaging studies and magnetic resonance imaging of the brain were reviewed, and the total number of metastatic regions was scored. Brain metastasis was detected in 66 (29.1%) patients. Although serum CEA, CYFRA 21-1, and CA 125 levels were significantly different between low total metastatic score group (score 1-3) and high total metastatic score group (score 4-7), only CEA level was significantly different between patients with brain metastasis and those without brain metastasis (p < 0.0001). The area under the receiver operating curve of serum CEA for the prediction of brain metastasis was 0.724 (p = 0.0001). The present study demonstrated that the pretreatment serum CEA level was significantly correlated with brain metastasis in advanced NSCLC. These findings suggested the possible role of CEA in the pathogenesis of brain invasion. More vigilant surveillance would be warranted in the high-risk group of patients with high serum CEA level and multiple synchronous metastasis.

  12. 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.

  13. 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.

  14. Dissection of the Process of Brain Metastasis Reveals Targets and Mechanisms for Molecular-based Intervention.

    PubMed

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

    2016-01-01

    Brain metastases outnumber the incidence of brain tumors by a factor of ten. Patients with brain metastases have a dismal prognosis and current treatment modalities achieve only a modest clinical benefit. We discuss the process of brain metastasis with respect to mechanisms and involved targets to outline options for therapeutic intervention and focus on breast and lung cancer, as well as melanoma. We describe the process of penetration of the blood-brain-barrier (BBB) by disseminated tumor cells, establishment of a metastatic niche, colonization and outgrowth in the brain parenchyma. Furthermore, the role of angiogenesis in colonization of the brain parenchyma, interactions of extravasated tumor cells with microglia and astrocytes, as well as their propensity for neuromimicry, is discussed. We outline targets suitable for prevention of metastasis and summarize targets suitable for treatment of established brain metastases. Finally, we highlight the implications of findings revealing druggable mutations in brain metastases that cannot be identified in matching primary tumors.

  15. Brain metastasis from pancreatic cancer: A case report and literature review.

    PubMed

    Matsumoto, Hiroaki; Yoshida, Yasuhisa

    2015-01-01

    A 68-year-old man presented to our hospital with a 1-month history of slowly progressing altered mental status and gait disturbance. Magnetic resonance imaging and abdominal computed tomography revealed advanced pancreatic cancer (PC) with brain and para-aortic lymph node metastases. Gross total resection of the brain metastatic tumor was performed. Although symptoms improved, the patient died 3 months postoperatively. In general, the prognosis for PC patients with brain metastasis is very poor. Surgical resection of brain metastasis may play a very limited role in allowing long-term survival of patients for whom the primary PC is controlled or with particular oncocytic-type tumors.

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

    PubMed

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

    2015-08-07

    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.

  17. Uterine cervical cancer with brain metastasis as the initial site of presentation.

    PubMed

    Sato, Yumi; Tanaka, Kei; Kobayashi, Yoichi; Shibuya, Hiromi; Nishigaya, Yoshiko; Momomura, Mai; Matsumoto, Hironori; Iwashita, Mitsutoshi

    2015-07-01

    Brain metastasis from uterine cervical cancer is rare, with an incidence of 0.5%, and usually occurs late in the course of the disease. We report a case of uterine cervical cancer with brain metastasis as the initial site of presentation. A 50-year-old woman with headache, vertigo, amnesia and loss of appetite was admitted for persistent vomiting. Contrast enhanced computed tomography showed a solitary right frontal cerebral lesion with ring enhancement and uterine cervical tumor. She was diagnosed with uterine cervical squamous cell carcinoma with parametrium invasion and no other distant affected organs were detected. The cerebral lesion was surgically removed and pathologically proved to be metastasis of uterine cervical squamous cell carcinoma. The patient underwent concurrent chemoradiotherapy, followed by cerebral radiation therapy, but multiple metastases to the liver and lung developed and the patient died 7 months after diagnosis of brain metastasis.

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

    PubMed

    Yang, Ge-Liang; Luo, Tian-Hang; Zhang, Hui-Qing; Ling, Chang-Quan; Li, Bai

    2016-04-01

    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.

  19. The Influence of Neuronal Activity on Breast Tumor Metastasis to the Brain

    DTIC Science & Technology

    2009-09-01

    drugs to alter brain activity: caffeine, methylphenidate and modafinil . While the smallest effect may be expected from caffeine which is not as potent...caffeine, we have initiated experiments to test the effects of modafinil on breast tumor metastasis to the brain in our model. Unfortunately, we have had

  20. The metastatic microenvironment: Claudin-1 suppresses the malignant phenotype of melanoma brain metastasis.

    PubMed

    Izraely, Sivan; Sagi-Assif, Orit; Klein, Anat; Meshel, Tsipi; Ben-Menachem, Shlomit; Zaritsky, Assaf; Ehrlich, Marcelo; Prieto, Victor G; Bar-Eli, Menashe; Pirker, Christine; Berger, Walter; Nahmias, Clara; Couraud, Pierre-Olivier; Hoon, Dave S B; Witz, Isaac P

    2015-03-15

    Brain metastases occur frequently in melanoma patients with advanced disease whereby the prognosis is dismal. The underlying mechanisms of melanoma brain metastasis development are not well understood. Identification of molecular determinants regulating melanoma brain metastasis would advance the development of prevention and therapy strategies for this disease. Gene expression profiles of cutaneous and brain-metastasizing melanoma variants from three xenograft tumor models established in our laboratory revealed that expression of tight junction component CLDN1 was lower in the brain-metastasizing variants than in cutaneous variants from the same melanoma. The objective of our study was to determine the significance of CLDN1 downregulation/loss in metastatic melanoma and its role in melanoma brain metastasis. An immunohistochemical analysis of human cells of the melanocyte lineage indicated a significant CLDN1 downregulation in metastatic melanomas. Transduction of melanoma brain metastatic cells expressing low levels of CLDN1 with a CLDN1 retrovirus suppressed their metastatic phenotype. CLDN1-overexpressing melanoma cells expressed a lower ability to migrate and adhere to extracellular matrix, reduced tumor aggressiveness in nude mice and, most importantly, eliminated the formation of micrometastases in the brain. In sharp contrast, the ability of the CLDN1-overexpressing cells to form lung micrometastases was not impaired. CLDN1-mediated interactions between these cells and brain endothelial cells constitute the mechanism underlying these results. Taken together, we demonstrated that downregulation or loss of CLDN1 supports the formation of melanoma brain metastasis, and that CLDN1 expression could be a useful prognostic predictor for melanoma patients with a high risk of brain metastasis.

  1. 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.

  2. 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.

  3. Cognition in patients with newly diagnosed brain metastasis: profiles and implications

    PubMed Central

    Gerstenecker, Adam; Nabors, Louis B.; Meneses, Karen; Fiveash, John B.; Marson, Daniel C.; Cutter, Gary; Martin, Roy C.; Meyers, Christina A.; Triebel, Kristen L.

    2015-01-01

    Cognitive impairment is a common symptom in patients with brain metastasis, and significant cognitive dysfunction is prevalent in a majority of patients who are still able to engage in basic self-care activities. In the current study, the neurocognitive performance of 32 patients with brain metastasis and 32 demographically-matched controls was examined using a battery of standardized neuropsychological tests, with the goal of comprehensively examining the cognitive functioning of newly diagnosed brain metastasis patients. The cognition of all patients was assessed within 1 week of beginning treatment for brain metastasis. Results indicated impairments in verbal memory, attention, executive functioning, and language in relation to healthy controls. Performance in relation to appropriate normative groups was also examined. Overall, cognitive deficits were prevalent and memory was the most common impairment. Given that cognitive dysfunction was present in this cohort of patients with largely minimal functional impairment, these results have implications for patients, caregivers and health care providers treating patients with brain metastasis. PMID:25035099

  4. Differentiation of Glioblastoma from Brain Metastasis: Qualitative and Quantitative Analysis Using Arterial Spin Labeling MR Imaging

    PubMed Central

    Sunwoo, Leonard; You, Sung-Hye; Yoo, Roh-Eul; Kang, Koung Mi; Choi, Seung Hong; Kim, Ji-hoon; Sohn, Chul-Ho; Park, Sun-Won; Jung, Cheolkyu; Park, Chul-Kee

    2016-01-01

    Purpose To evaluate the diagnostic performance of cerebral blood flow (CBF) by using arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging to differentiate glioblastoma (GBM) from brain metastasis. Materials and Methods The institutional review board of our hospital approved this retrospective study. The study population consisted of 128 consecutive patients who underwent surgical resection and were diagnosed as either GBM (n = 89) or brain metastasis (n = 39). All participants underwent preoperative MR imaging including ASL. For qualitative analysis, the tumors were visually graded into five categories based on ASL-CBF maps by two blinded reviewers. For quantitative analysis, the reviewers drew regions of interest (ROIs) on ASL-CBF maps upon the most hyperperfused portion within the tumor and upon peritumoral T2 hyperintensity area. Signal intensities of intratumoral and peritumoral ROIs for each subject were normalized by dividing the values by those of contralateral normal gray matter (nCBFintratumoral and nCBFperitumoral, respectively). Visual grading scales and quantitative parameters between GBM and brain metastasis were compared. In addition, the area under the receiver-operating characteristic curve was used to evaluate the diagnostic performance of ASL-driven CBF to differentiate GBM from brain metastasis. Results For qualitative analysis, GBM group showed significantly higher grade compared to metastasis group (p = 0.001). For quantitative analysis, both nCBFintratumoral and nCBFperitumoral in GBM were significantly higher than those in metastasis (both p < 0.001). The areas under the curve were 0.677, 0.714, and 0.835 for visual grading, nCBFintratumoral, and nCBFperitumoral, respectively (all p < 0.001). Conclusion ASL perfusion MR imaging can aid in the differentiation of GBM from brain metastasis. PMID:27861605

  5. Multimodal Imaging of Pathophysiological Changes and Their Role in Development of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2010-09-01

    time when systemic disease is under good control. In part, this may be du e to the fact that chemotherapeutic agents that show efficacy against...systemic disease , may have p oor penetration of the blood-brain barrier (BBB), which means that breast cancer metastasis in the brain may remain untreated...located betw een parenchyma and leptomeninges Metastatic lesions at brain parenchyma sho wed significan tly more perfusion, as compared to those l

  6. 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

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

    PubMed

    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

    2015-11-03

    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.

  8. Long-term Survival after Lapatinib Rechallenge in Isolated Brain Metastasis of HER2-positive Breast Cancer

    PubMed Central

    Karagöz, Bülent; Özgün, Alpaslan; Emirzeoğlu, Levent; Tunçel, Tolga; Çelik, Serkan; Bilgi, Oğuz; Kara, Kemal

    2015-01-01

    Lapatinib is an effective drug in HER2-positive breast cancer. We present a case with successful treatment of lapatinib in brain metastasis of HER2+ breast cancer. Forty-eight years old woman was admitted our clinic with early breast cancer. In third years after adjuvant chemotherapy and trastuzumab, isolated and multiple brain metastasis were detected. After whole brain RT, lapatinib (with capecitabine for 10 months and with letrozole for 3 months) has been used. Volumetric reduction of lesions was achieved and symptoms disappeared. When lapatinib discontinued, brain metastasis relapses. Lapatinib plus capecitabine reinduction has been started. Totally, longer survival than 45 months was achieved after first brain metastasis detection. Because both combinations of lapatinib with capecitabine and letrozole were effective and reinduction treatment was successful, presented case has strongly supported activity of lapatinib treatment in brain metastasis of HER2+ breast cancer.

  9. [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.

  10. 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.

  11. Identification of brain- and bone-specific breast cancer metastasis genes.

    PubMed

    Klein, Andreas; Olendrowitz, Christian; Schmutzler, Rita; Hampl, Juergen; Schlag, Peter M; Maass, Nicolai; Arnold, Norbert; Wessel, Ralf; Ramser, Juliane; Meindl, Alfons; Scherneck, Siegfried; Seitz, Susanne

    2009-04-18

    In breast cancer, metastases are relatively widely distributed, with the most common sites being bone, regional lymph nodes, lung, liver, and brain. The detailed mechanism of organ-specific metastasis is poorly understood. In this study, we initiated a search for genes that are implicated in brain or bone metastasis of primary human breast cancer. We generated gene expression profiles of 18 brain and eight bone metastases derived from primary breast tumors. We identified 73 genes differentially expressed between brain and bone metastases. Visualization of the differential gene expression profiles by correspondence and cluster analyses shows that the metastases clearly separate into two distinct groups as an exact reflection of their site of metastasis. Moreover, the analysis of this gene set in primary breast tumors relapsing to either bone or brain allowed accurate categorization of the tumors according to their metastatic site. The identified genes may prove to be excellent markers to predict the site of metastasis in breast cancer patients and could lead to tailor-made therapy to an individual patient.

  12. 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.

  13. Eribulin Mesylate Combined with Local Treatment for Brain Metastasis from Breast Cancer: Two Case Reports.

    PubMed

    Byun, Kyung-Do; Ahn, Sung Gwe; Baik, Hyung Joo; Lee, Anbok; Bae, Ki Beom; An, Min Sung; Kim, Kwang Hee; Shin, Jae Ho; Park, Ha Kyoung; Cho, Heunglae; Jeong, Joon; Kim, Tae Hyun

    2016-06-01

    The prognosis associated with brain metastasis arising from breast cancer is very poor. Eribulin is a microtubule dynamic inhibitor synthesized from halichondrin B, a natural marine product. In a phase III study (EMBRACE), eribulin improved overall survival in patients with heavily pretreated metastatic breast cancers. However, these studies included few patients with brain metastases. Metastatic brain tumors (MBT) were detected during first-line palliative chemotherapy in a 43-year-old woman with breast cancer metastasis to the lung and mediastinal nodes; the genetic subtype was luminal B-like human epidermal growth factor receptor 2 (HER2)-negative. Whole brain radiotherapy (WBRT) followed by eribulin treatment continuously decreased the size, and induced regression, of the MBT with systemic disease stability for 12 months. Another 48-year-old woman with metastatic breast cancer (HER2+ subtype) presented with MBT. Following surgical resection of the tumor, eribulin with concurrent WBRT showed regression of the MBT without systemic progression for 18 months.

  14. Oxidative Stress Increases the Blood Brain Barrier Permeability Resulting in Increased Incidence of Brain Metastasis in BRCA Mutation Carriers

    DTIC Science & Technology

    2014-08-01

    permeability and integrity of the brain endothelium using in vitro and in vivo models. 3) Determine the protective effects of PARP inhibitors and/or selenium ...in preventing BBB-induced damage by oxidative stress, and in inhibiting breast cancer metastasis to the brain. Further, since selenium has anti...inhibitor and ROS inhibitor of BMEC-TJs HBMEC cocultures were preincubated with PARP inhibitor (30mM) or with ROS inhibitor (10mM selenium ) for 6

  15. 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.

  16. Multimodal Imaging of Pathophysiological Changes and Their Role in Development of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2012-09-01

    model. Gordon Research Conference, Waterville, ME, 2012. 4) Zhao, D., Zhou, H., Stafford, J., Thorpe, P. Targeting phosphatidylserine enables the...metastasis in a mouse model. 2. Zhao, D., Zhou, H., Stafford, J., Thorpe, P. Phosphatidylserine -targeting antibody enables clear imaging of brain

  17. 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

  18. Blockade of Kv1.3 channels ameliorates radiation-induced brain injury

    PubMed Central

    Peng, Ying; Lu, Kui; Li, Zichen; Zhao, Yaodong; Wang, Yiping; Hu, Bin; Xu, Pengfei; Shi, Xiaolei; Zhou, Bin; Pennington, Michael; Chandy, K. George; Tang, Yamei

    2014-01-01

    Background Tumors affecting the head, neck, and brain account for significant morbidity and mortality. The curative efficacy of radiotherapy for these tumors is well established, but radiation carries a significant risk of neurologic injury. So far, neuroprotective therapies for radiation-induced brain injury are still limited. In this study we demonstrate that Stichodactyla helianthus (ShK)–170, a specific inhibitor of the voltage-gated potassium (Kv)1.3 channel, protected mice from radiation-induced brain injury. Methods Mice were treated with ShK-170 for 3 days immediately after brain irradiation. Radiation-induced brain injury was assessed by MRI scans and a Morris water maze. Pathophysiological change of the brain was measured by immunofluorescence. Gene and protein expressions of Kv1.3 and inflammatory factors were measured by quantitative real-time PCR, reverse transcription PCR, ELISA assay, and western blot analyses. Kv currents were recorded in the whole-cell configuration of the patch-clamp technique. Results Radiation increased Kv1.3 mRNA and protein expression in microglia. Genetic silencing of Kv1.3 by specific short interference RNAs or pharmacological blockade with ShK-170 suppressed radiation-induced production of the proinflammatory factors interleukin-6, cyclooxygenase-2, and tumor necrosis factor–α by microglia. ShK-170 also inhibited neurotoxicity mediated by radiation-activated microglia and promoted neurogenesis by increasing the proliferation of neural progenitor cells. Conclusions The therapeutic effect of ShK-170 is mediated by suppression of microglial activation and microglia-mediated neurotoxicity and enhanced neurorestoration by promoting proliferation of neural progenitor cells. PMID:24305723

  19. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2013-10-01

    3                          4                  Stack    Autoradiograph a b c I‐ 124 ‐PGN635 PET/CT 231BR normal d d. Detection and...in mice bearing brain metastases. PGN635F(ab’)2 were successfully labeled with I- 124 or I-125 to study its specific targeting of brain metastases...brain metastases in mice. 9 Fig. 4 Autoradiography and PET imaging of I- 124 /125 labeled PGN635 in targeting brain metastases. a

  20. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-12-01

    INVESTIGATOR: Dawen Zhao, M.D., Ph.D. CONTRACTING ORGANIZATION: University of Texas Southwestern Medical Center at Dallas Dallas, TX 75390 REPORT DATE...a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically to tumor...Furthermore, pretreatment with 10Gy of whole brain radiation significantly increased PGN635 binding to tumor vascular endothelial cells and tumor

  1. Imaging the efficacy of UVC irradiation on superficial brain tumors and metastasis in live mice at the subcellular level.

    PubMed

    Momiyama, Masashi; Suetsugu, Atsushi; Kimura, Hiroaki; Kishimoto, Hiroyuki; Aki, Ryoichi; Yamada, Akimitsu; Sakurada, Harumi; Chishima, Takashi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2013-02-01

    The effect of UVC irradiation was investigated on a model of brain cancer and a model of experimental brain metastasis. For the brain cancer model, brain cancer cells were injected stereotactically into the brain. For the brain metastasis model, lung cancer cells were injected intra-carotidally or stereotactically. The U87 human glioma cell line was used for the brain cancer model, and the Lewis lung carcinoma (LLC) was used for the experimental brain metastasis model. Both cancer cell types were labeled with GFP in the nucleus and RFP in the cytoplasm. A craniotomy open window was used to image single cancer cells in the brain. This double labeling of the cancer cells with GFP and RFP enabled apoptosis of single cells to be imaged at the subcellular level through the craniotomy open window. UVC irradiation, beamed through the craniotomy open window, induced apoptosis in the cancer cells. UVC irradiation was effective on LLC and significantly extended survival of the mice with experimental brain metastasis. In contrast, the U87 glioma was relatively resistant to UVC irradiation. The results of this study suggest the use of UVC for treatment of superficial brain cancer or metastasis.

  2. Raman and FTIR microspectroscopy for detection of brain metastasis

    NASA Astrophysics Data System (ADS)

    Bergner, Norbert; Romeike, Bernd F. M.; Reichart, Rupert; Kalff, Rolf; Krafft, Christoph; Popp, Jürgen

    2011-07-01

    Vibrational spectroscopic imaging methods are novel tools to visualise chemical component in tissue without staining. Fourier transform infrared (FTIR) imaging is more frequently applied than Raman imaging so far. FTIR images recorded with a FPA detector have been demonstrated to identify the primary tumours of brain metastases. However, the strong absorption of water makes it difficult to transfer the results to non-dried tissues. Raman spectroscopy with near infrared excitation can be used instead and allows collecting the chemical fingerprint of native specimens. Therefore, Raman spectroscopy is a promising tool for tumour diagnosis in neurosurgery. Scope of the study is to compare FTIR and Raman images to visualize the tumour border and identify spectral features for classification. Brain metastases were obtained from patients undergoing surgery at the university hospital. Brain tissue sections were shock frozen, cryosectioned, dried and the same areas were imaged with both spectroscopic method. To visualise the chemical components, multivariate statistical algorithms were applied for data analysis. Furthermore classification models were trained using supervised algorithms to predict the primary tumor of brain metastases. Principal component regression (PCR) was used for prediction based on FTIR images. Support vector machines (SVM) were used for prediction based on Raman images. The principles are shown for two specimens. In the future, the study will be extended to larger data sets.

  3. 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.

  4. Oxidative Stress Increases the Blood Brain Barrier Permeability Resulting in Increased Incidence of Brain Metastasis in BRCA Mutation Carriers

    DTIC Science & Technology

    2012-02-01

    inhibitors and/or selenium in preventing BBB-induced damage by oxidative stress, and in inhibiting breast cancer metastasis to the brain. Further...since selenium has anti- cancer properties that are linked with protection against oxidative stress and Poly (ADP-ribose) polymerase (PARP) inhibitors...BRCA1 in breast cancer cells resulted in an increase in cell proliferation, anchorage-independent growth, cell migration, invasion and a loss of p21

  5. Oncocytic-type intraductal papillary mucinous neoplasm (IPMN)-derived invasive oncocytic pancreatic carcinoma with brain metastasis - a case report.

    PubMed

    Chiang, Kun-Chun; Yu, Chi-Chang; Chen, Jim-Ray; Huang, Yu-Ting; Huang, Cheng-Cheng; Yeh, Chun-Nan; Tsai, Chien-Sheng; Chen, Li-Wei; Chen, Hsien-Cin; Hsu, Jun-Te; Wang, Cheng-Hsu; Chen, Huang-Yang

    2012-07-09

    Pancreatic cancer is a lethal disease without effective treatments at present. It ranks as s as 4th and 5th in cancer-related mortality in the western countries and worldwide. Locally advanced pancreatic duct carcinoma (PDAC) and metastatic PDAC, usually found the metastases over liver, peritoneum, or lung, have been shown to be with dismal prognosis. Brain metastasis is a rare entity and most cases reported before were found post-mortem. Intraductal papillary mucinous neoplasms of the pancreas (IPMN) has been deemed as a precursor of PDAC with very slow progression rate. Here we reported a case diagnosed with IPMN-derived PDAC with brain metastasis. After surgeries for PDAC and brain metastasis, subsequent chemotherapy and radiotherapy were also given. One and half year after surgery, this patient is still living with good performance status, which may warrant individualization of therapeutic strategy for PDAC with only brain metastasis.

  6. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2014-10-01

    care for these patients is whole brain radiotherapy (WBRT). WBRT, however, is often associated with neurological complications that preclude...offers an opportunity to selectively radiate tumor cells while sparing normal tissues. The high energy β- emitter, Yttrium-90 (90Y), a FDA approved...11. Penetrate the syringe needle into intercoastal space promptly through skin and muscle layers into the left ventricle under the guidance of

  7. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-12-01

    INVESTIGATOR: Rolf A. Brekken CONTRACTING ORGANIZATION: U niveristy of Texas Southwestern Medical Center Dallas, TX 75390-9105 REPORT DATE: December...COVERED (From - To) 30 Sep 2012 - 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Phosphatidylserine for Radioimmunotherapy of Breast...antibody, PGN635, a fully human monoclonal antibody, was used to target exposed PS in the brain metastases. Our data show that PGN635 binds specifically

  8. Integrating structure to protein-protein interaction networks that drive metastasis to brain and lung in breast cancer.

    PubMed

    Engin, H Billur; Guney, Emre; Keskin, Ozlem; Oliva, Baldo; Gursoy, Attila

    2013-01-01

    Blocking specific protein interactions can lead to human diseases. Accordingly, protein interactions and the structural knowledge on interacting surfaces of proteins (interfaces) have an important role in predicting the genotype-phenotype relationship. We have built the phenotype specific sub-networks of protein-protein interactions (PPIs) involving the relevant genes responsible for lung and brain metastasis from primary tumor in breast cancer. First, we selected the PPIs most relevant to metastasis causing genes (seed genes), by using the "guilt-by-association" principle. Then, we modeled structures of the interactions whose complex forms are not available in Protein Databank (PDB). Finally, we mapped mutations to interface structures (real and modeled), in order to spot the interactions that might be manipulated by these mutations. Functional analyses performed on these sub-networks revealed the potential relationship between immune system-infectious diseases and lung metastasis progression, but this connection was not observed significantly in the brain metastasis. Besides, structural analyses showed that some PPI interfaces in both metastasis sub-networks are originating from microbial proteins, which in turn were mostly related with cell adhesion. Cell adhesion is a key mechanism in metastasis, therefore these PPIs may be involved in similar molecular pathways that are shared by infectious disease and metastasis. Finally, by mapping the mutations and amino acid variations on the interface regions of the proteins in the metastasis sub-networks we found evidence for some mutations to be involved in the mechanisms differentiating the type of the metastasis.

  9. 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.

  10. Melanoma brain metastasis globally reconfigures chemokine and cytokine profiles in patient cerebrospinal fluid.

    PubMed

    Lok, Edwin; Chung, Amy S; Swanson, Kenneth D; Wong, Eric T

    2014-04-01

    The aggressiveness of melanoma is believed to be correlated with tumor-stroma-associated immune cells. Cytokines and chemokines act to recruit and then modulate the activities of these cells, ultimately affecting disease progression. Because melanoma frequently metastasizes to the brain, we asked whether global differences in immunokine profiles could be detected in the cerebrospinal fluid (CSF) of melanoma patients and reveal aspects of tumor biology that correlate with patient outcomes. We therefore measured the levels of 12 cytokines and 12 chemokines in melanoma patient CSF and the resulting data were analyzed to develop unsupervised hierarchical clustergrams and heat maps. Unexpectedly, the overall profiles of immunokines found in these samples showed a generalized reconfiguration of their expression in melanoma patient CSF, resulting in the segregation of individuals with melanoma brain metastasis from nondisease controls. Chemokine CCL22 and cytokines IL1α, IL4, and IL5 were reduced in most samples, whereas a subset including CXCL10, CCL4, CCL17, and IL8 showed increased expression. Further, analysis of clusters identified within the melanoma patient set comparing patient outcome suggests that suppression of IL1α, IL4, IL5, and CCL22, with concomitant elevation of CXCL10, CCL4, and CCL17, may correlate with more aggressive development of brain metastasis. These results suggest that global immunokine suppression in the host, together with a selective increase in specific chemokines, constitute a predominant immunomodulatory feature of melanoma brain metastasis. These alterations likely drive the course of this disease in the brain and variations in the immune profiles of individual patients may predict outcomes.

  11. A miRNA-based signature detected in primary melanoma tissue predicts development of brain metastasis

    PubMed Central

    Hanniford, Doug; Zhong, Judy; Koetz, Lisa; Gaziel-Sovran, Avital; Lackaye, Daniel J.; Shang, Shulian; Pavlick, Anna; Shapiro, Richard; Berman, Russell; Darvishian, Farbod; Shao, Yongzhao; Osman, Iman; Hernando, Eva

    2015-01-01

    Purpose Brain metastasis is the major cause of mortality among melanoma patients. A molecular prognostic test that can reliably stratify patients at initial melanoma diagnosis by risk of developing brain metastasis may inform the clinical management of these patients. Experimental Design We performed a retrospective, cohort-based study analyzing genome-wide and targeted microRNA expression profiling of primary melanoma tumors of three patient cohorts (n= 92, n= 119, n= 45) with extensive clinical follow up. We used Cox regression analysis to establish a microRNA-based signature that improves the ability of the current clinicopathologic staging system to predict the development of brain metastasis. Results Our analyses identified a 4-microRNA (miR-150–5p, miR-15b-5p, miR-16–5p, and miR-374b-3p) prognostic signature that, in combination with stage, distinguished primary melanomas that metastasized to the brain from non-recurrent and non-brain-metastatic primary tumors (training cohort: C-index=81.4%, validation cohort: C-index=67.4%, independent cohort: C-index=76.9%). Corresponding Kaplan-Meier curves of high- vs. low-risk patients displayed a clear separation in brain-metastasis-free and overall survival (training: p<0.001, p<0.001, validation: p=0.033, p=0.007, independent: p=0.021, p=0.022, respectively). Finally, of the microRNA in the prognostic model, we found that the expression of a key lymphocyte miRNA, miR-150–5p, which is less abundant in primary melanomas metastatic to brain, correlated with presence of CD45+ tumor infiltrating lymphocytes. Conclusions A prognostic assay based on the described miRNA expression signature combined with the currently used staging criteria may improve accuracy of primary melanoma patient prognoses and aid clinical management of patients, including selection for adjuvant treatment or clinical trials of adjuvant therapies. PMID:26089374

  12. 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.

  13. RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis.

    PubMed

    Sato, Ryo; Nakano, Teppei; Hosonaga, Mari; Sampetrean, Oltea; Harigai, Ritsuko; Sasaki, Takashi; Koya, Ikuko; Okano, Hideyuki; Kudoh, Jun; Saya, Hideyuki; Arima, Yoshimi

    2017-01-01

    Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non-small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.

  14. RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis

    PubMed Central

    Hosonaga, Mari; Koya, Ikuko

    2017-01-01

    Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients. PMID:28210624

  15. Selection of brain metastasis-initiating breast cancer cells determined by growth on hard agar.

    PubMed

    Guo, Lixia; Fan, Dominic; Zhang, Fahao; Price, Janet E; Lee, Ju-Seog; Marchetti, Dario; Fidler, Isaiah J; Langley, Robert R

    2011-05-01

    An approach that facilitates rapid isolation and characterization of tumor cells with enhanced metastatic potential is highly desirable. Here, we demonstrate that plating GI-101A human breast cancer cells on hard (0.9%) agar selects for the subpopulation of metastasis-initiating cells. The agar-selected cells, designated GI-AGR, were homogeneous for CD44(+) and CD133(+) and five times more invasive than the parental GI-101A cells. Moreover, mice injected with GI-AGR cells had significantly more experimental brain metastases and shorter overall survival than did mice injected with GI-101A cells. Comparative gene expression analysis revealed that GI-AGR cells were markedly distinct from the parental cells but shared an overlapping pattern of gene expression with the GI-101A subline GI-BRN, which was generated by repeated in vivo recycling of GI-101A cells in an experimental brain metastasis model. Data mining on 216 genes shared between GI-AGR and GI-BRN breast cancer cells suggested that the molecular phenotype of these cells is consistent with that of cancer stem cells and the aggressive basal subtype of breast cancer. Collectively, these results demonstrate that analysis of cell growth in a hard agar assay is a powerful tool for selecting metastasis-initiating cells in a heterogeneous population of breast cancer cells, and that such selected cells have properties similar to those of tumor cells that are selected based on their potential to form metastases in mice.

  16. Expression of endoplasmic reticulum stress proteins is a candidate marker of brain metastasis in both ErbB-2+ and ErbB-2- primary breast tumors.

    PubMed

    Sanz-Pamplona, Rebeca; Aragüés, Ramón; Driouch, Keltouma; Martín, Berta; Oliva, Baldo; Gil, Miguel; Boluda, Susana; Fernández, Pedro L; Martínez, Antonio; Moreno, Víctor; Acebes, Juan J; Lidereau, Rosette; Reyal, Fabien; Van de Vijver, Marc J; Sierra, Angels

    2011-08-01

    The increasing incidence of breast cancer brain metastasis in patients with otherwise well-controlled systemic cancer is a key challenge in cancer research. It is necessary to understand the properties of brain-tropic tumor cells to identify patients at risk for brain metastasis. Here we attempt to identify functional phenotypes that might enhance brain metastasis. To obtain an accurate classification of brain metastasis proteins, we mapped organ-specific brain metastasis gene expression signatures onto an experimental protein-protein interaction network based on brain metastatic cells. Thirty-seven proteins were differentially expressed between brain metastases and non-brain metastases. Analysis of metastatic tissues, the use of bioinformatic approaches, and the characterization of protein expression in tumors with or without metastasis identified candidate markers. A multivariate analysis based on stepwise logistic regression revealed GRP94, FN14, and inhibin as the best combination to discriminate between brain and non-brain metastases (ROC AUC = 0.85, 95% CI = 0.73 to 0.96 for the combination of the three proteins). These markers substantially improve the discrimination of brain metastasis compared with ErbB-2 alone (AUC = 0.76, 95% CI = 0.60 to 0.93). Furthermore, GRP94 was a better negative marker (LR = 0.16) than ErbB-2 (LR = 0.42). We conclude that, in breast carcinomas, certain proteins associated with the endoplasmic reticulum stress phenotype are candidate markers of brain metastasis.

  17. Eribulin Mesylate Combined with Local Treatment for Brain Metastasis from Breast Cancer: Two Case Reports

    PubMed Central

    Byun, Kyung-Do; Ahn, Sung Gwe; Baik, Hyung Joo; Lee, Anbok; Bae, Ki Beom; An, Min Sung; Kim, Kwang Hee; Shin, Jae Ho; Park, Ha Kyoung; Cho, Heunglae; Jeong, Joon

    2016-01-01

    The prognosis associated with brain metastasis arising from breast cancer is very poor. Eribulin is a microtubule dynamic inhibitor synthesized from halichondrin B, a natural marine product. In a phase III study (EMBRACE), eribulin improved overall survival in patients with heavily pretreated metastatic breast cancers. However, these studies included few patients with brain metastases. Metastatic brain tumors (MBT) were detected during first-line palliative chemotherapy in a 43-year-old woman with breast cancer metastasis to the lung and mediastinal nodes; the genetic subtype was luminal B-like human epidermal growth factor receptor 2 (HER2)-negative. Whole brain radiotherapy (WBRT) followed by eribulin treatment continuously decreased the size, and induced regression, of the MBT with systemic disease stability for 12 months. Another 48-year-old woman with metastatic breast cancer (HER2+ subtype) presented with MBT. Following surgical resection of the tumor, eribulin with concurrent WBRT showed regression of the MBT without systemic progression for 18 months. PMID:27382400

  18. 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

  19. 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.

  20. 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

    2016-04-27

    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

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

    PubMed Central

    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

  2. Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2016-03-01

    post-injection. It generally takes around 30- 60 days for MDA-MB-231 model to form brain metastasis in Rag 1 -/- mice. We have successfully finished...1 AWARD NUMBER: W81XWH-15-1-0021 TITLE: Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain ...Cancer Brain Metastasis 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0021 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Siyuan Zhang 5d. PROJECT

  3. Multi-drug resistance gene (MDR-1) and risk of brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer

    PubMed Central

    Matsuo, Koji; Eno, Michele L.; Ahn, Edward H.; Shahzad, Mian M.K.; Im, Dwight D.; Rosenshein, Neil B.; Sood, Anil K.

    2011-01-01

    Background To evaluate risk factors that predict brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. Methods All patients with FIGO stage I to IV who underwent initial cytoreductive surgery between January 1995 and January 2009 were evaluated. The tumor samples were evaluated for 7 markers including multi-drug resistance gene (MDR-1), DNA aneuploidity and S-phase fraction, human epidermal growth factor receptor 2, estrogen receptor, progesterone receptor, p53 mutation, epidermal growth factor receptor, and CD31. Biomarker expression was evaluated as a predictor of hematogenous metastasis to the following locations: (i) liver and spleen, (ii) lung, and (iii) brain. Results There were 309 cases identified during the period. Of those, five (1.6%, 95%CI 0.2-3.0%) women developed brain metastasis. Time to onset of brain metastasis was significantly longer than for other recurrent sites (median time to recurrence after initial cytoreduction, brain vs lung vs liver, 21.4 vs 12.6 vs 11.0 months, p<0.05). Significantly increased expression of MDR-1 was seen in tumors from women who developed brain metastasis (brain vs non-brain sites, 80% vs 4.2-24.3%, p=0.004). In multivariate analysis, MDR-1 was the only significant variable associated with the risk of brain metastasis. MDR-1 expression predicted brain metastasis (Receiver-operator-characteristic curve analysis, AUC 0.808, p=0.018), and with a 10% positive expression of MDR-1 as the cutoff value, sensitivity, specificity, positive predictive value, negative predictive value, accuracy of prediction of brain metastasis were 80%, 86.1%, 15.4%, 99.3%, and 85.9%, respectively (odds ratio 24.7, 95%CI 2.64-232, p=0.002). Conclusions Increased expression of MDR-1 in the tumor tissue obtained at initial cytoreduction is associated with increased risk of developing brain metastases in women with epithelial ovarian, fallopian tube, or peritoneal cancer. PMID:20921883

  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. Report on mutation in exon 15 of the APC gene in a case of brain metastasis.

    PubMed

    Pećina-Slaus, Nives; Majić, Zeljka; Musani, Vesna; Zeljko, Martina; Cupić, Hrvoje

    2010-03-01

    The study analyzes exon 15 of the adenomatous polyposis coli gene (APC) in a 49-year-old male patient with brain metastasis. The primary site was lung carcinoma. PCR method and direct DNA sequencing of the metastasis and autologous lymphocyte samples identified the presence of a somatic mutation. The substitution was at position 5883 G-A in the metastasis tissue. The mutation was confirmed by RFLP analysis using Msp I endonuclease, since the mutation strikes the Msp I restriction site. Immunohistochemical analysis revealed the lack of protein expression of this tumor suppressor gene. The main molecular activator of the wnt pathway, beta-catenin, was expressed, and located in the nucleus. The mutation is a silent mutation that might have consequences in the creation of a new splice site. Different single-base substitutions in APC exons need not only be evaluated by the predicted change in amino acid sequence, but rather at the nucleotide level itself. In our opinion, such silent mutations should also be incorporated in mutation detection rate and validation.

  7. Inhibition of type I insulin-like growth factor receptor signaling attenuates the development of breast cancer brain metastasis.

    PubMed

    Saldana, Sandra M; Lee, Heng-Huan; Lowery, Frank J; Khotskaya, Yekaterina B; Xia, Weiya; Zhang, Chenyu; Chang, Shih-Shin; Chou, Chao-Kai; Steeg, Patricia S; Yu, Dihua; Hung, Mien-Chie

    2013-01-01

    Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.

  8. [Extracranial metastases of brain tumors--a case report and survey of patients with extracranial metastasis sampled from a report on pathological autopsy cases in Japan].

    PubMed

    Nakamura, K; Hawkin, S; Aizawa, M; Maekubo, H; Kobayashi, N; Ozasa, T; Kunieda, Y; Hokari, I; Matsushima, T; Miyazaki, T

    1986-03-01

    A 36-year-old man who suffered from recurrence of hemangiopericytoma originating in the cerebellar tentorium and multiple extracranial metastasis over 14 years was reported. Analysis of the 104 cases of extracranial metastasis sampled from the Annual of the Pathological Autopsy Cases in Japan revealed that the frequency of extracranial metastasis is 3.8% of all brain tumors. Extracranial metastasis was frequently found in medulloblastoma, glioblastoma multiforme, malignant meningioma and ependymoma. Organs of frequent metastasis were the lung, bone, liver, pleura, and kidney. Bone metastasis was especially frequent in the vertebra.

  9. Triple-negative breast cancer with brain metastasis in a pregnant woman.

    PubMed

    Trinca, Francisco; Inácio, Mariana; Timóteo, Teresa; Dinis, Rui

    2017-02-20

    A woman aged 35 years was diagnosed with triple-negative breast cancer in October 2012. During the investigation, it was discovered that she was pregnant, the patient decided to have an abortion. She was submitted to a radical modified mastectomy and adjuvant chemotherapy followed by adjuvant breast radiotherapy of the left breast. 2 months after the adjuvant treatment, she began to have headaches and dizziness. The cranial MRI (head MRI) showed brain metastasis. She was then treated with whole brain radiotherapy, stereotactic radiosurgery and concomitant temozolomide which resulted in complete response. 1.5 year later, she was able to get pregnant and gave birth to a baby without complications. The previous imaging reassessment performed in September 2016 shows no evidence of recurrent breast cancer.

  10. Brain metastasis in human epidermal growth factor receptor 2-positive breast cancer: from biology to treatment

    PubMed Central

    Koo, Taeryool

    2016-01-01

    Overexpression of human epidermal growth factor receptor 2 (HER2) is found in about 20% of breast cancer patients. With treatment using trastuzumab, an anti-HER2 monoclonal antibody, systemic control is improved. Nonetheless, the incidence of brain metastasis does not be improved, rather seems to be increased in HER2-positive breast cancer. The mainstay treatment for brain metastases is radiotherapy. According to the number of metastatic lesions and performance status of patients, radiosurgery or whole brain radiotherapy can be performed. The concurrent use of a radiosensitizer further improves intracranial control. Due to its large molecular weight, trastuzumab has a limited ability to cross the blood-brain barrier. However, small tyrosine kinase inhibitors such as lapatinib, has been noted to be a promising agent that can be used as a radiosensitizer to affect HER2-positive breast cancer. This review will outline general management of brain metastases and will focus on preclinical findings regarding the radiosensitizing effect of small molecule HER2 targeting agents. PMID:27104161

  11. Unexpected detection of melanoma brain metastasis by PET with iodine-124 betaCIT.

    PubMed

    Cascini, Giuseppe Lucio; Ciarmiello, Andrea; Labate, Angelo; Tamburrini, Stefania; Quattrone, Aldo

    2009-10-01

    To study the potential impact of iodine-124-beta-carbomethoxy-3beta(4-iodophenyl)tropane (I-124 betaCIT) in Parkinson disease, a I-124 betaCIT-PET scan was performed in 30-year-old man with suspected early Parkinson disease. The scan showed normal striatum uptake together with a focal spot in the left parietal cortex. The subsequent magnetic resonance imaging of the brain revealed a corresponding nodular lesion, presumably representing a metastasis. After clinical and diagnostic evaluation, a malignant metastatic melanoma was discovered. betaCIT is a cocaine derivative with a high affinity for dopamine and serotonin transporters mainly used to image the density of the dopamine reuptake transporter. In fact the role of I-123 betaCIT is typically represented by Parkinsonian syndromes of uncertain classification. The iodine-124 betaCIT uptake is a marker of dopamine transporters density, and the presence of focal uptake corresponding to a lesion on magnetic resonance images suggests a specific binding in this case of melanoma brain metastasis.

  12. 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

  13. Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies

    PubMed Central

    Gril, Brunilde; Evans, Lynda; Palmieri, Diane; Steeg, Patricia S.

    2010-01-01

    Central nervous system (CNS) or brain metastasis is an emerging area of interest in organ-specific metastasis research. Lung and breast cancers are the most common types of primary tumors to develop brain metastases. This disease complication contributes significantly to the morbidity and mortality of both of these common cancers; as such, brain metastasis is designated an unmet medical need by the US Food and Drug Administration. Recently, an increase in incidence of CNS disease has been noted in the literature for breast cancer, while it has been an ongoing major complication from lung cancer. Progress in treating brain metastases has been hampered by a lack of model systems, a lack of human tissue samples, and the exclusion of brain metastatic patients from many clinical trials. While each of those is significant, the major impediment to effectively treating brain metastatic disease is the blood–brain barrier (BBB). This barrier excludes most chemotherapeutics from the brain and creates a sanctuary site for metastatic tumors. Recent findings on the biology of this disease and translational leads identified by molecular studies are discussed in this article. PMID:20303257

  14. FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies.

    PubMed

    Martínez-Aranda, Antonio; Hernández, Vanessa; Guney, Emre; Muixí, Laia; Foj, Ruben; Baixeras, Núria; Cuadras, Daniel; Moreno, Víctor; Urruticoechea, Ander; Gil, Miguel; Oliva, Baldo; Moreno, Ferran; González-Suarez, Eva; Vidal, Noemí; Andreu, Xavier; Seguí, Miquel A; Ballester, Rosa; Castella, Eva; Sierra, Angels

    2015-12-29

    Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83-9.71) and 2.55- (95%CI 1.52-4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.

  15. FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies

    PubMed Central

    Martínez-Aranda, Antonio; Hernández, Vanessa; Guney, Emre; Muixí, Laia; Foj, Ruben; Baixeras, Núria; Cuadras, Daniel; Moreno, Víctor; Urruticoechea, Ander; Gil, Miguel; Oliva, Baldo; Moreno, Ferran; González-Suarez, Eva; Vidal, Noemí; Andreu, Xavier; Seguí, Miquel A.; Ballester, Rosa; Castella, Eva; Sierra, Angels

    2015-01-01

    Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83–9.71) and 2.55- (95%CI 1.52–4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis. PMID:26497551

  16. 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

  17. Current treatment strategies for brain metastasis and complications from therapeutic techniques: a review of current literature.

    PubMed

    Platta, Christopher S; Khuntia, Deepak; Mehta, Minesh P; Suh, John H

    2010-08-01

    Each year approximately 170,000 patients are diagnosed with brain metastasis in the United States, making this the most common intracranial tumor in adults. Historically, treatment strategies focused on the use of whole brain radiation therapy (WBRT) for palliation, yielding a median survival time of only 3 to 6 months. The possible effect of WBRT on cognitive function has generated much concern and debate regarding the use of this modality. Thus, the use of WBRT alone, or in conjunction with other treatment modalities should take into account both risks and benefits, to ensure the best patient outcome with regard to disease state and functional status. The advent of technologies permitting local dose-escalation have clearly increased local control rates, and in select patients, even survival, thereby, further intensifying the debate regarding the use of WBRT. Here, we review the use of WBRT, radiosurgery, and resection for the treatment of brain metastases. Further, we will review the use of radiation sensitizers and blood-brain barrier penetrating cytotoxics such as temozolomide. Finally, we will discuss current treatment strategies for possibly maintaining and improving cognitive function for these patients.

  18. MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase.

    PubMed

    Zhang, Lixin; Sullivan, Peggy S; Goodman, Jerry C; Gunaratne, Preethi H; Marchetti, Dario

    2011-02-01

    Heparanase (HPSE) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in brain metastatic breast cancer (BMBC). However, little is known about the regulation of this potential therapeutic target in BMBC, which remains very poorly managed in the clinic. We hypothesized that HPSE gene expression might be regulated by micro RNA that might be exploited therapeutically. Using miRanda and RNAhybrid, we identified miR-1258 as a candidate micro RNA that may directly target HPSE and suppress BMBC. In support of our hypothesis, we found that miR-1258 levels inversely correlated with heparanase expression, enzymatic activity, and cancer cell metastatic propensities, being lowest in highly aggressive BMBC cell variants compared with either nontumorigenic or nonmetastatic human mammary epithelial cells. These findings were validated by analyses of miR-1258 and heparanase content in paired clinical specimens of normal mammary gland versus invasive ductal carcinoma, and primary breast cancer versus BMBC. In regulatory experiments, miR-1258 inhibited the expression and activity of heparanase in BMBC cells, whereas modulating heparanase blocked the phenotypic effects of miR-1258. In functional experiments, stable expression of miR-1258 in BMBC cells inhibited heparanase in vitro cell invasion and experimental brain metastasis. Together, our findings illustrate how micro RNA mechanisms are linked to brain metastatic breast cancer through heparanase control, and they offer a strong rationale to develop heparanase-based therapeutics for treatment of cancer patients with brain metastases, BMBC in particular.

  19. Evaluation of Different Score Index for Predicting Prognosis in Gamma Knife Radiosurgical Treatment for Brain Metastasis

    SciTech Connect

    Franzin, Alberto Snider, Silvia; Picozzi, Piero; Bolognesi, Angelo; Serra, Carlo; Vimercati, Alberto; Passarin, Olga; Mortini, Pietro

    2009-07-01

    Purpose: To assess the utility of the Radiation Therapy Oncology Group Recursive Partitioning Analysis (RPA) and Score Index for Radiosurgery (SIR) stratification systems in predicting survival in patients with brain metastasis treated with Gamma Knife radiosurgery (GKRS). Methods and Materials: A total of 185 patients were included in the study. Patients were stratified according to RPA and SIR classes. The RPA and SIR classes, age, Karnofsky Performance Status (KPS), and systemic disease were correlated with survival. Results: Five patients were lost to follow-up. Median survival in patients in RPA Class 1 (30 patients) was 17 months; in Class 2 (140 patients), 10 months; and in Class 3 (10 patients), 3 months. Median survival in patients in SIR Class 1 (30 patients) was 3 months; in Class 2 (135 patients), 8 months; and in Class 3 (15 patients), 20 months. In univariate testing, age younger than 65 years (p = 0.0004), KPS higher than 70 (p = 0.0001), RPA class (p = 0.0078), SIR class (p = 0.0002), and control of the primary tumor (p = 0.02) were significantly associated with improved outcome. In multivariate analysis, KPS (p < 0.0001), SIR class (p = 0.0008), and RPA class (p = 0.03) had statistical value. Conclusions: This study supports the use of GKRS as a single-treatment modality in this selected group of patients. Stratification systems are useful in the estimation of patient eligibility for GKRS. A second-line treatment was necessary in 30% of patients to achieve distal or local brain control. This strategy is useful to control brain metastasis in long-surviving patients.

  20. (18)F-FET PET Uptake Characteristics in Patients with Newly Diagnosed and Untreated Brain Metastasis.

    PubMed

    Unterrainer, Marcus; Galldiks, Norbert; Suchorska, Bogdana; Kowalew, Lara-Caroline; Wenter, Vera; Schmid-Tannwald, Christine; Niyazi, Maximilian; Bartenstein, Peter; Langen, Karl-Josef; Albert, Nathalie L

    2017-04-01

    In patients with brain metastasis, PET using labeled amino acids has gained clinical importance, mainly regarding the differentiation of viable tumor tissue from treatment-related effects. However, there is still limited knowledge concerning the uptake characteristics in patients with newly diagnosed and untreated brain metastases. Hence, we evaluated the uptake characteristics in these patients using dynamic O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) PET. Methods: Patients with newly diagnosed brain metastases without prior local therapy and (18)F-FET PET scanning were retrospectively identified in 2 centers. Static and dynamic PET parameters (maximal/mean tumor-to-brain-ratio [TBRmax/TBRmean], biologic tumor volume [BTV], and time-activity curves with minimal time to peak [TTPmin]) were evaluated and correlated with MRI parameters (maximal lesion diameter, volume of contrast enhancement) and originating primary tumor. Results: Forty-five brain metastases in 30 patients were included. Forty of 45 metastases (89%) had a TBRmax ≥ 1.6 and were classified as (18)F-FET-positive (median TBRmax, 2.53 [range, 1.64-9.47]; TBRmean, 1.86 [range, 1.63-5.48]; and BTV, 3.59 mL [range, 0.04-23.98 mL], respectively). In 39 of 45 brain metastases eligible for dynamic analysis, a wide range of TTPmin was observed (median, 22.5 min; range, 4.5-47.5 min). All (18)F-FET-negative metastases had a diameter of ≤ 1.0 cm, whereas metastases with a > 1.0 cm diameter all showed pathologic (18)F-FET uptake, which did not correlate with lesion size. The highest variability of uptake intensity was observed within the group of melanoma metastases. Conclusion: Untreated metastases predominantly show increased (18)F-FET uptake, and only a third of metastases < 1.0 cm were (18)F-FET-negative, most likely because of scanner resolution and partial-volume effects. In metastases > 1.0 cm, (18)F-FET uptake intensity was highly variable and independent of tumor size (even intraindividually). (18

  1. 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.

  2. Cystic brain metastasis is associated with poor prognosis in patients with advanced breast cancer

    PubMed Central

    Sun, Bing; Huang, Zhou; Wu, Shikai; Ding, Lijuan; Shen, Ge; Cha, Lei; Wang, Junliang; Song, Santai

    2016-01-01

    Purpose Brain metastasis (BM) with a cystic component from breast cancer is rare and largely uncharacterized. The purpose of this study was to identify the characteristics of cystic BM in a large cohort of breast cancer patients. Results A total of 35 eligible patients with cystic BM and 255 patients with solid BM were analyzed. Three factors were significantly associated with an increased probability of developing cystic lesions: age at diagnosis ≤ 40 years, age at BM ≤ 45 years, and poor histological grade (p < 0.05). Patients with cystic metastasis were also characterized by a larger metastasis volume, a shorter progression-free survival (PFS) following their first treatment for BM, and poor overall survival after BM (p < 0.05). Multivariate analysis further demonstrated that local control of cystic BM was only potentially achieved for HER2-negative primary tumors (p = 0.084). Methods Breast cancer patients with parenchymal BM were reviewed from consecutive cases treated at our institution. Cystic BM was defined when the volume of a cystic lesion was greater than 50% of the aggregated volume of all lesions present. Clinicopathologic and radiographic variables were correlated with development of cystic lesions and with prognosis of cystic BM. Conclusions This study shows that cystic BM from breast cancer, a special morphological type of BM, had worse prognosis than the more commonly observed solid BM. Younger age and low tumor grade were associated with the development of cystic lesions. Further comprehensive research and management of cystic BM are warranted to improve its poor prognosis. PMID:27659537

  3. 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.

  4. Perilesional edema in brain metastasis from non-small cell lung cancer (NSCLC) as predictor of response to radiosurgery (SRS).

    PubMed

    Tini, Paolo; Nardone, Valerio; Pastina, Pierpaolo; Battaglia, Giuseppe; Vinciguerra, Claudia; Carfagno, Tommaso; Rubino, Giovanni; Carbone, Salvatore Francesco; Sebaste, Lucio; Cerase, Alfonso; Federico, Antonio; Pirtoli, Luigi

    2017-03-04

    Radiosurgery (SRS) is widely used in the treatment of brain oligo-metastases from NSCLC. The aim of present study is to evaluate the extent of perilesional edema in brain metastases as predictive factor of treatment response. This single center retrospective study included 42 consecutive patients (January 2011-December 2014) with 1-2 brain metastasis from NSCLC treated with Radiosurgery (SRS). Extent of perilesional edema was measured as maximal extension from the edge of lesion and classified as minor (<10 mm) or major (≥10 mm). We analyzed Modality of Brain Recurrence (MBR), classified as in-field or out-of- field, and Brain Progression Free-Survival (BPFS) after treatment stratified according to extent of perilesional edema. Analyzing modality of brain recurrence and BPFS, after a median follow-up of 6 months, we found that patients with minor edema had a better radiological response to SRS with none in-field recurrences and a lower risk of the onset of new brain lesions (out-of-field recurrence). Instead, patients group with major edema had a worse response rate of lesions treated, further, a higher risk of out-of-field brain relapse. Extent of perilesional edema in brain metastasis from NSCLC could be a predictive factor of response and brain progression after SRS treatment alone.

  5. Ex vivo Evans blue assessment of the blood brain barrier in three breast cancer brain metastasis models.

    PubMed

    Do, John; Foster, Deshka; Renier, Corinne; Vogel, Hannes; Rosenblum, Sahar; Doyle, Timothy C; Tse, Victor; Wapnir, Irene

    2014-02-01

    The limited entry of anticancer drugs into the central nervous system represents a special therapeutic challenge for patients with brain metastases and is primarily due to the blood brain barrier (BBB). Albumin-bound Evans blue (EB) dye is too large to cross the BBB but can grossly stain tissue blue when the BBB is disrupted. The course of tumor development and the integrity of the BBB were studied in three preclinical breast cancer brain metastasis (BCBM) models. A luciferase-transduced braintropic clone of MDA-231 cell line was used. Nude mice were subjected to stereotactic intracerebral inoculation, mammary fat pad-derived tumor fragment implantation, or carotid artery injections. EB was injected 30 min prior to euthanasia at various timepoints for each of the BCBM model animals. Serial bioluminescent imaging demonstrated exponential tumor growth in all models. Carotid BCBM appeared as diffuse multifocal cell clusters. EB aided the localization of metastases ex vivo. Tumor implants stained blue at 7 days whereas gross staining was not evident until day 14 in the stereotactic model and day 28 for the carotid model. EB assessment of the integrity of the BBB provides useful information relevant to drug testing in preclinical BCBM models.

  6. 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).

  7. Incidence and treatment of brain metastasis in patients with esophageal carcinoma

    PubMed Central

    Feng, Wei; Zhang, Peng; Zheng, Xiao; Chen, Ming; Mao, Wei-Min

    2015-01-01

    Brain metastasis from esophageal carcinoma (BMEC) is very rare, but its incidence has increased in the United States, Japan, China and other counties. Reports on BMEC have largely been focused on examining whether adjuvant therapy for esophageal cancer influences the survival duration of BMEC patients and on the imaging characteristics of BMEC determined using new medical equipment. The difference between different pathological types of esophageal cancer, especially adenocarcinoma and squamous cell carcinoma, is one important factor used to assess the influence of BMEC. Adjuvant therapy, including radiotherapy and chemotherapy, for esophageal cancer with different characteristics in different countries may affect BMEC treatment outcomes. The degree of popularization of advanced medical equipment is a major concern related to the prevalence of BMEC. Furthermore, targeted BMEC treatment is under development in developed countries. In this article, we reviewed the debate surrounding BMEC and analyzed BMEC studies from different perspectives. PMID:26019444

  8. 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

    2015-10-06

    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.

  9. Vector-model-supported optimization in volumetric-modulated arc stereotactic radiotherapy planning for brain metastasis.

    PubMed

    Liu, Eva Sau Fan; Wu, Vincent Wing Cheung; Harris, Benjamin; Foote, Matthew; Lehman, Margot; Chan, Lawrence Wing Chi

    2017-03-17

    Long planning time in volumetric-modulated arc stereotactic radiotherapy (VMA-SRT) cases can limit its clinical efficiency and use. A vector model could retrieve previously successful radiotherapy cases that share various common anatomic features with the current case. The prsent study aimed to develop a vector model that could reduce planning time by applying the optimization parameters from those retrieved reference cases. Thirty-six VMA-SRT cases of brain metastasis (gender, male [n = 23], female [n = 13]; age range, 32 to 81 years old) were collected and used as a reference database. Another 10 VMA-SRT cases were planned with both conventional optimization and vector-model-supported optimization, following the oncologists' clinical dose prescriptions. Planning time and plan quality measures were compared using the 2-sided paired Wilcoxon signed rank test with a significance level of 0.05, with positive false discovery rate (pFDR) of less than 0.05. With vector-model-supported optimization, there was a significant reduction in the median planning time, a 40% reduction from 3.7 to 2.2 hours (p = 0.002, pFDR = 0.032), and for the number of iterations, a 30% reduction from 8.5 to 6.0 (p = 0.006, pFDR = 0.047). The quality of plans from both approaches was comparable. From these preliminary results, vector-model-supported optimization can expedite the optimization of VMA-SRT for brain metastasis while maintaining plan quality.

  10. Robustness of the neurological prognostic score in brain metastasis patients treated with Gamma Knife radiosurgery.

    PubMed

    Serizawa, Toru; Higuchi, Yoshinori; Nagano, Osamu; Matsuda, Shinji; Aoyagi, Kyoko; Ono, Junichi; Saeki, Naokatsu; Iwadate, Yasuo; Hirai, Tatsuo; Takemoto, Shinya; Shibamoto, Yuta

    2016-12-02

    OBJECTIVE The neurological prognostic score (NPS) was recently proposed as a means for predicting neurological outcomes, such as the preservation of neurological function and the prevention of neurological death, in brain metastasis patients treated with Gamma Knife radiosurgery (GKRS). NPS consists of 2 groups: Group A patients were expected to have better neurological outcomes, and Group B patients were expected to have poorer outcomes. NPS robustness was tested in various situations. METHODS In total, 3040 patients with brain metastases that were treated with GKRS were analyzed. The cumulative incidence of the loss of neurological function independence (i.e., neurological deterioration) was estimated using competing risk analysis, and NPS was compared between Groups A and B by employing Gray's model. NPS was tested to determine if it can be applied to 5 cancer categories-non-small cell lung cancer, small cell lung cancer, gastrointestinal tract cancer, breast cancer, and other cancers-as well as if it can be incorporated into the 5 major grading systems: recursive partitioning analysis (RPA), score index for stereotactic radiosurgery (SIR), basic score for brain metastases (BSBM), graded prognostic assessment (GPA), and modified-RPA (M-RPA). RESULTS There were 2263 patients in NPS Group A and 777 patients in Group B. Neurological deterioration was observed in 586 patients (19.2%). The cumulative incidences of neurological deterioration were 9.5% versus 21.0%, 14.1% versus 25.4%, and 17.6% versus 27.8% in NPS Groups A and B at 1, 2, and 5 years, respectively. Significant differences were detected between the NPS groups in all cancer categories. There were significant differences between NPS Groups A and B for all classes in terms of the BSBM, GPA, and M-RPA systems, but the differences failed to reach statistical significance in terms of RPA Class I and SIR Class 0 to 3. CONCLUSIONS The NPS was verified as being highly applicable to all cancer categories and

  11. 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.

  12. 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

    2015-10-06

    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.

  13. Tumor markers for early diagnosis for brain metastasis of hepatocellular carcinoma: A case series and literature review for effective loco-regional treatment.

    PubMed

    Kamimura, Kenya; Kobayashi, Yuji; Takahashi, Yoshifumi; Abe, Hiroyuki; Kumaki, Daisuke; Yokoo, Takeshi; Kamimura, Hiroteru; Sakai, Norihiro; Sakamaki, Akira; Abe, Satoshi; Takamura, Masaaki; Kawai, Hirokazu; Yamagiwa, Satoshi; Terai, Shuji

    2017-02-01

    Intrahepatic lesions of hepatocellular carcinoma (HCC) have been controlled by significant advances in treatment using loco-regional therapies, including, surgery, ablative therapy, catheter-based chemotherapy, and embolization. Consequently, the number of patients with extrahepatic metastatic lesions has increased. Their prognosis remains poor with approximately <1 y of survival from the time of diagnosis. A molecularly targeted drug, sorafenib, have been used to treat extrahepatic lesions and shown the prolonged survival time. However, the therapeutic benefit for the brain metastasis remains unclear, since it causes intratumor bleeding leading to the severe brain damage. No guidelines for the brain metastasis of HCC have been developed to date due to the shortage of the experiences and evidences. Therefore, the development of standard therapy for brain metastasis following the early diagnosis is essential by accumulating the information of clinical courses and evidences. For this purpose, we reviewed cases of HCC brain metastasis reported to date and analyzed additional 8 cases from our hospital, reviewing 592 advanced HCC cases to estimate the possible metastatic lesions in the brain. With careful review of cases and literature, we suggest that the cases with lung metastasis with increase tendency of tumor markers within recent 3-6 months have higher risks of brain metastasis. Therefore, they should be carefully followed by imaging modalities. In addition, the loco-regional treatment, including surgical resection and radiation therapy should be performed for better prognosis by preventing re-bleeding from the tumors.

  14. 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.

  15. 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.

  16. 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

  17. A case of radiation retinopathy of left eye after radiation therapy of right brain metastasis.

    PubMed

    Hong, Kwon Ho; Chang, Sung Dong

    2009-06-01

    A 37-year-old female, who had received modified radical mastectomy for cancer of her right breast, presented with decreased visual acuity in the left eye after radiation therapy for the management of the metastasis to her right brain 14 months ago. After ocular examination, we diagnosed her as radiation retinopathy. At the time of the first visit, the corrected best visual acuity was 0.4 in the left eye, and fundus examination revealed cotton wool spots and cystoid macular edema (CME). The findings in the right eye were normal except for cotton wool spots in the superior major arch. Fluorescein angiography (FA) showed marked telangiectasia and microaneurysms in her left eye but tiny microaneurysms in her right eye. Subsequent optical coherent tomography (OCT) showed CME. We injected intravitreal triamcinolone acetonide (TA). Two weeks after treatment, the visual acuity was improved to 0.6 and the retinal thickness was decreased. Three months later, the visual acuity in the left eye was dropped to 0.3 due to the recurrence of CME, so we injected intravitreal TA again. Five months later, visual acuity was improved to 0.5 and OCT revealed the improvement of CME. The incidence of radiation retinopathy is higher in the side nearer to radiation, but careful radiation blocking is also required on the opposite side of irradiation site considering the possibility of radiation retinopathy and careful observation is required on both sides of the eyes when performing fundus examination.

  18. 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.

  19. 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.

  20. Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer.

    PubMed

    Wu, Sheng-Kai; Chiang, Chi-Feng; Hsu, Yu-Hone; Lin, Tzu-Hung; Liou, Houng-Chi; Fu, Wen-Mei; Lin, Win-Li

    2014-01-01

    The blood-brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers.

  1. Disruption of tumour-host communication by downregulation of LFA-1 reduces COX-2 and e-NOS expression and inhibits brain metastasis growth

    PubMed Central

    Soto, Manuel Sarmiento; O'Brien, Emma R.; Andreou, Kleopatra; Scrace, Simon F.; Zakaria, Rasheed; Jenkinson, Michael D.; O'Neill, Eric; Sibson, Nicola R.

    2016-01-01

    Over 20% of cancer patients will suffer metastatic spread to the brain, and prognosis remains poor. Communication between tumour cells and host tissue is essential during metastasis, yet little is known of the processes underlying such interactions in the brain. Here we test the hypothesis that cross-talk between tumour cells and host brain cells, through tumour cell leukocyte function associated protein-1 (LFA-1), is critical in metastasis development. Temporal expression of LFA-1 and its major ligand intercellular adhesion molecule-1 (ICAM-1) was determined in two different mouse models of brain metastasis. Marked upregulation of both proteins was found, co-localising with astrocytes, microglia and tumour cells themselves. Silencing of LFA-1 expression in MDA231Br-GFP cells prior to intracerebral injection resulted in > 70% reduction in tumour burden compared to control MDA231Br-GFP cells (p < 0.005, n = 5). Subsequent qRT-PCR analysis of brain tissue revealed significant reductions in COX-2, VEGF and eNOS from host brain tissue, but not tumour cells, in mice injected with LFA-1 knockdown cells (p < 0.0001, n = 5). Finally, expression of both LFA-1 and ICAM-1 was demonstrated in human brain metastasis samples. The results of this study suggest LFA-1 as a new target in brain metastasis therapy and highlight the potential synergy with current anti-COX-2 and anti-NOS therapies. PMID:27447568

  2. Leptomeningeal metastasis.

    PubMed

    Chamberlain, Marc C

    2010-07-01

    Leptomeningeal metastasis occurs in ~5% of all patients with cancer and is the third most common metastatic complication of the central nervous system. Staging of leptomeningeal metastasis includes contrast-enhanced brain and spine magnetic resonance imaging and radionuclide cerebrospinal fluid (CSF) flow study. Treatment, when clinically indicated, often requires administration of involved-field radiotherapy to bulky or symptomatic disease sites as well as intra-CSF and systemic chemotherapy. The use of high-dose systemic therapy may benefit selected patients with breast- or lymphoma-related leptomeningeal metastasis and obviate the need for intra-CSF chemotherapy. Intra-CSF drug therapy primarily utilizes one of three chemotherapeutic agents (e.g., methotrexate, cytosine arabinoside, and thiotepa) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Beginning to be utilized are novel intra-CSF agents, such as the targeted monoclonal antibodies rituximab (anti-CD20 for B-cell lymphoma-related leptomeningeal metastasis) and trastuzumab (anti-Her2/neu for breast cancer-related leptomeningeal metastasis). Although treatment of leptomeningeal metastasis is palliative with median patient survival of 2 to 3 months, treatment may afford stabilization and protection from further neurologic deterioration in patients with leptomeningeal metastasis.

  3. Noninvasive imaging of the functional effects of anti-VEGF therapy on tumor cell extravasation and regional blood volume in an experimental brain metastasis model.

    PubMed

    JuanYin, Juan; Tracy, Kirsten; Zhang, Luhua; Munasinghe, Jeeva; Shapiro, Erik; Koretsky, Alan; Kelly, Kathleen

    2009-01-01

    Brain metastasis has become an increasing cause of morbidity and mortality in cancer patients as the treatment of systemic disease has improved. Brain metastases frequently are highly vascularized, a process driven primarily by VEGF. VEGF mediates numerous changes within the vasculature including endothelial cell retraction and increased permeability, vasodilation, and new vessel formation. Here we describe a xenograft brain metastasis model that mimics the critical steps of metastasis including tumor cell dissemination and vascular adhesion, tumor growth and tumor associated angiogenesis. Magnetic resonance (MR) imaging was used to evaluate two aspects of the functional response of brain metastasis to the anti-VEGF receptor therapeutic, AZD2171 (Cediranib, RECENTIN). MR tracking of individual cells demonstrated that cediranib did not impede tumor cell extravasation into the brain parenchyma despite evidence that anti-VEGF treatment decreases the permeability of the blood brain barrier. In a second assay, blood volume imaging using ultrasmall superparamagnetic iron oxide revealed that treatment of well-developed brain metastasis with cediranib for 7 days led to a heterogeneous response with respect to individual tumors. Overall, there was a significant average decrease in the tumor vascular bed volume. The majority of large tumors demonstrated substantially reduced central blood volumes relative to normal brain while retaining a rim of elevated blood volume at the tumor brain interface. Small tumors or occasional large tumors displayed a static response. Models and assays such as those described here will be important for designing mechanism-based approaches to the use of anti-angiogenesis therapies for the treatment of brain metastasis.

  4. 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.

  5. A multi-institutional outcome and prognostic factor analysis of radiosurgery (RS) for resectable single brain metastasis

    SciTech Connect

    Auchter, R.M.; Lamond, J.P.; Alexander, E.

    1995-12-31

    Recent randomized trials comparing resection of single brain metastasis (BM) in selected patients (pts) followed by whole brain radiotherapy (WBRT) to WBRT alone demonstrated statistically significant survival advantage for surgery. This multi-institutional retrospective study was performed in similar pts who were treated with RS and WBRT to provide a baseline for comparison for a future randomized trial. The RS databases of four institutions were reviewed to identify all pts who met the following criteria; single BM; ag > 18; surgically resectable lesion; independently functional (KPS {ge} 70); non-radiosensitive histology (small cell, lymphoma, myeloma, germ cell excluded); no prior cranial surgery or WBRT. 122 of 533 pts with BM treated with RS met these criteria.

  6. SU-E-T-306: Dosimetric Comparison of Leaf with Or Without Interdigitation in Multiple Brain Metastasis VMAT Treatment Planning

    SciTech Connect

    2015-06-15

    Purpose: To evaluate the effects of leaf with or without interdigitation in multiple brain metastasis volumetric modulated arc therapy (VMAT) plans. Methods: Twenty patients with 2 to 6 brain metastases of our hospital were retrospectively studied to be planned with dual arc VMAT using Monaco 3.3 TPS on the Elekta Synergy linear accelerator. The prescription dose of PTV was 60Gy/30 fractions. Two plans with or without leaf interdigitation were designed. The homogeneity index (HI), conformity index (CI), dose volume histograms (DVHs), monitor unit (MU), treatment time (T), the segments, the dose coverage of the target, were all evaluated. Results: The plans with leaf interdigitation could achieve better CI (p<0.05) than without leaf interdigitation, while no significant difference were found in HI (p> 0.05) and the dose coverage of the target (p> 0.05).The MU,T, and the segments of the plan with leaf interdigitation were more than the plan without leaf interdigitation (p<0.05). There was no significant difference found in radiation dose of spinal cord, lenses and parotids, while the maximum dose of brain stem of leaf without interdigitation was higher than leaf with interdigitation (p< 0.05). It was worth noting that the areas of low dose regions with leaf interdigitation plan were much less than the without leaf interdigitation plan in the doublication planes (p< 0.05). Conclusion: This study shows that leaf with interdigitation has some advantages than leaf without interdigitation in multiple brain metastasis VMAT plans although the clinical relevance remains to be proven.

  7. 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.

  8. A novel brain metastasis xenograft model for convection‑enhanced delivery of targeted toxins via a micro‑osmotic pump system enabled for real‑time bioluminescence imaging.

    PubMed

    Huang, Jun; Li, Yan Michael; Cheng, Quan; Vallera, Daniel A; Hall, Walter A

    2015-10-01

    Brain metastasis is a common cause of mortality in patients with cancer, and is associated with poor prognosis. There is a current requirement for the identification of relevant brain metastasis tumor models, which may be used to test novel therapeutic agents and delivery systems in pre‑clinical studies. The present study aimed to investigate the development of a murine model of brain metastasis, and the application of bioluminescence imaging (BLI) for monitoring tumor growth and response to targeted toxins (TT). A luciferase‑modified human brain metastasis cell line was implanted into the caudate‑putamen of athymic mice using a stereotactic frame. Tumor growth was monitored by BLI, and tumor volume was calculated from three‑dimensional measurements of serial histopathological sections. Histopathological analyses revealed the presence of tumor growth within the caudate‑putamen of all of the mice, and BLI was shown to be correlated with tumor volume. To evaluate whether this model would allow the detection of a therapeutic response, mice bearing metastatic brain tumor cell xenografts were treated with TT delivered by convection‑enhanced delivery (CED), via a micro‑osmotic pump system. The TT‑treated groups were submitted to metastatic brain tumor cell experiments, the results of which suggested that TT treatment delayed tumor growth, as determined by BLI monitoring, and significantly extended the survival of the mice. The results of the present study demonstrated the efficacy of a brain metastasis model for CED of TT via a micro‑osmotic pump system in athymic mice, in which tumor growth and response to therapy were accurately monitored by BLI. In conclusion, this model may be well‑suited for pre‑clinical testing of potential therapeutics for the treatment of patients with metastatic brain tumors.

  9. miR-15a-3p and miR-16-1-3p Negatively Regulate Twist1 to Repress Gastric Cancer Cell Invasion and Metastasis

    PubMed Central

    Wang, Tao; Hou, Jingjing; Li, Zengpeng; Zheng, Zihan; Wei, Jie; Song, Dan; Hu, Tao; Wu, Qiao; Yang, James Y.; Cai, Jian-chun

    2017-01-01

    MicroRNAs are a novel class of gene regulators that function as oncogenes or tumor suppressors. In our current study, we investigated the role of miR-15a-3p and miR-16-1-3p in the regulation of Twist1 expression and EMT process. Our bioinformatics analysis suggested that on the 3' UTR of Twist1, there are two conserved miRNA recognition sites for miR-15a-3p and miR-16-1-3p respectively. Interestingly, overexpression of miR-15a-3p and miR-16-1-3p significantly suppressed the activity of luciferase reporter containing Twist1-3' UTR, reduced mRNA and protein level of EMT related genes such as TWIST1, N-cadherin, α-SMA and Fibronectin, and repressed MMP9 and MMP2 activity, as well as cell migration and invasion. Conversely, inhibition of miR-15a-3p and miR-16-1-3p significantly increased TWIST1, N-cadherin, α-SMA and Fibronectin protein expression. In addition, Twist1 co-transfection significantly ameliorated the loss of cell migration and invasion. Moreover, overexpression of miR-15a-3p and miR-16-1-3p dramatically suppressed the ability of BGC823 cells to form colonies in vitro and develop tumors in vivo in nude mice. Finally, qPCR and Western blot analysis showed that miR-15a-3p and miR-16-1-3p were significantly reduced in clinical gastric cancer tissue, whereas Twist1 mRNA and protein were significantly up-regulated, suggesting that this aberrant down-regulation of miR-15a-3p and miR-16-1-3p might be associated with the abnormal regulation of Twist1 and the EMT process in gastric cancer development. Our results help to elucidate a novel and important mechanism for the regulation of Twist1 in the development of cancer. PMID:28123352

  10. 1,3-dinitrobenzene induces age- and region-specific oxidation to mitochondria-related proteins in brain.

    PubMed

    Kubik, Laura L; Landis, Rory W; Remmer, Henriette; Bergin, Ingrid L; Philbert, Martin A

    2015-05-01

    Regions of the brain with high energy requirements are especially sensitive to perturbations in mitochondrial function. Hence, neurotoxicant exposures that target mitochondria in regions of high energy demand have the potential to accelerate mitochondrial damage inherently occurring during the aging process. 1,3-Dinitrobenzene (DNB) is a model neurotoxicant that selectively targets mitochondria in brainstem nuclei innervated by the eighth cranial nerve. This study investigates the role of age in the regional susceptibility of brain mitochondria-related proteins (MRPs) to oxidation following exposure to DNB. Male F344 rats (1 month old [young], 3 months old [adult], 18 months old [aged]) were exposed to 10 mg/kg DNB prior to mitochondrial isolation and histopathology experiments. Using a high-throughput proteomic approach, 3 important region- and age-related increases in DNB-induced MRP oxidation were determined: (1) brainstem mitochondria are ×3 more sensitive to DNB-induced oxidation than cortical mitochondria; (2) oxidation of brainstem MRPs is significantly higher than in cortical counterparts; and (3) MRPs from the brainstems of older rats are significantly more oxidized than those from young or adult rats. Furthermore, lower levels of DNB cause signs of intoxication (ataxia, chromodacryorrhea) and vacuolation of the susceptible neuropil in aged animals, while neither is observed in DNB-exposed young rats. Additionally, methemoglobin levels increase significantly in DNB-exposed adult and aged animals, but not young DNB-exposed animals. This suggests that oxidation of key MRPs observed in brainstem of aged animals is necessary for DNB-induced signs of intoxication and lesion formation. These results provide compelling evidence that environmental chemicals such as DNB may aid in the acceleration of injury to specific brain regions by inducing oxidation of sensitive mitochondrial proteins.

  11. 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.

  12. In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways

    PubMed Central

    Daphu, Inderjit; Horn, Sindre; Stieber, Daniel; Varughese, Jobin K.; Spriet, Endy; Dale, Hege Avsnes; Skaftnesmo, Kai Ove; Bjerkvig, Rolf; Thorsen, Frits

    2014-01-01

    Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAFV600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas. PMID:24840574

  13. Development of Magnetic Nanovectors for Treatment and Imaging of Breast Cancer Metastasis to the Brain

    DTIC Science & Technology

    2014-10-01

    shell of a biodegradable polymer PEG-grafted chitosan (CP), which is then subsequently modified with PEI to promote endosomal escape, siRNA designed...knockdown the pro metastasis gene MENA) also are conjugated to the NP polymer overcoat. 15. SUBJECT TERMS Nanotechnology, Targeted Therapies...targeting peptide, chlorotoxin (CTX), and siRNA against the protein Mena is conjugated to the polymer overcoat of the NP. Mena is a protein which is

  14. Clinical characteristics and treatment outcomes of patients with colorectal cancer who develop brain metastasis: a single institution experience

    PubMed Central

    Fountzilas, Christos; Chang, Katherine; Hernandez, Brian; Michalek, Joel; Crownover, Richard; Floyd, John

    2017-01-01

    Background The development of brain metastasis (BM) in patients with colorectal cancer (CRC) is a rare and late event. We sought to investigate the clinical characteristics, disease course and safety using biologic agents in our patients with CRC who develop brain metastases. Methods A retrospective review of patients with CRC with brain metastases treated at our institution from 01/2005–01/2015 was performed. Survival analysis was performed using the Kaplan-Meier method. Results Forty patients were included in the analysis. Median age was 55.5 years, 67.5% were males, and 28% had a KRAS mutation. Twenty-four percent were treatment-naive at the time of BM diagnosis. Patients had a median of two brain lesions. Sixty-five percent of the patients were treated with radiotherapy alone, 22.5% had both surgical resection and brain radiotherapy. Median overall survival was 3.2 months after development of BM. Overall survival was longer in patients who received combined modality local therapy compared to patients treated with surgical resection or radiotherapy alone. Patients who received systemic treatment incorporating biologics following development of BM had a median overall survival of 18.6 months. Overall, the administration of biologic agents was safe and well tolerated. Conclusions In summary, BM is an uncommon and late event in the natural history of metastatic CRC. The ability to deliver combined-modality local brain therapy as well as availability of more systemic therapy options appear to lead to improved outcomes. PMID:28280609

  15. Overexpression of adenylate cyclase-associated protein 1 may predict brain metastasis in non-small cell lung cancer.

    PubMed

    Xie, Shuan-Shuan; Tan, Min; Lin, Hai-Yan; Xu, Lei; Shen, Chang-Xing; Yuan, Qing; Song, Xiao-Lian; Wang, Chang-Hui

    2015-01-01

    This study was designed to establish a biomarker risk model for predicting brain metastasis (BM) in non-small cell lung cancer (NSCLC). The model comprises 120 cases of NSCLC that were treated and followed up for 4 years. The patients were divided into the BM (n=50) and non-BM (other visceral metastasis and those without recurrence) (n=70) groups. Immunohistochemical and western blot analyses were performed in metastatic tissues of NSCLC. Multivariate regression analysis was performed to correlate the immunoreactive cyclase-associated protein 1 (CAP1) signal with BM. Survival analyses were performed by using the Kaplan-Meier method. CAP1 protein content and immunoreactivity were significantly increased in BM specimens compared to other-metastatic specimens. The survival analysis revealed that CAP1 overexpression was significantly associated with survival (P<0.05). The ROC test suggested that the area under the curve was 73.33% (P<0.001; 95% CI, 63.5-83.2%). When P=0.466, the sensitivity and specificity reached 79.5 and 67.1%, respectively. These findings suggested that CAP1 is involved in the BM of NSCLC, and that elevated levels of CAP1 expression may indicate a poor prognosis for patients with BM. The CAP1 molecular model may be useful in the prediction of the risk of BM in NSCLC.

  16. 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.

  17. 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.

  18. Circulating tight junction proteins mirror blood-brain barrier integrity in leukaemia central nervous system metastasis.

    PubMed

    Zhu, Jing-Cheng; Si, Meng-Ya; Li, Ya-Zhen; Chen, Huan-Zhu; Fan, Zhi-Cheng; Xie, Qing-Dong; Jiao, Xiao-Yang

    2016-03-21

    The aim of this study was to evaluate the clinical significance of circulating tight junction (TJ) proteins as biomarkers reflecting of leukaemia central nervous system (CNS) metastasis. TJs [claudin5 (CLDN5), occludin (OCLN) and ZO-1] concentrations were measured in serum and cerebrospinal fluid (CSF) samples obtained from 45 leukaemia patients. Serum ZO-1 was significantly higher (p < 0.05), but CSF ZO-1 levels were not significantly higher in the CNS leukaemia (CNSL) compared to the non-CNSL. The CNSL patients also had a lower CLDN5/ZO1 ratio in both serum and CSF than in non-CNSL patients (p < 0.05). The TJ index was negatively associated with WBCCSF , ALBCSF and BBB values in leukaemia patients. Among all of the parameters studied, CLDN5CSF had the highest specificity in discriminating between CNSL and non-CNSL patients. Therefore, analysing serum and CSF levels of CLDN5, OCLN and the CLDN5/ZO1 ratio is valuable in evaluating the potential of leukaemia CNS metastasis. Copyright © 2016 John Wiley & Sons, Ltd.

  19. SIRT1 is highly expressed in brain metastasis tissues of non-small cell lung cancer (NSCLC) and in positive regulation of NSCLC cell migration.

    PubMed

    Han, Lin; Liang, Xiao-Hua; Chen, Li-Xin; Bao, Shi-Min; Yan, Zhi-Qiang

    2013-01-01

    Brain metastases are a frequent and ongoing major complication of non-small cell lung cancer (NSCLC). To deepen our understanding to the underlying mechanisms by which NSCLC cells metastasize to brain and hence to improve the therapy, a high throughput RNAi screening with shRNA library of 153 epigenetic genes was subjected to A549, a NSCLC cell line with high migration ability, to examine the effects of these genes on cell migration by wound-healing assay. The screening results showed that knockdown of 2 genes (KDM5B and SIRT1) dramatically and specifically inhibits A549 migration but not affects the proliferation, which was subsequently confirmed through transwell migration assay. Furthermore, SIRT1 is found to be highly expressed in brain metastasis tissues of NSCLC, compared to the NSCLC tissues, suggesting that SIRT1 may play roles in brain metastasis of NSCLC. The relationship between SIRT1 expression and cell migration ability was further investigated in three NSCLC cell lines and the result indicated that SIRT1 expression is tightly correlated with cell migration ability. Collectively, our work provides potential biomarker and therapeutic target for brain metastasis of NSCLC.

  20. 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

  1. [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.

  2. 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.

  3. Complete remission through icotinib treatment in Non-small cell lung cancer epidermal growth factor receptor mutation patient with brain metastasis: A case report

    PubMed Central

    Wang, Tao; Wang, Ruimin; Dong, Zhouhuan; Liang, Naichao

    2016-01-01

    Abstract Brain metastasis (BM) has been universally recognized as a poor prognostic factor in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown efficacy in treating BM with an EGFR mutation. This paper reports a case of BM patient with EGFR-mutated NSCLC. According to the findings, a complete remission (CR) of the BM was achieved by icotinib treatment without conducting a radiotherapy, which was followed by a resection of the primary lung cancer lesion and lymph nodes. After one-year follow-up, the disease progressed to liver metastasis and liver lesion biopsy showed a T790M mutation. The patient responded well to the combination treatment of AZD9291 and icotinib after the failure of transcatheter arterial chemoembolization (TACE). This case report suggests that icotinib has a sustainable anticancer response to BM and the combination with icotinib and AZD9291 is effective for liver metastasis with T790M.

  4. 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.

  5. 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.

  6. Generation of an immortalized astrocyte cell line from H-2Kb-tsA58 mice to study the role of astrocytes in brain metastasis.

    PubMed

    Langley, Robert R; Fan, Dominic; Guo, Lixia; Zhang, Chenyu; Lin, Qingtang; Brantley, Emily C; McCarty, Joseph H; Fidler, Isaiah J

    2009-10-01

    Astrocytes play a critical role in maintaining cerebral homeostasis and their dysregulation is thought to contribute to the pathogenesis of several diseases, including brain cancer and metastasis. Similar to the human disease, we found that lung and melanoma metastases in the mouse brain are accompanied by a reactive gliosis. To begin to study the biology of astrocytes and examine how these cells might contribute to metastasis formation and progression in the brain, we generated a conditionally immortal astrocyte cell line from H-2Kb-tsA58 mice. Astrocytes grown in culture expressed glial fibrillary acid protein (GFAP), glutamate receptor 1, and the N-methyl-D-aspartate (NMDA) receptor. Astrocytes also expressed the glial-specific transporters excitatory amino acid transporter 1 (EAAT1) and EAAT2. Astrocytes grown under permissive conditions (33 degrees C) expressed SV40 large T antigen and had a doubling time of 36 h, whereas expression of SV40 large T antigen was negligible in astrocytes grown at 37 degrees C for 72 h, which coincided with a plateau in cell division. In a co-culture assay with human lung adenocarcinoma cells (PC14-PE6), astrocytes activated programs in the tumor cells that signal for cell division and survival. Hence, the immortalized cell line will be useful for studying the role of astrocytes in disease processes in the brain, such as metastasis.

  7. 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.

  8. 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

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

    PubMed

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

    2016-05-31

    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.

  10. The Influence of Neuronal Activity on Breast Tumor Metastasis to the Brain

    DTIC Science & Technology

    2008-09-01

    different drugs to alter brain activity: caffeine, methylphenidate and modafinil . While the smallest effect may be expected from caffeine which is not...another of the drugs (methylphenidate). Experiments with modafinil are planned to start next month. In the last year of the grant we plan on

  11. Uncommon case of brain metastasis in a patient with a history of heavy smoking.

    PubMed

    Scharl, M; Bode, B; Rushing, E; Knuth, A; Rordorf, T

    2014-10-01

    Primary sarcomas of the aorta are extremely uncommon. Depending on histomorphology and immunohistochemical pattern, intimal sarcomas can show angiosarcomatous differentiation. Here, we describe the case of a 60-year-old woman with a primary intimal sarcoma of the aortic arch and signs of cerebral metastatic disease as the initial manifestation. After the patient experienced the onset of severe headaches, ataxia, and left-sided weakness, magnetic resonance imaging showed several brain lesions. Histologic assessment of a brain biopsy specimen revealed a malignant tumour composed of large pleomorphic cells that were positive for pancytokeratin and CD10. Radiation to the brain did not significantly improve the patient's symptoms, and cranial computed tomography (ct) imaging revealed several metastases, indicating lack of response. Because of the patient's smoking history, the presence of central nervous system and skeletal metastases on combined positron-emission tomography and ct imaging, and the focal pan-cytokeratin positivity of the tumour, carcinoma of the lung was favoured as the primary tumour. Despite chemotherapy with cisplatin and etoposide, the patient's neurologic symptoms and general condition deteriorated rapidly, and she died within a few days. At autopsy, an undifferentiated intimal sarcoma of the aortic arch was diagnosed. The primary tumour in the aorta consisted of large pleomorphic cells. Immunohistochemical analysis of the aortic tumour and brain metastases demonstrated diffuse positivity for vimentin and p53 and focal S-100 staining. In summary, we report a challenging case of advanced intimal sarcoma of the aortic arch with brain and bone metastases at initial presentation. Our report demonstrates the difficulties in diagnosing and treating this disease, and the need for multicentre studies to accrue more patients for investigations of optimal therapy.

  12. Uncommon case of brain metastasis in a patient with a history of heavy smoking

    PubMed Central

    Scharl, M.; Bode, B.; Rushing, E.; Knuth, A.; Rordorf, T.

    2014-01-01

    Primary sarcomas of the aorta are extremely uncommon. Depending on histomorphology and immunohistochemical pattern, intimal sarcomas can show angiosarcomatous differentiation. Here, we describe the case of a 60-year-old woman with a primary intimal sarcoma of the aortic arch and signs of cerebral metastatic disease as the initial manifestation. After the patient experienced the onset of severe headaches, ataxia, and left-sided weakness, magnetic resonance imaging showed several brain lesions. Histologic assessment of a brain biopsy specimen revealed a malignant tumour composed of large pleomorphic cells that were positive for pancytokeratin and CD10. Radiation to the brain did not significantly improve the patient’s symptoms, and cranial computed tomography (ct) imaging revealed several metastases, indicating lack of response. Because of the patient’s smoking history, the presence of central nervous system and skeletal metastases on combined positron-emission tomography and ct imaging, and the focal pan-cytokeratin positivity of the tumour, carcinoma of the lung was favoured as the primary tumour. Despite chemotherapy with cisplatin and etoposide, the patient’s neurologic symptoms and general condition deteriorated rapidly, and she died within a few days. At autopsy, an undifferentiated intimal sarcoma of the aortic arch was diagnosed. The primary tumour in the aorta consisted of large pleomorphic cells. Immunohistochemical analysis of the aortic tumour and brain metastases demonstrated diffuse positivity for vimentin and p53 and focal S-100 staining. In summary, we report a challenging case of advanced intimal sarcoma of the aortic arch with brain and bone metastases at initial presentation. Our report demonstrates the difficulties in diagnosing and treating this disease, and the need for multicentre studies to accrue more patients for investigations of optimal therapy. PMID:25302044

  13. Comparison of prognostic indices in patients who undergo melanoma brain metastasis radiosurgery.

    PubMed

    Kano, Hideyuki; Morales-Restrepo, Alejandro; Iyer, Aditya; Weiner, Gregory M; Mousavi, Seyed H; Kirkwood, John M; Tarhini, Ahmad A; Flickinger, John C; Lunsford, L Dade

    2017-01-20

    OBJECTIVE The goal of this study was to use 4 prognostic indices to compare survival times of patients who underwent Gamma Knife stereotactic radiosurgery (SRS) to treat melanoma brain metastases. METHODS The authors analyzed 422 consecutive patients (1440 brain metastases) who underwent Gamma Knife SRS. The median total brain tumor volume was 4.7 cm(3) (range 0.3-69.3 cm(3)), and the median number of metastases was 2 (range 1-32). One hundred thirty-two patients underwent whole-brain radiation therapy. Survival times were compared using recursive partitioning analysis (RPA), the Score Index for Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), and the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA). RESULTS The overall survival times after SRS were compared. With the RPA index, survival times were 2.6 months (Class III, n = 27), 5.5 months (Class II, n = 348), and 13.0 months (Class I, n = 47). With the DS-GPA index, survival times were 2.8 months (Scores 0-1, n = 67), 4.2 months (Scores 1.5-2.0, n = 143), 6.6 months (Scores 2.5-3.0, n = 111), and 9.4 months (Scores 3.5-4.0, n = 101). With the SIR, survival times were 3.2 months (Scores 0-3, n = 56), 5.8 months (Scores 4-7, n = 319), and 12.7 months (Scores 8-10, n = 47). With the BSBM index, survival times were 2.6 months (BSBM0, n = 47), 5.4 months (BSBM1, n = 282), 11.0 months (BSBM2, n = 86), and 8.8 months (BSBM3, n = 7). The DS-GPA index was the most balanced by case numbers in each class and provided the overall best prognostic index for overall survival. CONCLUSIONS The DS-GPA index proved most balanced and predictive of survival for patients with melanoma who underwent SRS as part of management for brain metastases. Patients whose DS-GPA score was ≥ 2.5 had predictably improved survival times after SRS.

  14. Microarray expression profiling identifies genes, including cytokines, and biofunctions, as diapedesis, associated with a brain metastasis from a papillary thyroid carcinoma.

    PubMed

    Schulten, Hans-Juergen; Hussein, Deema; Al-Adwani, Fatima; Karim, Sajjad; Al-Maghrabi, Jaudah; Al-Sharif, Mona; Jamal, Awatif; Bakhashab, Sherin; Weaver, Jolanta; Al-Ghamdi, Fahad; Baeesa, Saleh S; Bangash, Mohammed; Chaudhary, Adeel; Al-Qahtani, Mohammed

    2016-01-01

    Brain metastatic papillary thyroid carcinomas (PTCs) are afflicted with unfavorable prognosis; however, the underlying molecular genetics of these rare metastases are virtually unknown. In this study, we compared whole transcript microarray expression profiles of a BRAF mutant, brain metastasis from a PTC, including its technical replicate (TR), with eight non-brain metastatic PTCs and eight primary brain tumors. The top 95 probe sets (false discovery rate (FDR) p-value < 0.05 and fold change (FC) > 2) that were differentially expressed between the brain metastatic PTC, including the TR, and both, non-brain metastatic PTCs and primary brain tumors were in the vast majority upregulated and comprise, e.g. ROS1, MYBPH, SLC18A3, HP, SAA2-SAA4, CP, CCL20, GFAP, RNU1-120P, DMBT1, XDH, CXCL1, PI3, and NAPSA. Cytokines were represented by 10 members in the top 95 probe sets. Pathway and network analysis (p-value < 0.05 and FC > 2) identified granulocytes adhesion and diapedesis as top canonical pathway. Most significant upstream regulators were lipopolysaccharide, TNF, NKkB (complex), IL1A, and CSF2. Top networks categorized under diseases & functions were entitled migration of cells, cell movement, cell survival, apoptosis, and proliferation of cells. Probe sets that were significantly shared between the brain metastatic PTC, the TR, and primary brain tumors include CASP1, CASP4, C1R, CC2D2B, RNY1P16, WDR72, LRRC2, ZHX2, CITED1, and the noncoding transcript AK128523. Taken together, this study identified a set of candidate genes and biofunctions implicated in, so far nearly uncharacterized, molecular processes of a brain metastasis from a PTC.

  15. Microarray expression profiling identifies genes, including cytokines, and biofunctions, as diapedesis, associated with a brain metastasis from a papillary thyroid carcinoma

    PubMed Central

    Schulten, Hans-Juergen; Hussein, Deema; Al-Adwani, Fatima; Karim, Sajjad; Al-Maghrabi, Jaudah; Al-Sharif, Mona; Jamal, Awatif; Bakhashab, Sherin; Weaver, Jolanta; Al-Ghamdi, Fahad; Baeesa, Saleh S; Bangash, Mohammed; Chaudhary, Adeel; Al-Qahtani, Mohammed

    2016-01-01

    Brain metastatic papillary thyroid carcinomas (PTCs) are afflicted with unfavorable prognosis; however, the underlying molecular genetics of these rare metastases are virtually unknown. In this study, we compared whole transcript microarray expression profiles of a BRAF mutant, brain metastasis from a PTC, including its technical replicate (TR), with eight non-brain metastatic PTCs and eight primary brain tumors. The top 95 probe sets (false discovery rate (FDR) p-value < 0.05 and fold change (FC) > 2) that were differentially expressed between the brain metastatic PTC, including the TR, and both, non-brain metastatic PTCs and primary brain tumors were in the vast majority upregulated and comprise, e.g. ROS1, MYBPH, SLC18A3, HP, SAA2-SAA4, CP, CCL20, GFAP, RNU1-120P, DMBT1, XDH, CXCL1, PI3, and NAPSA. Cytokines were represented by 10 members in the top 95 probe sets. Pathway and network analysis (p-value < 0.05 and FC > 2) identified granulocytes adhesion and diapedesis as top canonical pathway. Most significant upstream regulators were lipopolysaccharide, TNF, NKkB (complex), IL1A, and CSF2. Top networks categorized under diseases & functions were entitled migration of cells, cell movement, cell survival, apoptosis, and proliferation of cells. Probe sets that were significantly shared between the brain metastatic PTC, the TR, and primary brain tumors include CASP1, CASP4, C1R, CC2D2B, RNY1P16, WDR72, LRRC2, ZHX2, CITED1, and the noncoding transcript AK128523. Taken together, this study identified a set of candidate genes and biofunctions implicated in, so far nearly uncharacterized, molecular processes of a brain metastasis from a PTC. PMID:27822408

  16. A new brain perfusion imaging agent: [I-123]HIPDM:N,N,N'-trimethyl-N'-[2-hydroxy-3-methyl-5-iodobenzyl]-1,3-propanediamine.

    PubMed

    Kung, H F; Tramposch, K M; Blau, M

    1983-01-01

    Based on the pH-shift mechanism, a new brain imaging agent I-124 HIPDM (N,N,N'-trimethyl-N'-[2-hydroxy-3-methyl-5-[123I]iodobenzyl]-1,3-propanediamine ) has been developed. This agent can be prepared by a simple exchange reaction suitable for routine clinical use. The physicochemical parameters, partition coefficient vs. pH profile, and protein binding, as well as biodistribution in rats, were very similar to those of I-123 IMP (N-isopropyl-p-iodoamphetamine). High brain uptake was found in animals after i.v. injection. The brain radioactivity persists for at least 1 hr in rats and monkeys. Regional distribution in sections of rat brain appeared to reflect regional perfusion. In conjunction with single-photon emission tomography (SPECT), this agent may provide useful information on local cerebral perfusion in humans.

  17. 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

  18. Greater efficacy of chemotherapy plus bevacizumab compared to chemo- and targeted therapy alone on non-small cell lung cancer patients with brain metastasis.

    PubMed

    Tang, Ning; Guo, Jun; Zhang, Qianqian; Wang, Yali; Wang, Zhehai

    2016-01-19

    Control of non-small-cell lung cancer (NSCLC) with brain metastasis is clinically challenging. This study retrospectively evaluated the efficacy of different adjuvant therapies for 776 cases of advanced NSCLCs with brain metastasis who treated with chemotherapy, chemotherapy plus bevacizumab, tyrosine kinase inhibitor (TKI) alone, or supportive care. The median progression-free survival (mPFS) and median overall survival (mOS) of patients treated with chemotherapy plus bevacizumab were 8.5 and 10.5 months, respectively, which were better than those of patients treated with other three therapies(P < 0.01). For patients with EGFR-mutated NSCLC, the efficacy of TKI treatment was not statistically better than that of chemotherapy plus bevacizumab but was significantly better than that of other therapies. Moreover, for patients with EGFR wild-type NSCLC, the mPFS and mOS after chemotherapy plus bevacizumab were greater than those with other two therapies (P < 0.01). The local response rate (RR)and disease control rate (DCR)with regimen including pemetrexed were greater than those with regimen including paclitaxel (P < 0.05). Chemotherapy plus bevacizumab was more effective for NSCLC patients with brain metastasis. Further studies will investigate the benefit of TKI alone for patients with EGFR-mutated. For patients with EGFR wild-type, chemotherapy plus bevacizumab did improve PFS and OS. Furthermore, regimens including pemetrexed led to a greater RR.

  19. Greater efficacy of chemotherapy plus bevacizumab compared to chemo- and targeted therapy alone on non-small cell lung cancer patients with brain metastasis

    PubMed Central

    Tang, Ning; Guo, Jun; Zhang, Qianqian; Wang, Yali; Wang, Zhehai

    2016-01-01

    Control of non-small-cell lung cancer (NSCLC) with brain metastasis is clinically challenging. This study retrospectively evaluated the efficacy of different adjuvant therapies for 776 cases of advanced NSCLCs with brain metastasis who treated with chemotherapy, chemotherapy plus bevacizumab, tyrosine kinase inhibitor (TKI) alone, or supportive care. The median progression-free survival (mPFS) and median overall survival (mOS) of patients treated with chemotherapy plus bevacizumab were 8.5 and 10.5 months, respectively, which were better than those of patients treated with other three therapies(P < 0.01). For patients with EGFR-mutated NSCLC, the efficacy of TKI treatment was not statistically better than that of chemotherapy plus bevacizumab but was significantly better than that of other therapies. Moreover, for patients with EGFR wild-type NSCLC, the mPFS and mOS after chemotherapy plus bevacizumab were greater than those with other two therapies (P < 0.01). The local response rate (RR)and disease control rate (DCR)with regimen including pemetrexed were greater than those with regimen including paclitaxel (P < 0.05). Chemotherapy plus bevacizumab was more effective for NSCLC patients with brain metastasis. Further studies will investigate the benefit of TKI alone for patients with EGFR-mutated. For patients with EGFR wild-type, chemotherapy plus bevacizumab did improve PFS and OS. Furthermore, regimens including pemetrexed led to a greater RR. PMID:26498354

  20. 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.

  1. WE-EF-BRA-10: Prophylactic Cranial Irradiation Reduces the Incidence of Brain Metastasis in a Mouse Model of Metastatic Breast Cancerr

    SciTech Connect

    Smith, D; Debeb, B; Larson, R; Diagaradjane, P; Woodward, W

    2015-06-15

    Purpose: Prophylactic cranial irradiation (PCI) is a clinical technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with acute lymphoblastic leukemia and small-cell lung cancer. We examined whether PCI could benefit breast cancer patients at high risk of developing brain metastases. Methods: We utilized our mouse model in which 500k green fluorescent protein (GFP)-labeled breast cancer cells injected into the tail vein of SCID/Beige mice resulted in brain metastases in approximately two-thirds of untreated mice. To test the efficacy of PCI, one set of mice was irradiated five days after cell injection with a single fraction of 4-Gy (two 2-Gy opposing fields) whole-brain irradiation on the XRAD 225Cx small-animal irradiator. Four controls were included: a non-irradiated group, a group irradiated two days prior to cell injection, and two groups irradiated 3 or 6 weeks after cell injection. Mice were sacrificed four and eight weeks post-injection and were evaluated for the presence of brain metastases on a fluorescent stereomicroscope. Results: The incidence of brain metastasis in the non-irradiated group was 77% and 90% at four and eight weeks, respectively. The PCI group had a significantly lower incidence, 20% and 30%, whereas the other three control groups had incidence rates similar to the non-treated control (70% to 100%). Further, the number of metastases and the metastatic burden were also significantly lower in the PCI group compared to all other groups. Conclusion: The timing of irradiation to treat subclinical disease is critical, as a small dose of whole-brain irradiation given five days after cell injection abrogated tumor burden by greater than 90%, but had no effect when administered twenty-one days after cell injection. PCI is likely to benefit breast cancer patients at high risk of developing brain metastases and should be strongly considered in the clinic.

  2. 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

  3. 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

  4. Nanotrastuzumab in combination with radioimmunotherapy: Can it be a viable treatment option for patients with HER2-positive breast cancer with brain metastasis?

    PubMed

    Wang, Xuefei; Sun, Qiang; Shen, Songjie; Xu, Yali; Huang, Likun

    2016-03-01

    Brain metastasis of primary breast cancer (BCBM) has been rising during the last couple of decades. Approximately 25% of the patients with BCBM have a hormone receptor-negative, HER2-positive disease. Given the short life expectancy in patients with BCBM, researchers have tried many new approaches, including cesium-131(131Cs) brachytherapy, radretumab radioimmunotherapy and nanoparticles. Novel biological drug delivery techniques have successfully delivered nanobioconjugates across the blood-brain barrier (BBB). However, nanobioconjugates have significant toxicities and other drawbacks that prevent therapeutic concentrations of the active drug from being delivered to the brain lesions. Radretumab radioimmunotherapy combined with nanotrastruzumab can theoretically overcome this challenge. Radiotherapy can increase the BBB permeability, which can promote the transport and effect of nanotrastuzumab, reduce radretumab radioimmunotherapy dose and target patients with HER2-positive BCBM lesions more specifically. In this article, we propose that nanotrastuzumab in combination with radioimmunotherapy could be a viable treatment option for patients with HER2-positive breast cancer with brain metastasis.

  5. Neurocognitive function and quality of life in patients with newly diagnosed brain metastasis after treatment with intra-operative cesium-131 brachytherapy: a prospective trial.

    PubMed

    Pham, Anthony; Yondorf, Menachem Z; Parashar, Bhupesh; Scheff, Ronald J; Pannullo, Susan C; Ramakrishna, Rohan; Stieg, Philip E; Schwartz, Theodore H; Wernicke, A Gabriella

    2016-03-01

    Intraoperative permanent Cesium-131 (Cs-131) brachytherapy can provide a viable alternative to WBRT with excellent response rates and minimal toxicity. This study reports the results of the prospective trial of the impact of intraoperative Cs-131 on neurocognitive function and quality of life (QoL) in patients with resected brain metastases. Between 2010 and 2012, 24 patients with newly diagnosed metastasis to the brain were accrued on a prospective protocol and treated with Cs-131 brachytherapy seeds after surgical resection. Physicians administered the mini-mental status examination (MMSE) and functional assessment of cancer therapy-brain (FACT-Br) questionnaire to all patients before treatment and again every 2 months for the duration of 6 months with additional follow-up again at 12 months. Wilcoxon rank sum test was used to analyze statistically significant changes in MMSE over time and paired t test was used to analyze changes in FACT-BR. There was a statistical improvement in overall FACT-BR score at 4 and 6 months of follow-up when compared to baseline (162 vs. 143, P = 0.004; 164 vs. 143, P = 0.005 respectively) with a non-significant trend toward improvement at 2 and 12 months (154 vs. 143, P = 0.067; 159 vs. 149, P = 0.4). MMSE score was statistically improved at 4 and up to 12 months compared to pre-treatment MMSE (30 vs. 29, P = 0.017; 30 vs. 29, P = 0.001 respectively). Patients with brain metastasis who received intra-operative permanent Cs-131 brachytherapy implants saw an improvement of their neurocognitive status and self-assessment of QoL. In addition to the excellent local control of metastasis, this approach may contribute to the improvements in cognitive function and QOL.

  6. 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.

  7. 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.

  8. 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.

  9. Activity of pemetrexed and high-dose gefitinib in an EGFR-mutated lung adenocarcinoma with brain and leptomeningeal metastasis after response to gefitinib

    PubMed Central

    2012-01-01

    About 20% to 40% of patients with non-small cell lung cancer (NSCLC) will develop brain metastases during the natural course of their disease. The prognosis for such patients is very poor with limited survival. In addition to the standard whole brain radiation therapy (WBRT), some studies have shown that chemotherapy drugs and/or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) can improve the outcome of these patients. Here, we report a stage IIIA patient who developed multiple brain metastases one year after operation. Oral gefitinib with concurrent WBRT were given as first-line therapy. Complete response and a 50-month progression-free survival (PFS) were obtained. Double dosage of gefitinib (500 mg per day) together with pemetrexed were given as the second-line therapy after the patient developed new brain lesions and leptomeningeal metastasis during the maintenance therapy of gefitinib. The PFS for the second-line therapy was six months. In total, the patient obtained an overall survival of 59 months since the first diagnosis of brain metastases. Mutational analysis showed a 15-nucleotide deletion and a missense mutation in exon 19 of the EGFR gene, and a missense mutation at codon 12 of the K-ras gene. These underlying genetic changes might partially explain the long-term survival of this patient after brain metastases when treated with concurrent or sequential therapies of EGFR-TKI, radiotherapy and chemotherapy. PMID:23134665

  10. Maintaining unperturbed cerebral blood flow is key in the study of brain metastasis and its interactions with stress and inflammatory responses.

    PubMed

    Amit, Benbenishty; Niva, Segev-Amzaleg; Lee, Shaashua; Rivka, Melamed; Shamgar, Ben-Eliyahu; Pablo, Blinder

    2017-02-20

    Blood-borne brain metastases are associated with poor prognosis, but little is known about the interplay between cerebral blood flow, surgical stress responses, and the metastatic process. The intra-carotid inoculation approach, traditionally used in animal studies, involves permanent occlusion of the common carotid artery (CCA). Herein we introduced a novel intra-carotid inoculation approach that avoids CCA ligation, namely - assisted external carotid artery inoculation (aECAi) - and compared it to the traditional approach in C57/BL6 mice, assessing cerebral blood flow; particle distribution; blood-brain barrier (BBB) integrity; stress, inflammatory and immune responses; and brain tumor retention and growth. Doppler flowmetry and two-photon imaging confirmed that only in the traditional approach regional and capillary cerebral blood flux were significantly reduced. Corticosterone and plasma IL-6 levels were higher in the traditional approach, splenic numbers of NK, CD3+, granulocytes, and dendritic cells were lower, and many of these indices were more profoundly affected by surgical stress in the traditional approach. BBB integrity was unaffected. Administration of spherical beads indicated that CCA ligation significantly limited brain distribution of injected particles, and inoculation of D122-LLC syngeneic tumor cells resulted in 10-fold lower brain tumor-cell retention in the traditional approach. Last, while most of the injected tumor cells were arrested in extra-cranial head areas, our method improved targeting of brain-tissue by 7-fold. This head versus brain distribution difference, commonly overlooked, cannot be detected using in vivo bioluminescent imaging. Overall, it is crucial to maintain unperturbed cerebral blood flow while studying brain metastasis and interactions with stress and inflammatory responses.

  11. Whole-brain black-blood imaging with magnetization-transfer prepared spin echo-like contrast: a novel sequence for contrast-enhanced brain metastasis screening at 3T.

    PubMed

    Yoneyama, Masami; Nakamura, Masanobu; Tabuchi, Takashi; Takemura, Atsushi; Obara, Makoto; Tatsuno, Satoshi; Sawano, Seishi

    2013-07-01

    In contrast-enhanced (CE) brain metastasis screening, coexistence of enhanced blood vessel suppression and higher tumor-to-parenchyma contrast may improve radiologists' performances in detecting brain metastases compared with conventional sequences. In this study, we propose a new scheme, allowing both suppression of blood signals and improvement of tumor-to-parenchyma contrast, using motion-sensitized driven equilibrium prepared 3D low-refocusing flip-angle turbo spin echo (TSE) ("magnetization transfer prepared spin echo"-like contrast volume examination: MATLVE) for brain metastasis screening at 3.0 T, and we compare MATLVE to conventional three-dimensional (3D)-gradient recalled echo (GRE) and 3D-TSE sequences. With the use of MATLVE, the signal intensity of CE blood decreased substantially. Furthermore, the contrast ratio of tumor-to-white matter was significantly higher than in either conventional 3D-GRE or 3D-TSE. MATLVE can be used for 3D volumetric post-CE black-blood imaging, and it may be effective in detecting small brain metastases by selectively enhancing tumor signals while suppressing blood signals.

  12. Multiple Meningocerebral Metastasis and Extensive Skull Metastasis from Squamous Cell Carcinoma of Esophagus: A Case Report and Review of Literature

    PubMed Central

    Na, Min Kyun; Kim, Jae Min; Cheong, Jin Whan; Ryu, Je Il; Kim, Hyun Woo

    2016-01-01

    Esophageal carcinoma rarely metastasizes to the brain. Although some studies have mentioned esophageal cancer with solitary brain metastasis or with meningocerebral metastasis or with skull metastasis, multiple meningocerebral metastasis and extensive skull metastasis from squamous cell carcinoma of esophagus has not been reported in the literature. We encountered a case of an extensive osteolytic change of the skull and multiple meningocerebral metastases from esophageal carcinoma. PMID:27867927

  13. Radiosurgery in the management of brain metastasis: a retrospective single-center study comparing Gamma Knife and LINAC treatment.

    PubMed

    Tuleasca, Constantin; Negretti, Laura; Faouzi, Mohamed; Magaddino, Vera; Gevaert, Thierry; von Elm, Erik; Levivier, Marc

    2017-03-24

    OBJECTIVE The authors present a retrospective analysis of a single-center experience with treatment of brain metastases using Gamma Knife (GK) and linear accelerator (LINAC)-based radiosurgery and compare the results. METHODS From July 2010 to July 2012, 63 patients with brain metastases were treated with radiosurgery. Among them, 28 (with 83 lesions) were treated with a GK unit and 35 (with 47 lesions) with a LINAC. The primary outcome was local progression-free survival (LPFS), evaluated on a per-lesion basis. The secondary outcome was overall survival (OS), evaluated per patient. Statistical analysis included standard tests and Cox regression with shared-frailty models to account for the within-patient correlation. RESULTS The mean follow-up period was 11.7 months (median 7.9 months, range 1.7-32 months) for GK and 18.1 months (median 17 months, range 7.5-28.7 months) for LINAC. The median number of lesions per patient was 2.5 (range 1-9) in the GK group and 1 (range 1-3) in the LINAC group (p < 0.01, 2-sample t-test). There were more radioresistant lesions (e.g., melanoma) and more lesions located in functional areas in the GK group. Additional technical reasons for choosing GK instead of LINAC were limitations of LINAC movements, especially if lesions were located in the lower posterior fossa or multiple lesions were close to highly functional areas (e.g., the brainstem), precluding optimal dosimetry with LINAC. The median marginal dose was 24 Gy with GK and 20 Gy with LINAC (p < 0.01, 2-sample t-test). For GK, the actuarial LPFS rate at 3, 6, 9, 12, and 17 months was 96.96%, 96.96%, 96.96%, 88.1%, and 81.5%, remaining stable until 32 months. For LINAC the rate at 3, 6, 12, 17, 24, and 33 months was 91.5%, 91.5%, 91.5%, 79.9%, 55.5%, and 17.1% (log-rank p = 0.03). In the Cox regression with shared-frailty model, the risk of local progression in the LINAC group was almost twice that of the GK group (HR 1.92, p > 0.05). The mean OS was 16.0 months (95% CI 11

  14. 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.

  15. A new strategy of CyberKnife treatment system based radiosurgery followed by early use of adjuvant bevacizumab treatment for brain metastasis with extensive cerebral edema.

    PubMed

    Wang, Yang; Wang, Enmin; Pan, Li; Dai, Jiazhong; Zhang, Nan; Wang, Xin; Liu, Xiaoxia; Mei, Guanghai; Sheng, Xiaofang

    2014-09-01

    Bevacizumab blocks the effects of vascular endothelial growth factor in leakage-prone capillaries and has been suggested as a new treatment for cerebral radiation edema and necrosis. CyberKnife is a new, frameless stereotactic radiosurgery system. This work investigated the safety and efficacy of CyberKnife followed by early bevacizumab treatment for brain metastasis with extensive cerebral edema. The eligibility criteria of the patients selected for radiosurgery followed by early use of adjuvant bevacizumab treatment were: (1) brain tumors from metastasis with one solitary brain lesion and symptomatic extensive cerebral edema; (2) >18 years of age; (3) the patient refused surgery due to the physical conditions and the risk of surgery; (4) no contraindications for bevacizumab. (5) bevacizumab was applied for a minimum of 2 injections and a maximum of 6 injections with a 2-week interval between treatments, beginning within 2 weeks of the CyberKnife therapy; (6) Karnofsky performance status (KPS) ≥30. Tumor size and edema were monitored by magnetic resonance imaging (MRI). Dexamethasone dosage, KPS, adverse event occurrence and associated clinical outcomes were also recorded. Eight patients were accrued for this new treatment. Radiation dose ranged from 20 to 33 Gy in one to five sessions, prescribed to the 61-71 % isodose line. Bevacizumab therapy was administered 3-10 days after completion of CyberKnife treatment for a minimum of two cycles (5 mg/kg, at 2-week intervals). MRI revealed average reductions of 55.8 % (post-gadolinium) and 63.4 % (T2/FLAIR). Seven patients showed significant clinical neurological improvements. Dexamethasone was reduced in all patients, with five successfully discontinuing dexamethasone treatment 4 weeks after bevacizumab initiation. Hypertension, a bevacizumab-related adverse event, occurred in one patient. After 3-8 months, all patients studied were alive and primary brain metastases were under control, 2 developed new brain

  16. 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

  17. [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.

  18. Breast metastasis of anaplastic oligodendroglioma: a case report.

    PubMed

    Alacacioglu, Ahmet; Unal, Serkan; Canpolat, Selin; Yurt, Alaattin; Oztekin, Ozgur; Coskun, Ali; Karatas, Ayse; Postaci, Hakan; Sop, Gulten

    2012-11-01

    Extracranial metastasis of primary brain tumors is rarely observed. Of all brain malignancies, glioblastomas, medulloblastomas and astrocytomas metastasize most frequently. Metastasis of oligondendroglioma is rare. We present a case of breast metastasis in a 58-year-old man with an anaplastic oligodendroglioma.

  19. Bone Metastasis

    MedlinePlus

    ... metastasis, surgeons can stabilize the bone using metal plates, screws and nails (orthopedic fixation). Orthopedic fixation can ... that can't be easily reinforced with metal plates or screws, such as pelvic bones and bones ...

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

    ClinicalTrials.gov

    2016-12-13

    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

  1. 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.

  2. 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

    2016-04-07

    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.

  3. Multidrug resistance protein and topoisomerase 2 alpha expression in non-small cell lung cancer are related with brain metastasis postoperatively

    PubMed Central

    Huang, Huan; Liu, Jihong; Meng, Qinglian; Niu, Guozhong

    2015-01-01

    The aim of this study was to investigate association between expressions of multidrug resistance protein (MRP) and topoisomerase 2 alpha expression in non-small cell lung cancer (TOP2A) and brain metastasis operatively. The expression of MRP and TOP2A were performed using immunohistochemistry (IHC) staining, and the results were analyzed in correlation with clinicopathological data. A total of 286 NSCLC patients who underwent curative surgery between 2007 and 2013 were enrolled in this study. Positive expression of MRP and TOP2A were 62.2% and 37.8%. MRP positive expression in NSCLC was significantly correlated with tumor cell differentiation (P=0.028). TOP2A expression was significantly associated with patients’ smoking status, tumor histological type (P<0.05). The positive MRP group had significantly inferior survival rates for 2-year BMFS than did the negative MRP group (79.0% vs. 93.4%, P=0.003) by the Kaplan-Meier method and a log-rank test. Similarly, the positive TOP2A expression was inversely correlated with 2-year BMFS (84.2% vs. 93.4%, P=0.030). Multivariate analysis showed that gender, MRP expression and TOP2A expression were independent prognostic factors for BMFS (P<0.05). Positive expressions of MRP and TOP2A in the tumor tissue are associated with increased risk of developing brain metastases in NSCLC. PMID:26617887

  4. Brain metastasis development and poor survival associated with carcinoembryonic antigen (CEA) level in advanced non-small cell lung cancer: a prospective analysis

    PubMed Central

    2009-01-01

    Background Central nervous system is a common site of metastasis in NSCLC and confers worse prognosis and quality of life. The aim of this prospective study was to evaluate the prognostic significance of clinical-pathological factors (CPF), serum CEA levels, and EGFR and HER2 tissue-expression in brain metastasis (BM) and overall survival (OS) in patients with advanced NSCLC. Methods In a prospective manner, we studied 293 patients with NSCLC in IIIB-IV clinical stage. They received standard chemotherapy. CEA was measured prior to treatment; EGFR and HER2 were evaluated by immunohistochemistry. BM development was confirmed by MRI in symptomatic patients. Results BM developed in 27, and 32% of patients at 1 and 2 years of diagnosis with adenocarcinoma (RR 5.2; 95% CI, 1.002–29; p = 0.05) and CEA ≥ 40 ng/mL (RR 11.4; 95% CI, 1.7–74; p < 0.01) as independent associated factors. EGFR and HER2 were not statistically significant. Masculine gender (RR 1.4; 95% CI, 1.002–1.9; p = 0.048), poor performance status (RR 1.8; 95% CI, 1.5–2.3; p = 0.002), advanced clinical stage (RR 1.44; 95% CI, 1.02–2; p = 0.04), CEA ≥ 40 ng/mL (RR 1.5; 95% CI, 1.09–2.2; p = 0.014) and EGFR expression (RR 1.6; 95% CI, 1.4–1.9; p = 0.012) were independent associated factors to worse OS. Conclusion High CEA serum level is a risk factor for BM development and is associated with poor prognosis in patients with advanced NSCLC. Surface expression of CEA in tumor cells could be the physiopathological mechanism for invasion to CNS. PMID:19386089

  5. Radionecrosis versus disease progression in brain metastasis. Value of (18)F-DOPA PET/CT/MRI.

    PubMed

    Hernández Pinzón, J; Mena, D; Aguilar, M; Biafore, F; Recondo, G; Bastianello, M

    2016-01-01

    The use of (18)F-DOPA PET/CT with magnetic resonance imaging fusion and the use of visual methods and quantitative analysis helps to differentiate between changes post-radiosurgery vs. suspicion of disease progression in a patient with brain metastases from melanoma, thus facilitating taking early surgical action.

  6. 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.

  7. Intra-arterial administration improves temozolomide delivery and efficacy in a model of intracerebral metastasis, but has unexpected brain toxicity.

    PubMed

    Muldoon, Leslie L; Pagel, Michael A; Netto, Joao Prola; Neuwelt, Edward A

    2016-02-01

    We tested the hypothesis that intra-arterial (IA) infusion of temozolomide into the internal carotid artery would safely improve drug delivery to brain and enhance chemotherapy efficacy in a chemosensitive rat brain tumor model. Quantitative autoradiography after 25 µCi (14)C-temozolomide was given by oral, intravenous, or IA route of administration, or IA with osmotic blood-brain barrier disruption (BBBD) (n = 5-7 per group) showed that both IA and IA/BBBD administration increased drug delivery in tumor by over threefold compared to normal brain (P < 0.02), and also significantly elevated delivery throughout the infused right hemisphere. Temozolomide (20 mg/kg; ~150 mg/m(2)) increased median survival when given by oral (25.5 days), intravenous (25.5 days), or IA (33 days) route of administration, compared to 17.5 days in untreated controls (n = 8 per group; overall P < 0.0001). Survival time after IA temozolomide was significantly longer than all other groups (P < 0.01 for all comparisons). BBBD temozolomide was toxic in the efficacy study, but there was no evidence of symptomatic neurotoxicity in rats given IA temozolomide. After these promising animal results, a 49 year old male with glioblastoma multiforme who failed all standard therapy received temozolomide 100 mg/m(2) IA. Upon initiation of the second course of IA infusion the patient had increased heart rate, blood pressure, and rash, and the procedure was terminated without sequelae. Follow up IA infusion of temozolomide diluent in normal rats showed damaged cerebrovasculature as determined by dye leakage. These results demonstrate that IA infusion of temozolomide was toxic, with or without BBBD. We conclude that under the current formulation temozolomide is not safe for IA infusion in patients.

  8. Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

    PubMed Central

    Park, Y H; Park, M J; Ji, S H; Yi, S Y; Lim, D H; Nam, D H; Lee, J-I; Park, W; Choi, D H; Huh, S J; Ahn, J S; Kang, W K; Park, K; Im, Y-H

    2009-01-01

    In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM. PMID:19240719

  9. Brain metastasis is predetermined in early stages of cutaneous melanoma by CD44v6 expression through epigenetic regulation of the spliceosome.

    PubMed

    Marzese, Diego M; Liu, Michelle; Huynh, Jamie L; Hirose, Hajime; Donovan, Nicholas C; Huynh, Kelly T; Kiyohara, Eiji; Chong, Kelly; Cheng, David; Tanaka, Ryo; Wang, Jinhua; Morton, Donald L; Barkhoudarian, Garni; Kelly, Daniel F; Hoon, Dave S B

    2015-01-01

    Melanoma brain metastasis (MBM) is frequent and has a very poor prognosis with no current predictive factors or therapeutic molecular targets. Our study unravels the molecular alterations of cell-surface glycoprotein CD44 variants during melanoma progression to MBM. High expression of CD44 splicing variant 6 (CD44v6) in primary melanoma (PRM) and regional lymph node metastases from AJCC Stage IIIC patients significantly predicts MBM development. The expression of CD44v6 also enhances the migration of MBM cells by hyaluronic acid and hepatocyte growth factor exposure. Additionally, CD44v6-positive MBM migration is reduced by blocking with a CD44v6-specific monoclonal antibody or knocking down CD44v6 by siRNA. ESRP1 and ESRP2 splicing factors correlate with CD44v6 expression in PRM, and ESRP1 knockdown significantly decreases CD44v6 expression. However, an epigenetic silencing of ESRP1 is observed in metastatic melanoma, specifically in MBM. In advanced melanomas, CD44v6 expression correlates with PTBP1 and U2AF2 splicing factors, and PTBP1 knockdown significantly decreases CD44v6 expression. Overall, these findings open a new avenue for understanding the high affinity of melanoma to progress to MBM, suggesting CD44v6 as a potential MBM-specific factor with theranostic utility for stratifying patients.

  10. 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

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

    NASA Astrophysics Data System (ADS)

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

    2016-10-01

    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.

  12. Long-term complete remission following radiosurgery and immunotherapy in a melanoma patient with brain metastasis: immunologic correlates.

    PubMed

    Karbach, Julia; Gnjatic, Sacha; Biskamp, Melina; Atmaca, Akin; Weidmann, Eckhart; Brandt, Kathrin; Wahle, Claudia; Bernhard, Helga; Knuth, Alexander; Jäger, Elke

    2014-05-01

    A melanoma patient with brain metastases was treated by gamma-knife radiosurgery and immunotherapy with autologous tumor-lysate-loaded dendritic cells (DC). Ten years after the combined treatment, the patient remains in complete remission. Remarkable immunologic correlates to the clinical development were the transient induction of NY-ESO-1 antibody and the durable expansion of MAGE-A1p161-169 EADPTGHSY-specific CD8+ T cells. Although the induction of NY-ESO-1 antibody most likely resulted from gamma-knife-mediated "auto-vaccination," the persistence of circulating MAGE-A1-specific T cells, which are still detectable ex vivo in the absence of any tumor manifestation, coincides with DC-based vaccination administered monthly until today.

  13. 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

  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

    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.

  15. Dissecting and Targeting Latent Metastasis

    DTIC Science & Technology

    2013-09-01

    metastasis tends to be a late complication of cancer in the clinic [8,9] and is rare in mice with genetically engineered tumors that readily...4/5/2013 2013 AACR Annual Meeting–Co-Chairperson “ Genetic Determinants of Brain Metastasis” Washington, DC 4/17/2013...and Joan Massagué1,4,6,7 1 Cancer Biology and Genetics Program 2 Department of Medicine 3 Human Oncology and Pathogenesis Program 4 Brain Tumor

  16. Downregulation of solute carriers of glutamate in gliosomes and synaptosomes may explain local brain metastasis in anaplastic glioblastoma.

    PubMed

    Tong, Huaiyu; Yu, Xinguang; Lu, Xuechun; Wang, Peng

    2015-04-01

    Advanced grades of glioblastoma are highly aggressive, especially in terms of multisite spread within the brain or even to distant sites at the spinal cord. In advanced grades of glioblastoma, glutamate and glutamine are reported to be increased in concentration in the extracellular fluid. It has been reported that glutamate acts as an extracellular signaling molecule for facilitating local spread of advanced grades of glioblastoma. In the present study, we aimed to examine whether glutamate uptake mechanisms is impaired in advanced glioblastoma. The possible downregulated mechanisms of glutamate uptake would facilitate persistence of glutamate in the extracellular environment, rather than intracellular uptake. We obtained biobanked human specimens of glioblastoma and tested expression of proteins belonging to the solute carrier families of proteins that are known to function as membrane-located excitatory amino acid like glutamate transporters. The present study provides preliminary evidence of the downregulation of membrane expression of excitatory amino acid transporters solute carrier family 1 member 3 (SLC1A3) and its palmitoylated form in gliosomes, as well as SLC1A2 in the glio-synaptosomes. Compounds like riluzole used in the treatment of amyotrophic lateral sclerosis and the antibiotic ceftriaxone have the potential to facilitate glutamate uptake. These medications may be examined as adjunct chemotherapy in the massively aggressive tumor glioblastoma multiforme.

  17. Mixed inhibition of adenosine deaminase activity by 1,3-dinitrobenzene: a model for understanding cell-selective neurotoxicity in chemically-induced energy deprivation syndromes in brain.

    PubMed

    Wang, Yipei; Liu, Xin; Schneider, Brandon; Zverina, Elaina A; Russ, Kristen; Wijeyesakere, Sanjeeva J; Fierke, Carol A; Richardson, Rudy J; Philbert, Martin A

    2012-02-01

    Astrocytes are acutely sensitive to 1,3-dinitrobenzene (1,3-DNB) while adjacent neurons are relatively unaffected, consistent with other chemically-induced energy deprivation syndromes. Previous studies have investigated the role of astrocytes in protecting neurons from hypoxia and chemical injury via adenosine release. Adenosine is considered neuroprotective, but it is rapidly removed by extracellular deaminases such as adenosine deaminase (ADA). The present study tested the hypothesis that ADA is inhibited by 1,3-DNB as a substrate mimic, thereby preventing adenosine catabolism. ADA was inhibited by 1,3-DNB with an IC(50) of 284 μM, Hill slope, n = 4.8 ± 0.4. Native gel electrophoresis showed that 1,3-DNB did not denature ADA. Furthermore, adding Triton X-100 (0.01-0.05%, wt/vol), Nonidet P-40 (0.0015-0.0036%, wt/vol), or bovine serum albumin (0.05 mg/ml or changing [ADA] (0.2 and 2 nM) did not substantially alter the 1,3-DNB IC(50) value. Likewise, dynamic light scattering showed no particle formation over a (1,3-DNB) range of 149-1043 μM. Kinetics revealed mixed inhibition with 1,3-DNB binding to ADA (K(I) = 520 ± 100 μM, n = 1 ± 0.6) and the ADA-adenosine complex (K(IS) = 262 ± 7 μM, n = 6 ± 0.6, indicating positive cooperativity). In accord with the kinetics, docking predicted binding of 1,3-DNB to the active site and three peripheral sites. In addition, exposure of DI TNC-1 astrocytes to 10-500 μM 1,3-DNB produced concentration-dependent increases in extracellular adenosine at 24 h. Overall, the results demonstrate that 1,3-DNB is a mixed inhibitor of ADA and may thus lead to increases in extracellular adenosine. The finding may provide insights to guide future work on chemically-induced energy deprivation.

  18. Intramedullary metastasis.

    PubMed

    Moffie, D; Stefanko, S Z

    1980-01-01

    Three cases of intramedullary metastases and one of a metastasis into the medulla oblongata are described. In two cases the primary tumour was a bronchial carcinoma and in one case a carcinoma of the breast. In one patient a primary tumour could not be found. The literature on this condition is reviewed and the difficulties of clinical diagnosis are discussed. The question remains unanswered as to the mechanism by which these tumour-cells reach the spinal cord and there is, as yet, no satisfactory explanation for the relative rare occurrence of these metastases.

  19. 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.

  20. 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.

  1. Clinical and radiological pictures of hepatocellular carcinoma with intracranial metastasis.

    PubMed

    Yen, F S; Wu, J C; Lai, C R; Sheng, W Y; Kuo, B I; Chen, T Z; Tsay, S H; Lee, S D

    1995-01-01

    Hepatocellular carcinoma (HCC) with extrahepatic spreading is not uncommon. In order to delineate the clinical and radiological pictures of HCC with intracranial metastasis, 33 documented cases were analysed. Eighteen had brain parenchymal metastasis without skull involvement; the other 15 cases disclosed skull metastasis with brain invasion. The underlying HCC are mainly of expanding (13/33, 39.4%) and multifocal (13/33, 39.4%) types. Eighteen cases (18/33, 54.5%) had mental changes not related to hypoglycaemia or hepatic encephalopathy. Eighteen cases (18/20, 90%) disclosed hyperdense mass lesions by non-contrast computed tomography (CT) scans and 17 cases showed homogeneous enhancement (17/22, 77.3%) by post-contrast CT images. In the non-skull involved group, five cases (5/12, 41.7%) disclosed ring-shape enhancement and 14 cases (14/16, 87.5%) had perifocal oedema, which were not seen in the skull involved group. Eight cases (8/33, 24.2%) presented as intracerebral haemorrhage. Twelve (12/33, 36.4%) died of brain herniation. Most (14/18, 77.8%) non-skull involved cases had simultaneous lung metastasis without bony metastasis, while the skull involved group often (10/15, 66.7%) disclosed extracranial bony metastasis without lung metastasis. The difference in extracranial metastasis was statistically significant (P < 0.05). The multivariate survival analysis disclosed that lower lactate dehydrogenase level (< or = 316 U/L, P = 0.029) and treatments (surgery or radiation, P = 0.001) were positively associated with longer survival. In conclusion, HCC with intracranial metastasis is symptomatic and life-threatening. Half the cases may come from pulmonary metastasis and the other half may be from bony metastasis. Brain irradiation or surgery can prolong their survival.

  2. 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.

  3. Presumed choroidal metastasis of Merkel cell carcinoma

    SciTech Connect

    Small, K.W.; Rosenwasser, G.O.; Alexander, E. III; Rossitch, G.; Dutton, J.J. )

    1990-05-01

    Merkel cell carcinoma is a rare skin tumor of neural crest origin and is part of the amine precursor uptake and decarboxylase system. It typically occurs on the face of elderly people. Distant metastasis is almost uniformly fatal. Choroidal metastasis, to our knowledge, has not been described. We report a patient with Merkel cell carcinoma who had a synchronous solid choroidal tumor and a biopsy-proven brain metastasis. Our 56-year-old patient presented with a rapidly growing, violaceous preauricular skin tumor. Computed tomography of the head disclosed incidental brain and choroidal tumors. Light and electron microscopy of biopsy specimens of both the skin and the brain lesions showed Merkel cell carcinoma. Ophthalmoscopy, fluorescein angiography, and A and B echography revealed a solid choroidal mass. The brain and skin tumors responded well to irradiation. A radioactive episcleral plaque was applied subsequently to the choroidal tumor. All tumors regressed, and the patient was doing well 28 months later. To our knowledge this is the first case of presumed choroidal metastasis of Merkel cell carcinoma.

  4. Cerebral metastasis from malignant pleural mesothelioma.

    PubMed

    El Molla, Mohamed; Gragnaniello, Cristian; Al-Khawaja, Darweesh; Chiribao-Negri, Concepcion; Eftekhar, Behzad

    2013-09-26

    Malignant mesothelioma is an uncommon, highly invasive tumor derived from the mesothelial cells of pleura or peritoneum characterized by poor outcome. Mesothelioma was thought to metastasize locally only via direct invasion and not have distant spread. Distant metastases were discovered mostly on post-mortem examination. The authors present a case of 62-year-old man with pleural mesothelioma and brain metastasis.

  5. Integrins and metastasis

    PubMed Central

    Ganguly, Kirat Kumar; Pal, Sekhar; Moulik, Shuvojit; Chatterjee, Amitava

    2013-01-01

    Metastasis is a combination of biological events that makes the difference between cancer and other diseases. Metastasis requires flow of erroneous but precisely coordinated basic cellular activities like cell migration–invasion, cell survival–apoptosis, cell proliferation, etc. All of these processes require efficient regulation of cell attachment and detachment, which recruit integrin receptors in this flow of events. World literatures show several aspects of interrelation of integrins and metastasis. Integrin molecules are being used as prime target to battle metastasis. In this review we are collating the observations showing importance of integrin biology in regulation of metastasis and the strategies where integrin receptors are being used as targets to regulate metastasis. PMID:23563505

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 1,3-Dichloropropene

    Integrated Risk Information System (IRIS)

    EPA / 635 / R - 00 / 001 TOXICOLOGICAL REVIEW OF 1,3 - DICHLOROPROPENE ( CAS No . 542 - 75 - 6 ) In Support of Summary Information on the Integrated Risk Information System ( IRIS ) May 2000 U.S . Environmental Protection Agency Washington , DC DISCLAIMER This document has been reviewed in accordanc

  11. 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

  12. Role of Extracellular miR-122 in Breast Cancer Metastasis

    DTIC Science & Technology

    2015-02-01

    endothelial, lung fibroblasts, and brain astrocyte niche cells through secreting exosomal miR-122, a miRNA whose level in the circulation predicts metastasis ...cell types in the niche. Our in vivo data indicates that miR- 122 intervention can reduce metastasis to the brain and lung. ... Metastasis ” PRINCIPAL INVESTIGATOR: Miranda Fong CONTRACTING ORGANIZATION: Beckman Research Institute of the City of Hope Duarte, CA 91010

  13. Metastasis and AKT activation.

    PubMed

    Sheng, Shijie; Qiao, Meng; Pardee, Arthur B

    2009-03-01

    Metastasis, responsible for 90% of cancer patient deaths, is an inefficient process because many tumor cells die. The survival of metastatic tumor cells should be considered as a critical therapeutic target. This review provides a new perspective regarding the role of AKT in tumor survival, and the rationale to target AKT in anti-metastasis therapies.

  14. 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

  15. Hypoxia-mediated metastasis.

    PubMed

    Chang, Joan; Erler, Janine

    2014-01-01

    Metastasis is responsible for more than 90 % of deaths among cancer patient. It is a highly complex process that involves the interplay between cancer cells, the tumor microenvironment, and even noncancerous host cells. Metastasis can be seen as a step-wise process: acquisition of malignant phenotype, invasion into surrounding tissue, intravasation into blood vessels, survival in circulation, extravasation to distant sites, and colonization of new organs. Before the actual metastatic process, the secondary site is also prepared for the arrival of the cancer cells through formation of "premetastatic niches." Hypoxia (low oxygen tension) is commonly found in solid tumors more than a few millimeters cubed and often is associated with a poor prognosis. Hypoxia increases angiogenesis, cancer cell survival, and metastasis. This chapter described how hypoxia regulates each step of the metastatic process and how blocking hypoxia-driven metastasis through targeting hypoxia-inducible factor 1, or downstream effector molecules such as the lysyl oxidase family may represent highly effective preventive strategies against metastasis in cancer patients.

  16. Autophagy in Cancer Metastasis

    PubMed Central

    Mowers, Erin E.; Sharifi, Marina N.; Macleod, Kay F.

    2016-01-01

    Autophagy is a highly conserved self-degradative process that plays a key role in cellular stress responses and survival. Recent work has begun to explore the function of autophagy in cancer metastasis, which is of particular interest given the dearth of effective therapeutic options for metastatic disease. Autophagy is induced upon progression of various human cancers to metastasis and together with data from genetically engineered mice and experimental metastasis models, a role for autophagy at nearly every phase of the metastatic cascade has been identified. Specifically, autophagy has been shown to be involved in modulating tumor cell motility and invasion, cancer stem cell viability and differentiation, resistance to anoikis, epithelial-to-mesenchymal transition, tumor cell dormancy and escape from immune surveillance, with emerging functions in establishing the pre-metastatic niche and other aspects of metastasis. In this review, we provide a general overview of how autophagy modulates cancer metastasis and discuss the significance of new findings for disease management. PMID:27593926

  17. Breast Cancer Metastasis

    PubMed Central

    Marino, Natascia; Woditschka, Stephan; Reed, L. Tiffany; Nakayama, Joji; Mayer, Musa; Wetzel, Maria; Steeg, Patricia S.

    2014-01-01

    Despite important progress in adjuvant and neoadjuvant therapies, metastatic disease often develops in breast cancer patients and remains the leading cause of their deaths. For patients with established metastatic disease, therapy is palliative, with few breaks and with mounting adverse effects. Many have hypothesized that a personalized or precision approach (the terms are used interchangeably) to cancer therapy, in which treatment is based on the individual characteristics of each patient, will provide better outcomes. Here, we discuss the molecular basis of breast cancer metastasis and the challenges in personalization of treatment. The instability of metastatic tumors remains a leading obstacle to personalization, because information from a patient’s primary tumor may not accurately reflect the metastasis, and one metastasis may vary from another. Furthermore, the variable presence of tumor subpopulations, such as stem cells and dormant cells, may increase the complexity of the targeted treatments needed. Although molecular signatures and circulating biomarkers have been identified in breast cancer, there is lack of validated predictive molecular markers to optimize treatment choices for either prevention or treatment of metastatic disease. Finally, to maximize the information that can be obtained, increased attention to clinical trial design in the metastasis preventive setting is needed. PMID:23895915

  18. 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.

  19. Solitary midbrain metastasis.

    PubMed

    Ongerboer de Visser, B W; Moffie, D

    1981-01-01

    The available clinical and pathological data of 5 cases with solitary midbrain metastasis including 2 of the present study are reviewed. Progressive dementia occurred in one case and mild dementia in another who also developed ocular symptoms. Ocular symptoms with sensory and coordination disturbances were seen in one, and only ocular symptoms in another case. Right-sided hemiplegia of 5 years duration occurred in the remaining case. Survival in tegmentum lesions is short.

  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. Metastasis and AKT activation.

    PubMed

    Qiao, Meng; Sheng, Shijie; Pardee, Arthur B

    2008-10-01

    Metastasis is responsible for 90% of cancer patient deaths. More information is needed about the molecular basis for its potential detection and treatment. The activated AKT kinase is necessary for many events of the metastatic pathway including escape of cells from the tumor's environment, into and then out of the circulation, activation of proliferation, blockage of apoptosis, and activation of angiogenesis. A series of steps leading to metastatic properties can be initiated upon activation of AKT by phosphorylation on Ser-473. These findings lead to the question of how this activation is connected to metastasis. Activated AKT phosphorylates GSK-3beta causing its proteolytic removal. This increases stability of the negative transcription factor SNAIL, thereby decreasing transcription of the transmembrane protein E-cadherin that forms adhesions between adjacent cells, thereby permitting their detachment. How is AKT hyperactivated in metastatic cells? Increased PI3K or TORC2 kinase activity- or decreased PHLPP phosphatase could be responsible. Furthermore, a positive feedback mechanism is that the decrease of E-cadherin lowers PTEN and thereby increases PIP3, further activating AKT and metastasis.

  2. From Breast to Bone: Tracking Gene Expression Changes Responsible for Breast Cancer Metastasis in a Humanized Mouse Model with Molecular Imaging

    DTIC Science & Technology

    2015-11-01

    and their lymph nodes, lungs, livers , bones, and brains were imaged ex vivo. Knockdown of p53 did not alter the frequency of metastasis to any...the lungs, livers , bones, and brains was significant ly greater in mice bearing p53- deficient tumors, even when the photon flux was normalized...transcriptional profiling. Enrichment for lung metastasis resulted in enrichment for metastasis to the lymph nodes, bones, and liver (Fig. 6, right

  3. Tocotrienol and cancer metastasis.

    PubMed

    De Silva, Leanne; Chuah, Lay Hong; Meganathan, Puvaneswari; Fu, Ju-Yen

    2016-01-01

    Tumor metastasis involves some of the most complex and dynamic processes in cancer, often leading to poor quality of life and inevitable death. The search for therapeutic compounds and treatment strategies to prevent and/or manage metastasis is the ultimate challenge to fight cancer. In the past two decades, research focus on vitamin E has had a shift from saturated tocopherols to unsaturated tocotrienols (T3). Despite sharing structural similarities with tocopherols, T3 strive to gain scientific prominence due to their anti-cancer effects. Recent studies have shed some light on the anti-metastatic properties of T3. In this review, the roles of T3 in each step of the metastatic process are discussed. During the invasion process, signaling pathways that regulate the extracellular matrix and tumor cell motility have been reported to be modulated by T3. Although studies on T3 and tumor cell migration are fairly limited, they were shown to play a vital role in the suppression of angiogenesis. Furthermore, the anti-inflammatory effect of T3 could be highly promising in the regulation of tumor microenvironment, which is crucial in supporting tumor growth in distant organs.

  4. Syndecan-1 and Metastasis Dormancy

    DTIC Science & Technology

    2015-09-01

    Breast neoplasms, breast cancer, metastasis, dormancy, stroma, matrix, proteoglycans, migration , invasion, lung, syndecans 16. SECURITY CLASSIFICATION...2. KEYWORDS Breast neoplasms, breast cancer, metastasis, dormancy, stroma, matrix, proteoglycans, migration , invasion, lung, syndecans 3... animals of the different genotypes. This result was unexpected. It is currently unknown whether p38 activation is causally related to decreased

  5. 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.

  6. 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

  7. Is selenium a potential treatment for cancer metastasis?

    PubMed

    Chen, Yu-Chi; Prabhu, K Sandeep; Mastro, Andrea M

    2013-04-08

    Selenium (Se) is an essential micronutrient that functions as a redox gatekeeper through its incorporation into proteins to alleviate oxidative stress in cells. Although the epidemiological data are somewhat controversial, the results of many studies suggest that inorganic and organic forms of Se negatively affect cancer progression, and that several selenoproteins, such as GPXs, also play important roles in tumor development. Recently, a few scientists have examined the relationship between Se and metastasis, a late event in cancer progression, and have evaluated the potential of Se as an anti-angiogenesis or anti-metastasis agent. In this review, we present the current knowledge about Se compounds and selenoproteins, and their effects on the development of metastasis, with an emphasis on cell migration, invasion, and angiogenesis. In the cancers of breast, prostate, colorectal, fibrosarcoma, melanoma, liver, lung, oral squamous cell carcinoma, and brain glioma, there is either clinical evidence linking selenoproteins, such as thioredoxin reductase-1 to lymph node metastasis; in vitro studies indicating that Se compounds and selenoproteins inhibited cell motility, migration, and invasion, and reduced angiogenic factors in some of these cancer cells; or animal studies showing that Se supplementation resulted in reduced microvessel density and metastasis. Together, these data support the notion that Se may be an anti-metastastatic element in addition to being a cancer preventative agent.

  8. Site of metastasis and breast cancer mortality: a Danish nationwide registry-based cohort study.

    PubMed

    Ording, Anne Gulbech; Heide-Jørgensen, Uffe; Christiansen, Christian Fynbo; Nørgaard, Mette; Acquavella, John; Sørensen, Henrik Toft

    2017-01-01

    Survival among patients with metastatic breast cancer may vary according to the site of metastasis and receptor status. We used Danish nationwide medical registries to establish a cohort of patients with metastatic breast cancer (870 with de novo metastatic disease and 3518 with recurrent disease with distant metastasis) diagnosed during 1997-2011. We examined 1-year and >1 to 5-year mortality associated with first site of metastasis and receptor expression status of the primary tumor. Cox proportional regression was used to compute confounder-adjusted mortality rate ratios (MRRs) associated with site of metastasis, stratified by receptor status. Overall 1-year and >1 to 5-year mortality risks were 36 and 69 %, respectively. Risk of death within 1 year was highest for brain-only (62 %) and liver-only (43 %) involvement and nearly the same for patients with lung-only (32 %), bone-only (32 %) involvement, and other/combination of sites (34 %). Using bone-only metastasis as reference, women with brain-only metastasis had more than two-fold increased risk of dying. The adjusted MRR for women with liver-only metastasis also was increased, though less pronounced. Patients with lung-only [adjusted MRR 0.9 (95 % confidence interval (CI) 0.8, 1.1)] or other metastases [adjusted MRR 1.0 (95 % CI 0.9, 1.2)] had similar mortality as patients with bone-only metastasis. Positive hormonal receptor status was a favorable prognostic factor. Metastatic breast cancer has a serious prognosis. Patients with brain-only metastasis had the highest mortality. Positive hormonal receptor status on the primary tumor was a favorable prognostic factor for all metastatic sites.

  9. Novel Aptamers to Target Metastasis

    DTIC Science & Technology

    2012-11-01

    AD_________________ Award Number: W81XWH-09-1-0154 TITLE: Novel Aptamers To Target Metastasis...August 2012 4. TITLE AND SUBTITLE Novel Aptamers to Target Metastasis 5a. CONTRACT NUMBER . 5b. GRANT NUMBER W81XWH-09-1-0154 5c. PROGRAM ELEMENT...problems. Aptamers , which have proven clinical efficacy for non-neoplastic disease and are generally more specific and stable than antibodies, may have

  10. Gastric metastasis of bilateral breast cancer

    PubMed Central

    Belaïd, Asma; Mghirbi, Fahmi; Béhi, Khalil; Doghri, Raoudha; Benna, Farouk

    2017-01-01

    Breast cancer is the most common malignancy in women. The most frequent metastatic sites are lung, bone, liver and brain. On the other hand, gastric metastases are rare. Synchronous bilateral breast cancer (SBBC) occurs rarely. Lobular carcinoma is the histological type most often associated with bilateral breast carcinomas and gastric metastases. We made a retrospective study including four patients followed in the Salah Azaiez Institute, for a bilateral breast cancer with gastric metastases. We analyzed the epidemiological, anatomoclinical and therapeutic particularities of this rare entity. Symptoms were unspecific. The diagnosis of gastric metastasis of the SBBC was confirmed by a histopathological examination of an endoscopic biopsy. The median age was 46.2 years (range, 36–51 years) and the median time until the gastric involvement was 19 months (range, 0–41 months). None of patients had a surgical treatment for the gastric location. All Patients received at least one line of chemotherapy and radiotherapy. Median survival following the detection of gastric involvement was 22 months (range, 1–56 months). Gastric metastases from breast cancer are rare and frequently associated with other distant metastasis. Symptoms are unspecific and endoscopy may not be contributive. Therefore, gastric involvement is underestimated. Lobular infiltrating carcinoma (LIC) is the most histological type incriminated in its occurrence. The supply of immunohistochemistry is crucial to distinguish between primary or metastatic gastric cancer. PMID:28280631

  11. 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

  12. 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.

  13. 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.

  14. The challenge of targeting metastasis.

    PubMed

    Fidler, Isaiah J; Kripke, Margaret L

    2015-12-01

    Metastases that are resistant to conventional therapy are the major cause of death from cancer. In most patients, metastasis has already occurred by the time of diagnosis. Thus, the prevention of metastasis is unlikely to be of therapeutic benefit. The biological heterogeneity of metastases presents a major obstacle to treatment. However, the growth and survival of metastases depend on interactions between tumor cells and host homeostatic mechanisms. Targeting these interactions, in addition to the tumor cells, can produce synergistic therapeutic effects against existing metastases.

  15. Leptomeningeal metastasis from squamous cell carcinoma of oesophagus with unusual presentation

    PubMed Central

    Akhavan, Ali; Navabii, Hossein

    2012-01-01

    Oesophageal cancer rarely metastasis to the brain but advances in brain imaging and increasing survival of these patients has led to more detection of this condition. Although oesophageal cancer is common in the north of Iran it is less frequent in the central parts such as Yazd. Leptomeningeal metastasis is very uncommon in oesophageal cancer. This paper presents a 73-year-old man with leptomeningeal carcinomatosis from squamous cell carcinoma of oesophagus presented by hoarseness due to true vocal cord plegia. PMID:23174999

  16. Mitochondria in relation to cancer metastasis.

    PubMed

    Bhandary, Bidur; Marahatta, Anu; Kim, Hyung-Ryong; Chae, Han-Jung

    2012-12-01

    Mitochondria, also known as "Power House of cell," are crucial organelles, regulating energy metabolism. Recently, an involvement of mitochondria in cancer occurrence and metastasis has been proposed. The roles of mitochondria in cancer progression/metastasis include alteration of glycolysis, regulation of ROS and suppression of intrinsic apoptosis. This mini-review explains the specific mitochondrial characteristics during cancer metastasis with past and recent findings. It may contribute to understanding mitochondria-related mechanisms of cancer metastasis.

  17. 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...

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

    PubMed

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

    2015-07-14

    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.

  19. Long-term follow-up of papillary and follicular thyroid carcinomas with bone metastasis

    PubMed Central

    Chen, Szu-Tah; Hsueh, Chuen; Li, Chia-Lin; Chao, Tzu-Chieh

    2017-01-01

    The aims of this study were to investigate papillary and follicular thyroid carcinomas with bone metastasis in various clinical presentations and to determine the prognostic factors after multimodality treatment. A retrospective analysis was performed of 3,120 patients with papillary and follicular thyroid carcinoma. Of these patients, 131 (including 97 women, 71.8%) were diagnosed with bone metastasis and underwent follow-up at the Chang Gung Medical Center. Patients with bone metastasis were categorized into two groups. Group A was comprised of patients who were diagnosed with bone metastasis either before thyroidectomy or within 6 months of the initial thyroidectomy (90 patients, 68.7%). Group B was comprised of patients with bone metastasis who received a diagnosis 6 months post-thyroidectomy in the follow-up period (41 patients, 31.3%). After a mean follow-up period of 8.4 ± 7.0 years, there were 88 deaths (67.2%) attributed to thyroid cancer and 13 patients (9.9%) achieved disease-free status. A multivariate analysis showed that older age, early diagnosis, and brain metastasis were each associated with a poor prognosis. The difference in disease-specific mortality rates between groups A and B was significant (p < 0.0001). In conclusion, papillary and follicular thyroid cancers with bone metastasis have a high rate of mortality. Despite this high mortality, 9.9% patients still had an excellent response to treatment. PMID:28278295

  20. Genome remodelling in a basal-like breast cancer metastasis and xenograft.

    PubMed

    Ding, Li; Ellis, Matthew J; Li, Shunqiang; Larson, David E; Chen, Ken; Wallis, John W; Harris, Christopher C; McLellan, Michael D; Fulton, Robert S; Fulton, Lucinda L; Abbott, Rachel M; Hoog, Jeremy; Dooling, David J; Koboldt, Daniel C; Schmidt, Heather; Kalicki, Joelle; Zhang, Qunyuan; Chen, Lei; Lin, Ling; Wendl, Michael C; McMichael, Joshua F; Magrini, Vincent J; Cook, Lisa; McGrath, Sean D; Vickery, Tammi L; Appelbaum, Elizabeth; Deschryver, Katherine; Davies, Sherri; Guintoli, Therese; Lin, Li; Crowder, Robert; Tao, Yu; Snider, Jacqueline E; Smith, Scott M; Dukes, Adam F; Sanderson, Gabriel E; Pohl, Craig S; Delehaunty, Kim D; Fronick, Catrina C; Pape, Kimberley A; Reed, Jerry S; Robinson, Jody S; Hodges, Jennifer S; Schierding, William; Dees, Nathan D; Shen, Dong; Locke, Devin P; Wiechert, Madeline E; Eldred, James M; Peck, Josh B; Oberkfell, Benjamin J; Lolofie, Justin T; Du, Feiyu; Hawkins, Amy E; O'Laughlin, Michelle D; Bernard, Kelly E; Cunningham, Mark; Elliott, Glendoria; Mason, Mark D; Thompson, Dominic M; Ivanovich, Jennifer L; Goodfellow, Paul J; Perou, Charles M; Weinstock, George M; Aft, Rebecca; Watson, Mark; Ley, Timothy J; Wilson, Richard K; Mardis, Elaine R

    2010-04-15

    Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour.

  1. 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.

  2. MicroRNAs in gastric cancer metastasis.

    PubMed

    Shi, Zhaoqi; Wei, Qingxia; She, Junjun

    2014-01-01

    Gastric cancer (GC) is common worldwide and has a high rate of metastasis. The underlying molecular mechanism of metastasis are not entirely clear. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally and are reported to be involved in multiple steps of tumor metastasis. Clarifying their roles in GC metastasis will improve understanding of this disease. Here, we review the involvement of miRNAs in multiple steps of GC metastasis, including epithelial-mesenchymal transitions, anoikis, angiogenesis, invasion, and migration. The clinical application of miRNAs as prognostic biomarkers in GC is also discussed.

  3. Design and Construction of a Multi-Organ Microfluidic Chip Mimicking the in vivo Microenvironment of Lung Cancer Metastasis.

    PubMed

    Xu, Zhiyun; Li, Encheng; Guo, Zhe; Yu, Ruofei; Hao, Hualong; Xu, Yitong; Sun, Zhao; Li, Xiancheng; Lyu, Jianxin; Wang, Qi

    2016-10-05

    Metastasis is a complex pathophysiological process. As the main cause of cancer mortality in humans it represents a serious challenge to both basic researchers and clinicians. Here we report the design and construction of a multi-organ microfluidic chip that closely mimics the in vivo microenvironment of lung cancer metastasis. This multi-organs-on-a-chip includes an upstream "lung" and three downstream "distant organs", with three polydimethylsiloxane (PDMS) layers and two thin PDMS microporous membranes bonded to form three parallel microchannels. Bronchial epithelial, lung cancer, microvascular endothelial, mononuclear, and fibroblast cells were grown separated by the biomembrane in upstream "lung", while astrocytes, osteocytes, and hepatocytes were grown in distant chambers, to mimic lung cancer cell metastasis to the brain, bone, and liver. After culture in this system, lung cancer cells formed a "tumor mass", showed epithelial-mesenchymal transition (with altered expression of E-cadherin, N-cadherin, Snail1, and Snail2) and invasive capacity. A549 cells co-cultured with astrocytes overexpressed CXCR4 protein, indicating damage of astrocytes after cancer cell metastasis to the brain. Osteocytes overexpressed RANKL protein indicates damage of osteocytes after cancer cell metastasis to the bone, and hepatocytes overexpressed AFP protein indicates damage to hepatocytes after cancer cell metastasis to the liver. Finally, in vivo imaging of cancer growth and metastasis in a nude mice model validated the performance of metastasis in the organs-on-chip system. This system provides a useful tool to mimic the in vivo microenvironment of cancer metastasis and to investigate cell-cell interactions during metastasis.

  4. 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

  5. 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....

  6. 45 CFR 1216.1-3 - Policy.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 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) Volunteers enrolled or participating in...

  7. 45 CFR 1211.1-3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 false Definitions. 1211.1-3 Section 1211.1-3 Public Welfare Regulations Relating to Public Welfare (Continued) CORPORATION FOR NATIONAL AND COMMUNITY SERVICE VOLUNTEER GRIEVANCE PROCEDURES § 1211.1-3 Definitions. (a) Volunteer means a person enrolled and currently serving as a full-time volunteer...

  8. 45 CFR 1210.1-3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 false Definitions. 1210.1-3 Section 1210.1-3 Public Welfare Regulations Relating to Public Welfare (Continued) CORPORATION FOR NATIONAL AND COMMUNITY SERVICE VISTA TRAINEE DESELECTION AND VOLUNTEER EARLY TERMINATION PROCEDURES General § 1210.1-3 Definitions. (a) Trainee means a person enrolled in...

  9. 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...

  10. 43 CFR 8365.1-3 - Vehicles.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 43 Public Lands: Interior 2 2014-10-01 2014-10-01 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...

  11. 43 CFR 8365.1-3 - Vehicles.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 2 2013-10-01 2013-10-01 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...

  12. 43 CFR 8365.1-3 - Vehicles.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 2 2012-10-01 2012-10-01 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...

  13. 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...

  14. 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

  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. Cutaneous Metastasis From Sacral Chordoma.

    PubMed

    Gleghorn, Kristyna; Goodwin, Brandon; Sanchez, Ramon

    2017-04-01

    Chordoma is a rare primary bone malignancy of notochord origin, representing 1-4% of malignant bone tumors., Typically, chordomas follow a slow progressive course with aggressive local extension, multiple recurrences, and metastases. Of particular interest to this case, cutaneous metastasis is exceedingly rare. Diagnosis of this entity can be a challenge due to the rarity of chordoma, as well as the infrequent presentation of distant cutaneous metastasis and non-specific clinical skin findings. We report a case of a 61-year-old male with a history of sacral chordoma treated by wide local excision 8 years prior to presentation developed a nodule on his scalp for 6 weeks. Physical examination revealed a 1 cm rubbery, pink, shiny dome-shaped nodule on his left occipital scalp. Hematoxylin and eosin sections revealed a lobular dermal proliferation of small ovoid cells and larger physaliferous cells with hyperchromatic, displaced nuclei and finely vacuolated "soap-bubble" cytoplasm in a myxoid stroma. Immunohistochemistry of tumor cells showed positivity for both S-100 protein and pancytokeratin (AE1/AE3), while smooth muscle actin (SMA), P63, and CK7 were negative. Additionally, tumor cells stained positive for brachyury. The medical history, clinical presentation, histopathological appearance and immunohistochemical profile are consistent with cutaneous metastasis from sacral chordoma, known as chordoma cutis. This case illustrates the integral role of dermatopathology in the diagnosis of a rare and critical condition.

  17. Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis.

    PubMed

    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

    2015-06-01

    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.

  18. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.

    PubMed

    van Roosmalen, Wies; Le Dévédec, Sylvia E; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M; Look, Maxime P; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A C 't; Martens, John W M; Foekens, John A; Geiger, Benjamin; van de Water, Bob

    2015-04-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3-binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis.

  19. 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

  20. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

    PubMed Central

    van Roosmalen, Wies; Le Dévédec, Sylvia E.; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M.; Look, Maxime P.; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A.C. ‘t; Martens, John W.M.; Foekens, John A.; Geiger, Benjamin; van de Water, Bob

    2015-01-01

    Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3–binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis. PMID:25774502

  1. Expression of Aggrus/podoplanin in bladder cancer and its role in pulmonary metastasis

    PubMed Central

    Takagi, Satoshi; Oh-hara, Tomoko; Sato, Shigeo; Gong, Bo; Takami, Miho; Fujita, Naoya

    2014-01-01

    Platelet aggregation-inducing factor Aggrus, also known as podoplanin, is associated with tumor malignancy by promoting hematogenous metastasis. Aggrus overexpression has been reported in some tumor tissues including lung, esophagus, head and neck and brain. We here found the frequent upregulation of aggrus mRNA in urinary bladder cancers using cancer tissue panels from various organs. Immunohistochemical analysis confirmed Aggrus protein expression in urinary bladder cancers and suggested a positive correlation between Aggrus expression and metastatic tendency in bladder cancers. Endogenous expression of Aggrus protein on the cell surface was found in the mouse bladder cancer MBT-2 cell line and human bladder cancer SCaBER cell lines. Knockdown of Aggrus expression in MBT-2 cells decreased their ability to induce platelet aggregation and form pulmonary metastasis in syngeneic mouse models. Knockdown of Aggrus expression in the human bladder cancer SCaBER cells also attenuated their ability to induce platelet aggregation and form pulmonary metastasis in mice. Moreover, pulmonary metastasis of SCaBER cells was prevented by prior administration of our generated anti-Aggrus neutralizing monoclonal antibodies by attenuating their retention in lung. These results indicate that Aggrus plays an important role in bladder cancer metastasis. Thus, anti-Aggrus neutralizing antibodies would be useful for the prevention of hematogenous metastasis of Aggrus-positive bladder cancer. PMID:24222607

  2. Integrin activation controls metastasis in human breast cancer

    PubMed Central

    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.

    2001-01-01

    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 αvβ3 supports breast cancer cell attachment under blood flow conditions in an activation-dependent manner. Integrin αvβ3 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. PMID:11172040

  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. 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.

  5. [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.

  6. Rare Gingival Metastasis by Hepatocellular Carcinoma

    PubMed Central

    Xue, Li-Jun; Geng, Jian; Chen, Ya-Nan; Wang, Qian

    2017-01-01

    Hepatocellular carcinoma (HCC) uncommonly metastasizes to the gingiva, which always means a poor outcome. We reported a rare HCC case with multiple metastases to gingiva, lungs, and brain. A 60-year-old man was initially diagnosed as HCC with metastases to double lungs. He was subjected to a transarterial chemoembolization (TACE) (5-fluorouracil, 750 mg) and two cycles of intravenous chemotherapy (gemcitabine 1.8 g at days 1 and 8, oxaliplatin 200 mg at day 2, every 4 weeks). However, the volume of liver tumor still increased. A bean-size gingival nodule growing with occasional bleeding was also found. TACE (5-fluorouracil 750 mg, perarubicin 40 mg, cisplatin 20 mg) was performed again and an oral sorafenib therapy (400 mg, twice per day) was adopted. The disease maintained relatively stable for about 6 months until a second obvious progress. The gingival nodule was then palliatively excised and identified as a poorly differentiated metastatic HCC by histopathological examination. Best supportive treatments were made since the performance score was too bad. Finally, cerebral metastases occurred and the patient died of systemic failure. Upon review of previous reports, we discussed risk factors, clinical and pathological characteristics, treatments, and prognosis of gingival metastasis by HCC. PMID:28386283

  7. 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

  8. Immune cell promotion of metastasis

    PubMed Central

    Kitamura, Takanori; Qian, Bin-Zhi; Pollard, Jeffrey W.

    2015-01-01

    Metastatic disease is the major cause of death from cancer, and immunotherapy and chemotherapy have had limited success in reversing its progression. Data from mouse models suggest that the recruitment of immunosuppressive cells to tumours protects metastatic cancer cells from surveillance by killer cells, which nullifies the effects of immunotherapy and thus establishes metastasis. Furthermore, in most cases, tumour-infiltrating immune cells differentiate into cells that promote each step of the metastatic cascade and thus are novel targets for therapy. In this Review, we describe how tumour-infiltrating immune cells contribute to the metastatic cascade and we discuss potential therapeutic strategies to target these cells. PMID:25614318

  9. 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)...

  10. 45 CFR 1206.1-3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 false Definitions. 1206.1-3 Section 1206.1-3 Public Welfare Regulations Relating to Public Welfare (Continued) CORPORATION FOR NATIONAL AND COMMUNITY SERVICE GRANTS AND CONTRACTS-SUSPENSION AND TERMINATION AND DENIAL OF APPLICATION FOR REFUNDING Suspension and Termination of Assistance §...

  11. 21 CFR 1.3 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Definitions. 1.3 Section 1.3 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL GENERAL ENFORCEMENT... after shipment or delivery in interstate commerce. (b) Label means any display of written, printed,...

  12. Gestational Choriocarcinoma Presenting with Lacrimal Gland Metastasis: A First Reported Case

    PubMed Central

    Sait, Khalid; Anfnan, Nisreen; Farwan, Khader; Nizamuddin, S. H. M.

    2015-01-01

    Background. Gestational choriocarcinoma (GC) is a recognized clinicopathological subtype of gestational trophoblastic neoplasia that usually metastasizes hematogenously to highly vascular organs like the lung, liver, and brain. However, orbital metastasis to the choroid and lacrimal gland is a rare occurrence. Case Presentation. A 21-year-old female presented with headache and left orbital swelling one year after resection of a complete hydatidiform mole followed by adjuvant methotrexate chemotherapy. A metastatic imaging screening revealed multiple metastases in the lungs, brain, and adrenal gland, in addition to the choroid and lacrimal gland. Based on her modified WHO risk factors scoring she was started on chemotherapy and whole brain radiotherapy, which resulted in a complete response. At two-year follow-up, serum b-HCG level was with normal limits; imaging surveillance was uneventful. Conclusion. We present the first case of lacrimal gland metastasis in a young girl from GC relapse. PMID:26075121

  13. 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.

  14. 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.

  15. Intramedullary spinal metastasis of a carcinoid tumor.

    PubMed

    Kumar, Jay I; Yanamadala, Vijay; Shin, John H

    2015-12-01

    We report an intramedullary spinal cord metastasis from a bronchial carcinoid, and discuss its mechanisms and management. Intramedullary spinal cord metastases from any cancer are rare, and bronchial carcinoids account for only a small fraction of lung cancers. To our knowledge, an intramedullary spinal cord metastasis from a bronchial carcinoid has been described only once previously.

  16. Management of brain metastases.

    PubMed

    Soffietti, Riccardo; Rudā, Roberta; Mutani, Roberto

    2002-10-01

    Brain metastases occur in 20-40% of patients with cancer and their frequency has increased over time. Lung, breast and skin (melanoma) are the commonest sources of brain metastases, and in up to 15% of patients the primary site remains unknown. After the introduction of MRI, multiple lesions have outnumbered single lesions. Contrast-enhanced MRI is the gold standard for the diagnosis. There are no pathognomonic features on CT or MRI that distinguish brain metastases from primary malignant brain tumors or nonneoplastic conditions: therefore a tissue diagnosis by biopsy should be always obtained in patients with unknown primary tumor before undergoing radiotherapy and/or chemotherapy. Some factors are prognostically important: a high Performance Status, a solitary brain metastasis, an absence of systemic metastases, a controlled primary tumor and a younger age. Based on these factors, subgroups of patients with different prognosis have been identified (RPA class I, II, III). Symptomatic therapy includes corticosteroids to reduce vasogenic cerebral edema and anticonvulsants to control seizures. In patients with newly diagnosed brain metastases prophylactic anticonvulsants should not be used routinely. The combination of surgery and whole-brain radiotherapy (WBRT) is superior to WBRT alone for the treatment of single brain metastasis in patients with limited or absent systemic disease and good neurological condition. Complete surgical resection allows a relief of intracranial hypertension, seizures and focal neurological deficits. Radiosurgery, alone or in conjunction with WBRT, yields results which are comparable to those reported after surgery followed by WBRT, provided that lesion's diameter does not exceed 3-3.5 cm. Radiosurgery offers the potential of treating patients with surgically inaccessible metastases. Still controversial is the need for WBRT after surgery or radiosurgery: local control seems better with the combined approach, but overall survival does not

  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. The Current and Future Treatment of Brain Metastases.

    PubMed

    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.

  19. A 3q gene signature associated with triple negative breast cancer organ specific metastasis and response to neoadjuvant chemotherapy

    PubMed Central

    Qian, Jun; Chen, Heidi; Ji, Xiangming; Eisenberg, Rosana; Chakravarthy, A. Bapsi; Mayer, Ingrid A.; Massion, Pierre P.

    2017-01-01

    Triple negative breast cancers (TNBC) are aggressive tumors, with high rates of metastatic spread and targeted therapies are critically needed. We aimed to assess the prognostic and predictive value of a 3q 19-gene signature identified previously from lung cancer in a collection of 4,801 breast tumor gene expression data. The 3q gene signature had a strong association with features of aggressiveness such as high grade, hormone receptor negativity, presence of a basal-like or TNBC phenotype and reduced distant metastasis free survival. The 3q gene signature was strongly associated with lung metastasis only in TNBC (P < 0.0001, Hazard ratio (HR) 1.44, 95% confidence interval (CI), 1.31–1.60), significantly associated with brain but not bone metastasis regardless of TNBC status. The association of one 3q driver gene FXR1 with distant metastasis in TNBC (P = 0.01) was further validated by immunohistochemistry. In addition, the 3q gene signature was associated with better response to neoadjuvant chemotherapy in TNBC (P < 0.0001) but not in non-TNBC patients. Our study suggests that the 3q gene signature is a novel prognostic marker for lung and/or brain metastasis and a predictive marker for the response to neoadjuvant chemotherapy in TNBC, implying a potential role for 3q genes in the mechanism of organ-specific metastasis. PMID:28387221

  20. 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...

  1. 21 CFR 1.3 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 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...

  2. 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...

  3. Dissecting and Targeting Latent Metastasis

    DTIC Science & Technology

    2015-09-01

    Sox2 is genetically amplified in squamous carcinomas and small cell lung cancers (23, 24). Sox9 is upregulated in brain tumors and basal cell...carcinomas (25), and confers stem cell phenotype to breast cancer cells (21). Analysis of TCGA datasets confirmed a high incidence of Sox2 and Sox9 genetic ...the STAT1 and NF-κB pathways in brain metastatic cells, which support tumor growth and chemoresistance. The evidence that genetic inhibition of gap

  4. 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

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

    PubMed

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

    2016-01-29

    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. Common sites of metastatic spread include lung, lymph node, brain, and bone. 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. Although newer imaging methods utilizing multi-photon microscopy are able to evaluate metastasis at the cellular level, 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.

  6. Antibody-mediated p53 protein therapy prevents liver metastasis in vivo.

    PubMed

    Hansen, James E; Fischer, Laurice K; Chan, Grace; Chang, Sophia S; Baldwin, Scott W; Aragon, Robert J; Carter, Jacqueline J; Lilly, Michael; Nishimura, Robert N; Weisbart, Richard H; Reeves, Mark E

    2007-02-15

    To evaluate the clinical efficacy of monoclonal antibody (mAb) 3E10 Fv antibody-mediated p53 protein therapy, an Fv-p53 fusion protein produced in Pichia pastoris was tested on CT26.CL25 colon cancer cells in vitro and in vivo in a mouse model of colon cancer metastasis to the liver. In vitro experiments showed killing of CT26.CL25 cells by Fv-p53 but not Fv or p53 alone, and immunohistochemical staining confirmed that Fv was required for transport of p53 into cells. Prevention of liver metastasis in vivo was tested by splenic injection of 100 nmol/L Fv-p53 10 min and 1 week after injection of CT26.CL25 cancer cells into the portal vein of BALB/c mice. Mice were sacrificed 1 week after the second injection of Fv-p53 and assigned a quantitative metastasis score. Control mice had an average metastasis score of 3.3 +/- 1.3, whereas mice treated with Fv-p53 had an average metastasis score of 0.8 +/- 0.4 (P = 0.004). These results indicate that Fv-p53 treatment had a profound effect on liver metastasis and represent the first demonstration of effective full-length p53 protein therapy in vivo. mAb 3E10 Fv has significant clinical potential as a mediator of intracellular and intranuclear delivery of p53 for prevention and treatment of cancer metastasis.

  7. Mechanisms of Ovarian Cancer Metastasis: Biochemical Pathways

    PubMed Central

    Nakayama, Kentaro; Nakayama, Naomi; Katagiri, Hiroshi; Miyazaki, Kohji

    2012-01-01

    Ovarian cancer is the most lethal gynecologic malignancy. Despite advances in chemotherapy, the five-year survival rate of advanced ovarian cancer patients with peritoneal metastasis remains around 30%. The most significant prognostic factor is stage, and most patients present at an advanced stage with peritoneal dissemination. There is often no clearly identifiable precursor lesion; therefore, the events leading to metastatic disease are poorly understood. This article reviews metastatic suppressor genes, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment as they relate to ovarian cancer metastasis. Additionally, novel chemotherapeutic agents targeting the metastasis-related biochemical pathways are discussed. PMID:23109879

  8. 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.

  9. Metaplastic Breast Carcinoma With Multiple Muscle Metastasis

    PubMed Central

    Liu, Chung Hsiung; Chang, Chen; Sy, Edgar; Lai, Hung-Wen; Kuo, Yao-Lung

    2015-01-01

    Abstract Metaplastic breast carcinoma (MBC) is a rare type of breast carcinoma. Recurrence presenting as chest wall invasion is common but rarely as metastasis to distal skeletal muscle in which most patients present with a painful mass. Herein, we report a rare case of 65-year-old woman, with MBC and recurrence presenting as distal multiple muscle metastasis. The patient received surgical excision for symptomatic relief. Unfortunately, she died 12 months postoperatively due to disease progression with multiple lung metastasis. In addition to radiotherapy and chemotherapy, surgical excision is an alternative option in selected patients such as those with painful, isolated, and easily approachable mass. PMID:25929895

  10. Breast cancer metastasis to the pituitary gland.

    PubMed

    Magalhães, Julia Fragoso; Bacchin, Renata Prota; Costa, Priscila Scatena; Alves, Gisele Malavazi; Fraige Filho, Fadlo; Stella, Lenira Cristina

    2014-11-01

    Metastatic tumors to the pituitary gland are an unusual complication typically seen in elderly patients with diffuse malignant disease. Breast and lung are the commonest sites of the primary tumor. Prognosis of patients with breast cancer metastasis is poor and depends on the primary neoplastic extension. We report a 54 year-old woman with breast cancer metastasis to the pituitary stalk first diagnosed because of visual disturbance with no other symptoms. Pituitary gland stalk metastasis is a very uncommon find and this case report includes a literature review.

  11. Microbial production of 1,3-propanediol.

    PubMed

    Sauer, Michael; Marx, Hans; Mattanovich, Diethard

    2008-01-01

    The introduction of economic production processes for 1,3-propanediol is a success story for the creation of a new market for a (bulk) chemical. The compound and its favorable properties have long been known; also the fermentation of glycerol to 1,3-propanediol had been described more than 120 years ago. Nevertheless, the product remained a specialty chemical until recently, when two new processes were introduced, providing 1,3-propanediol at a competitive price. Remarkably, one of the processes is in the field of white biotechnology and based on microbial fermentation, converting a renewable carbon source into a bulk chemical. This review covers the most important patents that led to the commercialization of bio-based 1,3-propanediol. Furthermore, some of the recent developments towards a sustainable industry are addressed. Similar questions arise for a variety of products if they are to be produced bio-based in large scale. However, special emphasis is given to 1,3-propanediol production.

  12. 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

  13. Synthesis and analysis of potential α1,3-fucosyltransferase inhibitors.

    PubMed

    Seelhorst, Katrin; Piernitzki, Tomas; Lunau, Nathalie; Meier, Chris; Hahn, Ulrich

    2014-11-15

    Fucosyltransferases catalyze the transfer of l-fucose from an activated GDP-β-l-fucose to various acceptor molecules such as N-acetyllactosamine. Frequently fucosylation is the final step within the glycosylation machinery, and the resulting glycans are involved in various cellular processes such as cell-cell recognition, adhesion and inflammation or tumor metastasis. The selective blocking of these interactions would thus be a potential promising therapeutic strategy. The syntheses and analyses of various potential α1,3-fucosyltransferase inhibitors derived from GDP-β-l-fucose containing a triazole linker unit is summarized and the observed inhibitory effect was compared with that of small molecules such as GDP or fucose. To examine their specificity and selectivity, all inhibitors were tested with human α1,3-fucosyltransferase IX and Helicobacter pylori α1,3-fucosyltransferase, which is to date the only α1,3-fucosyltransferase with a known high resolution structure. Specific inhibitors which inhibit either H. pylori α1,3-fucosyltransferase or human fucosyltransferase IX with Ki values in the micromolar range were identified. In that regard, acetylated GDP-galactose derivative Ac-3 turned out to inhibit H. pylori α1,3-fucosyltransferase but not human fucosyltransferase IX, whereas GDP-6-amino-β-l-fucose 17 showed an appreciably better inhibitory effect on fucosyltransferase IX activity than on that of H. pylori fucosyltransferase.

  14. Organotropic metastasis: role of tumor exosomes.

    PubMed

    Liu, Yang; Cao, Xuetao

    2016-02-01

    A recent paper in Nature shows that tumor exosomes expressing unique integrins can determine organotropic metastasis by preparing pre-metastatic niche through their integrins-mediated fusion with and fertilization of organ-specific resident cells.

  15. Three-dimensional context regulation of metastasis.

    PubMed

    Erler, Janine T; Weaver, Valerie M

    2009-01-01

    Tumor progression ensues within a three-dimensional microenvironment that consists of cellular and non-cellular components. The extracellular matrix (ECM) and hypoxia are two non-cellular components that potently influence metastasis. ECM remodeling and collagen cross-linking stiffen the tissue stroma to promote transformation, tumor growth, motility and invasion, enhance cancer cell survival, enable metastatic dissemination, and facilitate the establishment of tumor cells at distant sites. Matrix degradation can additionally promote malignant progression and metastasis. Tumor hypoxia is functionally linked to altered stromal-epithelial interactions. Hypoxia additionally induces the expression of pro-migratory, survival and invasion genes, and up-regulates expression of ECM components and modifying enzymes, to enhance tumor progression and metastasis. Synergistic interactions between matrix remodeling and tumor hypoxia influence common mechanisms that maximize tumor progression and cooperate to drive metastasis. Thus, clarifying the molecular pathways by which ECM remodeling and tumor hypoxia intersect to promote tumor progression should identify novel therapeutic targets.

  16. Ovarian carcinoma presenting as cutaneous nasal metastasis*

    PubMed Central

    António, Ana Marta; Alves, João Vitor; Goulão, João; Bártolo, Elvira

    2016-01-01

    Metastatic ovarian cancer uncommonly presents with skin metastasis. When present, skin metastases of ovarian cancer are usually localized in the vicinity of the primary tumor. We report a case of a 58-year-old woman with a rapid growing erythematous, well-defined nodule localized on the left nasal ala. A skin biopsy was performed and histopathological and immunohistochemical findings were compatible with a cutaneous metastasis of adenocarcinoma. A systematic investigation revealed a bilateral ovarian cystadenocarcinoma associated with visceral dissemination, likely associated with nose cutaneous metastasis. We report a very uncommon case because of the presentation of ovarian carcinoma as cutaneous metastasis. To our knowledge, this atypical localization on the nose has not been described yet in the literature. PMID:28300910

  17. Invasion and metastasis in pancreatic cancer.

    PubMed

    Keleg, Shereen; Büchler, Peter; Ludwig, Roman; Büchler, Markus W; Friess, Helmut

    2003-01-22

    Pancreatic cancer remains a challenging disease with an overall cumulative 5-year survival rate below 1%. The process of cancer initiation, progression and metastasis is still not understood well. Invasion and tumor metastasis are closely related and both occur within a tumour-host microecology, where stroma and tumour cells exchange enzymes and cytokines that modify the local extracellular matrix, stimulate cell migration, and promote cell proliferation and tumor cell survival. During the last decade considerable progress has been made in understanding genetic alterations of genes involved in local and systemic tumor growth. The most important changes occur in genes which regulate cell cycle progression, extracellular matrix homeostasis and cell migration. Furthermore, there is growing evidence that epigenetic factors including angiogenesis and lymphangiogenesis may participate in the formation of tumor metastasis. In this review we highlight the most important genetic alterations involved in tumor invasion and metastasis and further outline the role of tumor angiogenesis and lymphangiogenesis in systemic tumor dissemination.

  18. Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2013-10-01

    www.paneuropeannetworks.com/ST9/#163/z 7 Stafford JH, Hao G, Best AM, Sun X, Thorpe PE. Highly specific PET imaging of prostate tumors in mice with an iodine - 124 ...vascular endothelial cells. • Autoradiography and PET imaging of radioactive iodine labeled PGN635 confirmed the targeting specificity of PGN635 and

  19. Mechanisms of CTC Biomarkers in Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2015-10-01

    APC-Cy7 (Biolegend, cat # 304015, 1:50 dilution), mouse anti-human EpCAM-PE CD326 (eBiosciences, cat # 12-9326-71, 1:40 dilution), anti-human CD24-PE...ML5 (Biolegend, cat # 311106, 1:20 dilution), anti-human CD44-PE-Cy7 IM7 (Biolegend, cat # 103030, 1:20 dilution), mouse anti-human uPAR (CD87...FITC (AbD Serotec cat # MCA2506FT, 1:10 dilution), anti-human int β 1 (CD29)-ApC TS2/16 (Biolegend, cat # 3030008, 1:50 dilution). Cells were confirmed

  20. Lysyl oxidase mediates hypoxic control of metastasis.

    PubMed

    Erler, Janine T; Giaccia, Amato J

    2006-11-01

    Hypoxic cancer cells pose a great challenge to the oncologist because they are especially aggressive, metastatic, and resistant to therapy. Recently, we showed that elevation of the extracellular matrix protein lysyl oxidase (LOX) correlates with metastatic disease and is essential for hypoxia-induced metastasis. In an orthotopic rodent model of breast cancer, a small-molecule or antibody inhibitor of LOX abolished metastasis, offering preclinical validation of this enzyme as a therapeutic target.

  1. Gastric metastasis by lung small cell carcinoma

    PubMed Central

    Casella, Giovanni; Bella, Camillo Di; Cambareri, Antonino Roberto; Buda, Carmelo Antonio; Corti, Gianluigi; Magri, Filippo; Crippa, Stefano; Baldini, Vittorio

    2006-01-01

    Metastatic tumors of the gastrointestinal tract are rare. We describe a case of gastric metastasis due to primary lung cancer, revealed by an upper gastrointestinal endoscopy (UGIE). Haematogenous metastases to the stomach are a rare event. To our knowledge, only 55 cases have been described in the international literature. In these patients, the prognosis is very poor. We report herein a case of gastric metastasis by lung small cell carcinoma, with a review of the literature about this rare entity. PMID:16810769

  2. 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…

  3. Concertedness of 1,3-Dipolar Cycloadditions.

    ERIC Educational Resources Information Center

    Haque, M. Serajul

    1984-01-01

    There are two conflicting views about the mechanism of 1,3-dipolar cycloadditions to multibonds. To reconcile these viewpoints a concerted, spin-paired, diradical mechanism, based on valence bond theory, is proposed. Each of these three mechanisms is discussed. (JN)

  4. C-type lectins facilitate tumor metastasis

    PubMed Central

    Ding, Dongbing; Yao, Yao; Zhang, Songbai; Su, Chunjie; Zhang, Yonglian

    2017-01-01

    Metastasis, a life-threatening complication of cancer, leads to the majority of cases of cancer-associated mortality. Unfortunately, the underlying molecular and cellular mechanisms of cancer metastasis remain to be fully elucidated. C-type lectins are a large group of proteins, which share structurally homologous carbohydrate-recognition domains (CRDs) and possess diverse physiological functions, including inflammation and antimicrobial immunity. Accumulating evidence has demonstrated the contribution of C-type lectins in different steps of the metastatic spread of cancer. Notably, a substantial proportion of C-type lectins, including selectins, mannose receptor (MR) and liver and lymph node sinusoidal endothelial cell C-type lectin, are important molecular targets for the formation of metastases in vitro and in vivo. The present review summarizes what has been found regarding C-type lectins in the lymphatic and hematogenous metastasis of cancer. An improved understanding the role of C-type lectins in cancer metastasis provides a comprehensive perspective for further clarifying the molecular mechanisms of cancer metastasis and supports the development of novel C-type lectins-based therapies the for prevention of metastasis in certain types of cancer. PMID:28123516

  5. C-type lectins facilitate tumor metastasis.

    PubMed

    Ding, Dongbing; Yao, Yao; Zhang, Songbai; Su, Chunjie; Zhang, Yonglian

    2017-01-01

    Metastasis, a life-threatening complication of cancer, leads to the majority of cases of cancer-associated mortality. Unfortunately, the underlying molecular and cellular mechanisms of cancer metastasis remain to be fully elucidated. C-type lectins are a large group of proteins, which share structurally homologous carbohydrate-recognition domains (CRDs) and possess diverse physiological functions, including inflammation and antimicrobial immunity. Accumulating evidence has demonstrated the contribution of C-type lectins in different steps of the metastatic spread of cancer. Notably, a substantial proportion of C-type lectins, including selectins, mannose receptor (MR) and liver and lymph node sinusoidal endothelial cell C-type lectin, are important molecular targets for the formation of metastases in vitro and in vivo. The present review summarizes what has been found regarding C-type lectins in the lymphatic and hematogenous metastasis of cancer. An improved understanding the role of C-type lectins in cancer metastasis provides a comprehensive perspective for further clarifying the molecular mechanisms of cancer metastasis and supports the development of novel C-type lectins-based therapies the for prevention of metastasis in certain types of cancer.

  6. 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.

  7. Visualization of GFP-expressing tumors and metastasis in vivo.

    PubMed

    Hoffman, R M

    2001-05-01

    We have developed mouse models of metastatic cancer with genetically fluorescent tumors that can be imaged in fresh tissue, in situ, as well as externally. To achieve this capability, we have transduced the green fluorescent protein (GFP) gene, cloned from the bioluminescent jellyfish Aequorea victoria, into a series of human and rodent cancer cell lines that were selected in vitro to stably express GFP in vivo after transplantation to metastatic rodent models. Techniques were also developed for transduction of tumors by GFP in vivo. With this fluorescent tool, we detected and visualized for the first time tumors and metastasis in fresh viable tissue or in situ in host organs down to the single-cell level. GFP tumors on the colon, prostate, breast, brain, liver, lymph nodes, lung, pancreas, bone, and other organs can also be visualized externally, transcutaneously by quantitative whole-body fluorescence optical imaging. Real-time tumor and metastatic growth and angiogenesis and inhibition by representative drugs can be imaged and quantified for rapid antitumor, antimetastatic, and antiangiogenesis drug screening. The GFP-transfected tumor cells enabled a fundamental advance in the visualization of tumor growth and metastasis in real time in vivo.

  8. Rectal carcinoid tumor metastasis to a skull base meningioma

    PubMed Central

    Huang, Jennifer; Gupta, Amit; Badve, Chaitra; Cohen, Mark L; Wolansky, Leo J

    2016-01-01

    Carcinoid tumors are rare, slow-growing neuroendocrine tumors that most frequently develop in the gastrointestinal tract or lungs and have high potential for metastasis. Metastasis to the brain is rare, but to another intracranial tumor is extremely rare. Of the intracranial tumors, meningiomas are the most common to host metastases, which may be related to its rich vascularity and E-cadherin expression. We describe the case of a 65-year-old female with active chemotherapy-treated neuroendocrine carcinoma who presented with left-sided facial numbness, headaches, and blurry vision. Initial imaging revealed a 1 cm irregular dural-based left petrous apex mass suggestive of a meningioma that was re-imaged four months later as a rapidly enlarging, extra-axial, mass extending into the cavernous sinus, effacing Meckel’s cave that resembled a trigeminal schwannoma. Pathology revealed a carcinoid tumor metastatic to meningioma. While the mass displayed characteristic imaging findings of a schwannoma, rapid growth in the setting of known active malignancy should prompt the clinician to consider mixed pathology from metastatic disease or a more aggressive meningioma. PMID:26825133

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

    PubMed

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

    2009-11-17

    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 (sLe(X)) on prostate cancer (PCa) cells is thought to promote metastasis by mediating PCa cell binding to microvascular endothelial (E)-selectin. Yet, regulation of sLe(X) 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 alpha1,3 fucosyltransferases (FT) 3, 6, and 7 are markedly elevated in bone- and liver-metastatic PCa and dictate synthesis of sLe(X) 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 alpha1,3 FTs could enhance metastatic efficiency of PCa by triggering an E-selectin-dependent trafficking mechanism.

  10. Mouse models of advanced spontaneous metastasis for experimental therapeutics

    PubMed Central

    Francia, Giulio; Cruz-Munoz, William; Man, Shan; Xu, Ping; Kerbel, Robert S.

    2015-01-01

    An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models. PMID:21258397

  11. Leptomeningeal metastasis of an intradural malignant peripheral nerve sheath tumor.

    PubMed

    Stark, Andreas M; Mehdorn, H Maximilian

    2013-08-01

    Malignant peripheral nerve sheath tumors (MPNST) are defined as any malignant tumor arising from or differentiating towards the peripheral nerve sheath. Intradural MPNST metastases are very rare. We report, to our knowledge, the first case of leptomeningeal metastasis of a MPNST to the spine and intracranial space. A 56-year-old woman with primary intradural MPNST of the S1 nerve root developed leptomeningeal metastases as well as brain metastases 19 months after diagnosis. The patient had a history of non-Hodgkins lymphoma for which she had received irradiation to the spine 15 years prior to this presentation. She had no stigmata of neurofibromatosis type 1. Patients with MPNST may also develop leptomeningeal metastases as demonstrated in this patient with intradural post-radiation MPNST.

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

    PubMed

    Zhao, Min; Li, Zhe; Qu, Hong

    2015-10-21

    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.

  13. 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

  14. 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.

  15. 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

  16. Spinal metastasis in head and neck cancer

    PubMed Central

    2012-01-01

    Background The incidence of head and neck cancer is relatively low in developed countries and highest in South East Asia. Notwithstanding advances in surgery and radiotherapy over the past several decades, the 5-year survival rate for head and neck cancer has stagnated and remains at 50–55%. This is due, in large part, to both regional and distant disease spread, including spinal metastasis. Spinal metastasis from head and neck cancer is rare, has a poor prognosis and can significantly impede end-stage quality of life; normally only palliative care is given. This study aims to conduct a systematic review of the evidence available on management of spinal metastasis from head and neck cancer and to use such evidence to draw up guiding principles in the management of the distant spread. Methods Systematic review of the electronic literature was conducted regarding the management of spinal metastasis of head and neck malignancies. Results Due to the exceptional rarity of head and neck cancers metastasizing to the spine, there is a paucity of good randomized controlled trials into the management of spinal metastasis. This review produced only 12 case studies/reports and 2 small retrospective cohort studies that lacked appropriate controls. Conclusion Management should aim to improve end-stage quality of life and maintain neurological function. This review has found that radiotherapy +/− medical adjuvant is considered the principle treatment of spinal metastasis of head and neck cancers. There is an absence of a definitive treatment protocol for head and neck cancer spinal metastasis. Our failure to find and cite high-quality scientific evidence only serves to stress the need for good quality research in this area. PMID:22716187

  17. Mitochondrial metabolism in cancer metastasis

    PubMed Central

    Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E; Flomenberg, Neal; Birbe, Ruth C; Witkiewicz, Agnieszka K; Howell, Anthony; Philp, Nancy J; Pestell, Richard G

    2012-01-01

    We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the “reverse Warburg effect,” because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TOMM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the “reverse Warburg effect,” our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TOMM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally “fuels” tumor progression and metastatic dissemination, by “feeding” mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TOMM20(-) “glycolytic” cancer cells were rarely observed, indicating that the conventional “Warburg effect” does not frequently occur in cancer-positive lymph node metastases. PMID:22395432

  18. 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

  19. 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

  20. Radiosurgery for brain metastases and cerebral edema.

    PubMed

    Gazit, Inbal; Har-Nof, Sagi; Cohen, Zvi R; Zibly, Zion; Nissim, Uzi; Spiegelmann, Roberto

    2015-03-01

    The objective of this study was to assess reduction in cerebral edema following linear accelerator radiosurgery (LINAC) as first line therapy for brain metastasis. We reviewed the medical records of all patients who underwent LINAC radiosurgery for brain metastasis at our institution during 2010-2012, and who had not previously undergone either surgery or whole brain radiotherapy. Data were analyzed for 55 brain metastases from 46 patients (24 males), mean age 59.9 years. During the 2 months following LINAC radiosurgery, the mean steroid dose decreased from 4.8 to 2.6 mg/day, the mean metastasis volume decreased from 3.79±4.12 cc to 2.8±4.48 cc (p=0.001), and the mean edema volume decreased from 16.91±30.15 cc to 12.85±24.47 cc (p=0.23). The 17 patients with reductions of more than 50% in brain edema volume had single metastases. Edema volume in the nine patients with two brain metastases remained stable in five patients (volume change <10%, 0-2 cc) and increased in four patients (by >10%, 2-14 cc). In a subanalysis of eight metastases with baseline edema volume greater than 40 cc, edema volume decreased from 77.27±37.21 cc to 24.84±35.6 cc (p=0.034). Reductions in brain edema were greater in metastases for which non-small-cell lung carcinoma and breast cancers were the primary diseases. Overall, symptoms improved in most patients. No patients who were without symptoms or who had no signs of increased intracranial pressure at baseline developed signs of intracranial pressure following LINAC radiosurgery. In this series, LINAC stereotactic radiosurgery for metastatic brain lesions resulted in early reduction in brain edema volume in single metastasis patients and those with large edema volumes, and reduced the need for steroids.

  1. Bone metastasis risk factors in breast cancer

    PubMed Central

    Pulido, Catarina; Vendrell, Inês; Ferreira, Arlindo R; Casimiro, Sandra; Mansinho, André; Alho, Irina; Costa, Luís

    2017-01-01

    Bone is the single most frequent site for bone metastasis in breast cancer patients. Patients with bone-only metastasis have a fairly good prognosis when compared with patients with visceral disease. Nevertheless, cancer-induced bone disease carries an important risk of developing skeletal related events that impact quality of life (QoL). It is therefore particularly important to stratify patients according to their risk of developing bone metastasis. In this context, several risk factors have been studied, including demographic, clinicopathological, genetic, and metabolic factors. Most of them show conflicting or non-definitive associations and are not validated for clinical use. Nonetheless, tumour intrinsic subtype is widely accepted as a major risk factor for bone metastasis development and luminal breast cancer carries an increased risk for bone disease. Other factors such as gene signatures, expression of specific cytokines (such as bone sialoprotein and bone morphogenetic protein 7) or components of the extracellular matrix (like bone crosslinked C-telopeptide) might also influence the development of bone metastasis. Knowledge of risk factors related with bone disease is of paramount importance as it might be a prediction tool for triggering the use of targeted agents and allow for better patient selection for future clinical trials. PMID:28194227

  2. Biodegradation of hexahydro-1,3,5-trinitro-1,3,5-triazine

    SciTech Connect

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

    1981-11-01

    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-dimethylhydrazine, 1,2-dimethylhydrazine, formaldehyde, and methanol. A scheme for the biodegradation of RDX is poposed 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.

  3. 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

  4. 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.

  5. [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.

  6. Intramolecular Diels–Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles

    PubMed Central

    Elliott, Gregory I.; Fuchs, James R.; Blagg, Brian S. J.; Ishikawa, Hayato; Tao, Houchao; Yuan, Z.-Q.; Boger, Dale L.

    2008-01-01

    Full details of a systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles are disclosed in which the scope and utility of the reaction are defined. PMID:16895427

  7. CMMI(Registered) for Acquisition, Version 1.3. CMMI-ACQ, V1.3

    DTIC Science & Technology

    2010-11-01

    So Norimatsu, Norimatsu Process Engineering Lab, Inc. Mary Lynn Penn, Lockheed Martin Corporation David (Mike) Phillips , Software Engineering...CMMI ® for Acquisition, Version 1.3 CMMI-ACQ, V1.3 CMMI Product Team Improving processes for acquiring better products and services...November 2010 TECHNICAL REPORT CMU/SEI-2010-TR-032 ESC-TR-2010-032 Software Engineering Process Management Program Unlimited distribution

  8. 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.

  9. 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.

  10. The Multiple Roles of Exosomes in Metastasis

    PubMed Central

    WEIDLE, H. ULRICH; BIRZELE, FABIAN; KOLLMORGEN, GWEN; RÜGER, RÜDIGER

    2016-01-01

    Exosomes are important contributors to cell−cell communication and their role as diagnostic markers for cancer and the pathogenesis for cancer is under intensive investigation. Here, we focus on their role in metastasis-related processes. We discuss their impact regarding promotion of invasion and migration of tumor cells, conditioning of lymph nodes, generation of premetastatic niches and organotropism of metastasis. Furthermore, we highlight interactions of exosomes with bone marrow and stromal components such as fibroblasts, endothelial cells, myeloid- and other immune-related cells in the context of metastases. For all processes as described above, we outline molecular and cellular components for therapeutic intervention with metastatic processes. PMID:28031234

  11. Tumor metastasis: molecular insights and evolving paradigms.

    PubMed

    Valastyan, Scott; Weinberg, Robert A

    2011-10-14

    Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances provide provocative insights into these cell-biological and molecular changes, which have implications regarding the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting.

  12. The Multiple Roles of Exosomes in Metastasis.

    PubMed

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

    2017-01-02

    Exosomes are important contributors to cell-cell communication and their role as diagnostic markers for cancer and the pathogenesis for cancer is under intensive investigation. Here, we focus on their role in metastasis-related processes. We discuss their impact regarding promotion of invasion and migration of tumor cells, conditioning of lymph nodes, generation of premetastatic niches and organotropism of metastasis. Furthermore, we highlight interactions of exosomes with bone marrow and stromal components such as fibroblasts, endothelial cells, myeloid- and other immune-related cells in the context of metastases. For all processes as described above, we outline molecular and cellular components for therapeutic intervention with metastatic processes.

  13. 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.

  14. 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

  15. 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.

  16. Breast metastasis from a pulmonary adenocarcinoma: Case report and review of the literature

    PubMed Central

    SANGUINETTI, ALESSANDRO; PUMA, FRANCESCO; LUCCHINI, ROBERTA; SANTOPRETE, STEFANO; CIROCCHI, ROBERTO; CORSI, ALESSIA; TRIOLA, ROBERTA; AVENIA, NICOLA

    2013-01-01

    Breast metastasis from extra-mammary malignancy is rare. An incidence of 0.4–1.3% has been reported in the literature. The primary malignancies most commonly metastasizing to the breast are leukemia, lymphoma and malignant melanoma. We present a case of metastasis to the breast from a pulmonary adenocarcinoma, diagnosed concomitantly with the primary tumor. A 43-year-old female presented with dyspnea and a dry cough of 3 weeks’ duration. A subsequent chest radiograph revealed a massive pleural effusion. Additionally, on physical examination, a poorly defined mass was noted in the upper outer quadrant of the right breast. The patient underwent bronchoscopy, simple right mastectomy and medical thoracoscopy. Following cytology, histology and immunohistochemistry, primary lung adenocarcinoma with metastasis to the breast and parietal pleura was diagnosed. Histologically, both the primary and metastatic anatomic sites demonstrated a micropapillary component, which has recently been recognized as an important prognostic factor. Although the patient received chemotherapy, she succumbed to her condition within 8 months. Accurate differentiation of metastasis from primary carcinoma is very important as the treatment and prognosis of the two differ significantly. PMID:23255943

  17. Breast metastasis from a pulmonary adenocarcinoma: Case report and review of the literature.

    PubMed

    Sanguinetti, Alessandro; Puma, Francesco; Lucchini, Roberta; Santoprete, Stefano; Cirocchi, Roberto; Corsi, Alessia; Triola, Roberta; Avenia, Nicola

    2013-01-01

    Breast metastasis from extra-mammary malignancy is rare. An incidence of 0.4-1.3% has been reported in the literature. The primary malignancies most commonly metastasizing to the breast are leukemia, lymphoma and malignant melanoma. We present a case of metastasis to the breast from a pulmonary adenocarcinoma, diagnosed concomitantly with the primary tumor. A 43-year-old female presented with dyspnea and a dry cough of 3 weeks' duration. A subsequent chest radiograph revealed a massive pleural effusion. Additionally, on physical examination, a poorly defined mass was noted in the upper outer quadrant of the right breast. The patient underwent bronchoscopy, simple right mastectomy and medical thoracoscopy. Following cytology, histology and immunohistochemistry, primary lung adenocarcinoma with metastasis to the breast and parietal pleura was diagnosed. Histologically, both the primary and metastatic anatomic sites demonstrated a micropapillary component, which has recently been recognized as an important prognostic factor. Although the patient received chemotherapy, she succumbed to her condition within 8 months. Accurate differentiation of metastasis from primary carcinoma is very important as the treatment and prognosis of the two differ significantly.

  18. 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

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

    PubMed

    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

    2016-04-12

    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

    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.

  1. 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

  2. GPR78 promotes lung cancer cell migration and metastasis by activation of Gαq-Rho GTPase pathway.

    PubMed

    Dong, Dan-Dan; Zhou, Hui; Li, Gao

    2016-11-01

    GPR78 is an orphan G-protein coupled receptor (GPCR) that is predominantly expressed in human brain tissues. Currently, the function of GPR78 is unknown. This study revealed that GPR78 was expressed in lung cancer cells and functioned as a novel regulator of lung cancer cell migration and metastasis. We found that knockdown of GPR78 in lung cancer cells suppressed cell migration. Moreover, GPR78 modulated the formation of actin stress fibers in A549 cells, in a RhoA- and Rac1-dependent manner. At the molecular level, GPR78 regulated cell motility through the activation of Gαq-RhoA/Rac1 pathway. We further demonstrated that in vivo, the knockdown of GPR78 inhibited lung cancer cell metastasis. These findings suggest that GPR78 is a novel regulator for lung cancer metastasis and may serve as a potential drug target against metastatic human lung cancer. [BMB Reports 2016; 49(11): 623-628].

  3. GPR78 promotes lung cancer cell migration and metastasis by activation of Gαq-Rho GTPase pathway

    PubMed Central

    Dong, Dan-Dan; Zhou, Hui; Li, Gao

    2016-01-01

    GPR78 is an orphan G-protein coupled receptor (GPCR) that is predominantly expressed in human brain tissues. Currently, the function of GPR78 is unknown. This study revealed that GPR78 was expressed in lung cancer cells and functioned as a novel regulator of lung cancer cell migration and metastasis. We found that knockdown of GPR78 in lung cancer cells suppressed cell migration. Moreover, GPR78 modulated the formation of actin stress fibers in A549 cells, in a RhoA- and Rac1-dependent manner. At the molecular level, GPR78 regulated cell motility through the activation of Gαq-RhoA/Rac1 pathway. We further demonstrated that in vivo, the knockdown of GPR78 inhibited lung cancer cell metastasis. These findings suggest that GPR78 is a novel regulator for lung cancer metastasis and may serve as a potential drug target against metastatic human lung cancer. PMID:27697106

  4. 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

  5. EGF as a New Therapeutic Target for Medulloblastoma Metastasis

    PubMed Central

    Rico-Varela, Jennifer; Singh, Tanya; McCutcheon, Sean; Vazquez, Maribel

    2015-01-01

    Medulloblastoma (MB) is a malignant pediatric brain tumor known for its aggressive metastatic potential. Despite the well-documented migration of MB cells to other parts of the brain and spinal column, MB chemotaxis is poorly understood. Herein, we examined the in vitro migratory and cellular responses of MB-derived cells to external signaling of Epidermal Growth Factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF-BB), and the stromal cell-derived factors 1-alpha (SDF-1). Experiments utilized transwell assays and immunocytochemistry to identify receptor activation in MB migration, and used a microfluidic platform to examine directionality, trajectory, and gradient-dependence of motile cells. Data illustrates that MB-derived cells respond strongly to EGF in a dosage and gradient-dependent manner with increased EGF-R activation, and show that high EGF gradient fields cause an increased number of cells to migrate longer directed distances. Our results provide evidence that EGF and its receptor play an important role than previously documented in MB chemotactic migration than previously documented and should be considered for developing migration-target therapies against MB metastasis. PMID:26594253

  6. Gallbladder metastasis: spectrum of imaging findings.

    PubMed

    Barretta, Maria Luisa; Catalano, Orlando; Setola, Sergio Venanzio; Granata, Vincenza; Marone, Ugo; D'Errico Gallipoli, Adolfo

    2011-12-01

    The objective of this study is to report the diagnostic features of hematogenous gallbladder metastasis using various imaging modalities. We carried out a single-center retrospective analysis of 13 patients with gallbladder metastasis. The primary malignancy was cutaneous melanoma (11 cases), hepatocellular carcinoma (1 case), and non-Hodgkin lymphoma (1 case). All patients underwent sonography (US), with color-power-Doppler assessment in 11 cases. Contrast-enhanced US (CEUS) was performed in 8 patients, MDCT in 8, and MR imaging in 1. Four subjects studied by whole-body PET. The gallbladder lesions were first detected with US in 9 cases and with MDCT in 3 cases. The remaining patient was investigated because of hepatic fluorodeoxyglucose uptake at PET; CEUS failed to detect any liver metastasis in this subject but identified a gallbladder lesion. Typical findings included multiplicity of gallbladder vegetations, broad base, limited mural thickening, presence of contrast enhancement, absence of gallstones and gallbladder bed infiltration, presence of combined lesions within other organs. Only two patients presented an isolated location in the gallbladder and were successfully treated with surgery. Gallbladder metastasis is a rare but possible occurrence. Knowledge of the typical imaging features and careful evaluation of the gallbladder may avoid an incorrect or false negative diagnosis.

  7. Three-dimensional context regulation of metastasis

    PubMed Central

    Erler, Janine T.; Weaver, Valerie M.

    2009-01-01

    Tumor progression ensues within a three-dimensional microenvironment that consists of cellular and non-cellular components. The extracellular matrix (ECM) and hypoxia are two non-cellular components that potently influence metastasis. ECM remodeling and collagen cross-linking stiffen the tissue stroma to promote transformation, tumor growth, motility and invasion, enhance cancer cell survival, enable metastatic dissemination, and facilitate the establishment of tumor cells at distant sites. Matrix degradation can additionally promote malignant progression and metastasis. Tumor hypoxia is functionally linked to altered stromal-epithelial interactions. Hypoxia additionally induces the expression of pro-migratory, survival and invasion genes, and up-regulates expression of ECM components and modifying enzymes, to enhance tumor progression and metastasis. Synergistic interactions between matrix remodeling and tumor hypoxia influence common mechanisms that maximize tumor progression and cooperate to drive metastasis. Thus, clarifying the molecular pathways by which ECM remodeling and tumor hypoxia intersect to promote tumor progression should identify novel therapeutic targets. PMID:18814043

  8. Neural Regulation of Breast Cancer Metastasis

    DTIC Science & Technology

    2009-10-01

    and F. Entschladen, The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta ... blockers . Int J Cancer, 2006. 118(11): p. 2744-9. 8. Draoui, A, B. Vandewalle, L. Hornez, F. Revillion, and J. Lefebvre, Beta-adrenergic receptors in

  9. Bioluminescence imaging of bone metastasis in rodents.

    PubMed

    Snoeks, Thomas J A; van Beek, Ermond; Que, Ivo; Kaijzel, Eric L; Löwik, Clemens W G M

    2012-01-01

    Optical imaging is a valuable technique for visualizing and quantifying biological processes in living -organisms. Optical imaging can be divided into two main imaging modalities: bioluminescence imaging and fluorescence imaging. This chapter describes the use of these imaging techniques to image tumour cells in mouse models of cancer and to detect early bone metastasis.

  10. Breast cancer metastasis and the lymphatic system

    PubMed Central

    RAHMAN, MUNAZZAH; MOHAMMED, SULMA

    2015-01-01

    Breast cancer remains the leading cause of cancer mortality worldwide, despite a significant decline in death rates due to early detection. The majority of cancer mortalities are due to the metastasis of tumor cells to other organs. Metastasis or tumor cell dissemination occurs via the hematogenous and lymphatic systems. For many carcinomas, the dissemination of tumor cells via lymphatic drainage of the tumor is the most common metastatic route. Such lymphatic drainage collects at the regional lymph nodes and the dissection and pathological examination of these nodes for lodged cancer cells is the gold standard procedure to detect metastasis. The present report provides an overview of the lymphatic system and its clinical significance as a prognostic factor, in addition to the interactions between the primary tumor and its microenvironment, and the influence of genomic subtypes on the resulting organ-specific pattern of tumor cell dissemination. It also examines the seemingly protracted asymptomatic period, during which the disseminated cells remain dormant, leading to the manifestation of metastasis decades after the successful treatment of the primary tumor. PMID:26622656

  11. Imaging Primary Prostate Cancer and Bone Metastasis

    DTIC Science & Technology

    2007-04-01

    Bone Metastasis PRINCIPAL INVESTIGATOR: Xiaoyuan Chen, Ph.D. CONTRACTING ORGANIZATION: Leland Stanford Junior University...ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Leland Stanford Junior University...Schonbrunn A. Bombesin receptors in a human duodenal tumor cell line: binding properties and function. Cancer Res 1994;54:818–24. [11] Chung DH, Evers

  12. 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

  13. 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

  14. Nuclear localization and functional characteristics of voltage-gated potassium channel Kv1.3.

    PubMed

    Jang, Soo Hwa; Byun, Jun Kyu; Jeon, Won-Il; Choi, Seon Young; Park, Jin; Lee, Bo Hyung; Yang, Ji Eun; Park, Jin Bong; O'Grady, Scott M; Kim, Dae-Yong; Ryu, Pan Dong; Joo, Sang-Woo; Lee, So Yeong

    2015-05-15

    It is widely known that ion channels are expressed in the plasma membrane. However, a few studies have suggested that several ion channels including voltage-gated K(+) (Kv) channels also exist in intracellular organelles where they are involved in the biochemical events associated with cell signaling. In the present study, Western blot analysis using fractionated protein clearly indicates that Kv1.3 channels are expressed in the nuclei of MCF7, A549, and SNU-484 cancer cells and human brain tissues. In addition, Kv1.3 is located in the plasma membrane and the nucleus of Jurkat T cells. Nuclear membrane hyperpolarization after treatment with margatoxin (MgTX), a specific blocker of Kv1.3 channels, provides evidence for functional channels at the nuclear membrane of A549 cells. MgTX-induced hyperpolarization is abolished in the nuclei of Kv1.3 silenced cells, and the effects of MgTX are dependent on the magnitude of the K(+) gradient across the nuclear membrane. Selective Kv1.3 blockers induce the phosphorylation of cAMP response element-binding protein (CREB) and c-Fos activation. Moreover, Kv1.3 is shown to form a complex with the upstream binding factor 1 in the nucleus. Chromatin immunoprecipitation assay reveals that Sp1 transcription factor is directly bound to the promoter region of the Kv1.3 gene, and the Sp1 regulates Kv1.3 expression in the nucleus of A549 cells. These results demonstrate that Kv1.3 channels are primarily localized in the nucleus of several types of cancer cells and human brain tissues where they are capable of regulating nuclear membrane potential and activation of transcription factors, such as phosphorylated CREB and c-Fos.

  15. Nuclear Localization and Functional Characteristics of Voltage-gated Potassium Channel Kv1.3*

    PubMed Central

    Jang, Soo Hwa; Byun, Jun Kyu; Jeon, Won-Il; Choi, Seon Young; Park, Jin; Lee, Bo Hyung; Yang, Ji Eun; Park, Jin Bong; O'Grady, Scott M.; Kim, Dae-Yong; Ryu, Pan Dong; Joo, Sang-Woo; Lee, So Yeong

    2015-01-01

    It is widely known that ion channels are expressed in the plasma membrane. However, a few studies have suggested that several ion channels including voltage-gated K+ (Kv) channels also exist in intracellular organelles where they are involved in the biochemical events associated with cell signaling. In the present study, Western blot analysis using fractionated protein clearly indicates that Kv1.3 channels are expressed in the nuclei of MCF7, A549, and SNU-484 cancer cells and human brain tissues. In addition, Kv1.3 is located in the plasma membrane and the nucleus of Jurkat T cells. Nuclear membrane hyperpolarization after treatment with margatoxin (MgTX), a specific blocker of Kv1.3 channels, provides evidence for functional channels at the nuclear membrane of A549 cells. MgTX-induced hyperpolarization is abolished in the nuclei of Kv1.3 silenced cells, and the effects of MgTX are dependent on the magnitude of the K+ gradient across the nuclear membrane. Selective Kv1.3 blockers induce the phosphorylation of cAMP response element-binding protein (CREB) and c-Fos activation. Moreover, Kv1.3 is shown to form a complex with the upstream binding factor 1 in the nucleus. Chromatin immunoprecipitation assay reveals that Sp1 transcription factor is directly bound to the promoter region of the Kv1.3 gene, and the Sp1 regulates Kv1.3 expression in the nucleus of A549 cells. These results demonstrate that Kv1.3 channels are primarily localized in the nucleus of several types of cancer cells and human brain tissues where they are capable of regulating nuclear membrane potential and activation of transcription factors, such as phosphorylated CREB and c-Fos. PMID:25829491

  16. A case report of thyroid gland metastasis associated with lung metastasis from colon cancer.

    PubMed

    Nakamura, Keisuke; Nozawa, Keijiro; Aoyagi, Yoshiko; Ishihara, Soichiro; Matsuda, Keiji; Fukushima, Junichi; Watanabe, Toshiaki

    2011-01-01

    Thyroid gland metastasis of malignant tumors is observed in 1.9% to 9.5% of histologically examined autopsy cases. Thyroid metastasis from colon cancer is extremely rare and the prognosis is poor. Here we report a case of lung metastasis and thyroid gland metastasis following sigmoid colon cancer surgery. In 2000, a 58-year-old woman underwent a sigmoid colectomy for sigmoid colon cancer. In 2005, a metastatic lung tumor was detected by chest CT. The patient underwent a partial thoracoscopic resection of the left lung in April 2005. On a CT scan taken 3 years and 4 months after the lung resection, a tumor mass was observed in the left lung and a low-absorption region with an unclear border was seen in the left lobe of the thyroid gland. Thyroid aspiration cytology showed adenocarcinoma, and a diagnosis of thyroid gland metastasis from sigmoid colon cancer was made. In April 2008 a subtotal thyroidectomy was performed. Following surgery, the patient underwent chemotherapy with mFOLFOX6 and bevacizumab. Nevertheless a number of lung metastases and expressions of lung metastasis were subsequently observed. Histopathological examination revealed a number of metastases of differentiated papillary adenocarcinoma in the thyroid gland from colon cancer.

  17. Organ Preference of Cancer Metastasis and Metastasis-Related Cell Adhesion Molecules Including Carbohydrates.

    PubMed

    Kawaguchi, Takanori

    2016-01-01

    This review starts on one of our special interests, the organ preference of metastasis. We examined data on 1,117 autopsy cases and found that the organ distribution of metastasis of cancers of the lung, pancreas, stomach, colon, rectum, uterine cervix, liver, bile duct, and esophagus involved the lung, liver, adrenal gland, bone/bone marrow, lymph node, and pleura/peritoneum. Cancers of the kidney, thyroid, ovary, choriocarcinoma, and breast, however, manifested different metastatic patterns. The distribution of leukemia and lymphoma metastases was quite different from that of epithelial cancers. On the basis of experimental studies, we believe that the anatomical-mechanical hypothesis should be replaced by the microinjury hypothesis, which suggests that tissue microinjury induced by temporal tumor cell embolization is crucial for successful metastasis. This hypothesis may actually reflect the so-called inflammatory oncotaxis concept. To clarify the mechanisms underlying metastasis, we developed an experimental model system of a rat hepatoma AH7974 that embraced substrate adhesiveness. This model did not prove a relationship between substrate-adhesion potential and metastatic lung-colonizing potential of tumor cells, but metastatic potential was correlated with the expression of the laminin carbohydrate that was recognized by Griffonia (Bandeiraea) simplicifolia isolectin G4. Therefore, we investigated the relationship between carbohydrate expression profiles and metastasis and prognosis. We indeed found an intimate relationship between the carbohydrate expression of cancer cells and the progression of malignant tumors, organ preference of metastasis, metastatic potential of tumor cells, and prognosis of patients.

  18. IRIS Toxicological Review of Hexahydro-1,3,5-Trinitro-1,3,5 ...

    EPA Pesticide Factsheets

    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 supporting the RDX assessment and release a final report of their review. Information regarding the peer review can be found on the SAB website. EPA is undertaking an update of the Integrated Risk Information System (IRIS) health assessment for RDX. The outcome of this project is an updated Toxicological Review and IRIS Summary for RDX that will be entered into the IRIS database.

  19. [A Case of an Abdominal Desmoplastic Small Round Cell Tumor with Metastasis in the Medulla Oblongata].

    PubMed

    Azami, Ayaka; Takano, Yoshinao; Honda, Michitaka; Todate, Yukitoshi; Tada, Takeshi; Waragai, Mitsuru; Fukushima, Daizo; Suzuki, Nobuyasu; Sato, Atai; Abe, Tsuyoshi; Teranishi, Yasushi; Sakuma, Hideo

    2016-11-01

    A desmoplastic small round cell tumor(DSRCT)is a very rare malignant tumor that mainly occurs in the intra-abdominal cavity in young adults.This neoplasm has an extremely poor prognosis, with a clinical course characterized by rapid progression and metastasis.We present a 31-year-old man who presented with chief complaints of dysphagia, ataxic gait, and hoarseness.He first underwent surgical resection of a tumor in the medulla oblongata; however, the lesion was suspected to be a metastatic neoplasm.Following a thorough medical examination, the patient was diagnosed with retroperitoneal DSRCT with multiple metastatic lesions.He received multidisciplinary treatment including debulking surgery for the primary lesion; radiotherapy for metastatic lesions in the brain, abdomen, and cervical lymph nodes; hepatic artery embolization for liver metastasis; and systemic chemotherapy.The patient died of progressive disease 17 months after the initial diagnosis.

  20. Pituitary Metastasis from Renal Cell Carcinoma: Description of a Case Report

    PubMed Central

    Wendel, Chloé; Campitiello, Marco; Plastino, Francesca; Eid, Nada; Hennequin, Laurent; Quétin, Philippe; Longo, Raffaele

    2017-01-01

    Patient: Male, 61 Final Diagnosis: Pituitary metastasis from renal cell carcinoma Symptoms: Deterioration of visual acuity and field • persisting headache • excess thirst • polyuria Medication: — Clinical Procedure: Total body CT-scan • brain MRI • trans-sphenoidal endoscopical surgery • radiotherapy • anti-angiogenic therapy Specialty: Oncology Objective: Rare disease Background: Pituitary metastasis is uncommon, breast and lung cancers being the most frequent primary tumors. Renal cell carcinoma (RCC) is a rare cause of pituitary metastases, with only a few cases described to date. Case Report: We report a case of a 61-year-old man who presented with a progressive deterioration of visual acuity and field associated with a bitemporal hemianopsia. Two years ago, he underwent radical right nephrectomy for a clear cell RCC (ccRCC). The biological tests showed pan-hypopituitarism and diabetes insipidus. Brain MRI revealed a large sellar tumor lesion bilaterally infiltrating the cavernous sinuses, which was surgically resected. Histology confirmed a ccRCC pituitary metastasis. The patient received post-surgical radiotherapy. Considering the presence of concomitant extra-pituitary metastases, treatment with sunitinib was started, followed by several lines of therapy with axitinib, everolimus, and sorafenib because of tumor progression. The patient also presented with a pituitary tumor recurrence, which was treated by stereotaxic radiotherapy. He died five years after the initial diagnosis of RCC and 30 months after the diagnosis of the pituitary metastasis. Conclusions: There are no standardized treatment guidelines for management of pituitary metastases. Pituitary surgery plays a role in symptom palliation, and it does not have any relevant impact on survival. Exclusive radiotherapy or stereotaxic radiotherapy could be an alternative to surgery in patients whose general condition is poor or who have concomitant extra-pituitary metastases. PMID:28044054

  1. Abnormal changes in voltage-gated sodium channels Na(V)1.1, Na(V)1.2, Na(V)1.3, Na(V)1.6 and in calmodulin/calmodulin-dependent protein kinase II, within the brains of spontaneously epileptic rats and tremor rats.

    PubMed

    Xu, Xiaoxue; Guo, Feng; Lv, Xintong; Feng, Rui; Min, Dongyu; Ma, Lihua; Liu, Yajing; Zhao, Jinsheng; Wang, Lei; Chen, Tianbao; Shaw, Chris; Hao, Liying; Cai, Jiqun

    2013-07-01

    Voltage-gated sodium channels (VGSCs) play a crucial role in epilepsy. The expressions of different VGSCs subtypes are varied in diverse animal models of epilepsy that may reflect their multiple phenotypes or the complexity of the mechanisms of epilepsy. In a previous study, we reported that NaV1.1 and NaV1.3 were up-regulated in the hippocampus of the spontaneously epileptic rat (SER). In this study, we further analyzed both the expression and distribution of the typical VGSC subtypes NaV1.1, NaV1.2, NaV1.3 and NaV1.6 in the hippocampus and in the cortex of the temporal lobe of two genetic epileptic animal models: the SER and the tremor rat (TRM). The expressions of calmodulin (CaM) and calmodulin-dependent protein kinase II (CaMKII) were also analyzed with the purpose of assessing the effect of the CaM/CaMKII pathway in these two models of epilepsy. Increased expression of the four VGSC subtypes and CaM, accompanied by a decrease in CaMKII was observed in the hippocampus of both the SERs and the TRM rats. However, the changes observed in the expression of VGSC subtypes and CaM were decreased with an elevated CaMKII in the cortex of their temporal lobes. Double-labeled immunofluorescence data suggested that in SERs and TRM rats, the four subtypes of the VGSC proteins were present throughout the CA1, CA3 and dentate gyrus regions of the hippocampus and temporal lobe cortex and these were co-localized in neurons with CaM. These data represent the first evidence of abnormal changes in expression of four VGSC subtypes (NaV1.1, NaV1.2, NaV1.3 and NaV1.6) and CaM/CaMKII in the hippocampus and temporal lobe cortex of SERs and TRM rats. These changes may be involved in the generation of epileptiform activity and underlie the observed seizure phenotype in these rat models of genetic epilepsy.

  2. 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

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

    PubMed

    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

    2013-10-10

    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.

  4. 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

  5. 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 ...

  6. Redox regulation of cancer metastasis: molecular signaling and therapeutic opportunities.

    PubMed

    Yang, Wenyong; Zou, Linzhi; Huang, Canhua; Lei, Yunlong

    2014-08-01

    Cancer metastasis is the major cause of cancer-related mortality. Accumulated evidence has shown that high-metastasis potential cancer cells have more reactive oxygen species (ROS) accumulation compared with low-metastasis potential cancer cells. ROS can function as second messengers to regulate multiple cancer metastasis-related signaling pathways via reversible oxidative posttranslational modifications of cysteine in key redox-sensitive proteins, which leads to the structural and functional change of these proteins. Because ROS can promote cancer metastasis, therapeutic strategies aiming at inducing/reducing cellular ROS level or targeting redox sensors involved in metastasis hold great potential in developing new efficient approaches for anticancer therapy. In this review, we summarize recent findings on regulation of tumor metastasis by key redox sensors and describe the potential of targeting redox signaling pathways for cancer therapy.

  7. 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

  8. Fluorescently labeled substrates for monitoring α1,3-fucosyltransferase IX activity.

    PubMed

    Lunau, Nathalie; Seelhorst, Katrin; Kahl, Stefanie; Tscherch, Kathrin; Stacke, Christina; Rohn, Sascha; Thiem, Joachim; Hahn, Ulrich; Meier, Chris

    2013-12-16

    Fucosylation is often the final process in glycan biosynthesis. The resulting glycans are involved in a variety of biological processes, such as cell adhesion, inflammation, or tumor metastasis. Fucosyltransferases catalyze the transfer of fucose residues from the activated donor molecule GDP-β-L-fucose to various acceptor molecules. However, detailed information about the reaction processes is still lacking for most fucosyltransferases. In this work we have monitored α1,3-fucosyltransferase activity. For both donor and acceptor substrates, the introduction of a fluorescent ATTO dye was the last step in the synthesis. The subsequent conversion of these substrates into fluorescently labeled products by α1,3-fucosyltransferases was examined by high-performance thin-layer chromatography coupled with mass spectrometry as well as dual-color fluorescence cross-correlation spectroscopy, which revealed that both fluorescently labeled donor GDP-β-L-fucose-ATTO 550 and acceptor N-acetyllactosamine-ATTO 647N were accepted by recombinant human fucosyltransferase IX and Helicobacter pylori α1,3-fucosyltransferase, respectively. Analysis by fluorescence cross-correlation spectroscopy allowed a quick and versatile estimation of the progress of the enzymatic reaction and therefore this method can be used as an alternative method for investigating fucosyltransferase reactions.

  9. Endosonographic surveillance of 1-3 cm gastric submucosal tumors originating from muscularis propria

    PubMed Central

    Hu, Ming-Luen; Wu, Keng-Liang; Changchien, Chi-Sin; Chuah, Seng-Kee; Chiu, Yi-Chun

    2017-01-01

    AIM To observe the natural course of 1-3 cm gastric submucosal tumors originating from the muscularis propria (SMTMPs). METHODS By reviewing the computerized medical records over a period of 14 years (2000-2013), patients with 1-3 cm gastric SMTMPs who underwent at least two endoscopic ultrasound (EUS) examinations were enrolled. Tumor progression was defined as a ≥ 1.2 times enlargement in tumor diameter observed during EUS surveillance. All patients were divided into stationary and progressive subgroups and further analyzed. We also reviewed the patients in the progressive subgroup again in 2016. RESULTS A total of 88 patients were studied, including 25 in the progressive subgroup. The mean time of EUS surveillance was 24.6 mo in the stationary subgroup and 30.7 mo in the progressive subgroup. Risk factors for tumor progression included larger tumor size and irregular border. Initial tumor size > 14.0 mm may be considered a cut-off size for predicting tumor progression. Seventeen patients underwent surgery, of whom 13 had gastrointestinal stromal tumors (GISTs) and 4 had leiomyomas. Tumor progression was found only in patients with GISTs. All of the tumors exhibited benign behaviors without metastasis until 2016. CONCLUSION Most 1-3 cm gastric SMTMPs (71.6%) are indolent. Tumor progression was found only in GISTs, and it is a good predictor for differentiating GISTs from leiomyomas. Predictors of tumor progression include larger tumor size (> 14.0 mm) and irregular border.

  10. FRZB up-regulation is correlated with hepatic metastasis and poor prognosis in colon carcinoma patients with hepatic metastasis.

    PubMed

    Shen, Yanping; Zhang, Fang; Lan, Huanrong; Chen, Ke; Zhang, Qi; Xie, Guoming; Teng, Lisong; Jin, Ketao

    2015-01-01

    Frizzled-related protein (FRZB) was up-regulated in hepatic metastasis samples compared with primary colon cancer samples in our previous work. However, the clinical relevance of FRZB in colon cancer hepatic metastasis remains uncertain. The aim of this study was to assess the prognostic value of FRZB in patients with colon carcinoma hepatic metastasis after hepatic resection. FRZB expression was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) primary colon carcinoma and paired hepatic metastasis tissues from 136 patients with liver metastasis from colon carcinoma that underwent hepatic resection. The relation between FRZB expression and clinicopathologic factors and long-term prognosis in these 136 patients was retrospectively examined. The prognostic significance of negative or positive FRZB expression in colon carcinoma hepatic metastasis was assessed using Kaplan-Meier survival analysis and log-rank tests. Positive expression of FRZB was correlated with liver metastasis of colon cancer. Univariate analysis indicated significantly worse overall survival (OS) for patients with a positive FRZB expression in colon carcinoma hepatic metastasis than for patients with a negative FRZB expression. Multivariate analysis showed positive-FRZB in colon carcinoma hepatic metastasis to be an independent prognostic factor for OS after hepatic resection (P = 0.001). Positive expression of FRZB was statistically significantly associated with poor prognosis of patients with colon carcinoma hepatic metastasis. FRZB could be a novel predictor for poor prognosis of patients with colon carcinoma hepatic metastasis after hepatic resection.

  11. Water Quality Criteria for Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX)

    DTIC Science & Technology

    1986-06-01

    epithelium, fatty degeneration of the liver, and areas of *, hyaline degeneration in heart muscle. No pathological Phanges have been W noted in the brain...kg/day, and elevated serum cholesterol levels seen in female mice at 35 mg/kg/day, and possibly 7 mg/kg/day, resulted in an NOEL of 1.5 mg/kg/day...25 9. Acute Toxicity of RDX to Bluegill (Levomis macrochirus) Under Varying Conditions of Water Quality During Statin

  12. Structural and thermal stabilities of layered Li(Ni 1/3Co 1/3Mn 1/3)O 2 materials in 18650 high power batteries

    NASA Astrophysics Data System (ADS)

    He, Yan-Bing; Ning, Feng; Yang, Quan-Hong; Song, Quan-Sheng; Li, Baohua; Su, Fangyuan; Du, Hongda; Tang, Zhi-Yuan; Kang, Feiyu

    The structural and thermal stabilities of the layered Li(Ni 1/3Co 1/3Mn 1/3)O 2 cathode materials under high rate cycling and abusive conditions are investigated using the commercial 18650 Li(Ni 1/3Co 1/3Mn 1/3)O 2/graphite high power batteries. The Li(Ni 1/3Co 1/3Mn 1/3)O 2 materials maintain their layered structure even when the power batteries are subjected to 200 cycles with 10 C discharge rate at temperatures of 25 and 50 °C, whereas their microstructure undergoes obvious distortion, which leads to the relatively poor cycling performance of power batteries at high charge/discharge rates and working temperature. Under abusive conditions, the increase in the battery temperature during overcharge is attributed to both the reactions of electrolyte solvents with overcharged graphite anode and Li(Ni 1/3Co 1/3Mn 1/3)O 2 cathode and the Joule heat that results from the great increase in the total resistance (R cell) of batteries. The reactions of fully charged Li(Ni 1/3Co 1/3Mn 1/3)O 2 cathodes and graphite anodes with electrolyte cannot be activated during short current test in the fully charged batteries. However, these reactions occur at around 140 °C in the fully charged batteries during oven test, which is much lower than the temperature of about 240 °C required for the reactions outside batteries.

  13. 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.

  14. Bis(1,3-dimethyl-1,3-diazinan-2-one)dinitratodioxidouranium(VI)

    PubMed Central

    Suzuki, Tomoya; Kawasaki, Takeshi; Ikeda, Yasuhisa

    2011-01-01

    The title compound, [U(NO3)2O2(C6H12N2O)2], exhibits a hexa­gonal–bipyramidal geometry around the UVI ion, which is situated on an inversion centre and coordinated by two oxide ligands in the axial positions, and four O atoms from two bidentate NO3 − and two O atoms from two 1,3-dimethyl-1,3-diazinan-2-one (DMPU) ligands in the equatorial plane. These ligands are located in trans positions. The –(CH2)3– moiety in the DMPU ligand is disordered over two positions in a 0.786 (11):0.214 (11) ratio. PMID:21522544

  15. Biodegradation of 1,3,5-trinitro-1,3,5-triazine (RDX).

    PubMed

    Lee, Sheng-Yih; Brodman, Bruce W

    2004-01-01

    Two bacteria were isolated from 1,3,5-trinitro-1,3,5-triazine (RDX) contaminated soil at Picatinny Arsenal, New Jersey. These organisms were subsequently identified as Rhiziobium rhizogenes BL and Burkholderia sp.BL by the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ, German Collection of Microorganisms and Cell Cultures). In addition a fungus, identified as Cladosporium cladosporioides by DSMZ, was found to be growing on water wet RDX. All of these organisms were found to degrade RDX. The two bacteria were found to represent new species that have not been reported before. It was found that these organisms along with an added carbon source could degrade RDX to simple gaseous products. Data are presented that elucidate the mechanisms of RDX biodegradation for these organisms.

  16. Synthesis of planar chiral ferrocenyl 1,3-diamines and 1,3-amino ethers.

    PubMed

    Anderson, James C; Blake, Alexander J; Arnall-Culliford, Jennifer C

    2003-10-21

    The efficient syntheses of novel planar chiral 1,3-diamines and 1,3-amino ethers with an oxy or amino function directly bound to the cyclopentadienyl ring of ferrocene has been developed. The key reaction is the Cu2O promoted substitution of (pR)-N,N-diisopropyl-2-iodoferrocenecarboxamide with either phthalimide or AcOH to introduce nitrogen or oxygen functionality onto the cyclopentadienyl ring. The enantiomerically pure iodoferrocene derivative is available from the known enantioselective ortho-lithiation of N,N-diisopropylferrocenecarboxamide with n-BuLi-sparteine. In the course of these studies the synthesis of a novel C2 symmetric C-2 dimer of N,N-dimethyl-1-ferrocenylethylamine was characterised by single crystal X-ray diffraction.

  17. Changes in the relative risk and sites of central nervous system metastasis with effective combined chemotherapy and radiation therapy for small cell carcinoma of the lung

    SciTech Connect

    Komaki, R.; Cox, J.D.; Holoye, P.Y.; Byhardt, R.W.

    1983-10-01

    Prolongation of survival of patients with small cell carcinoma of the lung with current effective systemic therapy has been accompanied by a marked increase in the frequency of relapse in the central nervous system (CNS). Prophylactic cranial irradiation (PCI) was shown to reduce the frequency of brain metastasis, but there was no increased short-term survival. Therefore, the necessity for PCI early in the course of treatment has been questioned, especially for patients with extensive disease. From January 1974 through March 1982, 205 patients with small cell carcinoma of the lung were treated at the Medical College of Wisconsin Affiliated Hospitals. None had clinical, radioisotopic, or computed tomographic evidence of brain metastasis. Eighty-two patients received radiotherapy and chemotherapy, but no PCI; 123 patients received combination chemotherapy and radiation therapy with PCI. The cumulative probability of brain metastasis without PCI was 36% at 12 months and 47% at 24 months; the probabilities were 6 and 10%, respectively with PCI. The 24-month probability of brain metastasis in patients with limited disease and no PCI was 45%; for those with extensive disease, it was 47%. No patient presented with extracranial central nervous system (ECNS) metastasis and no one without PCI developed it. Twelve patients who received PCI developed ECNS metastasis; the cumulative probabilities rose to 14% at 12 months and 22% at 24 months. The increased frequency of ECNS involvement has led to a phase I trial of PCI followed by six cycles of combination chemotherapy, without maintenance chemotherapy, followed by irradiation of the chest and spinal cord for patients with complete response.

  18. Genetic factors conferring metastasis in osteosarcoma.

    PubMed

    Maximov, Vadim V; Aqeilan, Rami I

    2016-07-01

    Osteosarcoma (OS) is a deadly bone malignancy affecting mostly children and adolescents. OS has outstandingly complex genetic alterations likely due to p53-independent genomic instability. Based on analysis of recent published research we claim existence of various genetic mechanisms of osteosarcomagenesis conferring great variability to different OS properties including metastatic potential. We also propose a model explaining how diverse genetic mechanisms occur and providing a framework for future research. P53-independent preexisting genomic instability, which precedes and frequently causes TP53 genetic alterations, is central in our model. In addition, our analyses reveal a possible cooperation between aberrantly activated HIF-1α and AP-1 genetic pathways in OS metastasis. We also review the involvement of noncoding RNA genes in OS metastasis.

  19. Colonic adenocarcinoma with metastasis to the gingiva.

    PubMed

    Alvarez-Alvarez, Carlos; Iglesias-Rodríguez, Begoña; Pazo-Irazu, Susana; Delgado-Sánchez-Gracián, Carlos

    2006-01-01

    Metastatic tumors involve the oral cavity, and the most common primary sites are the breast and lung. Most cases affect the mandible and maxilla in that order, although some of them can be located in the soft perioral tissues. We report the case of a 62-year-old male who had been diagnosed with sigmoid adenocarcinoma with nodal and liver metastasis, who presented 6 months later with a gingival polypoid tumor, at first considered as a primary neoplasm of gingiva, that was diagnosed in a biopsy as metastatic intestinal adenocarcinoma. The histological evaluation is essential to separate adenocarcinoma from the commoner in this site squamous cell carcinoma, and the immunohistochemical techniques are useful to distinguish metastatic tumor versus primary adenocarcinoma from the minor salivary glands of the area. The intraoral spread of a disseminated neoplasm is generally a sign of bad prognosis, although a longer survival can be expected if a radical surgical treatment of a solitary metastasis is carried out.

  20. Renal Clear Cell Carcinoma and Tonsil Metastasis

    PubMed Central

    Marcotullio, Dario; Iannella, Giannicola; Zelli, Melissa; Magliulo, Giuseppe

    2013-01-01

    Renal cell carcinoma is the most common renal tumor in adults. Clear cell carcinoma represents 85% of all histological subtypes. In February 2012 a 72-year-old woman came to our department due to the appearance of massive hemoptysis and pharyngodinia. Previously, this patient was diagnosed with a renal cell carcinoma treated with left nephrectomy. We observed an exophytic, grayish, and ulcerated mass in the left tonsillar lodge and decided to subject the patient to an immediate tonsillectomy. Postoperative histology showed nests of cells with highly hyperchromatic nuclei and clear cytoplasm. These features enabled us to make the diagnosis of renal clear cell carcinoma metastasis. Only few authors described metastasis of renal cell carcinoma in this specific site. PMID:24455373

  1. Renal clear cell carcinoma and tonsil metastasis.

    PubMed

    Marcotullio, Dario; Iannella, Giannicola; Macri, Gian Franco; Marinelli, Caterina; Zelli, Melissa; Magliulo, Giuseppe

    2013-01-01

    Renal cell carcinoma is the most common renal tumor in adults. Clear cell carcinoma represents 85% of all histological subtypes. In February 2012 a 72-year-old woman came to our department due to the appearance of massive hemoptysis and pharyngodinia. Previously, this patient was diagnosed with a renal cell carcinoma treated with left nephrectomy. We observed an exophytic, grayish, and ulcerated mass in the left tonsillar lodge and decided to subject the patient to an immediate tonsillectomy. Postoperative histology showed nests of cells with highly hyperchromatic nuclei and clear cytoplasm. These features enabled us to make the diagnosis of renal clear cell carcinoma metastasis. Only few authors described metastasis of renal cell carcinoma in this specific site.

  2. Microenvironmental regulation of tumor progression and metastasis

    PubMed Central

    Quail, DF; Joyce, JA

    2014-01-01

    Cancers develop in complex tissue environments, which they depend upon 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 reeducation of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here, we will discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, and recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects. PMID:24202395

  3. Macroscopic Stiffness of Breast Tumors Predicts Metastasis

    PubMed Central

    Fenner, Joseph; Stacer, Amanda C.; Winterroth, Frank; Johnson, Timothy D.; Luker, Kathryn E.; Luker, Gary D.

    2014-01-01

    Mechanical properties of tumors differ substantially from normal cells and tissues. Changes in stiffness or elasticity regulate pro-metastatic behaviors of cancer cells, but effects have been documented predominantly in isolated cells or in vitro cell culture systems. To directly link relative stiffness of tumors to cancer progression, we combined a mouse model of metastatic breast cancer with ex vivo measurements of bulk moduli of freshly excised, intact tumors. We found a high, inverse correlation between bulk modulus of resected tumors and subsequent local recurrence and metastasis. More compliant tumors were associated with more frequent, larger local recurrences and more extensive metastases than mice with relatively stiff tumors. We found that collagen content of resected tumors correlated with bulk modulus values. These data establish that relative differences in tumor stiffness correspond with tumor progression and metastasis, supporting further testing and development of tumor compliance as a prognostic biomarker in breast cancer. PMID:24981707

  4. 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

  5. Melanoma metastasis to the spleen: Laparoscopic approach

    PubMed Central

    Trindade, Manoel Roberto Maciel; Blaya, Rodrigo; Trindade, Eduardo Neubarth

    2009-01-01

    We report a case of minimally invasive surgery in the management of metastasis to the spleen. A 67-year-old male patient with possible splenic soft tissue melanoma metastasis was referred to our hospital. He had a history of an excised soft tissue melanoma from his back eight months earlier, and the control abdominal computer tomography (CT) scan revealed a hypodense spleen lesion. The patient underwent laparoscopic surgery to diagnose and treat the splenic lesion. The splenectomy was performed and the histological examination revealed a melanoma. The patient had a good postoperative course and was discharged on the second postoperative day. On his 12-month follow-up there was no sign of recurrence. The laparoscopic approach is a safe and effective alternative for treatment of splenic metastases. PMID:19547681

  6. 2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein (VCP or p97).

    PubMed

    Bursavich, Matthew G; Parker, Daniel P; Willardsen, J Adam; Gao, Zhong-Hua; Davis, Thaylon; Ostanin, Kirill; Robinson, Rosann; Peterson, Ashley; Cimbora, Daniel M; Zhu, Ju-Fen; Richards, Burt

    2010-03-01

    Valosin-containing protein (VCP; also known as p97) is a member of the AAA ATPase family with a central role in the ubiquitin-degradation of misfolded proteins. VCP also exhibits antiapoptotic function and metastasis via activation of nuclear factor kappa-B signaling pathway. We have discovered that 2-anilino-4-aryl-1,3-thiazoles are potent drug-like inhibitors of this enzyme. The identified compounds show low nanomolar VCP potency, demonstrate SAR trends, and show activity in a mechanism based cellular assay. This series of compounds represents the first steps towards a novel, small molecule VCP inhibitor as a cancer therapeutic.

  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. Developmental therapeutics for patients with breast cancer and central nervous system metastasis: current landscape and future perspectives.

    PubMed

    Costa, R; Carneiro, B A; Wainwright, D A; Santa-Maria, C A; Kumthekar, P; Chae, Y K; Gradishar, W J; Cristofanilli, M; Giles, F J

    2016-10-03

    Breast cancer is the second-leading cause of metastatic disease in the central nervous system (CNS). Recent advances in the biological understanding of breast cancer have facilitated an unprecedented increase of survival in a subset of patients presenting with metastatic breast cancer. Patients with HER2 positive (HER2+) or triple negative breast cancer are at highest risk of developing CNS metastasis, and typically experience a poor prognosis despite treatment with local and systemic therapies. Among the obstacles ahead in the realm of developmental therapeutics for breast cancer CNS metastasis is the improvement of our knowledge on its biological nuances and on the interaction of the blood brain barrier with new compounds. This manuscript reviews recent discoveries related to the underlying biology of breast cancer brain metastases, clinical progress to date and suggests rational approaches for investigational therapies.

  9. Prostate Cancer Presenting with Parietal Bone Metastasis

    PubMed Central

    Pare, Abdoul Karim; Abubakar, Babagana Mustapha; Kabore, Moussa

    2017-01-01

    Bone metastases from prostate cancer are very common. They are usually located on the axial skeleton. However, cranial bone metastases especially to the parietal bone are rare. We report a case of metastatic prostate cancer presenting with left parietal bone metastasis in a patient with no urological symptoms or signs. We should consider prostate cancer in any man above 60 years presenting unusual bone lesions.

  10. Macrophage Efferocytosis and Prostate Cancer Bone Metastasis

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0408 TITLE: Macrophage Efferocytosis and Prostate Cancer Bone Metastasis PRINCIPAL INVESTIGATOR: Jacqueline D. Jones...average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed...and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of

  11. Thymoma Metastasis to the Semimembranosus Muscle

    PubMed Central

    Taniguchi, Kenta; Susa, Michiro; Ogata, Sho; Ozeki, Yuichi; Chiba, Kazuhiro

    2017-01-01

    Thymoma is the most common thymic epithelial tumor whose classification was first introduced in 1999. Type B2 thymoma is considered a moderate/high-risk tumor; however, extrathoracic metastases are extremely rare with limited reports to date. In this report, we present a rare thymoma metastasis to the semimembranosus muscle, which was resected with a wide margin after confirmation by open biopsy. At the final follow-up after 1 year, no local recurrence has been observed. PMID:28203162

  12. pH-Responsive Wormlike Micelles with Sequential Metastasis Targeting Inhibit Lung Metastasis of Breast Cancer.

    PubMed

    He, Xinyu; Yu, Haijun; Bao, Xiaoyue; Cao, Haiqiang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

    2016-02-18

    Cancer metastasis is the main cause for the high mortality in breast cancer patients. Herein, we first report succinobucol-loaded pH-responsive wormlike micelles (PWMs) with sequential targeting capability to inhibit lung metastasis of breast cancer. PWMs can in a first step be delivered specifically to the sites of metastases in the lungs and then enable the intracellular pH-stimulus responsive drug release in cancer cells to improve the anti-metastatic effect. PWMs are identified as nanofibrillar assemblies with a diameter of 19.9 ± 1.9 nm and a length within the 50-200 nm range, and exhibited pH-sensitive drug release behavior in response to acidic intracellular environments. Moreover, PWMs can obviously inhibit the migration and invasion abilities of metastatic 4T1 breast cancer cells, and reduce the expression of the metastasis-associated vascular cell adhesion molecule-1 (VCAM-1) at 400 ng mL(-1) of succinobucol. In particular, PWMs can induce a higher specific accumulation in lung and be specifically delivered to the sites of metastases in lung, thereby leading to an 86.6% inhibition on lung metastasis of breast cancer. Therefore, the use of sequentially targeting PWMs can become an encouraging strategy for specific targeting and effective treatment of cancer metastasis.

  13. Chemokines: novel targets for breast cancer metastasis

    PubMed Central

    Ali, Simi; Lazennec, Gwendal

    2007-01-01

    Recent studies have highlighted the possible involvement of chemokines and their receptors in breast cancer progression and metastasis. Chemokines and their receptors constitute a superfamily of signalling factors whose prognosis value in breast cancer progression remains unclear. We will examine here the expression pattern of chemokines and their receptors in mammary gland physiology and carcinogenesis. The nature of the cells producing chemokines or harboring chemokine receptors appears to be crucial in certain conditions for example, the infiltration of the primary tumor by leukocytes and angiogenesis. In addition, chemokines, their receptors and the interaction with glycosaminoglycan (GAGs) are key players in the homing of cancer cells to distant metastasis sites. Several lines of evidence, including in vitro and in vivo models, suggest that the mechanism of action of chemokines in cancer development involves the modulation of proliferation, apoptosis, invasion, leukocyte recruitment or angiogenesis. Furthermore, we will discuss the regulation of chemokine network in tumor neovascularity by decoy receptors. The reasons accounting for the deregulation of chemokines and chemokine receptors expression in breast cancer are certainly crucial for the comprehension of chemokine role in breast cancer and are in several cases linked to estrogen receptor status. The targeting of chemokines and chemokine receptors by antibodies, small molecule antagonists, viral chemokine binding proteins and heparins appears as promising tracks to develop therapeutic strategies. Thus there is significant interest in developing strategies to antagonize the chemokine function, and an opportunity to interfere with metastasis, the leading cause of death in most patients. PMID:17717637

  14. 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

  15. 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

  16. Cutaneous metastasis from lung cancer. Case report.

    PubMed

    Fratus, Giorgio; Tagliabue, Fabio; Mariani, Pierpaolo; Bottazzi, Enrico Coppola; Spinelli, Luisella; Novellino, Lorenzo

    2014-07-21

    Il cancro del polmone rappresenta la patologia maligna maggiormente diagnosticata a livello mondiale. La diffusione metastatica della malattia è piuttosto frequente. Oltre ai classici siti di metastatizzazione (ossea, surreni, fegato, cervello) un sito particolare è rappresentato dalla cute. Il caso presentato riguarda appunto un paziente di 66 anni con metastasi cutanea da neoplasia del polmone. Un uomo di 66 anni, con anamnesi positiva per anuerisma aortico sottorenale, BPCO, cardiopatico e diabetico, giunge alla nostra osservazione per neoplasia del lobo inferiore del polmone sinistro. Dopo un accurato staging preoperatorio, il paziente viene sottoposto a lobectomia inferiore sinistra. L’esito dell’esame istologico è di carcinoma squamocellulare moderatamente e scarsamente differenziato G2-3 pT2bN0. Il paziente viene pertanto inviato al collega oncologo per il regolare follow up. Dopo circa 6 mesi il paziente ritorna alla nostra attenzione per la comparsa a livello del fianco/fossa iliaca di destra di nodulo cutaneo, duro, discromico, dolente ed ulcerato. Le biopsie eseguite, hanno dato esito di carcinoma squamocellulare moderatamente e scarsamente differenziato. Il paziente veniva sottoposto a un TC torace- addome che evidenziava in sede della parete addominale l’assenza d’infiltrazione dei piani muscolo-aponeurotici da parte della neoformazione. Il paziente è stato quindi sottoposto ad intervento chirurgico di asportazione della lesione cutanea. L’esame istologico del pezzo operatorio ha confermato trattarsi di carcinoma squamocellulare metastatico. Le metastasi cutanee da carcinoma del polmone si presentano nel 2,5 - 7,5% dei casi. La sopravvivenza mediana di questi pazienti è di circa 2,9 mesi. L’istotipo maggiormente coinvolto, secondo autori Giapponesi, è l’adenocarcinoma seguito dal carcinoma squamocellulare. Alcuni studi hanno dimostrato la validità dell’approccio chirurgico seguito dalla chemioterapia nei casi di metastasi singole

  17. CAPACITY OF PATIENTS WITH BRAIN METASTASES TO MAKE TREATMENT DECISIONS

    PubMed Central

    Triebel, Kristen L.; Gerstenecker, Adam; Meneses, Karen; Fiveash, John B.; Meyers, Christina A.; Cutter, Gary; Marson, Daniel C.; Martin, Roy C.; Eakin, Amanda; Watts, Olivia; Nabors, Louis B.

    2015-01-01

    OBJECTIVE To investigate medical decision-making capacity (MDC) in patients with brain metastasis. METHODS Participants were 41 adults with brain metastases with Karnofsky Performance Status scores ≥70 were recruited from an academic medical center and 41 demographically-matched controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument (CCTI) and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant with brain metastasis using cutoff scores derived statistically from the performance of the control group. RESULTS The brain metastases patient group performed significantly below controls on consent standards of understanding and reasoning. Capacity compromise was defined as performance ≤1.5 standard deviations (SD) below the control group mean. Using this definition, approximately 60% of the participants with brain metastases demonstrated capacity compromise on at least one MDC standard. CONCLUSION When defining capacity compromise as performance ≤1.5 SD below the control group mean, over half of patients with brain metastases have reduced capacity to make treatment decisions. This impairment is demonstrated shortly after initial diagnosis of brain metastases and highlights the importance of routine clinical assessment of MDC following diagnosis of brain metastasis. These results also indicate a need for the development and investigation of interventions to support or improve MDC in this patient population. PMID:25613039

  18. 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.

  19. MicroRNA-421 inhibits breast cancer metastasis by targeting metastasis associated 1.

    PubMed

    Pan, Yongqin; Jiao, Genlong; Wang, Cunchuan; Yang, Jingge; Yang, Wah

    2016-10-01

    Dysregulation of microRNAs is involved in the initiation and progression of several human cancers, including breast cancer, as strong evidence of miRNAs acting as oncogenes or tumour suppressor genes has been found. This study was performed to investigate the biological functions of microRNA-421 (miR-421) in breast cancer and the underlying mechanisms. The expression level of miR-421 was detected in 50 pairs of surgical specimens and human breast cancer cell lines. The results showed that miR-421 is downregulated in breast cancer tissues and metastatic cell lines. In addition, the decrease in miR-421 levels was significantly associated with lymph node metastasis, recurrence/metastasis, or pTNM stage. Functions of miR-421 in cell migration and invasion were assessed through its silencing and overexpression. The results showed that miR-421 knockdown promotes invasion and metastasis in MCF-7 cells and its overexpression suppresses invasion and metastasis in MDA-MB-231 cells. The specific target genes of miR-421 were predicted by TargetScan algorithm and determined by dual luciferase reporter assay, quantitative reverse transcriptase PCR, and western blot analysis. miR-421 could suppress luciferase activity of the reporter containing 3'-untranslated region of metastasis associated 1 (MTA1), a potent oncogene. miR-421 overexpression or knockdown had no effect on the mRNA expression of MTA1, but it could modulate MTA1 protein level. Furthermore, MTA1 knockdown receded the effect of miR-421 inhibitor on invasion and metastasis of MCF-7 cells, and its overexpression receded the effect of miR-421 on invasion and metastasis of MDA-MB-231 cells. Our findings clearly demonstrate that miR-421 suppresses breast cancer metastasis by directly inhibiting MTA1 expression. The present study provides a new insight into the tumour suppressor roles of miR-421 and suggests that miR-421/MTA1 pathway is a putative therapeutic target in breast cancer.

  20. Electrochemical characteristics of layered LiNi 1/3Co 1/3Mn 1/3O 2 and with different synthesis conditions

    NASA Astrophysics Data System (ADS)

    He, Ping; Wang, Haoran; Qi, Lu; Osaka, Tetsuya

    LiNi 1/3Mn 1/3Co 1/3O 2 had been successfully prepared from spherical composite carbonate via a simple uniform-phase precipitation method [P. He, H. Wang, L. Qi, T. Osaka, J. Power Sources, in press] at normal pressure, using nickel, cobalt and manganese sulfate and ammonia bicarbonate as reactants. The preparation of spherical composite carbonate was significantly dependant on synthetic condition, such as the reaction temperature, feed rate, molar ratio of these reactants, etc. The optimized condition resulted in spherical composite carbonate of which the particle size distribution was uniform, as observed by scanning electronic microscopy (SEM). Calcination of the uniform composite carbonate with lithium carbonate at high temperature led to a well-ordered layer structured LiNi 1/3Mn 1/3Co 1/3O 2 as confirmed by X-ray diffraction (XRD), without obvious change in shape. Due to the homogeneity of the composite carbonate, the final product, LiNi 1/3Mn 1/3Co 1/3O 2, was also significantly uniform, i.e., the average particle size was of about 10 μm in diameter and the distribution was relatively narrow. As a result, the corresponding tap density was also high, approximately 2.32 g cm -3, of which the value is very near to that of commercialized LiCoO 2. In the voltage range of 2.8-4.2, 2.8-4.35 and 2.8-4.5 V, the discharge capacities of LiNi 1/3Mn 1/3Co 1/3O 2 electrode were 159, 168 and 179 mAh g -1, respectively, with good cyclability.

  1. 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.

  2. HER2 mediated de novo production of TGFβ leads to SNAIL driven epithelial-to-mesenchymal transition and metastasis of breast cancer.

    PubMed

    Gupta, Parul; Srivastava, Sanjay K

    2014-12-01

    HER2 is an important determinant of poor prognosis in breast cancer patients. Studies indicate that HER2 positive tumors are mostly resistant to therapy and have high metastatic potential however, the underlying mechanisms remain unknown. In this study, MDA-MB-231 and MCF-7 breast cancer cells with their HER2 overexpressing syngeneic variants were used to delineate the role of HER2 in EMT and metastasis. Our results demonstrated that HER2 overexpression increased the invasive potential of cells. Our results also showed that HER2 overexpression lead to the production of TGFβ resulting in the activation of TGFβ/SMAD signaling. Furthermore, activation of SNAIL, SLUG and ZEB-1, the transcriptional repressors of E-cadherin and increased mesenchymal characteristics were observed in high HER2 cells. Interestingly, EMT by HER2 was mediated through TGFβ. Intravenous injection of high HER2 MDA-MB-231 (HH) cells in athymic nude mice showed early and substantial metastasis as compared to the parent cells establishing the direct role of HER2 in metastasis. Our results showed that inhibition of HER2 mediated EMT by cucurbitacin B a triterpenoid, resulted in the suppression of brain metastasis of breast cancer cells. Taken together, our results identify a novel mechanism of HER2 in promoting breast cancer metastasis through de novo synthesis of TGFβ leading to EMT, an initial and essential step of metastasis.

  3. Spinal Cord Ischemia Secondary to Epidural Metastasis from Small Cell Lung Carcinoma

    PubMed Central

    Yasui, Hirotoshi; Ozawa, Naoya; Mikami, Satoshi; Shimizu, Kenji; Hatta, Takahiro; Makino, Nami; Fukushima, Mayu; Baba, Satoshi; Makino, Yasushi

    2017-01-01

    Patient: Male, 56 Final Diagnosis: Small cell lung carcinoma Symptoms: Back pain • paralysis Medication: — Clinical Procedure: MRI Specialty: Pulmonology Objective: Unusual clinical course Background: Spinal cord ischemia is an uncommon event that is mainly caused by dissociation of the ascending aorta as a complication after aortic surgery. Spinal arteries can develop collateral circulation; therefore, the frequency of spinal infarction is about 1% of that in the brain. Few cases of spinal cord ischemia developing in the course of lung cancer have been reported. Case Report: We presented the case of a 56-year-old man with small cell lung carcinoma, cT4N2M1a (stage IV). He was treated with irradiation and 2 courses of platinum and etoposide combination chemotherapy. He complained of back pain followed by quadriplegia and sensory disturbance after cessation of chemotherapy. With a diagnosis of spinal cord metastasis, steroids were administered. However, diaphragmatic paralysis appeared a few hours later. He was started on palliative care and died after 6 days. Autopsy showed epidural metastasis and spinal ischemia at the C5 level. Conclusions: Epidural metastasis can compress the spinal artery and cause circulatory disorders. Spinal cord ischemia should be considered in patients with rapid paralysis in the course of lung cancer. PMID:28302996

  4. Spinal Cord Ischemia Secondary to Epidural Metastasis from Small Cell Lung Carcinoma.

    PubMed

    Yasui, Hirotoshi; Ozawa, Naoya; Mikami, Satoshi; Shimizu, Kenji; Hatta, Takahiro; Makino, Nami; Fukushima, Mayu; Baba, Satoshi; Makino, Yasushi

    2017-03-17

    BACKGROUND Spinal cord ischemia is an uncommon event that is mainly caused by dissociation of the ascending aorta as a complication after aortic surgery. Spinal arteries can develop collateral circulation; therefore, the frequency of spinal infarction is about 1% of that in the brain. Few cases of spinal cord ischemia developing in the course of lung cancer have been reported. CASE REPORT We presented the case of a 56-year-old man with small cell lung carcinoma, cT4N2M1a (stage IV). He was treated with irradiation and 2 courses of platinum and etoposide combination chemotherapy. He complained of back pain followed by quadriplegia and sensory disturbance after cessation of chemotherapy. With a diagnosis of spinal cord metastasis, steroids were administered. However, diaphragmatic paralysis appeared a few hours later. He was started on palliative care and died after 6 days. Autopsy showed epidural metastasis and spinal ischemia at the C5 level. CONCLUSIONS Epidural metastasis can compress the spinal artery and cause circulatory disorders. Spinal cord ischemia should be considered in patients with rapid paralysis in the course of lung cancer.

  5. Inactivation of ABL kinases suppresses non–small cell lung cancer metastasis

    PubMed Central

    Gu, Jing Jin; Rouse, Clay; Wang, Jun; Onaitis, Mark W.

    2016-01-01

    Current therapies to treat non–small cell lung carcinoma (NSCLC) have proven ineffective owing to transient, variable, and incomplete responses. Here we show that ABL kinases, ABL1 and ABL2, promote metastasis of lung cancer cells harboring EGFR or KRAS mutations. Inactivation of ABL kinases suppresses NSCLC metastasis to brain and bone, and other organs. ABL kinases are required for expression of prometastasis genes. Notably, ABL1 and ABL2 depletion impairs extravasation of lung adenocarcinoma cells into the lung parenchyma. We found that ABL-mediated activation of the TAZ and β-catenin transcriptional coactivators is required for NSCLC metastasis. ABL kinases activate TAZ and β-catenin by decreasing their interaction with the β-TrCP ubiquitin ligase, leading to increased protein stability. High-level expression of ABL1, ABL2, and a subset of ABL-dependent TAZ- and β-catenin–target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature. PMID:28018973

  6. Detection value of tumor cells in cerebrospinal fluid in the diagnosis of meningeal metastasis from lung cancer by immuno-FISH technology

    PubMed Central

    Lv, Yuan; Mu, Ning; Ma, Chunhua; Jiang, Rong; Wu, Qiaoli; Li, Jinduo; Wang, Bin; Sun, Liwei

    2016-01-01

    To investigate the detection value of tumor cells in cerebrospinal fluid (CSF) in the adjuvant diagnosis of meningeal metastasis from lung cancer by immunofluorescence in situ hybridization (immuno-FISH) technology. The circulating tumor cells (CTCs) in the CSF of 16 patients with meningeal metastasis from lung cancer and 8 with non-tumor diseases in the brain were detected using immuno-FISH technology. The diagnosis of meningeal metastasis from lung cancer was based on neurological symptoms, enhanced magnetic resonance imaging (MRI) scans and CSF cytological examination. The number of CTCs in the patients with meningeal metastasis from lung cancer was significantly higher than those with non-tumor diseases in the brain (P<0.01). The critical point of the maximum correct diagnostic index (Youden index) was regarded as the judging criterion for positive tumor cells in CSF according to the receiver operating characteristic curve. When there was one tumor cell in 7.5 ml CSF, the area under curve was 0.875 (95% confidence interval, 0.705~1.000). The diagnostic sensitivity, specificity, effectiveness, positive and negative predictive values were 75.0, 100.0, 83.3, 100.0 and 66.7%, respectively. There may be great clinical value in the detection of CTCs in CSF for the diagnosis of meningeal metastasis from lung cancer by immuno-FISH technology. PMID:28105214

  7. 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.

  8. 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.

  9. Regulation of Prostate Cancer Bone Metastasis by DKK1

    DTIC Science & Technology

    2012-09-01

    0030 TITLE: Regulation of Prostate Cancer Bone Metastasis by DKK1 PRINCIPAL INVESTIGATOR: Gregory A. Clines, MD, PhD CONTRACTING...of Prostate Cancer Bone Metastasis by DKK1 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-08-1-0030 5c. PROGRAM ELEMENT...Osteoblastic bone metastasis is a common complication of advanced prostate cancer, resulting in pain and pathologic fracture. Dickkopf homolog 1 ( DKK1 ) is a

  10. Regulation of Prostate Cancer Bone Metastasis by DKK1

    DTIC Science & Technology

    2010-04-01

    0030 TITLE: Regulation of Prostate Cancer Bone Metastasis by DKK1 PRINCIPAL INVESTIGATOR: Gregory A. Clines, MD, PhD CONTRACTING...AND SUBTITLE Regulation of Prostate Cancer Bone Metastasis by DKK1 5a. CONTRACT NUMBER W81XWH-08-1-0030 5b. GRANT NUMBER...metastasis is a common complication of advanced prostate cancer, resulting in pain and pathologic fracture. Dickkopf homolog 1 ( DKK1 ) is a secreted

  11. Mouse models for studying prostate cancer bone metastasis

    PubMed Central

    Dai, Jinlu; Hensel, Janine; Wang, Ning; Kruithof-de Julio, Marianna; Shiozawa, Yusuke

    2016-01-01

    Once tumor cells metastasize to the bone, the prognosis for prostate cancer patients is generally very poor. The mechanisms involved in bone metastasis, however, remain elusive, because of lack of relevant animal models. In this manuscript, we describe step-by-step protocols for the xenograft mouse models that are currently used for studying prostate cancer bone metastasis. The different routes of tumor inoculation (intraosseous, intracardiac, intravenous and orthotopic) presented are useful for exploring the biology of bone metastasis. PMID:26916039

  12. The Role of Megakaryocytes in Breast Cancer Metastasis to Bone

    DTIC Science & Technology

    2011-05-01

    and TPO -/- mice, and femurs collected over time. Bone cytokines also will be assessed. 15. SUBJECT TERMS Megakaryocytes, breast cancer, bone...conditions of metastasis or non-metastasis. Thrombopoietin ( TPO -/-) knockout mice will be used to test metastasis in mice with a megakaryocyte deficiency...1. Begin the process of creating TPO -/-mice on a Balb/c background. We had received permission from Genentech to obtain frozen embryos of TPO

  13. MMP-8: A Breast Cancer Bone Metastasis Suppressor Gene

    DTIC Science & Technology

    2005-08-01

    embedded in paraffin and stained with Gomori trichrome. (A) distal femur , control mouse. (B) distal femur , mouse with osteolytic metastasis . Note...A AD_______ Award Number: W81XWH-04-1-0687 TITLE: MMP-8: A Breast Cancer Bone Metastasis Suppressor Gene PRINCIPAL INVESTIGATOR: Nagarajan...CONTRACT NUMBER MMP-8: A Breast Cancer Bone Metastasis Suppressor Gene 5b. GRANT NUMBER W81 XWH-04-1-0687 6c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d

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

    PubMed

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

    2014-05-01

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

  15. Knockout of MDA-9/Syntenin (SDCBP) expression in the microenvironment dampens tumor-supporting inflammation and inhibits melanoma metastasis

    PubMed Central

    Das, Swadesh K.; Guo, Chunqing; Pradhan, Anjan K.; Bhoopathi, Praveen; Talukdar, Sarmistha; Shen, Xue-Ning; Emdad, Luni; Subler, Mark A.; Windle, Jolene J.; Sarkar, Devanand; Wang, Xiang-Yang; Fisher, Paul B.

    2016-01-01

    Cancer development and progression to metastasis is a complex process, which largely depends on bidirectional communication between tumor cells and their microenvironment. Melanoma differentiation associated gene-9 (mda-9, also known as Syntenin-1, SDCBP), a gene first cloned by our group, is robustly expressed in multiple cancers including melanoma and contributes to invasion and metastasis in a tumor cell-intrinsic manner. However, the role of MDA-9/Syntenin in the tumor cell-extrinsic microenvironment remains unclear even though MDA-9/Syntenin is ubiquitously expressed in most organs that are active metastatic sites for melanoma, e.g., lung, lymph node, brain, and liver. In this study, we explored the effect of environmental mda-9/syntenin expression on melanoma growth and metastasis using multiple immunocompetent animal models, syngeneic B16 xenograft and intravenous B16 mouse model and a genetically engineered mouse (GEM) model of melanoma. Host-deficient expression of mda-9/syntenin in mice negatively impacted on subcutaneously implanted B16 tumor growth and lung metastasis. Absence of MDA-9/Syntenin in the lung microenvironment suppressed tumor growth by modulating in situ Interleukin 17A (IL17A) expression and impaired the recruitment of myeloid derived suppressor cells (MDSCs) and Th17 cells as compared to genetically wild type animals. Additionally, loss of mda-9/syntenin expression in a spontaneous melanoma model (melanocyte-specific pten loss and BrafV600E mutation) significantly delayed tumor initiation and suppressed metastasis to the lymph nodes and lungs. The present study highlights a novel role of mda-9/syntenin in tumor-promoting inflammation and immune suppression. These observations along with other documented roles of MDA-9/Syntenin in cancer and metastasis support the potential relevance of MDA-9/Syntenin in the carcinogenic process and as a target for developing improved therapies by using either genetic or pharmacologic approaches to treat

  16. Port-site metastasis after laparoscopic surgery for gastrointestinal cancer.

    PubMed

    Emoto, Shigenobu; Ishigami, Hironori; Yamaguchi, Hironori; Ishihara, Soichiro; Sunami, Eiji; Kitayama, Joji; Watanabe, Toshiaki

    2017-03-01

    Although the incidence of port-site metastasis after laparoscopic surgery for colorectal cancer has markedly decreased since laparoscopic colectomy was first reported in 1991, it still has not reached zero. In colorectal cancer, the safety of laparoscopic surgery, including the low incidence of port-site metastasis, has been proven in large, randomized trials. In gastric cancer, reports of port-site metastasis are extremely rare, but we should await the results of ongoing trials. This brief review summarizes the current knowledge regarding port-site metastasis after laparoscopic surgery for colorectal and gastric cancer.

  17. Metastasis of prostate adenocarcinoma to the frontal and ethmoid sinus

    PubMed Central

    Akdemir, Fatih; Aldemir, Mustafa; Çakar, Hasan; Güler, Gülnur

    2016-01-01

    Intracranial metastasis of prostate cancer is rarely seen, and there are few studies in this regard in the literature. Most of these studies in the literature comprise the metastasis of prostate cancer to the sphenoid sinus, and metastasis to the frontal and ethmoid sinus is a much rare entity. Association of visual symptoms, epistaxis, headache, and hematuria may indicate a urologic malignancy in terms of the origin of the primary tumor. This study was aimed to present the prostate cancer case of a 73-year-old patient whose paranasal sinus tomograms revealed the presence of frontal and ethmoid sinus metastasis. PMID:27909626

  18. Isolated pancreatic metastasis of hepatocellular carcinoma after curative resection.

    PubMed

    Woo, Sang Myung; Park, Joong-Won; Han, Sung-Sik; Choi, Joon-Il; Lee, Woo Jin; Park, Sang Jae; Hong, Eun Kyung; Kim, Chang-Min

    2010-04-15

    Hepatocellular carcinoma (HCC) is a highly malignant tumor and extrahepatic metastasis is not rare. The most common organ of HCC metastasis is lung, followed by bone and adrenal gland. To the best of our knowledge, isolated pancreatic metastasis of HCC that developed after curative resection has not been described previously. We report a case of solitary pancreatic metastasis of HCC, which was found 28 mo after left hemihepatectomy for HCC. The lesion was successfully resected with the pancreas, and no other metastatic lesions have been found in follow-up.

  19. [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.

  20. An Autopsy Case of Lepidic Pulmonary Metastasis from Cholangiocarcinoma

    PubMed Central

    Nagayoshi, Yohsuke; Yamamoto, Kazuko; Hashimoto, Satoru; Hisatomi, Keiko; Doi, Seiji; Nagashima, Seiji; Kurohama, Hirokazu; Ito, Masahiro; Takazono, Takahiro; Nakamura, Shigeki; Miyazaki, Taiga; Kohno, Shigeru

    2016-01-01

    We herein report the first case of pulmonary metastasis with lepidic growth that originated from cholangiocarcinoma. A 77-year-old man was admitted to our hospital due to exertional dyspnea and liver dysfunction. Computed tomography showed widespread infiltration and a ground-glass opacity in the lung and dilation of the intrahepatic bile duct. The pulmonary lesion progressed rapidly, and the patient died of respiratory failure. Cholangiocarcinoma and lepidic pulmonary metastasis were pathologically diagnosed by an autopsy. Lepidic pulmonary growth is an atypical pattern of metastasis, and immunopathological staining is useful to distinguish pulmonary metastasis from extrapulmonary cancer and primary pulmonary adenocarcinoma. PMID:27725547

  1. Blood-brain barrier-penetrating amphiphilic polymer nanoparticles deliver docetaxel for the treatment of brain metastases of triple negative breast cancer.

    PubMed

    He, Chunsheng; Cai, Ping; Li, Jason; Zhang, Tian; Lin, Lucy; Abbasi, Azhar Z; Henderson, Jeffrey T; Rauth, Andrew Michael; Wu, Xiao Yu

    2017-01-28

    Brain metastasis is a fatal disease with limited treatment options and very short survival. Although systemic chemotherapy has some effect on peripheral metastases of breast cancer, it is ineffective in treating brain metastasis due largely to the blood-brain barrier (BBB). Here we developed a BBB-penetrating amphiphilic polymer-lipid nanoparticle (NP) system that efficiently delivered anti-mitotic drug docetaxel (DTX) for the treatment of brain metastasis of triple negative breast cancer (TNBC). We evaluated the biodistribution, brain accumulation, pharmacokinetics and efficacy of DTX-NP in a mouse model of brain metastasis of TNBC. Confocal fluorescence microscopy revealed extravasation of dye-loaded NPs from intact brain microvessels in healthy mice. DTX-NP also extravasated from brain microvessels and accumulated in micrometastasis lesions in the brain. Intravenously injected DTX-NPs increased the blood circulation time of DTX by 5.5-fold and the AUC0-24h in tumor-bearing brain by 5-fold compared to the clinically used DTX formulation Taxotere®. The kinetics of NPs in the brain, determined by ex vivo fluorescence imaging, showed synchronization with DTX kinetics in the brain measured by LC-MS/MS. This result confirmed successful delivery of DTX by the NPs into the brain and suggested that ex vivo fluorescence imaging of NP could be an effective and quick means for probing drug disposition in the brain. Treatment with the DTX-NP formulation delayed tumor growth by 11-fold and prolonged median survival of tumor-bearing mice by 94% compared to an equivalent dose of Taxotere®, without inducing histological changes in the major organs.

  2. The Biology of Breast Cancer Metastasis

    DTIC Science & Technology

    2002-10-01

    Breast cancer is the second most common cause of brain metastases, diagnosed in 10 to 15% of breast cancer patients and found at autopsy in 20 to 30...Relatively little is known about how breast cancer cells metastasize to the brain , and what phenotypes characterize these cells. This is due in...breast cancer brain metastases, using intra-carotid artery injection of breast cancer cells into nude mice.

  3. 21 CFR 172.712 - 1,3-Butylene glycol.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Other Specific Usage Additives § 172.712 1,3-Butylene glycol. The food additive 1,3-butylene glycol (CAS... 20740, or may be examined at the Center for Food Safety and Applied Nutrition's Library, Food and...

  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, 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...

  6. 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...

  7. 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...

  8. 1,3,2-Dioxaarsolanes. Attempts to synthesize hydrospiroarsoranes

    SciTech Connect

    Gamayurova, V.S.; Niyazov, N.A.

    1986-04-20

    2-Hydroxyalkoxyloxy-1,3,2-dioxaarsolanes were obtained by the interaction of trialkyl arsenites with diols and in the absence of steric hindrance were inclined toward dimerization with the formation of 2,2-ethylenedioxybis(1,3,2-dioxaarsolanes). o-Hydroxyphenylenoxy-benzo-1,3,2-dioxaarsole in solution is in equilibrium with 2-hydro-2,2-spirodibenzo-1,3,2-di-oxaarsoranide.

  9. Separation of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane and 1,3,5-trinitro-1,3,5- triazacyclohexane by molecularly imprinted solid-phase extraction.

    PubMed

    Wang, Jian; Meng, Zi-Hui; Xue, Min; Qiu, Li-Li; Zhang, Chen-Fan

    2017-03-01

    Synthesis of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane and 1,3,5-trinitro-1,3,5-triazacyclohexane by the Bachmann process leads to a mixture of both. The separation of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane and 1,3,5-trinitro-1,3,5-triazacyclohexane from their mixture is difficult because the sizes and physical properties of these homologous compounds are similar. For this purpose, seven molecularly imprinted polymers have been synthesized for each explosive, and a selective solid-phase extraction procedure has been developed. A molecularly imprinted polymer, synthesized with 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane as the template, methacrylic acid as the monomer and trimethylolpropane trimethacrylate as the cross-linking agent in a molar ratio of 1:8:8 showed the best separation capability. A packed cartridge containing this polymer can be reused for 23 solid-phase extraction cycles without repacking, and the total separation capability toward 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane reached 6.81 mg per gram of polymer. 1,3,5-Trinitro-1,3,5-triazacyclohexane was not detected in the separated 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane by high-performance liquid chromatography and vice versa. This newly developed method had the advantages of high recovery (100%) and purity, environmental friendliness, and room temperature operability. This study showed that some molecularly imprinted polymers that cannot absorb target analytes well in the solvent in which the polymers were polymerized might have high-binding capacity for the analytes and show imprinting effects in other solvents.

  10. Upregulation of MEK5 by Stat3 promotes breast cancer cell invasion and metastasis.

    PubMed

    Liu, Fang; Zhang, Hao; Song, Hui

    2017-01-01

    Mitogen extracellular-signal-regulated kinase kinase 5 (MEK5) plays an important role in promoting cell proliferation and tumorigenesis. The aberrant expression of MEK5 has been reported in various malignant diseases including cancers of breast, prostate, lung, colorectal and brain. However, the function and regulation of MEK5 signaling pathway are ambiguous and remain elusive with respect to its oncogenic roles in various cancers, especially in the regulation of the initiation and progression of cancer invasion and metastasis. Ectopic expression of MEK5 or knockdown of MEK5 by shRNA with in vitro cell based models demonstrated the role of MEK5 in regulation of epithelial mesenchymal transition (EMT) and breast cancer invasion and metastasis. Here, we show that MEK5 upregulated by Stat3 promotes breast cancer cell invasion through EMT. Further study demonstrated that Stat3 could bind to promoter region of MEK5 and enhanced MEK5 transcription and expression. In addition, the phosphorylation of MEK5 significantly increased in breast cancer cells corresponding to metastatic capability of breast cancer cells. The depletion of MEK5 by shRNA significantly decreased breast cancer invasion. Ectopic expression of MEK5 could confer non-invasive breast cancer cells to become invasion capable cells. Moreover, the phosphorylation of Erk5, a MEK5-regulated downstream kinase, was also upregulated consistent with the increased level of active MEK5. Our studies provide insights into a molecular mechanism by which MEK5 transcriptionally upregulated by Stat3 augments breast cancer cell EMT, which subsequently enhances cancer cell invasion and metastasis. This finding may suggest that Stat3 and MEK5/Erk5 pathways could be an effective therapeutic target for inhibition of breast cancer invasion and metastasis.

  11. 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

  12. Metastasis-associated gene, mag-1 improves tumour microenvironmental adaptation and potentiates tumour metastasis.

    PubMed

    Wang, Yan; Jia, Haiquan; Lin, Huiyun; Tan, Xiaogang; Du, Zhiyan; Chen, Huihua; Xu, Yuanji; Han, Xiaoxi; Zhang, Jiakai; Zhao, Siyang; Yu, Xiaodan; Lu, Yinglin

    2012-12-01

    Metastasis is a major cause of death from malignant diseases, and the underlying mechanisms are still largely not known. A detailed probe into the factors which may regulate tumour invasion and metastasis contributes to novel anti-metastatic therapies. We previously identified a novel metastasis-associated gene 1 (mag-1) by means of metastatic phenotype cloning. Then we characterized the gene expression profile of mag-1 and showed that it promoted cell migration, adhesion and invasion in vitro. Importantly, the disruption of mag-1 via RNA interference not only inhibited cellular metastatic behaviours but also significantly reduced tumour weight and restrained mouse breast cancer cells to metastasize to lungs in spontaneous metastatic assay in vivo. Furthermore, we proved that mag-1 integrates dual regulating mechanisms through the stabilization of HIF-1α and the activation of mTOR signalling pathway. We also found that mag-1-induced metastatic promotion could be abrogated by mTOR specific inhibitor, rapamycin. Taken together, the findings identified a direct role that mag-1 played in metastasis and implicated its function in cellular adaptation to tumour microenvironment.

  13. 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 ...

  14. 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...

  15. 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...

  16. 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...

  17. 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,...

  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. 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...

  20. 43 CFR 3862.1-3 - Evidence of title.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 43 Public Lands: Interior 2 2012-10-01 2012-10-01 false Evidence of title. 3862.1-3 Section 3862.1-3 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) MINERAL PATENT APPLICATIONS Lode Mining Claim Patent Applications § 3862.1-3 Evidence of...

  1. 43 CFR 3862.1-3 - Evidence of title.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 43 Public Lands: Interior 2 2013-10-01 2013-10-01 false Evidence of title. 3862.1-3 Section 3862.1-3 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) MINERAL PATENT APPLICATIONS Lode Mining Claim Patent Applications § 3862.1-3 Evidence of...

  2. 43 CFR 3862.1-3 - Evidence of title.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 2 2011-10-01 2011-10-01 false Evidence of title. 3862.1-3 Section 3862.1-3 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND MANAGEMENT, DEPARTMENT OF THE INTERIOR MINERALS MANAGEMENT (3000) MINERAL PATENT APPLICATIONS Lode Mining Claim Patent Applications § 3862.1-3 Evidence of...

  3. The industrial production and use of 1,3-butadiene.

    PubMed Central

    Morrow, N L

    1990-01-01

    This presentation provides a brief overview of the production and use of 1,3-butadiene in the United States. Starting as a coproduct of ethylene, the 1,3-butadiene monomer is extracted and purified, then transferred to consumers. Major uses of 1,3-butadiene include the manufacture of styrene-butadiene rubber, polybutadiene rubber, and adiponitrile. PMID:2205493

  4. 49 CFR 1.3 - Organization of the Department.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 1 2011-10-01 2011-10-01 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...

  5. Direct, Regioselective N-Alkylation of 1,3-Azoles.

    PubMed

    Chen, Shuai; Graceffa, Russell F; Boezio, Alessandro A

    2016-01-04

    Regioselective N-alkylation of 1,3-azoles is a valuable transformation. Organomagnesium reagents were discovered to be competent bases to affect regioselective alkylation of various 1,3-azoles. Counterintuitively, substitution selectively occurred at the more sterically hindered nitrogen atom. Numerous examples are provided, on varying 1,3-azole scaffolds, with yields ranging from 25 to 95%.

  6. 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 REPOSITORY Implementation Guidelines § 960.3-1-3 Regionality. In making site recommendations for...

  7. 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 REPOSITORY Implementation Guidelines § 960.3-1-3 Regionality. In making site recommendations for...

  8. 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 REPOSITORY Implementation Guidelines § 960.3-1-3 Regionality. In making site recommendations for...

  9. 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 REPOSITORY Implementation Guidelines § 960.3-1-3 Regionality. In making site recommendations for...

  10. 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...

  11. 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

  12. [Orthopaedic management of long bones metastasis].

    PubMed

    Fleury, Thierry Rod; Holzer, Nicolas; Fleury, Mapi; Hoffmeyer, Pierre J

    2012-12-19

    The recent progress in oncologic management of patients with metastatic disease has permitted a significant improvement of their life expectancy. Many of these patients will suffer from complications related to bone metastasis. Unfortunately an orthopaedic treatment is seldom offered to them, mainly because of the misconception that this would not bring them any benefice. However these patients are often good candidates for an orthopaedic management, which objectives are to relieve pain and to re-establish their quality of life. The available surgical techniques are well described and the management protocols are clearly defined, as are the expectable complications and the errors that must not be done.

  13. Isolated Abdominal Wall Metastasis of Endometrial Carcinoma

    PubMed Central

    Simões, Jorge; Gonçalves, Matilde; Matos, Isabel

    2014-01-01

    A woman in her mid-60s presented with a bulky mass on the anterior abdominal wall. She had a previous incidental diagnosis of endometrial adenocarcinoma FIGO stage IB following a vaginal hysterectomy. Physical exam and imaging revealed a well circumscribed bulging tumour at the umbilical region, measuring 10 × 9 × 9 cm, with overlying intact skin and subcutaneous tissue. Surgical resection was undertaken, and histological examination showed features of endometrial carcinoma. She began chemotherapy and is alive with no signs of recurrent disease one year after surgery. This case brings up to light an atypical location of a solitary metastasis of endometrial carcinoma. PMID:25349753

  14. 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

  15. The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis.

    PubMed

    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

    2016-02-12

    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.

  16. Early versus late distant metastasis and adjuvant chemotherapy alone versus both radiotherapy and chemotherapy in molecular apocrine breast cancer.

    PubMed

    Liu, Xiaozhen; Yang, Yang; Feng, Xiaolong; Shen, Honghong; Liu, Jian; Liu, Xia; Niu, Yun

    2016-08-02

    As a new subtype of breast cancer, molecular apocrine breast cancer (MABC) is estrogen receptor (ER) and progesterone receptor (PR) negative expression, but androgen receptor (AR) positive expression. The prognostic significance and clinical biological behavior of MABC have remained unclear up to now. This study aimed to analysis the distant metastasis behavior and response to adjuvant radiotherapy and chemotherapy of MABC subgroup. The report showed that there were significant differences between early and late distant metastasizing tumors with respect to Ki67, epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) expressions by a retrospective analysis consisting of 410 invasive breast cancer patients, which included 205 MABC and 205 nonMABC cases. MABC subgroup metastasized earlier than nonMABC subgroup, and MABC showed a tendency for a higher metastasis rate in lung, liver and brain, but lower in bone. HER2-positive or VEGF-positive tumors were more inclined to develop bone metastasis within MABC subgroup. The survival rate was superior for patients undergone both adjuvant radiotherapy and chemotherapy than those undergone chemotherapy alone in nonMABC subgroup, but there was no significant difference in MABC subgroup. Our data suggested that MABC subgroup seemed to develop distant metastasis earlier than nonMABC subgroup, and patients with MABC indicated poor prognosis. This study might also provide a foundation for helping patients receive reasonable treatments according to molecular subtype.

  17. Early versus late distant metastasis and adjuvant chemotherapy alone versus both radiotherapy and chemotherapy in molecular apocrine breast cancer

    PubMed Central

    Liu, Xiaozhen; Yang, Yang; Feng, Xiaolong; Shen, Honghong; Liu, Jian; Liu, Xia; Niu, Yun

    2016-01-01

    As a new subtype of breast cancer, molecular apocrine breast cancer (MABC) is estrogen receptor (ER) and progesterone receptor (PR) negative expression, but androgen receptor (AR) positive expression. The prognostic significance and clinical biological behavior of MABC have remained unclear up to now. This study aimed to analysis the distant metastasis behavior and response to adjuvant radiotherapy and chemotherapy of MABC subgroup. The report showed that there were significant differences between early and late distant metastasizing tumors with respect to Ki67, epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) expressions by a retrospective analysis consisting of 410 invasive breast cancer patients, which included 205 MABC and 205 nonMABC cases. MABC subgroup metastasized earlier than nonMABC subgroup, and MABC showed a tendency for a higher metastasis rate in lung, liver and brain, but lower in bone. HER2-positive or VEGF-positive tumors were more inclined to develop bone metastasis within MABC subgroup. The survival rate was superior for patients undergone both adjuvant radiotherapy and chemotherapy than those undergone chemotherapy alone in nonMABC subgroup, but there was no significant difference in MABC subgroup. Our data suggested that MABC subgroup seemed to develop distant metastasis earlier than nonMABC subgroup, and patients with MABC indicated poor prognosis. This study might also provide a foundation for helping patients receive reasonable treatments according to molecular subtype. PMID:27340922

  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. 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 ...

  20. 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, ...

  1. Brain components

    MedlinePlus Videos and Cool Tools

    The brain is composed of more than a thousand billion neurons. Specific groups of them, working in concert, provide ... of information. The 3 major components of the brain are the cerebrum, cerebellum, and brain stem. The ...

  2. 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.

  3. von Willebrand factor expression in osteosarcoma metastasis.

    PubMed

    Eppert, Kolja; Wunder, Jay S; Aneliunas, Vicky; Kandel, Rita; Andrulis, Irene L

    2005-03-01

    A number of genes are implicated in the initiation and progression of osteosarcoma; however, cytogenetic and comparative genomic hybridization studies indicate the involvement of additional unidentified genes. An examination of gene expression profiles in 22 high-grade osteosarcoma tumor specimens from 15 patients (including paired primary and metastatic samples from five patients) indicated that von Willebrand factor (vWF) mRNA expression may increase during tumor progression. vWF, a large glycoprotein previously considered to be expressed exclusively by endothelial cells and megakaryocytes, is involved in platelet aggregation and adhesion to the subendothelial matrix, processes critical to hematogenous tumor cell metastasis to the lung. Analysis of paired primary and metastatic osteosarcoma tumor samples from 10 patients revealed an increase in vWF gene expression in metastases (P=0.005). Immunohistochemistry showed that, in addition to the endothelial cells, vWF protein was also detected in osteosarcoma cells in vivo in 13 of 29 tumor specimens as well as in SAOS2, an osteosarcoma cell line. The tumor cell staining correlated positively with high vWF expression in the sample (P=0.006). Although vascular endothelial cells contribute to the vWF mRNA detected in the tumor samples, there was neither any correlation between vascular density (VD) and vWF mRNA expression nor between VD and clinical outcome. These findings suggest that vWF expression is deregulated in osteosarcoma tumors, potentially contributing to metastasis.

  4. 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.

  5. Supratentorial extraventricular anaplastic ependymoma with extracranial metastasis.

    PubMed

    Pachella, Laura A; Kamiya-Matsuoka, Carlos; Lee, Eva Lu T; Olar, Adriana; Yung, W K Alfred

    2015-03-01

    Ependymoma is a relatively rare malignancy accounting for 2.0% of all primary central nervous system tumors in adults. Extracranial metastasis is a very uncommon complication of gliomas, especially of anaplastic ependymomas. The objective of this paper is to show that ependymomas can metastasize to soft tissue and lymph nodes as well as to share our approach to this challenge. We report a male patient with anaplastic ependymoma that recurred, metastasizing to the neck and lymph nodes. Metastatic disease was diagnosed based on clinical presentation of a palpable nodule on the right neck and diffuse cervical lymphadenopathies. A biopsy was obtained and pathology revealed anaplastic ependymoma. Whole-body fluorodeoxyglucose positron emission tomography scan showed metastatic disease in the right mastoid region with diffuse uptake in the cervical lymph nodes. Clinical and radiologic response was achieved after three chemotherapy cycles of etoposide, cisplatin, vincristine, and cyclophosphamide. This case highlights extracranial metastasis to the soft tissue as an atypical presentation of recurrent anaplastic ependymoma. Other reported instances of extracranial metastatic ependymoma with this presentation are discussed. The possible metastatic pathways of intracranial disease are discussed. It also illustrates how extracranial disease remains stable with systemic chemotherapy.

  6. Hypothyroidism Enhances Tumor Invasiveness and Metastasis Development

    PubMed Central

    Martínez-Iglesias, Olaia; García-Silva, Susana; Regadera, Javier; Aranda, Ana

    2009-01-01

    Background Whereas there is increasing evidence that loss of expression and/or function of the thyroid hormone receptors (TRs) could result in a selective advantage for tumor development, the relationship between thyroid hormone levels and human cancer is a controversial issue. It has been reported that hypothyroidism might be a possible risk factor for liver and breast cancer in humans, but a lower incidence of breast carcinoma has been also reported in hypothyroid patients Methodology/Principal Findings In this work we have analyzed the influence of hypothyroidism on tumor progression and metastasis development using xenografts of parental and TRβ1–expressing human hepatocarcinoma (SK-hep1) and breast cancer cells (MDA-MB-468). In agreement with our previous observations tumor invasiveness and metastasis formation was strongly repressed when TRβ–expressing cells were injected into euthyroid nude mice. Whereas tumor growth was retarded when cells were inoculated into hypothyroid hosts, tumors had a more mesenchymal phenotype, were more invasive and metastatic growth was enhanced. Increased aggressiveness and tumor growth retardation was also observed with parental cells that do not express TRs. Conclusions/Significance These results show that changes in the stromal cells secondary to host hypothyroidism can modulate tumor progression and metastatic growth independently of the presence of TRs on the tumor cells. On the other hand, the finding that hypothyroidism can affect differentially tumor growth and invasiveness can contribute to the explanation of the confounding reports on the influence of thyroidal status in human cancer. PMID:19641612

  7. miR-200 Inhibits Lung Adenocarcinoma Cell Invasion and Metastasis by Targeting Flt1/VEGFR1

    PubMed Central

    Roybal, Jonathon D.; Zang, Yi; Ahn, Young-Ho; Yang, Yanan; Gibbons, Don L.; Baird, Brandi N.; Alvarez, Cristina; Thilaganathan, Nishan; Liu, Diane D.; Saintigny, Pierre; Heymach, John V.; Creighton, Chad J.; Kurie, Jonathan M.

    2011-01-01

    The microRNA-200 (miR-200) family is part of a gene expression signature that predicts poor prognosis in lung cancer patients. In a mouse model of K-ras/p53-mutant lung adenocarcinoma, miR-200 levels are suppressed in metastasis-prone tumor cells, and forced miR-200 expression inhibits tumor growth and metastasis, but the miR-200 target genes that drive lung tumorigenesis have not been fully elucidated. Here, we scanned the genome for putative miR-200 binding sites and found them in the 3′-untranslated region (3′-UTR) of 35 genes that are amplified in human cancer. Mining of a database of resected human lung adenocarcinomas revealed that the levels of one of these genes, Flt1/VEGFR1, correlate inversely with duration of survival. Forced miR-200 expression suppressed Flt1 levels in metastasis-prone lung adenocarcinoma cells derived from K-ras/p53-mutant mice, and negatively regulated the Flt1 3′-UTR in reporter assays. Cancer-associated fibroblasts (CAFs) isolated from murine lung adenocarcinomas secreted abundant VEGF and enhanced tumor cell invasion in coculture studies. CAF-induced tumor cell invasion was abrogated by VEGF neutralization or Flt1 knockdown in tumor cells. Flt1 knockdown decreased the growth and metastasis of tumor cells in syngeneic mice. We conclude that miR-200 suppresses lung tumorigenesis by targeting Flt1. PMID:21115742

  8. Bilateral Cystic Adrenal Neuroblastoma with Cystic Liver metastasis

    PubMed Central

    Aslan, Mine; Kalyoncu, Ayse Ucar; Habibi, Hatice Arioz; Ozdemir, Gul Nihal; Koc, Basak; Adaletli, Ibrahim

    2017-01-01

    Bilateral congenital cystic adrenal neuroblastoma (NB) with cystic liver metastasis is a very rare condition and only few cases have been reported in the literature. Herein we report a case of a congenital bilateral cystic adrenal NB with cystic liver metastasis and briefly discuss characteristic imaging features of cystic NB. PMID:28163998

  9. [Metastasis of hepatocellular carcinoma to the urinary bladder].

    PubMed

    Kurimoto, S; Komatsu, H; Doi, N; Wakumoto, Y; Tominaga, T; Nishimura, Y

    1993-01-01

    We report a case of metastasis of a hepatocellular carcinoma to the bladder. Clinically the tumor was suspected to be a primary bladder tumor with subsequent metastasis to the liver. However, the pathological diagnosis yielded different results. The tumor cells resembled liver cells and sometimes bile production was even observed. No therapy was available and the patient died of cachexia 6 months later.

  10. Preventing Prostate Cancer Metastasis by Targeting Exosome Secretion

    DTIC Science & Technology

    2014-10-01

    Exosome Secretion PRINCIPAL INVESTIGATOR: Christine Vogel CONTRACTING ORGANIZATION: New York University, New York, NY 10012...30 Sep 2013 - 29 Sep 2014 4. TITLE AND SUBTITLE Preventing Prostate Cancer Metastasis by Targeting Exosome Secretion 5a. CONTRACT...NUMBER Preventing Prostate Cancer Metastasis by Targeting Exosome Secretion 5b. GRANT NUMBER W81XWH-13-1-0467 5c. PROGRAM ELEMENT

  11. Unusual location of a urinary bladder cancer metastasis.

    PubMed

    Forte, Serafino; Kos, Sebastian; Hoffmann, Adrienne

    2009-01-01

    Bladder cancer is the fourth most common malignancy among men in the Western world. Bone metastasis occurs in 27 % of the cases. Usually, the location is the spine. The present report describes the first case of a proven distant bone metastasis to the acromion from a urinary bladder carcinoma in a patient with shoulder pain.

  12. Systemic inflammation: Cancer's long-distance reach to maximize metastasis

    PubMed Central

    Coffelt, Seth B.; de Visser, Karin E.

    2016-01-01

    ABSTRACT While major improvements have been made in targeting primary tumor growth, metastasis and combating cancer spread remain an enigma. We recently identified a systemic inflammatory cascade involving IL17-producing γδ T cells and neutrophils that advance breast cancer metastasis. These data provide insights into how immune cells promote cancer spread. PMID:27057449

  13. Systemic inflammation: Cancer's long-distance reach to maximize metastasis.

    PubMed

    Coffelt, Seth B; de Visser, Karin E

    2016-02-01

    While major improvements have been made in targeting primary tumor growth, metastasis and combating cancer spread remain an enigma. We recently identified a systemic inflammatory cascade involving IL17-producing γδ T cells and neutrophils that advance breast cancer metastasis. These data provide insights into how immune cells promote cancer spread.

  14. Platelet aggregation in the formation of tumor metastasis

    PubMed Central

    Tsuruo, Takashi; Fujita, Naoya

    2008-01-01

    Metastasis is the major cause of death from cancer, yet the optimal strategy against it remains uncertain. The pathogenesis of hematogenous metastasis is dynamic and consists of the following steps: 1) detachment of tumor cells from the primary site, 2) invasion into the host’s blood vessels, 3) migration in the host’s blood stream, 4) transport along the circulation, 5) arrest in or adhesion to the capillary in a distant organ, 6) extravasation, and 7) proliferation within the foreign tissues. A key to successful hematogenous metastasis is tumor survival in the bloodstream because most circulating tumor cells are rapidly destroyed by the shear forces or are attacked by the immune system. Less than 0.01% of these cells result in metastasis. Tumor cell–induced platelet aggregation has been reported to facilitate hematogenous metastasis by increasing the arrest of tumor cell emboli in the microcirculation. Platelet aggregation is also believed to protect tumor cells from immunological assault in the circulation. We have identified Aggrus as a platelet–aggregating factor expressed on a number of human cancers. Because hematogenous metastasis is reduced when neutralizing antibodies or eliminating carbohydrates attenuates Aggrus function, Aggrus’s main contribution to hematogenous metastasis of Aggrus–expressing cells, then, is by promoting platelet aggregation. Aggrus could serve as an ideal target for drug development to block metastasis. PMID:18941298

  15. Global secretome analysis identifies novel mediators of bone metastasis

    PubMed Central

    Blanco, Mario Andres; LeRoy, Gary; Khan, Zia; Alečković, Maša; Zee, Barry M; Garcia, Benjamin A; Kang, Yibin

    2012-01-01

    Bone is the one of the most common sites of distant metastasis of solid tumors. Secreted proteins are known to influence pathological interactions between metastatic cancer cells and the bone stroma. To comprehensively profile secreted proteins associated with bone metastasis, we used quantitative and non-quantitative mass spectrometry to globally analyze the secretomes of nine cell lines of varying bone metastatic ability from multiple species and cancer types. By comparing the secretomes of parental cells and their bone metastatic derivatives, we identified the secreted proteins that were uniquely associated with bone metastasis in these cell lines. We then incorporated bioinformatic analyses of large clinical metastasis datasets to obtain a list of candidate novel bone metastasis proteins of several functional classes that were strongly associated with both clinical and experimental bone metastasis. Functional validation of selected proteins indicated that in vivo bone metastasis can be promoted by high expression of (1) the salivary cystatins CST1, CST2, and CST4; (2) the plasminogen activators PLAT and PLAU; or (3) the collagen functionality proteins PLOD2 and COL6A1. Overall, our study has uncovered several new secreted mediators of bone metastasis and therefore demonstrated that secretome analysis is a powerful method for identification of novel biomarkers and candidate therapeutic targets. PMID:22688892

  16. Probing the Fifty Shades of EMT in Metastasis.

    PubMed

    Li, Wenyang; Kang, Yibin

    2016-02-01

    The involvement of epithelial-to-mesenchymal transition (EMT) in metastasis has long been under debate. Recent efforts to probe the occurrence and functional significance of EMT in clinical samples and animal models have produced exciting but sometimes conflicting findings. The diversity of EMT underlies the challenge in studying its role in metastasis.

  17. Isolated mucinous adrenal metastasis in a breast cancer patient.

    PubMed

    Demirci, Umut; Buyukberber, Suleyman; Cakir, Tansel; Poyraz, Aylar; Baykara, Meltem; Karakus, Esra; Tufan, Gulnihal; Benekli, Mustafa; Coskun, Ugur

    2011-12-01

    Mucinous breast carcinoma (MBC) is a rare histological type of breast cancer and rarely associated with advanced disease. We report a case that had MBC with an isolated adrenal metastasis which was removed by laparoscopic adrenelectomy. This case is unique due to the unexpected metastasis of pure mucinous carcinoma developed after 4 years of hormone therapy.

  18. Muc1 promotes migration and lung metastasis of melanoma cells

    PubMed Central

    Wang, Xiaoli; Lan, Hongwen; Li, Jun; Su, Yushu; Xu, Lijun

    2015-01-01

    Early stages of melanoma can be successfully treated by surgical resection of the tumor, but there is still no effective treatment once it is progressed to metastatic phases. Although growing family of both melanoma metastasis promoting and metastasis suppressor genes have been reported be related to metastasis, 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 melanoma. In the present study, we found that muc1 is involved in the metastasis of melanoma cells and demonstrated that muc1 disruption impairs melanoma cells migration and metastasis. The requirement of muc1 in the migration of melanoma cells was further confirmed by gene silencing in vitro. In corresponding to this result, over-expression of muc1 significantly promoted the migratory of melanoma cells. Moreover, down-regulation of muc1 expression strikingly inhibits melanoma cellular metastasis in vivo. Finally, we found that muc1 promotes melanoma migration through the protein kinase B (Akt) signaling pathway. To conclude, our findings suggest a novel mechanism underlying the metastasis of melanoma cells which might serve as a new intervention target for the treatment of melanoma. PMID:26609470

  19. Superbinding in Integrative Brain Function and Memory

    DTIC Science & Technology

    2007-11-02

    A:\\basar.doc 1 SUPERBINDING IN INTEGRATIVE BRAIN FUNCTION AND MEMORY E. Basar1,2, M. Özgören1,2, S. Karakas1,3 1TUBITAK Brain Dynamics...percepts and integrative brain function. Keywords- superbinding, oscillations, binding, coherence 1 Aim of the report The present report aims to...introduce the superbinding theory to describe the machineries of integrative brain function instead of single neuron doctrine. This concept is based on

  20. 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