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Sample records for deadly brain cancer

  1. Are Brain Dead Individuals Dead? Grounds for Reasonable Doubt.

    PubMed

    Brugger, E Christian

    2016-06-01

    According to the biological definition of death, a human body that has not lost the capacity to holistically organize itself is the body of a living human individual. Reasonable doubt against the conclusion that it has lost the capacity exists when the body appears to express it and no evidence to the contrary is sufficient to rule out reasonable doubt against the conclusion that the apparent expression is a true expression (i.e., when the conclusion that what appears to be holistic organization is in fact holistic organization remains a reasonable explanatory hypothesis in light of the best evidence to the contrary). This essay argues that the evidence and arguments against the conclusion that the signs of complex bodily integration exhibited in ventilated brain dead bodies are true expressions of somatic integration are unpersuasive; that is, they are not adequate to exclude reasonable doubt against the conclusion that BD bodies are dead. Since we should not treat as corpses what for all we know might be living human beings, it follows that we have an obligation to treat BD individuals as if they were living human beings. PMID:27075192

  2. [Japanese ethos and organ transplantation from brain-dead donors].

    PubMed

    Akiba, Etsuko

    2010-12-01

    A trend observed since the 1980s in the Japanese academic scene is the overturning of Hippocratic ethics by American individualistic bioethics. However, the Japanese ethos is more sympathetic to personalistic bioethics rooted in Hippocratic ethics, which assumes the universal view of the 'interdependent self' clearly marked off from the 'independent self' specific to American culture. In Japan, organ transplantation from brain-dead donors is promoted despite the lack of consensus on whether brain death signifies death of the individual. From the viewpoint of personalistic bioethics, this situation is problematic because it violates the dictum primum non nocere of the Hippocratic Oath. We should therefore first establish consensus on brain death and then promote a 'culture of donation' based on human dignity.

  3. Inflammatory Signalling Associated with Brain Dead Organ Donation: From Brain Injury to Brain Stem Death and Posttransplant Ischaemia Reperfusion Injury

    PubMed Central

    Watts, Ryan P.; Thom, Ogilvie; Fraser, John F.

    2013-01-01

    Brain death is associated with dramatic and serious pathophysiologic changes that adversely affect both the quantity and quality of organs available for transplant. To fully optimise the donor pool necessitates a more complete understanding of the underlying pathophysiology of organ dysfunction associated with transplantation. These injurious processes are initially triggered by catastrophic brain injury and are further enhanced during both brain death and graft transplantation. The activated inflammatory systems then contribute to graft dysfunction in the recipient. Inflammatory mediators drive this process in concert with the innate and adaptive immune systems. Activation of deleterious immunological pathways in organ grafts occurs, priming them for further inflammation after engraftment. Finally, posttransplantation ischaemia reperfusion injury leads to further generation of inflammatory mediators and consequent activation of the recipient's immune system. Ongoing research has identified key mediators that contribute to the inflammatory milieu inherent in brain dead organ donation. This has seen the development of novel therapies that directly target the inflammatory cascade. PMID:23691272

  4. Lung Cancer Brain Metastases.

    PubMed

    Goldberg, Sarah B; Contessa, Joseph N; Omay, Sacit B; Chiang, Veronica

    2015-01-01

    Brain metastases are common among patients with lung cancer and have been associated with significant morbidity and limited survival. However, the treatment of brain metastases has evolved as the field has advanced in terms of central nervous system imaging, surgical technique, and radiotherapy technology. This has allowed patients to receive improved treatment with less toxicity and more durable benefit. In addition, there have been significant advances in systemic therapy for lung cancer in recent years, and several treatments including chemotherapy, targeted therapy, and immunotherapy exhibit activity in the central nervous system. Utilizing systemic therapy for treating brain metastases can avoid or delay local therapy and often allows patients to receive effective treatment for both intracranial and extracranial disease. Determining the appropriate treatment for patients with lung cancer brain metastases therefore requires a clear understanding of intracranial disease burden, tumor histology, molecular characteristics, and overall cancer prognosis. This review provides updates on the current state of surgery and radiotherapy for the treatment of brain metastases, as well as an overview of systemic therapy options that may be effective in select patients with intracranial metastases from lung cancer.

  5. "Brain Death" and dead donor rule. Discussion and proposals on the thesis of Truog.

    PubMed

    Bruzzone, Paolo

    2015-01-01

    The introduction in 1968 by the "ad hoc" Harvard committee of the concept of "Brain Death" gave birth to the worldwide diffusion of organ transplantation. Recently "Total Brain Failure" has been proposed as preferred term, instead of "Brain Death", by the President's Council on Bioethics. The concepts of "brain death" and of "dead donor rule" remain the ethical and moral support of organ transplantation. However both criteria has been questioned , either separately or all together , by many authors and particularly by Dr. Robert D. Truog.

  6. Iranian nurses’ experiences of brain dead donors care in intensive care units: A phenomenological study

    PubMed Central

    Salehi, Shayesteh; Kanani, Tahereh; Abedi, Heidarali

    2013-01-01

    Background: Care of brain dead donors is complex, critical, and sensitive and has a direct and positive impact on the end result of organ and tissue transplantation process. This study describes the nurses’ experiences of care of brain dead donors in intensive care units (ICU). Materials and Methods: This research was performed by phenomenological method that is a qualitative approach. Purposive sampling was used to gather the data. The researcher reached to data saturation by deep interviews conducted with eight participants from ICU nurses in Isfahan hospitals who cooperated in care of brain dead donors. Data analysis was performed according to Colaizzi analysis method. Results: Interviews were analyzed and the results of analysis led to “Excruciating tasks” as the main theme formed by psychological effects of facing the situation, heavy and stressful care, defect of scientific knowledge, conflict between feeling and duty, outcome of attitude change in behavior, emotional responses to perceived psychological afflictions, doubt to medical diagnosis, spiritual perceptions, and biological responses when faced with the situation. Conclusion: Caring of brain dead organ donors is difficult and stressful for intensive care nurses and can be a threat for nurses’ health and quality of nursing care. So, providing suitable physical, mental, and working conditions is necessary to make suitable background to maintain and increase nurses’ health and quality of care and effective cooperation of this group of health professionals in organ procurement process. PMID:24554946

  7. The proactive brain and the fate of dead hypotheses

    PubMed Central

    Tal, Amir; Bar, Moshe

    2014-01-01

    A substantial portion of information flow in the brain is directed top-down, from high processing areas downwards. Signals of this sort are regarded as conveying prior expectations, biasing the processing and eventual perception of incoming stimuli. In this perspective we describe a framework of top-down processing in the visual system in which predictions on the identity of objects in sight aid in their recognition. Focus is placed, in particular, on a relatively uncharted ramification of this framework, that of the fate of initial predictions that are eventually rejected during the process of selection. We propose that such predictions are rapidly inhibited in the brain after a competing option has been selected. Empirical support, along with behavioral, neuronal and computational aspects of this proposal are discussed, and future directions for related research are offered. PMID:25408645

  8. The ethics of extracorporeal membrane oxygenation in brain-dead potential organ donors.

    PubMed

    Dalle Ave, Anne L; Gardiner, Dale; Shaw, David M

    2016-05-01

    Organ-preserving extracorporeal membrane oxygenation (OP-ECMO) is defined as the use of extracorporeal support for the primary purpose of preserving organs for transplantation, rather than to save the patient's life. This paper discusses the ethics of using OP-ECMO in donation after brain determination of death (DBDD) to avoid the loss of organs for transplantation. We review case reports in the literature and analyze the ethical issues raised. We conclude that there is little additional ethical concern in continuing OP-ECMO in patients already on ECMO if they become brain dead. The implementation of OP-ECMO in hemodynamically unstable brain-dead patients is ethically permissible in certain clinical situations but requires specific consent from relatives if the patient's wish to donate is not clear. If no evidence of a patient's wish to donate is available, OP-ECMO is not recommended. In countries with presumed consent legislation, failure to opt out should be considered as a positive wish to donate. If a patient is not-yet brain-dead or is undergoing testing for brain death, OP-ECMO is not recommended. Further research on OP-ECMO is needed to better understand the attitudes of professionals, families, and lay people to ensure agreement on key ethical issues. PMID:26987689

  9. Immunotherapy of Brain Cancer.

    PubMed

    Roth, Patrick; Preusser, Matthias; Weller, Michael

    2016-01-01

    The brain has long been considered an immune-privileged site precluding potent immune responses. Nevertheless, because of the failure of conventional anti-cancer treatments to achieve sustained control of intracranial neoplasms, immunotherapy has been considered as a promising strategy for decades. However, several efforts aimed at exploiting the immune system as a therapeutic weapon were largely unsuccessful. The situation only changed with the introduction of the checkpoint inhibitors, which target immune cell receptors that interfere with the activation of immune effector cells. Following the observation of striking effects of drugs that target CTLA-4 or PD-1 against melanoma and other tumor entities, it was recognized that these drugs may also be active against metastatic tumor lesions in the brain. Their therapeutic activity against primary brain tumors is currently being investigated within clinical trials. In parallel, other immunotherapeutics such as peptide vaccines are at an advanced stage of clinical development. Further immunotherapeutic strategies currently under investigation comprise adoptive immune cell transfer as well as inhibitors of metabolic pathways involved in the local immunosuppression frequently found in brain tumors. Thus, the ongoing implementation of immunotherapeutic concepts into clinical routine may represent a powerful addition to the therapeutic arsenal against various brain tumors. PMID:27260656

  10. Long-term heart rate fluctuations in postoperative and brain-dead patients.

    PubMed

    Tamura, T; Maekawa, T; Nakajima, K; Sadamitsu, D; Tateishi, A

    1998-11-01

    Long-term heart rate fluctuations in postoperative and brain-dead patients were investigated. Heart rates were monitored continuously, and the data were stored, edited, and interpolated to allow for data lost during calibration and disconnection of the sensors for various treatments. Heart rate power spectra were calculated using the fast Fourier transform method. The power spectra of the patients who recovered showed that the heart rate fluctuated and produced a 1/f relationship, termed 1/f fluctuations, whereas those of patients who died in the intensive care unit (ICU) consisted of white-noise-like signals. The power spectra in brain-dead patients showed a 1/f relationship under steady-state conditions, while the power density and variation of the frequency distribution were lower than those in a normal subject. Therefore, 1/f fluctuations appear to be universal and occur independent of the central nervous system. PMID:9844751

  11. Breast, Cervical Cancer More Deadly in Developing Nations: Report

    MedlinePlus

    ... More Health News on: Breast Cancer Cervical Cancer Health Disparities Recent Health News Related MedlinePlus Health Topics Breast Cancer Cervical Cancer Health Disparities About MedlinePlus Site Map FAQs Contact Us Get ...

  12. Human Split-Thickness Skin Allograft from Brain-Dead Donors

    PubMed Central

    Khodadadi, A.; Olang, O; Makhllough, A; Nozary Heshmati, B.; Azmoudeh Ardalan, F.; Tavakoli, S. A.

    2016-01-01

    Background: Looking for an appropriate skin substitute for temporary and permanent coverage of wounds remains one of the main obstacles of medical researchers. Objective: To investigate the rate of inflammation, symbiosis, and survival of grafted allograft skin from brain-dead donors (BDDs) in rabbits. Methods: After receiving negative serologic tests of BDDs, we prepared partial thickness skin grafts. They were then used in treating wounds of 5 rabbits in comparison with split-thickness skins taken from cardiac dead donors. Results: On histopathological examinations, we found no difference between the skins. All samples were separated from the baseline in 15–20 days. Conclusion: Gamma-irradiated freeze-dried human split-thickness skin taken from BDDs is safe and can be used for the treatment of deep skin burns. PMID:27721966

  13. Targeting complement activation in brain-dead donors improves renal function after transplantation.

    PubMed

    Damman, Jeffrey; Hoeger, Simone; Boneschansker, Leo; Theruvath, Ashok; Waldherr, Ruediger; Leuvenink, Henri G; Ploeg, Rutger J; Yard, Benito A; Seelen, Marc A

    2011-05-01

    Kidneys recovered from brain-dead donors have inferior outcomes after transplantation compared to kidneys from living donors. Since complement activation plays an important role in renal transplant related injury, targeting complement activation in brain-dead donors might improve renal function after transplantation. Brain death (BD) was induced in Fisher rats by inflation of an epidurally placed balloon catheter and ventilated for 6h. BD animals were treated with soluble complement receptor 1 (sCR1) 1h before or 1h after BD. Kidney transplantation was performed and 7 days after transplantation animals were sacrificed. Plasma creatinine and urea were measured at days 0, 1, 3, 5 and 7 after transplantation. Renal function was significantly better at day 1 after transplantation in recipients receiving a sCR1 pre-treated donor kidney compared to recipients of a non-treated donor graft. Also treatment with sCR1, 1h after the diagnosis of BD, resulted in a better renal function after transplantation. Gene expression of IL-6, IL-1beta and TGF-beta were significantly lower in renal allografts recovered from treated donors. This study shows that targeting complement activation, during BD in the donor, leads to an improved renal function after transplantation in the recipient.

  14. 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.

  15. Basal Breast Cancer: A Complex and Deadly Molecular Subtype

    PubMed Central

    Bertucci, F; Finetti, P; Birnbaum, D

    2012-01-01

    During the last decade, gene expression profiling of breast cancer has revealed the existence of five molecular subtypes and allowed the establishment of a new classification. The basal subtype, which represents 15-25% of cases, is characterized by an expression profile similar to that of myoepithelial normal mammary cells. Basal tumors are frequently assimilated to triple-negative (TN) breast cancers. They display epidemiological and clinico-pathological features distinct from other subtypes. Their pattern of relapse is characterized by frequent and early relapses and visceral locations. Despite a relative sensitivity to chemotherapy, the prognosis is poor. Recent characterization of their molecular features, such as the dysfunction of the BRCA1 pathway or the frequent expression of EGFR, provides opportunities for optimizing the systemic treatment. Several clinical trials dedicated to basal or TN tumors are testing cytotoxic agents and/or molecularly targeted therapies. This review summarizes the current state of knowledge of this aggressive and hard-to-treat subtype of breast cancer. PMID:22082486

  16. Brain metastases of breast cancer.

    PubMed

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

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

  17. Organ retrieval and banking in brain dead trauma patients: Our experience at level-1 trauma centre and current views

    PubMed Central

    Sawhney, Chhavi; Kaur, Manpreet; Lalwani, Sanjeev; Gupta, Babita; Balakrishnan, Ira; Vij, Aarti

    2013-01-01

    Background: Organ retrieval from brain dead patients is getting an increased attention as the waiting list for organ recipients far exceeds the organ donor pool. In our country, despite a large population the number of brain dead donors undergoing organ donation is very less (2% in our study). Aims: The present study was undertaken to address issues related to organ donation and share our experience for the same. Methods: A retrospective case record analysis of over 5 years from September 2007 to August 2012 was performed and the patients fulfilling brain death criterion as per Transplantation of Human Organs and Tissue (Amendment) Act were included. Patient demographics (age, sex), mode of injury, time from injury to the diagnosis of brain death, time from diagnosis of brain death to organ retrieval and complications were analysed. Statistics Analysis: Student's t test was used for parametric data and Chi square was used for categorical data. Results: Out of 205 patients who were identified as brain dead, only 10 patients became potential organ donors. Conclusion: Aggressive donor management, increasing public awareness about the concept of organ donation, good communication between clinician and the family members and a well-trained team of transplant coordinators can help in improving the number of organ donations. PMID:23983281

  18. One life ends, another begins: Management of a brain-dead pregnant mother-A systematic review-

    PubMed Central

    2010-01-01

    Background An accident or a catastrophic disease may occasionally lead to brain death (BD) during pregnancy. Management of brain-dead pregnant patients needs to follow special strategies to support the mother in a way that she can deliver a viable and healthy child and, whenever possible, also be an organ donor. This review discusses the management of brain-dead mothers and gives an overview of recommendations concerning the organ supporting therapy. Methods To obtain information on brain-dead pregnant women, we performed a systematic review of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). The collected data included the age of the mother, the cause of brain death, maternal medical complications, gestational age at BD, duration of extended life support, gestational age at delivery, indication of delivery, neonatal outcome, organ donation of the mothers and patient and graft outcome. Results In our search of the literature, we found 30 cases reported between1982 and 2010. A nontraumatic brain injury was the cause of BD in 26 of 30 mothers. The maternal mean age at the time of BD was 26.5 years. The mean gestational age at the time of BD and the mean gestational age at delivery were 22 and 29.5 weeks, respectively. Twelve viable infants were born and survived the neonatal period. Conclusion The management of a brain-dead pregnant woman requires a multidisciplinary team which should follow available standards, guidelines and recommendations both for a nontraumatic therapy of the fetus and for an organ-preserving treatment of the potential donor. PMID:21087498

  19. DDX4 (DEAD box polypeptide 4) colocalizes with cancer stem cell marker CD133 in ovarian cancers

    SciTech Connect

    Kim, Ki Hyung; Kang, Yun-Jeong; Jo, Jin-Ok; Ock, Mee Sun; Moon, Soo Hyun; Suh, Dong Soo; Yoon, Man Soo; Park, Eun-Sil; Jeong, Namkung; Eo, Wan-Kyu; Kim, Heung Yeol; Cha, Hee-Jae

    2014-05-02

    Highlights: • Germ cell marker DDX4 was significantly increased in ovarian cancer. • Ovarian cancer stem cell marker CD133 was significantly increased in ovarian cancer. • DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. • CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4. • Germ cell marker DDX4 has the potential of ovarian cancer stem cell marker. - Abstract: DDX4 (DEAD box polypeptide 4), characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), is an RNA helicase which is implicated in various cellular processes involving the alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. DDX4 is known to be a germ cell-specific protein and is used as a sorting marker of germline stem cells for the production of oocytes. A recent report about DDX4 in ovarian cancer showed that DDX4 is overexpressed in epithelial ovarian cancer and disrupts a DNA damage-induced G2 checkpoint. We investigated the relationship between DDX4 and ovarian cancer stem cells by analyzing the expression patterns of DDX4 and the cancer stem cell marker CD133 in ovarian cancers via tissue microarray. Both DDX4 and CD133 were significantly increased in ovarian cancer compared to benign tumors, and showed similar patterns of expression. In addition, DDX4 and CD133 were mostly colocalized in various types of ovarian cancer tissues. Furthermore, almost all CD133 positive ovarian cancer cells also express DDX4 whereas CD133-negative cells did not possess DDX4, suggesting a strong possibility that DDX4 plays an important role in cancer stem cells, and/or can be used as an ovarian cancer stem cell marker.

  20. Preclinical pulmonary capillary endothelial dysfunction is present in brain dead subjects.

    PubMed

    Glynos, Constantinos; Athanasiou, Chariclea; Kotanidou, Anastasia; Korovesi, Ioanna; Kaziani, Katerina; Livaditi, Olga; Dimopoulou, Ioanna; Maniatis, Nikolaos A; Tsangaris, Iraklis; Roussos, Charis; Armaganidis, Apostolos; Orfanos, Stylianos E

    2013-04-01

    Pulmonary endothelium is a major metabolic organ affecting pulmonary and systemic vascular homeostasis. Brain death (BD)-induced physiologic and metabolic derangements in donors' lungs, in the absence of overt lung pathology, may cause pulmonary dysfunction and compromise post-transplant graft function. To explore the impact of BD on pulmonary endothelium, we estimated pulmonary capillary endothelium-bound (PCEB)-angiotensin converting enzyme (ACE) activity, a direct and quantifiable index of pulmonary endothelial function, in eight brain-dead patients and ten brain-injured mechanically ventilated controls. No subject suffered from acute lung injury or any other overt lung pathology. Applying indicator-dilution type techniques, we measured single-pass transpulmonary percent metabolism (%M) and hydrolysis (v) of the synthetic, biologically inactive, and highly specific for ACE substrate (3)H-benzoyl-Phe-Ala-Pro, under first order reaction conditions, and calculated lung functional capillary surface area (FCSA). Substrate %M (35 ± 6.8%) and v (0.49 ± 0.13) in BD patients were decreased as compared to controls (55.9 ± 4.9, P = 0.033 and 0.9 ± 0.15, P = 0.033, respectively), denoting decreased pulmonary endothelial enzyme activity at the capillary level; FCSA, a reflection of endothelial enzyme activity per vascular bed, was also decreased (BD patients: 1,563 ± 562 mL/min vs 4,235 ± 559 in controls; P = 0.003). We conclude that BD is associated with subtle pulmonary endothelial injury, expressed by decreased PCEB-ACE activity. The applied indicator-dilution type technique provides direct and quantifiable indices of pulmonary endothelial function at the bedside that may reveal the existence of preclinical lung pathology in potential lung donors. PMID:24015344

  1. Preclinical pulmonary capillary endothelial dysfunction is present in brain dead subjects

    PubMed Central

    Glynos, Constantinos; Athanasiou, Chariclea; Kotanidou, Anastasia; Korovesi, Ioanna; Kaziani, Katerina; Livaditi, Olga; Dimopoulou, Ioanna; Maniatis, Nikolaos A.; Tsangaris, Iraklis; Roussos, Charis; Armaganidis, Apostolos; Orfanos, Stylianos E.

    2013-01-01

    Pulmonary endothelium is a major metabolic organ affecting pulmonary and systemic vascular homeostasis. Brain death (BD)-induced physiologic and metabolic derangements in donors’ lungs, in the absence of overt lung pathology, may cause pulmonary dysfunction and compromise post-transplant graft function. To explore the impact of BD on pulmonary endothelium, we estimated pulmonary capillary endothelium-bound (PCEB)-angiotensin converting enzyme (ACE) activity, a direct and quantifiable index of pulmonary endothelial function, in eight brain-dead patients and ten brain-injured mechanically ventilated controls. No subject suffered from acute lung injury or any other overt lung pathology. Applying indicator-dilution type techniques, we measured single-pass transpulmonary percent metabolism (%M) and hydrolysis (v) of the synthetic, biologically inactive, and highly specific for ACE substrate 3H-benzoyl-Phe-Ala-Pro, under first order reaction conditions, and calculated lung functional capillary surface area (FCSA). Substrate %M (35 ± 6.8%) and v (0.49 ± 0.13) in BD patients were decreased as compared to controls (55.9 ± 4.9, P = 0.033 and 0.9 ± 0.15, P = 0.033, respectively), denoting decreased pulmonary endothelial enzyme activity at the capillary level; FCSA, a reflection of endothelial enzyme activity per vascular bed, was also decreased (BD patients: 1,563 ± 562 mL/min vs 4,235 ± 559 in controls; P = 0.003). We conclude that BD is associated with subtle pulmonary endothelial injury, expressed by decreased PCEB-ACE activity. The applied indicator-dilution type technique provides direct and quantifiable indices of pulmonary endothelial function at the bedside that may reveal the existence of preclinical lung pathology in potential lung donors. PMID:24015344

  2. Therapeutic nanomedicine for brain cancer

    PubMed Central

    Tzeng, Stephany Y; Green, Jordan J

    2013-01-01

    Malignant brain cancer treatment is limited by a number of barriers, including the blood–brain barrier, transport within the brain interstitium, difficulties in delivering therapeutics specifically to tumor cells, the highly invasive quality of gliomas and drug resistance. As a result, the prognosis for patients with high-grade gliomas is poor and has improved little in recent years. Nanomedicine approaches have been developed in the laboratory, with some technologies being translated to the clinic, in order to address these needs. This review discusses the obstacles to effective treatment that are currently faced in the field, as well as various nanomedicine techniques that have been used or are being explored to overcome them, with a focus on liposomal and polymeric nanoparticles. PMID:23738667

  3. Pediatric Brain Tumor Foundation

    MedlinePlus

    ... you insights into your child's treatment. LEARN MORE Brain tumors and their treatment can be deadly so ... Cancer Foundation joins the PBTF Read more >> Pediatric Brain Tumor Foundation 302 Ridgefield Court, Asheville, NC 28806 ...

  4. Arguments against promoting organ transplants from brain-dead donors, and views of contemporary Japanese on life and death.

    PubMed

    Asai, Atsushi; Kadooka, Yasuhiro; Aizawa, Kuniko

    2012-05-01

    As of 2009, the number of donors in Japan is the lowest among developed countries. On July 13, 2009, Japan's Organ Transplant Law was revised for the first time in 12 years. The revised and old laws differ greatly on four primary points: the definition of death, age requirements for donors, requirements for brain-death determination and organ extraction, and the appropriateness of priority transplants for relatives. In the four months of deliberations in the National Diet before the new law was established, various arguments regarding brain death and organ transplantation were offered. An amazing variety of opinions continue to be offered, even after more than 40 years have elapsed since the first heart organ transplant in Japan. Some are of the opinion that with the passage of the revised law, Japan will finally become capable of performing transplants according to global standards. Contrarily, there are assertions that organ transplants from brain-dead donors are unacceptable because they result in organs being taken from living human beings. Considering the current conditions, we will organize and introduce the arguments for and against organ transplants from brain-dead donors in contemporary Japan. Subsequently, we will discuss the primary arguments against organ transplants from brain-dead donors from the perspective of contemporary Japanese views on life and death. After introducing the recent view that brain death should not be regarded as equivalent to the death of a human being, we would like to probe the deeply-rooted views on life and death upon which it is based.

  5. Signaling the Unfolded Protein Response in primary brain cancers.

    PubMed

    Le Reste, Pierre-Jean; Avril, Tony; Quillien, Véronique; Morandi, Xavier; Chevet, Eric

    2016-07-01

    The Unfolded Protein Response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress in the Endoplasmic Reticulum (ER). During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply; exposure to chemotherapies) challenges, with which they must cope to survive. Primary brain tumors are relatively rare but deadly and present a significant challenge in the determination of risk factors in the population. These tumors are inherently difficult to cure because of their protected location in the brain. As such surgery, radiation and chemotherapy options carry potentially lasting patient morbidity and incomplete tumor cure. Some of these tumors, such as glioblastoma, were reported to present features of ER stress and to depend on UPR activation to sustain growth, but to date there is no clear general representation of the ER stress status in primary brain tumors. In this review, we describe the key molecular mechanisms controlling the UPR and their implication in cancers. Then we extensively review the literature reporting the status of ER stress in various primary brain tumors and discuss the potential impact of such observation on patient stratification and on the possibility of developing appropriate targeted therapies using the UPR as therapeutic target. PMID:27016056

  6. Nanoparticles for imaging and treating brain cancer

    PubMed Central

    Meyers, Joseph D; Doane, Tennyson; Burda, Clemens; Basilion, James P

    2013-01-01

    Brain cancer tumors cause disruption of the selective properties of vascular endothelia, even causing disruptions in the very selective blood–brain barrier, which are collectively referred to as the blood–brain–tumor barrier. Nanoparticles (NPs) have previously shown great promise in taking advantage of this increased vascular permeability in other cancers, which results in increased accumulation in these cancers over time due to the accompanying loss of an effective lymph system. NPs have therefore attracted increased attention for treating brain cancer. While this research is just beginning, there have been many successes demonstrated thus far in both the laboratory and clinical setting. This review serves to present the reader with an overview of NPs for treating brain cancer and to provide an outlook on what may come in the future. For NPs, just like the blood–brain–tumor barrier, the future is wide open. PMID:23256496

  7. 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

  8. Phase II Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer

    ClinicalTrials.gov

    2016-04-18

    Extensive Stage Small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Tumors Metastatic to Brain; Metastatic Breast Cancer

  9. Protocolized fluid therapy in brain-dead donors: The multi-center randomized MOnIToR trial

    PubMed Central

    Al-Khafaji, Ali; Elder, Michele; Lebovitz, Daniel J; Murugan, Raghavan; Souter, Michael; Stuart, Susan; Wahed, Abdus S.; Keebler, Ben; Dils, Dorrie; Mitchell, Stephanie; Shutterly, Kurt; Wilkerson, Dawn; Pearse, Rupert; Kellum, John A

    2015-01-01

    BACKGROUND Critical shortages of organs for transplantation jeopardize many lives. Observational data suggest that better fluid management for deceased organ donors could increase organ recovery. We conducted the first large multi-center randomized trial in brain-dead donors to determine whether protocolized fluid therapy increases organs transplanted. METHODS We randomly assigned donors to either protocolized or usual care in eight organ procurement organizations. A “protocol-guided fluid therapy” algorithm targeting cardiac index, mean arterial pressure and pulse pressure variation was used. Our primary outcome was the number of organs transplanted per donor and our primary analysis was intention-to-treat. Secondary analyses included: 1) modified intention-to-treat where only subjects able to receive the intervention were included, and 2) twelve-month survival in transplant recipients. The study was stopped early. RESULTS We enrolled 556 donors; 279 protocolized care, 277 usual care. Groups had similar characteristics at baseline. The study protocol could be implemented in 76% of subjects randomized to the intervention. There was no significant difference in mean number of organs transplanted per donor: 3.39 organs per donor, (95%CI: 3.14-3.63) with protocolized care, compared to usual care 3.29 (95%CI: 3.04-3.54) (mean difference, 0.1, 95%CI: -0.25 to 0.45; p=0.56). In modified intention-to-treat analysis the mean number of organs increased (3.52 organs per donor, 95%CI: 3.23-3.8) but was not statistically significant (mean difference, 0.23, 95%CI: -0.15-0.61; p=0.23). Among the 1430 recipients of organs from study subjects, with data available, 56 deaths (7.8%) occurred in the protocolized care arm and 56 (7.9%) in the usual care arm in the first year (Hazard Ratio: 0.97, p=0.86). CONCLUSIONS In brain-dead organ donors, protocol-guided fluid therapy compared to usual care may not increase the number of organs transplanted per donor. PMID:25583616

  10. Brain metastases from breast cancer during pregnancy

    PubMed Central

    Sharma, Ashish; Nguyen, Ha Son; Lozen, Andrew; Sharma, Abhishiek; Mueller, Wade

    2016-01-01

    Background: Brain metastasis during pregnancy is a rare occurrence. In particular, there have only been three prior cases regarding breast cancer metastasis. We report a patient with breast cancer metastasis to the brain during pregnancy and review the literature. Case Description: The patient was a 35-year-old female with a history of breast cancer (estrogen receptor/progesterone receptor negative, human epidermal growth factor receptor 2/neu positive, status post-neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab therapy, status post-bilateral mastectomies), and prior right frontal brain metastases (status post-resection, capecitabine/lapatinib/temozolomide therapy, and cyberknife treatment). Patient was found to be pregnant at 9 weeks’ gestation while on chemotherapy; the patient elected to continue with the pregnancy and chemotherapy was discontinued. At 14 weeks’ gestation, she returned with recurrent right frontal disease. She was taken for a craniotomy at 16 weeks’ gestation, which confirmed metastases. Six weeks later, patient returned with worsening headaches and fatigue, with more recurrent right frontal disease. She was started on decadron and chemotherapy (5-fluorouracil, adriamycin, and cyclophosphamide). Serial magnetic resonance imaging (MRI) demonstrated enlarging right frontal lesions. She underwent a craniotomy at 27 weeks’ gestation, and chemotherapy was discontinued promptly. Starting at 30 weeks’ gestation, she received whole brain radiation for 2 weeks. Subsequently, she delivered a baby girl via cesarean section at 32 weeks’ gestation. At 6 weeks follow-up, an MRI brain demonstrated no new intracranial disease, with stable postoperative findings. Conclusion: There is a lack of guidelines and clinical consensus on medical and surgical treatment for breast cancer metastases in pregnant patients. Treatment usually varies based upon underlying tumor burden, location, gestational age of the fetus, and patient's preference and

  11. Intraoperative brain cancer detection with Raman spectroscopy in humans.

    PubMed

    Jermyn, Michael; Mok, Kelvin; Mercier, Jeanne; Desroches, Joannie; Pichette, Julien; Saint-Arnaud, Karl; Bernstein, Liane; Guiot, Marie-Christine; Petrecca, Kevin; Leblond, Frederic

    2015-02-11

    Cancers are often impossible to visually distinguish from normal tissue. This is critical for brain cancer where residual invasive cancer cells frequently remain after surgery, leading to disease recurrence and a negative impact on overall survival. No preoperative or intraoperative technology exists to identify all cancer cells that have invaded normal brain. To address this problem, we developed a handheld contact Raman spectroscopy probe technique for live, local detection of cancer cells in the human brain. Using this probe intraoperatively, we were able to accurately differentiate normal brain from dense cancer and normal brain invaded by cancer cells, with a sensitivity of 93% and a specificity of 91%. This Raman-based probe enabled detection of the previously undetectable diffusely invasive brain cancer cells at cellular resolution in patients with grade 2 to 4 gliomas. This intraoperative technology may therefore be able to classify cell populations in real time, making it an ideal guide for surgical resection and decision-making.

  12. Proteoglycans and their roles in brain cancer

    PubMed Central

    Wade, Anna; Robinson, Aaron E.; Engler, Jane R.; Petritsch, Claudia; James, C. David; Phillips, Joanna J.

    2013-01-01

    Glioblastoma (GBM), a malignant brain cancer, is characterized by abnormal activation of receptor tyrosine kinase (RTK) signaling pathways and poor prognosis. Extracellular proteoglycans, including heparan sulfate and chondroitin sulfate, play critical roles in the regulation of cell signaling and migration via interactions with extracellular ligands, growth factor receptors, extracellular matrix components, and intracellular enzymes and structural proteins. In cancer, proteoglycans help drive multiple oncogenic pathways in tumor cells and promote critical tumor-microenvironment interactions. In this review, we summarize the evidence for proteoglycan function in gliomagenesis and we examine the expression of proteoglycans and their modifying enzymes in human GBM using data from The Cancer Genome Atlas (TCGA). Furthermore, we demonstrate an association between specific proteoglycan alterations and changes in RTKs. Based on these data we propose a model in which proteoglycans and their modifying enzymes promote RTK signaling and progression in GBM, and we suggest cancer associated proteoglycans are promising biomarkers for disease and therapeutic targets. PMID:23281850

  13. 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.

  14. Extensive Surgery Best for an Aggressive Brain Cancer

    MedlinePlus

    ... fullstory_159415.html Extensive Surgery Best for an Aggressive Brain Cancer: Study Although larger procedure carries more ... News) -- When it comes to battling a particularly aggressive form of brain tumor, more extensive surgeries may ...

  15. DEAD-box helicase DP103 defines metastatic potential of human breast cancers

    PubMed Central

    Shin, Eun Myoung; Sin Hay, Hui; Lee, Moon Hee; Goh, Jen Nee; Tan, Tuan Zea; Sen, Yin Ping; Lim, See Wee; Yousef, Einas M.; Ong, Hooi Tin; Thike, Aye Aye; Kong, Xiangjun; Wu, Zhengsheng; Mendoz, Earnest; Sun, Wei; Salto-Tellez, Manuel; Lim, Chwee Teck; Lobie, Peter E.; Lim, Yoon Pin; Yap, Celestial T.; Zeng, Qi; Sethi, Gautam; Lee, Martin B.; Tan, Patrick; Goh, Boon Cher; Miller, Lance D.; Thiery, Jean Paul; Zhu, Tao; Gaboury, Louis; Tan, Puay Hoon; Hui, Kam Man; Yip, George Wai-Cheong; Miyamoto, Shigeki; Kumar, Alan Prem; Tergaonkar, Vinay

    2014-01-01

    Despite advancement in breast cancer treatment, 30% of patients with early breast cancers experience relapse with distant metastasis. It is a challenge to identify patients at risk for relapse; therefore, the identification of markers and therapeutic targets for metastatic breast cancers is imperative. Here, we identified DP103 as a biomarker and metastasis-driving oncogene in human breast cancers and determined that DP103 elevates matrix metallopeptidase 9 (MMP9) levels, which are associated with metastasis and invasion through activation of NF-κB. In turn, NF-κB signaling positively activated DP103 expression. Furthermore, DP103 enhanced TGF-β–activated kinase-1 (TAK1) phosphorylation of NF-κB–activating IκB kinase 2 (IKK2), leading to increased NF-κB activity. Reduction of DP103 expression in invasive breast cancer cells reduced phosphorylation of IKK2, abrogated NF-κB–mediated MMP9 expression, and impeded metastasis in a murine xenograft model. In breast cancer patient tissues, elevated levels of DP103 correlated with enhanced MMP9, reduced overall survival, and reduced survival after relapse. Together, these data indicate that a positive DP103/NF-κB feedback loop promotes constitutive NF-κB activation in invasive breast cancers and activation of this pathway is linked to cancer progression and the acquisition of chemotherapy resistance. Furthermore, our results suggest that DP103 has potential as a therapeutic target for breast cancer treatment. PMID:25083991

  16. Role of the neural niche in brain metastatic cancer.

    PubMed

    Termini, John; Neman, Josh; Jandial, Rahul

    2014-08-01

    Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically, brain metastases were rarely investigated because patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts, the brain. The central nervous system is the most complex biologic system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us toward new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of bidirectional interactions between the brain milieu and metastatic cancer.

  17. Novel Nanotechnologies for Brain Cancer Therapeutics and Imaging.

    PubMed

    Ferroni, Letizia; Gardin, Chiara; Della Puppa, Alessandro; Sivolella, Stefano; Brunello, Giulia; Scienza, Renato; Bressan, Eriberto; D'Avella, Domenico; Zavan, Barbara

    2015-11-01

    Despite progress in surgery, radiotherapy, and in chemotherapy, an effective curative treatment of brain cancer, specifically malignant gliomas, does not yet exist. The efficacy of current anti-cancer strategies in brain tumors is limited by the lack of specific therapies against malignant cells. Besides, the delivery of the drugs to brain tumors is limited by the presence of the blood-brain barrier. Nanotechnology today offers a unique opportunity to develop more effective brain cancer imaging and therapeutics. In particular, the development of nanocarriers that can be conjugated with several functional molecules including tumor-specific ligands, anticancer drugs, and imaging probes, can provide new devices which are able to overcome the difficulties of the classical strategies. Nanotechnology-based approaches hold great promise for revolutionizing brain cancer medical treatments, imaging, and diagnosis.

  18. Treatment of brain metastases of lung cancer in the era of precision medicine.

    PubMed

    Haughton, Michael E; Chan, Michael D; Watabe, Kounosuke; Bonomi, Marcelo; Debinski, Waldemar; Lesser, Glenn J; Ruiz, Jimmy

    2016-01-01

    Common and deadly complications of non-small cell lung cancer (NSCLC) are brain metastases (BM). BM portends a poorer prognosis with limited effective treatment options and current management strategies present several challenges from iatrogenic complications of supportive medications, optimal delivery of drug across the blood-brain barrier, and preservation of neurocognitive function. Long term side effects and survivorship issues have become more evident in the era of targeted therapy where a systemic disease is much better controlled. Targeted therapies and immunotherapy are beginning to provide improvements in responses and survival rates. With further advancements and experience, our knowledge in this era of precision medicine will likely lead to strides in improving the quality of life and overall survival of patients with BM from NSCLC. In this review, we present the most recent updates in treatment of BM in NSCLC in regards to targeted and immunotherapy. PMID:26709658

  19. Cediranib Maleate and Whole Brain Radiation Therapy in Patients With Brain Metastases From Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-03-07

    Male Breast Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer; Tumors Metastatic to Brain

  20. Cancer of the Brain and Other Nervous System

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 23,770 % of All New Cancer Cases 1.4% Estimated Deaths in 2016 16,050 % of All Cancer ... of This Cancer : In 2013, there were an estimated 152,751 people living with brain and other ...

  1. Brain cancer mortality at a manufacturer of aerospace electromechanical systems.

    PubMed

    Park, R M; Silverstein, M A; Green, M A; Mirer, F E

    1990-01-01

    Standardized proportional mortality ratios and mortality odds ratios were calculated for 583 deaths between 1950 and 1986 among employees who had worked for at least 10 years at a facility manufacturing missile and aircraft guidance systems. There was a statistically significant excess of brain cancer proportional mortality (PMR = 16/3.8 = 4.2, p = .0001). Among hourly employees, 12 brain cancer deaths occurred for 2.7 expected (PMR = 4.4, p = .00005). The PMR for brain cancer increased from 1.8 (p = .45) among hourly workers with less than 20 years to 8.7 (p = .000003) in those with more than 20 years employment. Work in "clean rooms," where gyroscopes were assembled, was associated with the brain cancer excess but did not fully account for it. Among 105 deceased hourly women, all three brain cancer deaths occurred among gyro assemblers working in clean rooms, and the risk increased with duration in clean rooms. Although the proportion of brain cancer deaths among hourly men with clean-room experience was similar to that for women, only three of the seven male brain cancer deaths occurred in this group. The suspect agents include gyro fluids and chlorofluorocarbon solvents.

  2. SU-D-210-04: Using Radiotherapy Biomaterials to Brand and Track Deadly Cancer Cells

    SciTech Connect

    Altundal, Y; Sajo, E; Ngwa, W

    2015-06-15

    Purpose: Metastasis accounts for over 90% of all cancer associated suffering and death and arguably presents the most formidable challenges in cancer management. The detection of metastatic or rare circulating tumor cells (CTCs) in blood or lymph nodes remains a formidable technological challenge. In this study, we investigated the time needed to label each cancer cell in-situ (right at the source tumor) with sufficient number of GNPs that will allow enhanced non-invasive detection via photoacoustic imaging in the lymph nodes. Such in-situ labeling can be achieved via sustained release of the GNPs from Radiotherapy (RT) biomaterials (e.g. fiducials, spacers) coated/loaded with the GNP. Methods: The minimum concentration (1000 GNPs/cell for 50nm GNPs) to detect GNPs with photoacoustic imaging method was experimentally measured by Mallidi et al. and fixed at the tumor sub-volume periphery. In this work, the GNPs were assumed to diffuse from a point source, placed in the middle of a 2–3cm tumor, with an initial concentration of 7–30 mg/g. The time required to label the cells with GNPs was calculated by solving the three dimensional diffusion-reaction equation analytically. The diffusion coefficient of 10nm GNPs was experimentally determined previously. Stokes-Einstein equation was used to calculate the diffusion coefficients for other sizes (2–50nm) of GNPs. The cellular uptake rate constants for several sizes of GNPs were experimentally measured by Jin et al. Results: The time required to label the cells was found 0.635–15.91 days for 2–50nm GNPs with an initial concentration of 7 mg/g GNPs in a 2 cm tumor; 1.379–34.633 days for 2–50nm GNPs with an initial concentration of 30 mg/g GNPs in a 3cm tumor. Conclusion: Our results highlight new potential for labeling CTCs with GNPs released from smart RT biomaterials (i.e. fiducials or spacers loaded with the GNP) towards enhanced non-invasive imaging/detection via photoacoustic imaging.

  3. 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.

  4. RO4929097 and Whole-Brain Radiation Therapy or Stereotactic Radiosurgery in Treating Patients With Brain Metastases From Breast Cancer

    ClinicalTrials.gov

    2015-01-22

    Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Male Breast Cancer; Recurrent Breast Cancer; Recurrent Melanoma; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Breast Cancer; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Tumors Metastatic to Brain; Unspecified Adult Solid Tumor, Protocol Specific

  5. Gamma Knife Radiosurgery for Brain Metastases From Primary Breast Cancer

    SciTech Connect

    Kased, Norbert; Binder, Devin K.; McDermott, Michael W.; Nakamura, Jean L.; Huang, Kim; Berger, Mitchel S.; Wara, William M.; Sneed, Penny K.

    2009-11-15

    Purpose: The relative roles of stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) in the treatment of patients with brain metastases from breast cancer remain undefined. In this study, we reviewed our experience with these patients. Materials and Methods: We retrospectively reviewed all patients treated between 1991 and 2005 with Gamma Knife SRS for brain metastases from breast cancer. The actuarial survival and freedom from progression endpoints were calculated using the Kaplan-Meier method. Results: Between 1991 and 2005, 176 patients underwent SRS for brain metastases from breast cancer. The median survival time was 16.0 months for 95 newly diagnosed patients and 11.7 months for 81 patients with recurrent brain metastases. In the newly diagnosed patients, omission of upfront WBRT did not significantly affect the MST (p = .20), brain freedom from progression (p = .75), or freedom from new brain metastases (p = .83). Longer survival was associated with age <50 years, Karnofsky performance score >=70, primary tumor control, estrogen receptor positivity, and Her2/neu overexpression. No association was found between the number of treated brain metastases and the survival time. Conclusion: We have described prognostic factors for breast cancer patients treated with SRS for newly diagnosed or recurrent brain metastases. Most patient subsets had a median survival time of >=11 months. Unexpectedly, upfront WBRT did not appear to improve brain freedom from progression, and a larger number of brain metastases was not associated with a shorter survival time. Breast cancer might be distinct from other primary sites in terms of prognostic factors and the roles of WBRT and SRS for brain metastases.

  6. Post-mortem pregnancy: a proposed methodology for the resolution of conflicts over whether a brain dead pregnant woman should be maintained on life-sustaining treatment.

    PubMed

    Gregorian, Alexis

    2010-01-01

    In this article, the author examines conflicts over whether to maintain a brain dead pregnant woman on life-sustaining treatment. The author cautions that on the rare occasions when courts are confronted with such a conflict, they should employ a consistent methodology for resolution of the conflict and attempt to honor the wishes of the post-mortem mother and her family. The author draws on relevant areas of law to demonstrate the existence of a legal fiction that protects the interests of post-mortem pregnant women in refusing medical treatment. This article then proceeds to propose a methodology that enables courts to account for a post-mortem pregnant woman's interests, her family's interests, and the state's interests in resolving conflicts over whether to remove a post-mortem pregnant woman from life-sustaining treatment. PMID:21443149

  7. [Effectiveness of a Simulation of the Donor Surgery with Other Extraction Teams to Improve Various Problems in Pulmonary Extraction from a Brain-dead Donor].

    PubMed

    Niikawa, Hiromichi; Okada, Yoshinori; Noda, Masafumi; Watanabe, Tatsuaki; Notsuda, Hirotsugu; Matsuda, Yasushi; Sakurada, Akira; Hoshikawa, Yasushi; Endo, Chiaki; Adachi, Osamu; Miyagi, Shigehito; Kondo, Takashi

    2015-08-01

    The pulmonary extraction from a brain-dead donor is one of the important elements for the success of lung transplantation, but the current scarcity of practical training opportunities is a major problem. We performed a simulation of the donor surgery of multiple organs using a pig with other extraction teams to provide more training opportunities. The effectiveness of this simulation lies in its potential to improve the surgical procedure;furthermore, it may solve problems associated with communicating with other extraction teams. However, it is difficult to judge whether the donor lung is suitable for transplantation, as it would be inappropriate to use such a lung for simulation in training. Since this simulation system is considered to be effective to solve various problems in the current donor surgery, it should be available more frequently to improve a technical level of the donor surgery and to aid surgeons in the rapid implementation of next-generation techniques.

  8. Post-mortem pregnancy: a proposed methodology for the resolution of conflicts over whether a brain dead pregnant woman should be maintained on life-sustaining treatment.

    PubMed

    Gregorian, Alexis

    2010-01-01

    In this article, the author examines conflicts over whether to maintain a brain dead pregnant woman on life-sustaining treatment. The author cautions that on the rare occasions when courts are confronted with such a conflict, they should employ a consistent methodology for resolution of the conflict and attempt to honor the wishes of the post-mortem mother and her family. The author draws on relevant areas of law to demonstrate the existence of a legal fiction that protects the interests of post-mortem pregnant women in refusing medical treatment. This article then proceeds to propose a methodology that enables courts to account for a post-mortem pregnant woman's interests, her family's interests, and the state's interests in resolving conflicts over whether to remove a post-mortem pregnant woman from life-sustaining treatment.

  9. Performance of QuantiFERON TB Gold test in detecting latent tuberculosis infection in brain-dead organ donors in Iran: a brief report.

    PubMed

    Tabarsi, Payam; Yousefzadeh, Amir; Najafizadeh, Katayoun; Droudinia, Atousa; Bayati, Rouzbeh; Marjani, Majid; Shafaghi, Shadi; Farokhzad, Banafsheh; Javanmard, Pedram; Velayati, Ali Akbar

    2014-11-01

    With regard to the significant morbidity and mortality due to tuberculosis in lung transplant recipients, the identification of brain-dead organ donors with latent tuberculosis by use of the QuantiFERON TB Gold (QFT-G) test may be of help to reduce the risk of TB reactivation and mortality in lung recipients. This study was conducted in the National Research Institute of Tuber-culosis and Lung Diseases (NRITLD) in Iran, from January to March 2013. A total of 38 conse-cutive brain-dead donors, not currently infected with active tuberculosis, were recruited. The medi-cal records of all the study enrollees were reviewed. A whole-blood IFN- release assay (IGRA) in reaction to early secreted antigenic target 6 (ESAT-6), culture filtrate protein 10 (CFP-10), and TB7.7 antigens, was performed and the released Interferon- was measured via enzyme-linked immunosorbent assay (ELISA). The data was analyzed with QFT-G software which was provided by the company. The demographic, characteristics and other variables were entered into SPSS version 11.5. The QFT-G test results of three donors (7.9%) turned out to be positive, negative for 24 donors (63.1%), and indeterminate for 11 cases (28.9%). Our study revealed the potential advantages of QFT-G in lowering the incidence of donor-derived post-transplant tuberculosis among lung recipients. However, a high rate of indeterminate results restricted the performance of QFT-G in this study.

  10. Determination of Death and the Dead Donor Rule: A Survey of the Current Law on Brain Death.

    PubMed

    Nikas, Nikolas T; Bordlee, Dorinda C; Moreira, Madeline

    2016-06-01

    Despite seeming uniformity in the law, end-of-life controversies have highlighted variations among state brain death laws and their interpretation by courts. This article provides a survey of the current legal landscape regarding brain death in the United States, for the purpose of assisting professionals who seek to formulate or assess proposals for changes in current law and hospital policy. As we note, the public is increasingly wary of the role of organ transplantation in determinations of death, and of the variability of brain death diagnosing criteria. We urge that any attempt to alter current state statutes or to adopt a national standard must balance the need for medical accuracy with sound ethical principles which reject the utilitarian use of human beings and are consistent with the dignity of the human person. Only in this way can public trust be rebuilt. PMID:27097648

  11. 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.

  12. "Facilis Descensus Averni" Mind, Brain, Education, and Ethics: Highway to Hell, Stairway to Heaven, or Passing Dead End?

    ERIC Educational Resources Information Center

    della Chiesa, Bruno

    2010-01-01

    Are human beings born unequal when it comes to ethics? Or are ethical standards acquired? Or both nature and nurture? Neuroscience is on its way to discovering biological underpinnings of ethics in our brains. Whatever the upcoming findings on this front will be, our philosophical, political, and educational views, and even the way we look at…

  13. Breast cancer brain metastases: new directions in systemic therapy

    PubMed Central

    Lin, Nancy U

    2013-01-01

    The management of patients with brain metastases from breast cancer continues to be a major clinical challenge. The standard initial therapeutic approach depends upon the size, location, and number of metastatic lesions and includes consideration of surgical resection, whole-brain radiotherapy, and stereotactic radiosurgery. As systemic therapies for control of extracranial disease improve, patients are surviving long enough to experience subsequent progression events in the brain. Therefore, there is an increasing need to identify both more effective initial treatments as well as to develop multiple lines of salvage treatments for patients with breast cancer brain metastases. This review summarises the clinical experience to date with respect to cytotoxic and targeted systemic therapies for the treatment of brain metastases, highlights ongoing and planned trials of novel approaches and identifies potential targets for future investigation. PMID:23662165

  14. Brain metastases free survival differs between breast cancer subtypes

    PubMed Central

    Berghoff, A; Bago-Horvath, Z; De Vries, C; Dubsky, P; Pluschnig, U; Rudas, M; Rottenfusser, A; Knauer, M; Eiter, H; Fitzal, F; Dieckmann, K; Mader, R M; Gnant, M; Zielinski, C C; Steger, G G; Preusser, M; Bartsch, R

    2012-01-01

    Background: Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010. Methods: Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test. Results: Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34–16.66) compared with 18 months (95% CI: 14.46–21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71–44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014). Conclusion: Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes. PMID:22233926

  15. Targeted Therapies for Brain Metastases from Breast Cancer.

    PubMed

    Venur, Vyshak Alva; Leone, José Pablo

    2016-01-01

    The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%-30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways.

  16. Targeted Therapies for Brain Metastases from Breast Cancer

    PubMed Central

    Venur, Vyshak Alva; Leone, José Pablo

    2016-01-01

    The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%–30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways. PMID:27649142

  17. Targeted Therapies for Brain Metastases from Breast Cancer.

    PubMed

    Venur, Vyshak Alva; Leone, José Pablo

    2016-01-01

    The discovery of various driver pathways and targeted small molecule agents/antibodies have revolutionized the management of metastatic breast cancer. Currently, the major targets of clinical utility in breast cancer include the human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor, mechanistic target of rapamycin (mTOR) pathway, and the cyclin-dependent kinase 4/6 (CDK-4/6) pathway. Brain metastasis, however, remains a thorn in the flesh, leading to morbidity, neuro-cognitive decline, and interruptions in the management of systemic disease. Approximately 20%-30% of patients with metastatic breast cancer develop brain metastases. Surgery, whole brain radiation therapy, and stereotactic radiosurgery are the traditional treatment options for patients with brain metastases. The therapeutic paradigm is changing due to better understanding of the blood brain barrier and the advent of tyrosine kinase inhibitors and monoclonal antibodies. Several of these agents are in clinical practice and several others are in early stage clinical trials. In this article, we will review the common targetable pathways in the management of breast cancer patients with brain metastases, and the current state of the clinical development of drugs against these pathways. PMID:27649142

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

    PubMed Central

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

    2014-01-01

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

  19. Breast cancer brain metastases: biology and new clinical perspectives.

    PubMed

    Witzel, Isabell; Oliveira-Ferrer, Leticia; Pantel, Klaus; Müller, Volkmar; Wikman, Harriet

    2016-01-19

    Because of improvements in the treatment of patients with metastatic breast cancer, the development of brain metastases (BM) has become a major limitation of life expectancy and quality of life for many breast cancer patients. The improvement of management strategies for BM is thus an important clinical challenge, especially among high-risk patients such as human epidermal growth factor receptor 2-positive and triple-negative patients. However, the formation of BM as a multistep process is thus far poorly understood. To grow in the brain, single tumor cells must pass through the tight blood-brain barrier (BBB). The BBB represents an obstacle for circulating tumor cells entering the brain, but it also plays a protective role against immune cell and toxic agents once metastatic cells have colonized the cerebral compartment. Furthermore, animal studies have shown that, after passing the BBB, the tumor cells not only require close contact with endothelial cells but also interact closely with many different brain residential cells. Thus, in addition to a genetic predisposition of the tumor cells, cellular adaptation processes within the new microenvironment may also determine the ability of a tumor cell to metastasize. In this review, we summarize the biology of breast cancer that has spread into the brain and discuss the implications for current and potential future treatment strategies.

  20. α-Melanocyte Stimulating Hormone Treatment in Pigs Does Not Improve Early Graft Function in Kidney Transplants from Brain Dead Donors

    PubMed Central

    van Rijt, Willem G.; Secher, Niels; Keller, Anna K.; Møldrup, Ulla; Chynau, Yahor; Ploeg, Rutger J.; van Goor, Harry; Nørregaard, Rikke; Birn, Henrik; Frøkiaer, Jørgen; Nielsen, Søren; Leuvenink, Henri G. D.; Jespersen, Bente

    2014-01-01

    Delayed graft function and primary non-function are serious complications following transplantation of kidneys derived from deceased brain dead (DBD) donors. α-melanocyte stimulating hormone (α-MSH) is a pleiotropic neuropeptide and its renoprotective effects have been demonstrated in models of acute kidney injury. We hypothesized that α-MSH treatment of the recipient improves early graft function and reduces inflammation following DBD kidney transplantation. Eight Danish landrace pigs served as DBD donors. After four hours of brain death both kidneys were removed and stored for 18 hours at 4°C in Custodiol preservation solution. Sixteen recipients were randomized in a paired design into two treatment groups, transplanted simultaneously. α-MSH or a vehicle was administered at start of surgery, during reperfusion and two hours post-reperfusion. The recipients were observed for ten hours following reperfusion. Blood, urine and kidney tissue samples were collected during and at the end of follow-up. α-MSH treatment reduced urine flow and impaired recovery of glomerular filtration rate (GFR) compared to controls. After each dose of α-MSH, a trend towards reduced mean arterial blood pressure and increased heart rate was observed. α-MSH did not affect expression of inflammatory markers. Surprisingly, α-MSH impaired recovery of renal function in the first ten hours following DBD kidney transplantation possibly due to hemodynamic changes. Thus, in a porcine experimental model α-MSH did not reduce renal inflammation and did not improve short-term graft function following DBD kidney transplantation. PMID:24728087

  1. Exosome Delivered Anticancer Drugs Across the Blood-Brain Barrier for Brain Cancer Therapy in Danio Rerio

    PubMed Central

    Yang, Tianzhi; Martin, Paige; Fogarty, Brittany; Brown, Alison; Schurman, Kayla; Phipps, Roger; Yin, Viravuth P.; Lockman, Paul

    2015-01-01

    Purpose The blood–brain barrier (BBB) essentially restricts therapeutic drugs from entering into the brain. This study tests the hypothesis that brain endothelial cell derived exosomes can deliver anticancer drug across the BBB for the treatment of brain cancer in a zebrafish (Danio rerio) model. Materials and Methods Four types of exosomes were isolated from brain cell culture media and characterized by particle size, morphology, total protein, and transmembrane protein markers. Transport mechanism, cell uptake, and cytotoxicity of optimized exosome delivery system were tested. Brain distribution of exosome delivered anticancer drugs was evaluated using transgenic zebrafish TG (fli1: GFP) embryos and efficacies of optimized formations were examined in a xenotransplanted zebrafish model of brain cancer model. Results Four exosomes in 30–100 diameters showed different morphologies and exosomes derived from brain endothelial cells expressed more CD63 tetraspanins transmembrane proteins. Optimized exosomes increased the uptake of fluorescent marker via receptor mediated endocytosis and cytotoxicity of anticancer drugs in cancer cells. Images of the zebrafish showed exosome delivered anticancer drugs crossed the BBB and entered into the brain. In the brain cancer model, exosome delivered anticancer drugs significantly decreased fluorescent intensity of xenotransplanted cancer cells and tumor growth marker. Conclusions Brain endothelial cell derived exosomes could be potentially used as a carrier for brain delivery of anticancer drug for the treatment of brain cancer. PMID:25609010

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

    PubMed

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

    2016-01-01

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

  3. Brain cancer probed by native fluorescence and stokes shift spectroscopy

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-hui; He, Yong; Pu, Yang; Li, Qingbo; Wang, Wei; Alfano, Robert R.

    2012-12-01

    Optical biopsy spectroscopy was applied to diagnosis human brain cancer in vitro. The spectra of native fluorescence, Stokes shift and excitation spectra were obtained from malignant meningioma, benign, normal meningeal tissues and acoustic neuroma benign tissues. The wide excitation wavelength ranges were used to establish the criterion for distinguishing brain diseases. The alteration of fluorescence spectra between normal and abnormal brain tissues were identified by the characteristic fluorophores under the excitation with UV to visible wavelength range. It was found that the ratios of the peak intensities and peak position in both spectra of fluorescence and Stokes shift may be used to diagnose human brain meninges diseases. The preliminary analysis of fluorescence spectral data from cancer and normal meningeal tissues by basic biochemical component analysis model (BBCA) and Bayes classification model based on statistical methods revealed the changes of components, and classified the difference between cancer and normal human brain meningeal tissues in a predictions accuracy rate is 0.93 in comparison with histopathology and immunohistochemistry reports (gold standard).

  4. Statins are Associated With a Reduced Risk of Brain Cancer

    PubMed Central

    Chen, Brian K.; Chiu, Hui-Fen; Yang, Chun-Yuh

    2016-01-01

    Abstract The aim of this study was to investigate whether statin utilization is associated with brain cancer risk. A population-based case–control study was conducted using nationally representative claims data from the National Health Insurance Bureau in Taiwan. Cases included all patients 50 years and older who received an index diagnosis of brain cancer between 2004 and 2011. Our controls were matched by age, sex, and index date. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression. We examined 213 brain cancer cases and 852 controls. The unadjusted ORs for any statin prescription was 0.77 (95% CI = 0.50–1.18) and the adjusted OR was 0.59 (95% CI = 0.37–0.96). Compared with no use of statins, the adjusted ORs were 0.68 (95% CI = 0.38–1.24) for the group having been prescribed with statins with cumulative defined daily dose (DDD) below 144.67 DDDs and 0.50 (95% CI = 0.28–0.97) for the group with the cumulative statin use of 144.67 DDDs or more. The results of this study suggest that statins may reduce the risk of brain cancer. PMID:27124024

  5. 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.

  6. Dye-Enhanced Multimodal Confocal Imaging of Brain Cancers

    NASA Astrophysics Data System (ADS)

    Wirth, Dennis; Snuderl, Matija; Sheth, Sameer; Curry, William; Yaroslavsky, Anna

    2011-04-01

    Background and Significance: Accurate high resolution intraoperative detection of brain tumors may result in improved patient survival and better quality of life. The goal of this study was to evaluate dye enhanced multimodal confocal imaging for discriminating normal and cancerous brain tissue. Materials and Methods: Fresh thick brain specimens were obtained from the surgeries. Normal and cancer tissues were investigated. Samples were stained in methylene blue and imaged. Reflectance and fluorescence signals were excited at 658nm. Fluorescence emission and polarization were registered from 670 nm to 710 nm. The system provided lateral resolution of 0.6 μm and axial resolution of 7 μm. Normal and cancer specimens exhibited distinctively different characteristics. H&E histopathology was processed from each imaged sample. Results and Conclusions: The analysis of normal and cancerous tissues indicated clear differences in appearance in both the reflectance and fluorescence responses. These results confirm the feasibility of multimodal confocal imaging for intraoperative detection of small cancer nests and cells.

  7. 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

  8. No increase in brain cancer rates during period of expanding cell phone use

    Cancer.gov

    In a new examination of United States cancer incidence data, investigators at the National Cancer Institute (NCI) reported that incidence trends have remained roughly constant for glioma, the main type of brain cancer hypothesized to be related to cell ph

  9. Experiencing brain cancer: what physicians should know about patients

    PubMed Central

    Lucchiari, Claudio; Botturi, Andrea; Manzini, Laura; Masiero, Marianna; Pravettoni, Gabriella

    2015-01-01

    During the last 20 years, numerous studies have highlighted the need to consider Quality of Life (QoL) issues in the treatment of brain cancer. However, gaps in scientific knowledge are still present as we have poor data surrounding the whole experience in patients and regarding their needs. The present study was aimed at evaluating QoL in brain cancer patients and correlated aspects. In particular, we aimed to assess QoL, mood state, and emotional issues in order to describe the patients’ experience to find out the critical aspects involved. Methods We obtained data from 85 patients during chemotherapy treatment at the National Neurological Institute ‘C. Besta’ of Milan, Italy. We used standardised questionnaires to assess different aspects of patients’ QoL. In particular, the functional assessment of cancer therapy-brain (FACT-Br) and the Hamilton scale were used. We also performed a semi-structured ad hoc interview in order to collect ­narrative data about patients’ experience. Results Our data depict a difficult adjustment process to the illness, even though positive elements emerged. Indeed, patients reported a satisfying self-perceived QoL, although specific concerns are still present. Further, even if many patients report depressive symptoms, only a minority have a severe condition. Conclusion Brain cancer may heavily affect patients’ QoL and well being. However, some element of the context may improve the ­adjustment to the disease. In particular, we found that most patients found psychosocial resources to cope with cancer and that spiritual well being also seems to play a key role. These issues deserve further studies in order to obtain significant clinical recommendations. PMID:26635895

  10. Dead Nano-Sized Lactobacillus plantarum Inhibits Azoxymethane/Dextran Sulfate Sodium-Induced Colon Cancer in Balb/c Mice.

    PubMed

    Lee, Hyun Ah; Kim, Hyunung; Lee, Kwang-Won; Park, Kun-Young

    2015-12-01

    The chemopreventive effects of dead nano-sized Lactobacillus plantarum (nLp) on colon carcinogenesis, induced by dextran sulfate sodium and azoxymethane, were evaluated using Balb/c mice and compared with the effects of pure live L. plantarum (pLp). nLp is a dead shrunken form of L. plantarum derived from kimchi and has a particle size of 0.5-1.0 μm. Animals fed nLp showed less weight loss, longer colons, lower colon weight/length ratios, and fewer colonic tumors compared with pLp. In addition, the administration of nLp significantly reduced the expression of inflammatory markers, mediated the expression of cell cycle and apoptotic markers in colon tissues, and elevated fecal IgA levels more than pLp. Accordingly, the present study shows that the anticolorectal cancer activities of nLp are greater than those of pLp and suggests this is due to the suppression of inflammation, the induction of cell cycle arrest and apoptosis, and enhanced IgA secretion. PMID:26595186

  11. Dead Nano-Sized Lactobacillus plantarum Inhibits Azoxymethane/Dextran Sulfate Sodium-Induced Colon Cancer in Balb/c Mice.

    PubMed

    Lee, Hyun Ah; Kim, Hyunung; Lee, Kwang-Won; Park, Kun-Young

    2015-12-01

    The chemopreventive effects of dead nano-sized Lactobacillus plantarum (nLp) on colon carcinogenesis, induced by dextran sulfate sodium and azoxymethane, were evaluated using Balb/c mice and compared with the effects of pure live L. plantarum (pLp). nLp is a dead shrunken form of L. plantarum derived from kimchi and has a particle size of 0.5-1.0 μm. Animals fed nLp showed less weight loss, longer colons, lower colon weight/length ratios, and fewer colonic tumors compared with pLp. In addition, the administration of nLp significantly reduced the expression of inflammatory markers, mediated the expression of cell cycle and apoptotic markers in colon tissues, and elevated fecal IgA levels more than pLp. Accordingly, the present study shows that the anticolorectal cancer activities of nLp are greater than those of pLp and suggests this is due to the suppression of inflammation, the induction of cell cycle arrest and apoptosis, and enhanced IgA secretion.

  12. Brain-targeted delivery of docetaxel by glutathione-coated nanoparticles for brain cancer.

    PubMed

    Grover, Aditya; Hirani, Anjali; Pathak, Yashwant; Sutariya, Vijaykumar

    2014-12-01

    Gliomas are some of the most aggressive types of cancers but the blood-brain barrier acts as an obstacle to therapeutic intervention in brain-related diseases. The blood-brain barrier blocks the permeation of potentially toxic compounds into neural tissue through the interactions of brain endothelial cells with glial cells (astrocytes and pericytes) which induce the formation of tight junctions in endothelial cells lining the blood capillaries. In the present study, we characterize a glutathione-coated docetaxel-loaded PEG-PLGA nanoparticle, show its in vitro drug release data along with cytotoxicity data in C6 and RG2 cells, and investigate its trans-blood-brain barrier permeation through the establishment of a Transwell cellular co-culture. We show that the docetaxel-loaded nanoparticle's size enables its trans-blood-brain barrier permeation; the nanoparticle exhibits a steady, sustained release of docetaxel; the drug is able to induce cell death in glioma models; and the glutathione-coated nanoparticle is able to permeate through the Transwell in vitro blood-brain barrier model.

  13. High performance nanobio photocatalyst for targeted brain cancer therapy.

    SciTech Connect

    Rozhkova, E.; Ulasov, I.; Dimitrijevic, N. M.; Lesniak, M.; Rajh, T.; Lai, B.; Center for Nanoscale Materials

    2009-09-01

    We report pronounced and specific antiglioblastoma cell phototoxicity of 5 nm TiO{sub 2} particles covalently tethered to an antibody via a dihydroxybenzene bivalent linker. The linker application enables absorption of a visible part of the solar spectrum by the nanobio hybrid. The phototoxicity is mediated by reactive oxygen species (ROS) that initiate programmed death of the cancer cell. Synchrotron X-ray fluorescence microscopy (XFM) was applied for direct visualization of the nanobioconjugate distribution through a single brain cancer cell at the submicrometer scale.

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2014-02-01

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

  16. [Advances in Bevacizumab Therapy for Non-small Cell Lung Cancer 
with Brain Metastases].

    PubMed

    Qu, Liyan; Geng, Rui; Song, Xia

    2016-08-20

    Brain metastases are frequently encountered in patients with non-small cell lung cancer (NSCLC) and are a significant cause of morbidity and mortality. Antiangiogenesis therapy plays a major role in the management of brain metastases in lung cancer. Bevacizumab have become the novel method for the treatment of lung cancer with brain metastases beyond the whole brain radiation therapy, stereotactic radiosurgery and chemotherapy. Recently, more and more studies and trials laid emphasis on the bevacizumab for NSCLC with brain metastases treatment. The key point is the efficacy and safety. In this review, bevacizumab therapy of NSCLC with brain metastases were summarized. PMID:27561800

  17. 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

  18. Metabolic therapy: a new paradigm for managing malignant brain cancer.

    PubMed

    Seyfried, Thomas N; Flores, Roberto; Poff, Angela M; D'Agostino, Dominic P; Mukherjee, Purna

    2015-01-28

    Little progress has been made in the long-term management of glioblastoma multiforme (GBM), considered among the most lethal of brain cancers. Cytotoxic chemotherapy, steroids, and high-dose radiation are generally used as the standard of care for GBM. These procedures can create a tumor microenvironment rich in glucose and glutamine. Glucose and glutamine are suggested to facilitate tumor progression. Recent evidence suggests that many GBMs are infected with cytomegalovirus, which could further enhance glucose and glutamine metabolism in the tumor cells. Emerging evidence also suggests that neoplastic macrophages/microglia, arising through possible fusion hybridization, can comprise an invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells, as well as for the more rapidly proliferating cancer stem cells. Therapies that increase inflammation and energy metabolites in the GBM microenvironment can enhance tumor progression. In contrast to current GBM therapies, metabolic therapy is designed to target the metabolic malady common to all tumor cells (aerobic fermentation), while enhancing the health and vitality of normal brain cells and the entire body. The calorie restricted ketogenic diet (KD-R) is an anti-angiogenic, anti-inflammatory and pro-apoptotic metabolic therapy that also reduces fermentable fuels in the tumor microenvironment. Metabolic therapy, as an alternative to the standard of care, has the potential to improve outcome for patients with GBM and other malignant brain cancers. PMID:25069036

  19. Corticosteroids in brain cancer patients: benefits and pitfalls

    PubMed Central

    Dietrich, Jörg; Rao, Krithika; Pastorino, Sandra; Kesari, Santosh

    2011-01-01

    Glucocorticoids have been used for decades in the treatment of brain tumor patients and belong to the most powerful class of agents in reducing tumor-associated edema and minimizing side effects and the risk of encephalopathy in patients undergoing radiation therapy. Unfortunately, corticosteroids are associated with numerous and well-characterized adverse effects, constituting a major challenge in patients requiring long-term application of corticosteroids. Novel anti-angiogenic agents, such as bevacizumab (Avastin®), which have been increasingly used in cancer patients, are associated with significant steroid-sparing effects, allowing neuro-oncologists to reduce the overall use of corticosteroids in patients with progressive malignant brain tumors. Recent experimental studies have revealed novel insights into the mechanisms and effects of corticosteroids in cancer patients, including modulation of tumor biology, angiogenesis and steroid-associated neurotoxicity. This article summarizes current concepts of using corticosteroids in brain cancer patients and highlights potential pitfalls in their effects on both tumor and neural progenitor cells. PMID:21666852

  20. 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

  1. Primary brain tumors, neural stem cell, and brain tumor cancer cells: where is the link?

    PubMed Central

    Germano, Isabelle; Swiss, Victoria; Casaccia, Patrizia

    2010-01-01

    The discovery of brain tumor-derived cells (BTSC) with the properties of stem cells has led to the formulation of the hypothesis that neural stem cells could be the cell of origin of primary brain tumors (PBT). In this review we present the most common molecular changes in PBT, define the criteria of identification of BTSC and discuss the similarities between the characteristics of these cells and those of the endogenous population of neural stem cells (NPCs) residing in germinal areas of the adult brain. Finally, we propose possible mechanisms of cancer initiation and progression and suggest a model of tumor initiation that includes intrinsic changes of resident NSC and potential changes in the microenvironment defining the niche where the NSC reside. PMID:20045420

  2. Whole brain radiotherapy 'has no effect' in patients whose lung cancer has spread.

    PubMed

    2016-09-28

    Whole brain radiotherapy makes little or no difference to survival rates or quality of life in patients with non-small cell lung cancer (NSCLC) that has spread to the brain, say researchers. PMID:27682542

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

    PubMed

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

    2015-09-01

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

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

    PubMed

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

    2015-09-01

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

  5. Parental Exposure to Pesticides and Childhood Brain Cancer: U.S. Atlantic Coast Childhood Brain Cancer Study

    PubMed Central

    Shim, Youn K.; Mlynarek, Steven P.; van Wijngaarden, Edwin

    2009-01-01

    Background The etiology of childhood brain cancer remains largely unknown. However, previous studies have yielded suggestive associations with parental pesticide use. Objectives We aimed to evaluate parental exposure to pesticides at home and on the job in relation to the occurrence of brain cancer in children. Methods We included 526 one-to-one–matched case–control pairs. Brain cancer cases were diagnosed at < 10 years of age, and were identified from statewide cancer registries of four U.S. Atlantic Coast states. We selected controls by random digit dialing. We conducted computer-assisted telephone interviews with mothers. Using information on residential pesticide use and jobs held by fathers during the 2-year period before the child’s birth, we assessed potential exposure to insecticides, herbicides, and fungicides. For each job, two raters independently classified the probability and intensity of exposure; 421 pairs were available for final analysis. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, after adjustment for maternal education. Results A significant risk of astrocytoma was associated with exposures to herbicides from residential use (OR = 1.9; 95% CI, 1.2–3.0). Combining parental exposures to herbicides from both residential and occupational sources, the elevated risk remained significant (OR = 1.8; 95% CI, 1.1–3.1). We observed little association with primitive neuroectodermal tumors (PNET) for any of the pesticide classes or exposure sources considered. Conclusions Our observation is consistent with a previous literature reporting suggestive associations between parental exposure to pesticides and risk of astrocytoma in offspring but not PNET. However, these findings should be viewed in light of limitations in exposure assessment and effective sample size. PMID:19590697

  6. Bone marrow-derived stem cell therapy for metastatic brain cancers.

    PubMed

    Kaneko, Yuji; Tajiri, Naoki; Staples, Meaghan; Reyes, Stephanny; Lozano, Diego; Sanberg, Paul R; Freeman, Thomas B; van Loveren, Harry; Kim, Seung U; Borlongan, Cesar V

    2015-01-01

    We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood-brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumor-derived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases.

  7. Association of brain cancer with dental x-rays and occupation in Missouri

    SciTech Connect

    Neuberger, J.S.; Brownson, R.C.; Morantz, R.A.; Chin, T.D. )

    1991-01-01

    This investigation of a brain cancer cluster in Missouri used two approaches to investigate associations with potential risk factors. In a case-control study in a rural town, we interviewed surrogates of cases and controls about potential risk factors. We found a statistically significant positive association of brain cancer with reported exposure to dental x-rays. Occupation was not associated with the cluster in the rural town. In a standardized proportional mortality study for the state of Missouri, we calculated the observed and expected proportion of brain cancers by occupation and industry in Missouri decedents. We found that motor vehicle manufacturers, beauty shop workers, managers and administrators, elementary school teachers, and hairdressers and cosmetologists had significantly elevated proportions of brain cancer. Brain tumors are inconsistently associated with occupation in the literature. Further study of brain cancer etiology with respect to dental x-ray exposures seems warranted.

  8. βIII-Tubulin Regulates Breast Cancer Metastases to the Brain

    PubMed Central

    Kanojia, Deepak; Morshed, Ramin A.; Zhang, Lingjiao; Miska, Jason M.; Qiao, Jian; Kim, Julius W.; Pytel, Peter; Balyasnikova, Irina V.; Lesniak, Maciej S.; Ahmed, Atique U.

    2015-01-01

    Brain metastases occur in about 10–30% of breast cancer patients, which culminates in a poor prognosis. It is therefore critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII tubulin, Nestin and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2 and MDA-MB-468) which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells. PMID:25724666

  9. βIII-Tubulin Regulates Breast Cancer Metastases to the Brain.

    PubMed

    Kanojia, Deepak; Morshed, Ramin A; Zhang, Lingjiao; Miska, Jason M; Qiao, Jian; Kim, Julius W; Pytel, Peter; Balyasnikova, Irina V; Lesniak, Maciej S; Ahmed, Atique U

    2015-05-01

    Brain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells.

  10. Brain network alterations and vulnerability to simulated neurodegeneration in breast cancer.

    PubMed

    Kesler, Shelli R; Watson, Christa L; Blayney, Douglas W

    2015-08-01

    Breast cancer and its treatments are associated with mild cognitive impairment and brain changes that could indicate an altered or accelerated brain aging process. We applied diffusion tensor imaging and graph theory to measure white matter organization and connectivity in 34 breast cancer survivors compared with 36 matched healthy female controls. We also investigated how brain networks (connectomes) in each group responded to simulated neurodegeneration based on network attack analysis. Compared with controls, the breast cancer group demonstrated significantly lower fractional anisotropy, altered small-world connectome properties, lower brain network tolerance to systematic region (node), and connection (edge) attacks and significant cognitive impairment. Lower tolerance to network attack was associated with cognitive impairment in the breast cancer group. These findings provide further evidence of diffuse white matter pathology after breast cancer and extend the literature in this area with unique data demonstrating increased vulnerability of the post-breast cancer brain network to future neurodegenerative processes.

  11. Human brain cancer studied by resonance Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Liu, Cheng-Hui; Sun, Yi; Pu, Yang; Boydston-White, Susie; Liu, Yulong; Alfano, Robert R.

    2012-11-01

    The resonance Raman (RR) spectra of six types of human brain tissues are examined using a confocal micro-Raman system with 532-nm excitation in vitro. Forty-three RR spectra from seven subjects are investigated. The spectral peaks from malignant meningioma, stage III (cancer), benign meningioma (benign), normal meningeal tissues (normal), glioblastoma multiforme grade IV (cancer), acoustic neuroma (benign), and pituitary adenoma (benign) are analyzed. Using a 532-nm excitation, the resonance-enhanced peak at 1548 cm-1 (amide II) is observed in all of the tissue specimens, but is not observed in the spectra collected using the nonresonance Raman system. An increase in the intensity ratio of 1587 to 1605 cm-1 is observed in the RR spectra collected from meningeal cancer tissue as compared with the spectra collected from the benign and normal meningeal tissue. The peak around 1732 cm-1 attributed to fatty acids (lipids) are diminished in the spectra collected from the meningeal cancer tumors as compared with the spectra from normal and benign tissues. The characteristic band of spectral peaks observed between 2800 and 3100 cm-1 are attributed to the vibrations of methyl (-CH3) and methylene (-CH2-) groups. The ratio of the intensities of the spectral peaks of 2935 to 2880 cm-1 from the meningeal cancer tissues is found to be lower in comparison with that of the spectral peaks from normal, and benign tissues, which may be used as a distinct marker for distinguishing cancerous tissues from normal meningeal tissues. The statistical methods of principal component analysis and the support vector machine are used to analyze the RR spectral data collected from meningeal tissues, yielding a diagnostic sensitivity of 90.9% and specificity of 100% when two principal components are used.

  12. Phase relation changes between the firings of alpha and gamma-motoneurons and muscle spindle afferents in the sacral micturition centre during continence functions in brain-dead human and patients with spinal cord injury.

    PubMed

    Schalow, G

    2010-01-01

    1. Single-nerve fibre action potentials (APs) were recorded with 2 pairs of wire electrodes from lower sacral nerve roots during surgery in patients with spinal cord injury and in a brain-dead human. Conduction velocity distribution histograms were constructed for afferent and efferent fibres, nerve fibre groups were identified and simultaneous impulse patterns of alpha and gamma-motoneurons and secondary muscle spindle afferents (SP2) were constructed. Temporal relations between afferent and efferent APs were analyzed by interspike interval (II) and phase relation changes to explore the coordinated self-organization of somatic and parasympathetic neuronal networks in the sacral micturition centre during continence functions under physiologic (brain-dead) and pathophysiologic conditions (spinal cord injury). 2. In a paraplegic with hyperreflexia of the bladder, urinary bladder stretch (S1) and tension receptor afferents (ST) fired already when the bladder was empty, and showed a several times higher bladder afferent activity increase upon retrograde bladder filling than observed in the brain-dead individual. Two alpha2-motoneurons (FR) innervating the external bladder sphincter were already oscillatory firing to generate high activity levels when the bladder was empty. They showed activity levels with no bladder filling, comparable to those measured at a bladder filling of 600 ml in the brain-dead individual. A bladder storage volume of 600 ml was thus lost in the paraplegic, due to a too high bladder afferent input to the sacral micturition center, secondary to inflammation and hypertrophy of the detrusor. 3. In a brain-dead human, 2 phase relations existed per oscillation period of 160 ms between the APs of a sphincteric oscillatory firing alpha2-motoneuron, a dynamic fusimotor and a secondary muscle spindle afferent fibre. Following stimulation of mainly somatic afferent fibres, the phase relations changed only little. 4. In a paraplegic with dyssynergia of the

  13. Altered resting brain connectivity in persistent cancer related fatigue

    PubMed Central

    Hampson, Johnson P.; Zick, Suzanna M.; Khabir, Tohfa; Wright, Benjamin D.; Harris, Richard E.

    2015-01-01

    There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P < 0.05 FDR corrected). This enhanced connectivity was associated with increased physical fatigue (P = 0.04, r = 0.52) and poor sleep quality (P = 0.04, r = 0.52) in the fatigued group. In contrast greater connectivity in the non-fatigued group was found between the right precuneus to the periaqueductal gray as well as the left IPL to subgenual cortex (P < 0.05 FDR corrected). Mental fatigue scores were associated with greater default mode network (DMN) connectivity to the superior frontal gyrus (P = 0.05 FDR corrected) among fatigued subjects (r = 0.82) and less connectivity in the non-fatigued group (r = −0.88). These findings indicate that there is enhanced intrinsic DMN connectivity to the frontal gyrus in breast cancer survivors with persistent fatigue. As

  14. Altered resting brain connectivity in persistent cancer related fatigue.

    PubMed

    Hampson, Johnson P; Zick, Suzanna M; Khabir, Tohfa; Wright, Benjamin D; Harris, Richard E

    2015-01-01

    There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P < 0.05 FDR corrected). This enhanced connectivity was associated with increased physical fatigue (P = 0.04, r = 0.52) and poor sleep quality (P = 0.04, r = 0.52) in the fatigued group. In contrast greater connectivity in the non-fatigued group was found between the right precuneus to the periaqueductal gray as well as the left IPL to subgenual cortex (P < 0.05 FDR corrected). Mental fatigue scores were associated with greater default mode network (DMN) connectivity to the superior frontal gyrus (P = 0.05 FDR corrected) among fatigued subjects (r = 0.82) and less connectivity in the non-fatigued group (r = -0.88). These findings indicate that there is enhanced intrinsic DMN connectivity to the frontal gyrus in breast cancer survivors with persistent fatigue. As

  15. Identifying radiotherapy target volumes in brain cancer by image analysis

    PubMed Central

    Cheng, Kun; Montgomery, Dean; Feng, Yang; Steel, Robin; Liao, Hanqing; McLaren, Duncan B.; Erridge, Sara C.; McLaughlin, Stephen

    2015-01-01

    To establish the optimal radiotherapy fields for treating brain cancer patients, the tumour volume is often outlined on magnetic resonance (MR) images, where the tumour is clearly visible, and mapped onto computerised tomography images used for radiotherapy planning. This process requires considerable clinical experience and is time consuming, which will continue to increase as more complex image sequences are used in this process. Here, the potential of image analysis techniques for automatically identifying the radiation target volume on MR images, and thereby assisting clinicians with this difficult task, was investigated. A gradient-based level set approach was applied on the MR images of five patients with grades II, III and IV malignant cerebral glioma. The relationship between the target volumes produced by image analysis and those produced by a radiation oncologist was also investigated. The contours produced by image analysis were compared with the contours produced by an oncologist and used for treatment. In 93% of cases, the Dice similarity coefficient was found to be between 60 and 80%. This feasibility study demonstrates that image analysis has the potential for automatic outlining in the management of brain cancer patients, however, more testing and validation on a much larger patient cohort is required. PMID:26609418

  16. Radiosurgery for Brain Metastases From Unknown Primary Cancers

    SciTech Connect

    Niranjan, Ajay; Kano, Hideyuki; Khan, Aftab; Kim, In-Young; Kondziolka, Douglas; Flickinger, John C.; Lunsford, L. Dade

    2010-08-01

    Purpose: We evaluated the role of Gamma Knife stereotactic radiosurgery in the multidisciplinary management of brain metastases from an undiagnosed primary cancer. Methods and Materials: Twenty-nine patients who had solitary or multiple brain metastases without a detectable primary site underwent stereotactic radiosurgery between January 1990 and March 2007 at the University of Pittsburgh. The median patient age was 61.7 years (range, 37.9-78.7 years). The median target volume was 1.0 cc (range, 0.02-23.6 cc), and the median margin radiosurgical dose was 16 Gy (range, 20-70 Gy). Results: After radiosurgery, the local tumor control rate was 88.5%. Twenty four patients died and 5 patients were living at the time of this analysis. The overall median survival was 12 months. Actuarial survival rates from stereotactic radiosurgery at 1 and 2 years were 57.2% and 36.8%, respectively. Factors associated with poor progression-free survival included large tumor volume (3 cc or more) and brainstem tumor location. Conclusions: Radiosurgery is an effective and safe minimally invasive option for patients with brain metastases from an unknown primary site.

  17. [Dreams and the dead].

    PubMed

    Mestre, Claire

    2006-01-01

    In this article, the author examines the issue of dreams and the dead as an essential tool for transcultural psychotherapy and how the dreamlike vision of the dead and its interpretation constitute a turning point in transcultural therapy. Drawing from a clinical example, the author illustrates how the spatial analogy between dreams and the world of the dead has allowed a patient to reconstruct a psychological space severely disturbed by trauma endured.

  18. Brain damage following prophylactic cranial irradiation in lung cancer survivors.

    PubMed

    Simó, Marta; Vaquero, Lucía; Ripollés, Pablo; Jové, Josep; Fuentes, Rafael; Cardenal, Felipe; Rodríguez-Fornells, Antoni; Bruna, Jordi

    2016-03-01

    Long-term toxic effects of prophylactic cranial irradiation (PCI) on cognition in small cell lung cancer (SCLC) patients have not yet been well-established. The aim of our study was to examine the cognitive toxic effects together with brain structural changes in a group of long-term SCLC survivors treated with PCI. Eleven SCLC patients, who underwent PCI ≥ 2 years before, were compared with an age and education matched healthy control group. Both groups were evaluated using a neuropsychological battery and multimodal structural magnetic resonance imaging. Voxel-based morphometry and Tract-based Spatial Statistics were used to study gray matter density (GMD) and white matter (WM) microstructural changes. Cognitive deterioration was correlated with GMD and Fractional Anisotropy (FA). Finally, we carried out a single-subject analysis in order to evaluate individual structural brain changes. Nearly half of the SCLC met criteria for cognitive impairment, all exhibiting a global worsening of cognitive functioning. Patients showed significant decreases of GMD in basal ganglia bilaterally (putamen and caudate), bilateral thalamus and right insula, together with WM microstructural changes of the entire corpus callosum. Cognitive deterioration scores correlated positively with mean FA values in the corpus callosum. Single-subject analysis revealed that GMD and WM changes were consistently observed in nearly all patients. This study showed neuropsychological deficits together with brain-specific structural differences in long-term SCLC survivors. Our results suggest that PCI therapy, possibly together with platinum-based chemotherapy, was associated to permanent long-term cognitive and structural brain effects in a SCLC population.

  19. Ruta 6 selectively induces cell death in brain cancer cells but proliferation in normal peripheral blood lymphocytes: A novel treatment for human brain cancer.

    PubMed

    Pathak, Sen; Multani, Asha S; Banerji, Pratip; Banerji, Prasanta

    2003-10-01

    Although conventional chemotherapies are used to treat patients with malignancies, damage to normal cells is problematic. Blood-forming bone marrow cells are the most adversely affected. It is therefore necessary to find alternative agents that can kill cancer cells but have minimal effects on normal cells. We investigated the brain cancer cell-killing activity of a homeopathic medicine, Ruta, isolated from a plant, Ruta graveolens. We treated human brain cancer and HL-60 leukemia cells, normal B-lymphoid cells, and murine melanoma cells in vitro with different concentrations of Ruta in combination with Ca3(PO4)2. Fifteen patients diagnosed with intracranial tumors were treated with Ruta 6 and Ca3(PO4)2. Of these 15 patients, 6 of the 7 glioma patients showed complete regression of tumors. Normal human blood lymphocytes, B-lymphoid cells, and brain cancer cells treated with Ruta in vitro were examined for telomere dynamics, mitotic catastrophe, and apoptosis to understand the possible mechanism of cell-killing, using conventional and molecular cytogenetic techniques. Both in vivo and in vitro results showed induction of survival-signaling pathways in normal lymphocytes and induction of death-signaling pathways in brain cancer cells. Cancer cell death was initiated by telomere erosion and completed through mitotic catastrophe events. We propose that Ruta in combination with Ca3(PO4)2 could be used for effective treatment of brain cancers, particularly glioma.

  20. Gadolinium uptake by brain cancer cells: Quantitative analysis with X-PEEM spectromicroscopy for cancer therapy

    NASA Astrophysics Data System (ADS)

    De Stasio, Gelsomina; Gilbert, B.; Perfetti, P.; Margaritondo, G.; Mercanti, D.; Ciotti, M. T.; Casalbore, P.; Larocca, L. M.; Rinelli, A.; Pallini, R.

    2000-05-01

    We present the first X-PEEM spectromicroscopy semi-quantitative data, acquired on Gd in glioblastoma cell cultures from human brain cancer. The cells were treated with a Gd compound for the optimization of GdNCT (Gadolinium Neutron Capture Therapy). We analyzed the kinetics of Gd uptake as a function of exposure time, and verified that a quantitative analytical technique gives the same results as our MEPHISTO X-PEEM, demonstrating the feasibility of semi-quantitative spectromicroscopy.

  1. Brain Metastases in Gastrointestinal Cancers: Is there a Role for Surgery?

    PubMed Central

    Lemke, Johannes; Scheele, Jan; Kapapa, Thomas; von Karstedt, Silvia; Wirtz, Christian Rainer; Henne-Bruns, Doris; Kornmann, Marko

    2014-01-01

    About 10% of all cancer patients will develop brain metastases during advanced disease progression. Interestingly, the vast majority of brain metastases occur in only three types of cancer: Melanoma, lung and breast cancer. In this review, we focus on summarizing the prognosis and impact of surgical resection of brain metastases originating from gastrointestinal cancers such as esophageal, gastric, pancreatic and colorectal cancer. The incidence of brain metastases is <1% in pancreatic and gastric cancer and <4% in esophageal and colorectal cancer. Overall, prognosis of these patients is very poor with a median survival in the range of only months. Interestingly, a substantial number of patients who had received surgical resection of brain metastases showed prolonged survival. However, it should be taken into account that all these studies were not randomized and it is likely that patients selected for surgical treatment presented with other important prognostic factors such as solitary brain metastases and exclusion of extra-cranial disease. Nevertheless, other reports have demonstrated long-term survival of patients upon resection of brain metastases originating from gastrointestinal cancers. Thus, it appears to be justified to consider aggressive surgical approaches for these patients. PMID:25247579

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

    PubMed

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

    2014-02-27

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

  3. Investigating Aquatic Dead Zones

    ERIC Educational Resources Information Center

    Testa, Jeremy; Gurbisz, Cassie; Murray, Laura; Gray, William; Bosch, Jennifer; Burrell, Chris; Kemp, Michael

    2010-01-01

    This article features two engaging high school activities that include current scientific information, data, and authentic case studies. The activities address the physical, biological, and chemical processes that are associated with oxygen-depleted areas, or "dead zones," in aquatic systems. Students can explore these dead zones through both…

  4. Day of the Dead

    ERIC Educational Resources Information Center

    Dann, Tammy; Murphy, Amy

    2012-01-01

    Foreign Language in Elementary School (FLES) teachers in the West Des Moines schools incorporate the Day of the Dead into the fourth grade curriculum each year. The teachers discuss the Day of the Dead celebration at the Art Center, and many ask for volunteers from fourth grade to participate in the event. Student presentations include a wide…

  5. ROS1 rearranged non-small cell lung cancer brain metastases respond to low dose radiotherapy.

    PubMed

    Lukas, Rimas V; Hasan, Yasmin; Nicholas, Martin K; Salgia, Ravi

    2015-12-01

    We present a young woman with ROS1 gene rearranged non-small cell lung cancer (NSCLC) with brain metastases. ROS is a proto-oncogene tyrosine protein kinase. The patient received a partial course of whole brain radiation therapy and experienced a sustained partial response in the brain. We hypothesize that ROS1 rearranged NSCLC brain metastases may be particularly sensitive to radiation therapy.

  6. Molecular advances to treat cancer of the brain.

    PubMed

    Fathallah-Shaykh, H M; Zhao, L J; Mickey, B; Kafrouni, A I

    2000-06-01

    Malignant primary and metastatic brain tumours continue to be associated with poor prognosis. Nevertheless, recent advances in molecular medicine, specifically in the strategies of gene therapy, targeting tumour cells, anti-angiogenesis and immunotherapy, have created novel tools that may be of therapeutic value. To date, gene therapy trials have not yet demonstrated clinical efficacy because of inherent defects in vector design. Despite this, advances in adenoviral technology, namely the helper-dependent adenoviral constructs (gutless) and the uncovering of brain parenchymal cells as effective and necessary targets for antitumour benefits of adenoviral-mediated gene transfer, suggest that developments in vector design may be approaching the point of clinical utility. Targeting tumour cells refers to strategies that destroy malignant but spare normal cells. A new assortment of oncolytic viruses have emerged, capable of specific lysis of cancer tissue while sparing normal cells and propagating until they reach the tumour borders. Furthermore, peptides have been transformed into bullets that specifically seek and destroy cancer cells. The concept of tumour angiogenesis has been challenged by new but still very controversial findings that tumour cells themselves may form blood channels. These results may lead to the redirecting of the molecular targets toward anti-angiogenesis in some tumours including glioblastoma multiform. Unfortunately, our knowledge regarding the immunological ignorance of the tumour is still limited. Even so, newly discovered molecules have shed light on novel pathways leading to the escape of the tumour from the immune system. Finally, significant limitations in our current experimental tumour models may soon be overcome by firstly, the development of models of reproducible organ-specific tumours in non-inbred animals and secondly applying genomics to individualize therapy for a particular tumour in a specific patient.

  7. Neural networks improve brain cancer detection with Raman spectroscopy in the presence of light artifacts

    NASA Astrophysics Data System (ADS)

    Jermyn, Michael; Desroches, Joannie; Mercier, Jeanne; St-Arnaud, Karl; Guiot, Marie-Christine; Petrecca, Kevin; Leblond, Frederic

    2016-03-01

    It is often difficult to identify cancer tissue during brain cancer (glioma) surgery. Gliomas invade into areas of normal brain, and this cancer invasion is frequently not detected using standard preoperative magnetic resonance imaging (MRI). This results in enduring invasive cancer following surgery and leads to recurrence. A hand-held Raman spectroscopy is able to rapidly detect cancer invasion in patients with grade 2-4 gliomas. However, ambient light sources can produce spectral artifacts which inhibit the ability to distinguish between cancer and normal tissue using the spectral information available. To address this issue, we have demonstrated that artificial neural networks (ANN) can accurately classify invasive cancer versus normal brain tissue, even when including measurements with significant spectral artifacts from external light sources. The non-parametric and adaptive model used by ANN makes it suitable for detecting complex non-linear spectral characteristics associated with different tissues and the confounding presence of light artifacts. The use of ANN for brain cancer detection with Raman spectroscopy, in the presence of light artifacts, improves the robustness and clinical translation potential for intraoperative use. Integration with the neurosurgical workflow is facilitated by accounting for the effect of light artifacts which may occur, due to operating room lights, neuronavigation systems, windows, or other light sources. The ability to rapidly detect invasive brain cancer under these conditions may reduce residual cancer remaining after surgery, and thereby improve patient survival.

  8. Brain cancer mortality rates increase with Toxoplasma gondii seroprevalence in France

    USGS Publications Warehouse

    Vittecoq, Marion; Elguero, Eric; Lafferty, Kevin D.; Roche, Benjamin; Brodeur, Jacques; Gauthier-Clerc, Michel; Missé, Dorothée; Thomas, Frédéric

    2012-01-01

    The incidence of adult brain cancer was previously shown to be higher in countries where the parasite Toxoplasma gondii is common, suggesting that this brain protozoan could potentially increase the risk of tumor formation. Using countries as replicates has, however, several potential confounding factors, particularly because detection rates vary with country wealth. Using an independent dataset entirely within France, we further establish the significance of the association between T. gondii and brain cancer and find additional demographic resolution. In adult age classes 55 years and older, regional mortality rates due to brain cancer correlated positively with the local seroprevalence of T. gondii. This effect was particularly strong for men. While this novel evidence of a significant statistical association between T. gondii infection and brain cancer does not demonstrate causation, these results suggest that investigations at the scale of the individual are merited.

  9. 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.

  10. Highlights of Children with Cancer UK’s Workshop on Drug Delivery in Paediatric Brain Tumours

    PubMed Central

    Nailor, Audrey; Walker, David A; Jacques, Thomas S; Warren, Kathy E; Brem, Henry; Kearns, Pamela R; Greenwood, John; Penny, Jeffrey I; Pilkington, Geoffrey J; Carcaboso, Angel M; Fleischhack, Gudrun; Macarthur, Donald; Slavc, Irene; Meijer, Lisethe; Gill, Steven; Lowis, Stephen; van Vuurden, Dannis G; Pearl, Monica S; Clifford, Steven C; Morrissy, Sorana; Ivanov, Delyan P; Beccaria, Kévin; Gilbertson, Richard J; Straathof, Karin; Green, Jordan J; Smith, Stuart; Rahman, Ruman; Kilday, John-Paul

    2016-01-01

    The first Workshop on Drug Delivery in Paediatric Brain Tumours was hosted in London by the charity Children with Cancer UK. The goals of the workshop were to break down the barriers to treating central nervous system (CNS) tumours in children, leading to new collaborations and further innovations in this under-represented and emotive field. These barriers include the physical delivery challenges presented by the blood–brain barrier, the underpinning reasons for the intractability of CNS cancers, and the practical difficulties of delivering cancer treatment to the brains of children. Novel techniques for overcoming these problems were discussed, new models brought forth, and experiences compared. PMID:27110286

  11. 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.

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

    PubMed

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

    2015-02-20

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

  13. Dead Sea Scrolls

    NASA Technical Reports Server (NTRS)

    1994-01-01

    A consortium of researchers from Jet Propulsion Laboratory and three other organizations used charged coupled devices (CCDs) and other imaging enhancement technology to decipher previously unreadable portions of the Dead Sea Scrolls. The technique has potentially important implications for archeology.

  14. Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics.

    PubMed

    Bollig-Fischer, Aliccia; Michelhaugh, Sharon K; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

    2015-06-10

    Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.

  15. Clinical study and numerical simulation of brain cancer dynamics under radiotherapy

    NASA Astrophysics Data System (ADS)

    Nawrocki, S.; Zubik-Kowal, B.

    2015-05-01

    We perform a clinical and numerical study of the progression of brain cancer tumor growth dynamics coupled with the effects of radiotherapy. We obtained clinical data from a sample of brain cancer patients undergoing radiotherapy and compare it to our numerical simulations to a mathematical model of brain tumor cell population growth influenced by radiation treatment. We model how the body biologically receives a physically delivered dose of radiation to the affected tumorous area in the form of a generalized LQ model, modified to account for the conversion process of sublethal lesions into lethal lesions at high radiation doses. We obtain good agreement between our clinical data and our numerical simulations of brain cancer progression given by the mathematical model, which couples tumor growth dynamics and the effect of irradiation. The correlation, spanning a wide dataset, demonstrates the potential of the mathematical model to describe the dynamics of brain tumor growth influenced by radiotherapy.

  16. Clinical applications of modern imaging technology: stereo image formation and location of brain cancer

    NASA Astrophysics Data System (ADS)

    Wang, Dezong; Wang, Jinxiang

    1994-05-01

    It is very important to locate the tumor for a patient, who has cancer in his brain. If he only gets X-CT or MRI pictures, the doctor does not know the size, shape location of the tumor and the relation between the tumor and other organs. This paper presents the formation of stereo images of cancer. On the basis of color code and color 3D reconstruction. The stereo images of tumor, brain and encephalic truncus are formed. The stereo image of cancer can be round on X, Y, Z-coordinates to show the shape from different directions. In order to show the location of tumor, stereo image of tumor and encephalic truncus are provided on different angles. The cross section pictures are also offered to indicate the relation of brain, tumor and encephalic truncus on cross sections. In this paper the calculating of areas, volume and the space between cancer and the side of the brain are also described.

  17. 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.

  18. Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells

    PubMed Central

    Mouhieddine, Tarek H.; Nokkari, Amaly; Itani, Muhieddine M.; Chamaa, Farah; Bahmad, Hisham; Monzer, Alissar; El-Merahbi, Rabih; Daoud, Georges; Eid, Assaad; Kobeissy, Firas H.; Abou-Kheir, Wassim

    2015-01-01

    Background: Gliomas and neuroblastomas pose a great health burden worldwide with a poor and moderate prognosis, respectively. Many studies have tried to find effective treatments for these primary malignant brain tumors. Of interest, the AMP-activated protein kinase (AMPK) pathway was found to be associated with tumorigenesis and tumor survival, leading to many studies on AMPK drugs, especially Metformin, and their potential role as anti-cancer treatments. Cancer stem cells (CSCs) are a small population of slowly-dividing, treatment-resistant, undifferentiated cancer cells that are being discovered in a multitude of cancers. They are thought to be responsible for replenishing the tumor with highly proliferative cells and increasing the risk of recurrence. Methods: Metformin and 9-β-d-Arabinofuranosyl Adenine (Ara-a) were used to study the role of the AMPK pathway in vitro on U251 (glioblastoma) and SH-SY5Y (neuroblastoma) cell lines. Results: We found that both drugs are able to decrease the survival of U251 and SH-SY5Y cell lines in a 2D as well as a 3D culture model. Metformin and Ara-a significantly decreased the invasive ability of these cancer cell lines. Treatment with these drugs decreased the sphere-forming units (SFU) of U251 cells, with Ara-a being more efficient, signifying the extinction of the CSC population. However, if treatment is withdrawn before all SFUs are extinguished, the CSCs regain some of their sphere-forming capabilities in the case of Metformin but not Ara-a treatment. Conclusion: Metformin and Ara-a have proved to be effective in the treatment of glioblastomas and neuroblastomas, in vitro, by targeting their cancer stem/progenitor cell population, which prevents recurrence. PMID:26635517

  19. A pilot case-cohort study of brain cancer in poultry and control workers.

    PubMed

    Gandhi, S; Felini, M J; Ndetan, H; Cardarelli, K; Jadhav, S; Faramawi, M; Johnson, E S

    2014-01-01

    We conducted an exploratory study to investigate which exposures (including poultry oncogenic viruses) are associated with brain cancer in poultry workers. A total of 46,819 workers in poultry and nonpoultry plants from the same union were initially followed for mortality. Brain cancer was observed to be in excess among poultry workers. Here we report on a pilot case-cohort study with cases consisting of 26 (55%) of the 47 brain cancer deaths recorded in the cohort, and controls consisting of a random sample of the cohort (n = 124). Exposure information was obtained from telephone interviews, and brain cancer mortality risk estimated by odds ratios. Increased risk of brain cancer was associated with killing chickens, odds ratio (OR) = 5.8 (95% confidence interval, 1.2-28.3); working in a shell-fish farm, OR = 13.0 (95% CI, 1.9-84.2); and eating uncooked fish, OR = 8.2 (95% CI, 1.8-37.0). Decreased risks were observed for chicken pox illness, OR = 0.2 (95% CI, 0.1-0.6), and measles vaccination, OR = 0.2 (95% CI, 0.1-0.6). Killing chickens, an activity associated with the highest occupational exposure to poultry oncogenic viruses, was associated with brain cancer mortality, as were occupational and dietary shellfish exposures. These findings are novel.

  20. Electrical conductivity changes during irreversible electroporation treatment of brain cancer.

    PubMed

    Garcia, Paulo A; Rossmeisl, John H; Davalos, Rafael V

    2011-01-01

    Irreversible electroporation (IRE) is a new minimally invasive technique to kill tumors and other undesirable tissue in a non-thermal manner. During an IRE treatment, a series of short and intense electric pulses are delivered to the region of interest to destabilize the cell membranes in the tissue and achieve spontaneous cell death. The alteration of the cellular membrane results in a dramatic increase in electrical conductivity during IRE as in other electroporation-based-therapies. In this study, we performed the planning and execution of an IRE brain cancer treatment using MRI reconstructions of the tumor and a multichannel array that served as a stereotactic fiducial and electrode guide. Using the tumor reconstructions within our numerical simulations, we developed equations relating the increase in tumor conductivity to calculated currents and volumes of tumor treated with IRE. We also correlated the experimental current measured during the procedure to an increase in tumor conductivity ranging between 3.42-3.67 times the baseline conductivity, confirming the physical phenomenon that has been detected in other tissues undergoing similar electroporation-based treatments. PMID:22254416

  1. Pesticides and brain cancer linked in orchard farmers of Kashmir

    PubMed Central

    Bhat, Abdul Rashid; Wani, Muhammed Afzal; Kirmani, A. R.; Raina, T. H.

    2010-01-01

    were unrelated to pesticides. Out of 389 patients, 71.7% (279 out of 389) were males and 28.3% (110 out of 389) including 7 members of three families, 6 were females and 1 male. Conclusion: All orchard-related 389 patients had high grade tumors as compared to the non-pesticide tumors. Mortality in pesticide exposed tumors was 12%. Higher levels of SCE were found in 31.9% (124 out of 389) patients and decreased levels in only 45.3% (176 out of 389) orchard-related patients. The significantcase/control odds ratio (OR) of 0.28, hospital control SCE OR of 1.1 and family control SCE OR of 1.5, points the finger of suspicion toward the link between pesticides and brain cancer. PMID:21584215

  2. A brain-dead pregnant woman with prolonged somatic support and successful neonatal outcome: A grand rounds case with a detailed review of literature and ethical considerations.

    PubMed

    Said, Abuhasna; Amer, Al Jundi; Masood, Ur Rahman; Dirar, Abdallah; Faris, Chedid

    2013-07-01

    There are increased reports in the medical literature of brain death during pregnancy. In these rare cases, the decision was either to consider discontinuing homeostatic support and mechanical ventilation with an understanding that the fetus then will also die, or to continue full support in an attempt to prolong pregnancy for the purpose of maintaining the fetus alive until maturity. We report the first case in the United Arab Emirates and in literature of somatic support that extended up to 110 days with the successful delivery of a viable fetus. A 35-year-old woman suffered intracranial hemorrhage during the 16(th) week of pregnancy that lead to brain death despite maximal surgical and medical management. Upon confirmation of this diagnosis, the patient received full ventilatory and homeostatic support required to prolong gestation and improve the survival prognosis of her fetus. The status of the patient was discussed in a multidisciplinary approach and with the full involvement of her family. Somatic support continued until the patient was 32 of weeks gestation. Obstetric complications of the patient were frequently assessed and managed. Lower segment cesarean section (LSCS) was then performed. A preterm male in breech presentation was delivered with an average weight of 750 gm, and an Apgar score of 6, 7, and 9 at 1, 5, and 10 minutes, respectively. Prolonging somatic support in a pregnant woman with brain death to allow fetal survival resulted in a successful outcome in terms of saving the life of the fetus. The results are consistent with previous published case reports in the literature on the appropriateness and safety of such a strategy that involved an intensive multidisciplinary approach. Despite being a tragedy, maternal death can represent an opportunity to save the life of the fetus and for organ donation. Consensus future recommendations that can guide the management of similar conditions may also be adapted, especially with the growing medical

  3. Decreased spontaneous activity in AMPK α2 muscle specific kinase dead mice is not caused by changes in brain dopamine metabolism.

    PubMed

    Møller, Lisbeth L V; Sylow, Lykke; Gøtzsche, Casper R; Serup, Annette K; Christiansen, Søren H; Weikop, Pia; Kiens, Bente; Woldbye, David P D; Richter, Erik A

    2016-10-01

    It is well known that physical activity has several health benefits, yet many people do not exercise. Dopamine levels in the striatum of the brain are thought to be important for the motivation to exercise. Conversely, we hypothesized that muscle quality can affect the motivation to exercise through alterations of the brain dopamine levels specifically in the striatal region. To test this hypothesis, transgenic mice overexpressing an inactivatable dominant negative α2 AMPK construct (AMPK α2 KD) in muscles and littermate wildtype (WT) mice were tested. AMPK α2 KD mice have impaired running capacity and display reduced voluntary wheel running activity. Striatal content of dopamine and its metabolites were measured under basal physiological conditions and after cocaine-induced dopamine efflux from the ventral striatum by in vivo microdialysis. Moreover, cocaine-induced locomotor activity was tested in an open field test. Furthermore, we investigated maximal running capacity and voluntary running over a period of 19days. AMPK α2 KD mice ran 30% less in daily distance compared to WT. Furthermore, AMPK α2 KD mice showed significantly decreased locomotor activity in the open field test compared to WT when treated with saline or cocaine, respectively, but the increase induced by cocaine was similar in AMPK α2 KD and WT mice. The efflux of dopamine in ventral striatum after cocaine treatment increased similarly by 2.5-fold in the two genotypes, and basal levels of dopamine and its metabolites DOPAC and HVA were also similar between genotypes. These findings show that decreased AMPK activity in muscle leads to decreased voluntary activity which is not due to secondary abnormalities in dopamine levels in the ventral striatum or sensitivity to cocaine. Thus, decreased voluntary activity in AMPK muscle deficient mice is most likely unrelated to regulation of brain dopamine content and metabolism. PMID:27306083

  4. Radiological Patterns of Brain Metastases in Breast Cancer Patients: A Subproject of the German Brain Metastases in Breast Cancer (BMBC) Registry.

    PubMed

    Laakmann, Elena; Witzel, Isabell; Scriba, Verena; Grzyska, Ulrich; Zu Eulenburg, Christine; Burchardi, Nicole; Hesse, Tobias; Würschmidt, Florian; Fehm, Tanja; Möbus, Volker; von Minckwitz, Gunter; Loibl, Sibylle; Park-Simon, Tjoung-Won; Mueller, Volkmar

    2016-01-01

    Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment. PMID:27669228

  5. Radiological Patterns of Brain Metastases in Breast Cancer Patients: A Subproject of the German Brain Metastases in Breast Cancer (BMBC) Registry.

    PubMed

    Laakmann, Elena; Witzel, Isabell; Scriba, Verena; Grzyska, Ulrich; Zu Eulenburg, Christine; Burchardi, Nicole; Hesse, Tobias; Würschmidt, Florian; Fehm, Tanja; Möbus, Volker; von Minckwitz, Gunter; Loibl, Sibylle; Park-Simon, Tjoung-Won; Mueller, Volkmar

    2016-01-01

    Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment.

  6. Radiological Patterns of Brain Metastases in Breast Cancer Patients: A Subproject of the German Brain Metastases in Breast Cancer (BMBC) Registry

    PubMed Central

    Laakmann, Elena; Witzel, Isabell; Scriba, Verena; Grzyska, Ulrich; zu Eulenburg, Christine; Burchardi, Nicole; Hesse, Tobias; Würschmidt, Florian; Fehm, Tanja; Möbus, Volker; von Minckwitz, Gunter; Loibl, Sibylle; Park-Simon, Tjoung-Won; Mueller, Volkmar

    2016-01-01

    Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment. PMID:27669228

  7. "Living versus Dead":

    PubMed Central

    Chakrabarti, Pratik

    2010-01-01

    Summary The Semple antirabies vaccine was developed by David Semple in India in 1911. Semple introduced a peculiarly British approach within the Pasteurian tradition by using carbolized dead virus. This article studies this unique phase of vaccine research between 1910 and 1935 to show that in the debates and laboratory experiments around the potency and safety of vaccines, categories like "living" and "dead" were often used as ideological and moral denominations. These abstract and ideological debates were crucial in defining the final configuration of the Semple vaccine, the most popular antirabies vaccine used globally, and also in shaping international vaccination policies. PMID:21037397

  8. Differentiation of cancerous and normal brain tissue using label free fluorescence and Stokes shift spectroscopy

    NASA Astrophysics Data System (ADS)

    Zhou, Yan; Wang, Leana; Liu, Cheng-hui; He, Yong; Yu, Xinguang; Cheng, Gangge; Wang, Peng; Shu, Cheng; Alfano, Robert R.

    2016-03-01

    In this report, optical biopsy was applied to diagnose human brain cancer in vitro for the identification of brain cancer from normal tissues by native fluorescence and Stokes shift spectra (SSS). 77 brain specimens including three types of human brain tissues (normal, glioma and brain metastasis of lung cancers) were studied. In order to observe spectral changes of fluorophores via fluorescence, the selected excitation wavelength of UV at 300 and 340 nm for emission spectra and a different Stokes Shift spectra with intervals Δλ = 40 nm were measured. The fluorescence spectra and SSS from multiple key native molecular markers, such as tryptophan, collagen, NADH, alanine, ceroid and lipofuscin were observed in normal and diseased brain tissues. Two diagnostic criteria were established based on the ratios of the peak intensities and peak position in both fluorescence and SSS spectra. It was observed that the ratio of the spectral peak intensity of tryptophan (340 nm) to NADH (440 nm) increased in glioma, meningioma (benign), malignant meninges tumor, and brain metastasis of lung cancer tissues in comparison with normal tissues. The ratio of the SS spectral peak (Δλ = 40 nm) intensities from 292 nm to 366 nm had risen similarly in all grades of tumors.

  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. PMID:27561803

  10. Preliminary Results of Whole Brain Radiotherapy With Concurrent Trastuzumab for Treatment of Brain Metastases in Breast Cancer Patients

    SciTech Connect

    Chargari, Cyrus; Idrissi, Hind Riahi; Pierga, Jean-Yves; Bollet, Marc A.; Dieras, Veronique; Campana, Francois; Cottu, Paul; Fourquet, Alain; Kirova, Youlia M.

    2011-11-01

    Purpose: To assess the use of trastuzumab concurrently with whole brain radiotherapy (WBRT) for patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer. Methods and Materials: Between April 2001 and April 2007, 31 patients with brain metastases from human epidermal growth factor receptor-2-positive breast cancer were referred for WBRT with concurrent trastuzumab. At brain progression, the median age was 55 years (range, 38-73), and all patients had a performance status of 0-2. The patients received trastuzumab 2 mg/kg weekly (n = 17) or 6 mg/kg repeated every 21 days (n = 14). In 26 patients, concurrent WBRT delivered 30 Gy in 10 daily fractions. In 6 patients, other fractionations were chosen because of either poor performance status or patient convenience. Results: After WBRT, radiologic responses were observed in 23 patients (74.2%), including 6 (19.4%) with a complete radiologic response and 17 (54.8%) with a partial radiologic response. Clinical responses were observed in 27 patients (87.1%). The median survival time from the start of WBRT was 18 months (range, 2-65). The median interval to brain progression was 10.5 months (range, 2-27). No Grade 2 or greater acute toxicity was observed. Conclusion: The low toxicity of trastuzumab concurrently with WBRT should probably not justify delays. Although promising, these preliminary data warrant additional validation of trastuzumab as a potential radiosensitizer for WBRT in brain metastases from breast cancer in the setting of a clinical trial.

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

    PubMed Central

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

    2014-01-01

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

  12. Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain.

    PubMed

    Palmieri, Diane; Bronder, Julie L; Herring, Jeanne M; Yoneda, Toshiyuki; Weil, Robert J; Stark, Andreas M; Kurek, Raffael; Vega-Valle, Eleazar; Feigenbaum, Lionel; Halverson, Douglas; Vortmeyer, Alexander O; Steinberg, Seth M; Aldape, Kenneth; Steeg, Patricia S

    2007-05-01

    Retrospective studies of breast cancer patients suggest that primary tumor Her-2 overexpression or trastuzumab therapy is associated with a devastating complication: the development of central nervous system (brain) metastases. Herein, we present Her-2 expression trends from resected human brain metastases and data from an experimental brain metastasis assay, both indicative of a functional contribution of Her-2 to brain metastatic colonization. Of 124 archival resected brain metastases from breast cancer patients, 36.2% overexpressed Her-2, indicating an enrichment in the frequency of tumor Her-2 overexpression at this metastatic site. Using quantitative real-time PCR of laser capture microdissected epithelial cells, Her-2 and epidermal growth factor receptor (EGFR) mRNA levels in a cohort of 12 frozen brain metastases were increased up to 5- and 9-fold, respectively, over those of Her-2-amplified primary tumors. Co-overexpression of Her-2 and EGFR was also observed in a subset of brain metastases. We then tested the hypothesis that overexpression of Her-2 increases the colonization of breast cancer cells in the brain in vivo. A subclone of MDA-MB-231 human breast carcinoma cells that selectively metastasizes to brain (231-BR) overexpressed EGFR; 231-BR cells were transfected with low (4- to 8-fold) or high (22- to 28-fold) levels of Her-2. In vivo, in a model of brain metastasis, low or high Her-2-overexpressing 231-BR clones produced comparable numbers of micrometastases in the brain as control transfectants; however, the Her-2 transfectants yielded 3-fold greater large metastases (>50 microm(2); P < 0.001). Our data indicate that Her-2 overexpression increases the outgrowth of metastatic tumor cells in the brain in this model system. PMID:17483330

  13. 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.

  14. Semen collection requirement from multiple-organs brain-dead donors: report of two cases and analysis of the available Brazilian legislation.

    PubMed

    Sardinha, L A C; Dantas Filho, V P; Montone, E B B; Athayde, M V O; Rodrigues, S L L; Panunto, M R; Araújo, S; Zambelli, H J L

    2013-04-01

    Along with developments in transplantation there have been major breakthroughs in the techniques of assisted reproduction. The areas of common interest include requesting semen collection from organ donors with a diagnosis of brain death. After the recent report of two cases in the Search Service of Organs and Tissues, we analyzed legislation in our country, which still lacks specific guidance in such situations. Organ transplantation progressively established itself as an effective therapeutic option in our country since the 1960s. It represents viable alternative to improve both the quality and length of life as well as to decrease long-term costs of patients with severe end-stage organ failure. These programs have specific rules and laws that are necessary to guide all stages of transplantation: donor identification, authorization and execution as well as recipients selection of implantation techniques. Assisted reproduction also needs legislation specific for human infertility, a public health problem that affects medical, psychological, and legitimate desires of people. The World Health Organization estimates that infertility reaches 20% of the population demanding the development and use of techniques for its treatment. Brazilian legislation includes regulations for transplantation of organs and tissues in law no. 9434 of February 04, 1997; it provides for the removal of organs, tissues, and human body parts for transplantation and other treatments. This law is regulated by Decree no. 2268 of June 30, 1997, establishing the National Transplant System, which standardizes these processes. The postmortem organ and tissue provision must be preceded by a diagnosis of via the Brain Death Protocol (Federal Council of Medicine-Brazil). The sole paragraph of Article 1 makes clear that its provisions do not apply to blood, sperm, or ovules as confirmed by the sole paragraph of Article 1 in the Decree 2.268/97 regulation. Since there is no specific legislation, assisted

  15. Semen collection requirement from multiple-organs brain-dead donors: report of two cases and analysis of the available Brazilian legislation.

    PubMed

    Sardinha, L A C; Dantas Filho, V P; Montone, E B B; Athayde, M V O; Rodrigues, S L L; Panunto, M R; Araújo, S; Zambelli, H J L

    2013-04-01

    Along with developments in transplantation there have been major breakthroughs in the techniques of assisted reproduction. The areas of common interest include requesting semen collection from organ donors with a diagnosis of brain death. After the recent report of two cases in the Search Service of Organs and Tissues, we analyzed legislation in our country, which still lacks specific guidance in such situations. Organ transplantation progressively established itself as an effective therapeutic option in our country since the 1960s. It represents viable alternative to improve both the quality and length of life as well as to decrease long-term costs of patients with severe end-stage organ failure. These programs have specific rules and laws that are necessary to guide all stages of transplantation: donor identification, authorization and execution as well as recipients selection of implantation techniques. Assisted reproduction also needs legislation specific for human infertility, a public health problem that affects medical, psychological, and legitimate desires of people. The World Health Organization estimates that infertility reaches 20% of the population demanding the development and use of techniques for its treatment. Brazilian legislation includes regulations for transplantation of organs and tissues in law no. 9434 of February 04, 1997; it provides for the removal of organs, tissues, and human body parts for transplantation and other treatments. This law is regulated by Decree no. 2268 of June 30, 1997, establishing the National Transplant System, which standardizes these processes. The postmortem organ and tissue provision must be preceded by a diagnosis of via the Brain Death Protocol (Federal Council of Medicine-Brazil). The sole paragraph of Article 1 makes clear that its provisions do not apply to blood, sperm, or ovules as confirmed by the sole paragraph of Article 1 in the Decree 2.268/97 regulation. Since there is no specific legislation, assisted

  16. Dead reckoner navigation project

    NASA Technical Reports Server (NTRS)

    Ellis, R.; Sweet, L.

    1981-01-01

    A previous dead reckoner involved a classical gyrocompass, a Hewlett-Packard minicomputer, and a true airspeed sensor. In an effort to bring the cost of this system more in line with the realities of general aviation, recent work was done on replacing the minicomputer with a microcomputer and implementing a fluidic rate sensor in the compass system in place of the directional gyro.

  17. 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.

  18. Breast cancer brain metastases: evidence for neuronal-like adaptation in a ‘breast-to-brain’ transition?

    PubMed Central

    2014-01-01

    Brain metastases remain a significant challenge in the treatment of breast cancer patients due to the unique environment posed by the central nervous system. A better understanding of the biology of breast cancer cells that have metastasized to the brain is required to develop improved therapies. A recent Proceedings of the National Academy of Sciences article demonstrates that breast cancer cells in the brain microenvironment express γ-aminobutyric acid (GABA)-related genes, enabling them to utilize GABA as an oncometabolite, thus gaining a proliferative advantage. In this viewpoint, we highlight these findings and their potential impact on the treatment of breast cancer brain metastases. PMID:25679873

  19. The Dead Sea

    NASA Technical Reports Server (NTRS)

    2006-01-01

    The Dead Sea is the lowest point on Earth at 418 meters below sea level, and also one of the saltiest bodies of water on Earth with a salinity of about 300 parts-per-thousand (nine times greater than ocean salinity). It is located on the border between Jordan and Israel, and is fed by the Jordan River. The Dead Sea is located in the Dead Sea Rift, formed as a result of the Arabian tectonic plate moving northward away from the African Plate. The mineral content of the Dead Sea is significantly different from that of ocean water, consisting of approximately 53% magnesium chloride, 37% potassium chloride and 8% sodium chloride. In the early part of the 20th century, the Dead Sea began to attract interest from chemists who deduced that the Sea was a natural deposit of potash and bromine. From the Dead Sea brine, Israel and Jordan produce 3.8 million tons potash, 200,000 tons elemental bromine, 45,000 tons caustic soda, 25, 000 tons magnesium metal, and sodium chloride. Both countries use extensive salt evaporation pans that have essentially diked the entire southern end of the Dead Sea.

    With its 14 spectral bands from the visible to the thermal infrared wavelength region, and its high spatial resolution of 15 to 90 meters (about 50 to 300 feet), ASTER images Earth to map and monitor the changing surface of our planet.

    ASTER is one of five Earth-observing instruments launched December 18, 1999, on NASA's Terra satellite. The instrument was built by Japan's Ministry of Economy, Trade and Industry. A joint U.S./Japan science team is responsible for validation and calibration of the instrument and the data products.

    The broad spectral coverage and high spectral resolution of ASTER provides scientists in numerous disciplines with critical information for surface mapping, and monitoring of dynamic conditions and temporal change. Example applications are: monitoring glacial advances and retreats; monitoring potentially active volcanoes; identifying crop

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

    PubMed

    Ebben, Johnathan D; You, Ming

    2016-09-01

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

  1. 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.

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

    PubMed Central

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

    2016-01-01

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

  3. Extremely low frequency electromagnetic fields (EMF) and brain cancer in adults and children: review and comment.

    PubMed Central

    Gurney, J. G.; van Wijngaarden, E.

    1999-01-01

    Epidemiologic and experimental research on the potential carcinogenic effects of extremely low frequency electromagnetic fields (EMF) has now been conducted for over two decades. Cancer epidemiology studies in relation to EMF have focused primarily on brain cancer and leukemia, both from residential sources of exposure in children and adults and from occupational exposure in adult men. Because genotoxic effects of EMF have not been shown, most recent laboratory research has attempted to show biological effects that could be related to cancer promotion. In this report, we briefly review residential and occupational EMF studies on brain cancer. We also provide a general review of experimental studies as they relate both to the biological plausibility of an EMF-brain cancer relation and to the insufficiency of such research to help guide exposure assessment in epidemiologic studies. We conclude from our review that no recent research, either epidemiologic or experimental, has emerged to provide reasonable support for a causal role of EMF on brain cancer. PMID:11550314

  4. Factors Predictive of Improved Survival in Patients With Brain Metastases From Gynecologic Cancer

    PubMed Central

    Gressel, Gregory M.; Lundsberg, Lisbet S.; Altwerger, Gary; Katchi, Tasleem; Azodi, Masoud; Schwartz, Peter E.; Ratner, Elena S.

    2015-01-01

    Objective The reported incidence of brain metastasis from epithelial ovarian cancer (EOC), endometrial cancer (EC), and cervical cancer (CC) is exceedingly rare. As the long-term survival for patients with gynecologic cancer increases, there has been a corresponding increase in the number of diagnosed intracranial metastases. We seek to report our experience with managing brain metastatic disease (BMD) in patients with gynecologic cancer. Methods A retrospective review of all patients with EOC, EC, and CC at our institution revealed 47 patients with concurrent BMD between 2000 and 2013. Demographic data, risk factors, treatment modalities, progression-free data, and overall survival data were collected. Results Median survival time in patients with brain metastasis from EOC, EC, and CC was 9.0, 4.5, and 3.0 months, respectively. Two-year overall survival rates were 31.6%, 13.6%, and 0%, respectively. Patients received surgery, radiation therapy alone, palliative care, or radiation plus surgery. Radiation combined with surgical resection resulted in a significant hazards ratio of 0.36 (95% confidence interval, 0.15–0.86), compared with radiation alone. Conclusions Our report provides a large single-institution experience of brain metastases from gynecologic cancer. Patients with BMD have poor prognoses; however, treatment with multimodal therapy including surgical resection and radiation may prolong overall survival. PMID:26332394

  5. Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy

    SciTech Connect

    Yang, Heekyoung; Yoon, Su Jin; Jin, Juyoun; Choi, Seung Ho; Seol, Ho Jun; Lee, Jung-Il; and others

    2011-03-04

    Research highlights: {yields} The most important therapeutic tool in brain metastasis is radiation therapy. {yields} Radiosensitivity of cancer cells was enhanced with treatment of Chk1 inhibitor. {yields} Depletion of Chk1 in cancer cells showed an enhancement of sensitivity to radiation. {yields} Chk1 can be a good target for enhancement of radiosensitivity. -- Abstract: The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, signal pathways about DNA damage checkpoints after irradiation have been noticed. We investigated the radiosensitivity can be enhanced with treatment of Chk1 inhibitor, AZD7762 in lung cancer cell lines and xenograft models of lung cancer brain metastasis. Clonogenic survival assays showed enhancement of radiosensitivity with AZD7762 after irradiation of various doses. AZD7762 increased ATR/ATM-mediated Chk1 phosphorylation and stabilized Cdc25A, suppressed cyclin A expression in lung cancer cell lines. In xenograft models of lung cancer (PC14PE6) brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation. Depletion of Chk1 using shRNA also showed an enhancement of sensitivity to radiation in PC14PE6 cells. The results of this study support that Chk1 can be a good target for enhancement of radiosensitivity.

  6. Molecular Genetics Techniques to Develop New Treatments for Brain Cancers

    SciTech Connect

    Fox, Jacob; Fathallan-Shaykh, Hassan

    2006-09-22

    The objectives of this report are: (1) to devise novel molecular gene therapies for malignant brain tumors, (2) advance our understanding of the immune system in the central nervous system; and (3) apply genomics to find molecular probes to diagnose brain tumors, predict prognosis, biological behavior and their response to treatment.

  7. Brain

    MedlinePlus

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

  8. Nanomedicine and nanotoxicology: the pros and cons for neurodegeneration and brain cancer.

    PubMed

    Catalan-Figueroa, Johanna; Palma-Florez, Sujey; Alvarez, Gonzalo; Fritz, Hans F; Jara, Miguel O; Morales, Javier O

    2016-01-01

    Current strategies for brain diseases are mostly symptomatic and noncurative. Nanotechnology has the potential to facilitate the transport of drugs across the blood-brain barrier and to enhance their pharmacokinetic profile. However, to reach clinical application, an understanding of nanoneurotoxicity in terms of oxidative stress and inflammation is required. Emerging evidence has also shown that nanoparticles have the ability to alter autophagy, which can induce inflammation and oxidative stress, or vice versa. These effects may increase neurodegenerative processes damage, but on the other hand, they may have benefits for brain cancer therapies. In this review, we emphasize how nanomaterials may induce neurotoxic effects focusing on neurodegeneration, and how these effects could be exploited toward brain cancer treatment.

  9. Salmonella as a biological "Trojan horse" for neoplasia: future possibilities including brain cancer.

    PubMed

    Mlynarczyk, Gregory S A; Berg, Carrie A; Withrock, Isabelle C; Fick, Meghan E; Anderson, Stephen J; Laboissonniere, Lauren A; Jefferson, Matthew A; Brewer, Matthew T; Stock, Matthew L; Lange, Jennifer K; Luna, K C; Acharya, Sreemoyee; Kanuri, Sriharsha; Sharma, Shaunik; Kondru, Naveen C; McCormack, Garrett R; Carlson, Steve A

    2014-09-01

    This manuscript considers available evidence that a specific Salmonella strain could be used as an effective orally-administered option for cancer therapy involving the brain. It has been established that Salmonella preferentially colonizes neoplastic tissue and thrives as a facultative anaerobe in the intra-tumor environment. Although Salmonella accumulates in tumors by passive processes, it is still possible for lipopolysaccharide to cause sepsis and endotoxic shock during the migration of bacteria to the tumor site. An LPS-free version of a recently identified Salmonella isolate may have the capability to circumvent the blood brain barrier and provide a safer method of reaching brain tumors. This isolate merits further research as a "Trojan horse" for future oral biotherapy of brain cancer.

  10. Communicating with the Dead

    NASA Astrophysics Data System (ADS)

    Kurtz, Paul

    2000-03-01

    Communicating with dead persons is popular in the new paranatural (paranormal-spiritual) paradigm that has emerged today. This view violates physicalist principles. Scientists have investigated survival questions for over 150 years. Beginning with the Fox sisters in 1848, they have examined reports of apparitions and ghosts, rappings, table turnings, teleportation, levitation, and other alleged physicalist manifestations in séances. Such reports were discredited by uncovering hoaxes by alleged mediums, e.g. Eusapia Palladino (1910s), Marjorie Crandon (1920s), etc. In recent decades there has been a revival of interest in survival with reports of near-death experiences. Skeptics ask: Are such persons clinically dead? Today, channelers such as James Van Praagh, John Edwards, and Sylvia Browne claim to communicate directly with the dead (the "Sixth Sense"). There is no attempt at physical confirmation or independent eyewitness corroboration so essential for scientific inquiry. Subjective claims are uncritically accepted at their face value, though alternative naturalistic explanations can be given for the alleged phenomena.

  11. Three-Dimensional Magnetic Resonance Spectroscopic Imaging of Brain and Prostate Cancer1

    PubMed Central

    Kurhanewicz, John; Vigneron, Daniel B; Nelson, Sarah J

    2000-01-01

    Abstract Clinical applications of magnetic resonance spectroscopic imaging (MRSI) for the study of brain and prostate cancer have expanded significantly over the past 10 years. Proton MRSI studies of the brain and prostate have demonstrated the feasibility of noninvasively assessing human cancers based on metabolite levels before and after therapy in a clinically reasonable amount of time. MRSI provides a unique biochemical “window” to study cellular metabolism noninvasively. MRSI studies have demonstrated dramatic spectral differences between normal brain tissue (low choline and high N-acetyl aspartate, NAA) and prostate (low choline and high citrate) compared to brain (low NAA, high choline) and prostate (low citrate, high choline) tumors. The presence of edema and necrosis in both the prostate and brain was reflected by a reduction of the intensity of all resonances due to reduced cell density. MRSI was able to discriminate necrosis (absence of all metabolites, except lipids and lactate) from viable normal tissue and cancer following therapy. The results of current MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy as well as the magnitude and time course of metabolic changes after therapy can improve our understanding of cancer aggressiveness and mechanisms of therapeutic response. Clinically, combined MRI/MRSI has already demonstrated the potential for improved diagnosis, staging and treatment planning of brain and prostate cancer. Additionally, studies are under way to determine the accuracy of anatomic and metabolic parameters in providing an objective quantitative basis for assessing disease progression and response to therapy. PMID:10933075

  12. MicroRNAs Linked to Trastuzumab Resistance, Brain Metastases | Division of Cancer Prevention

    Cancer.gov

    Researchers have tied increased levels of a microRNA (miRNA) to resistance to the targeted therapy trastuzumab (Herceptin) in women with HER2-positive breast cancer. Another research team has discovered a “signature” of miRNAs in brain metastases in patients with melanoma—a signature that is also present in the primary tumor and could identify melanoma patients at increased risk of brain metastases. |

  13. New Breast Cancer Recursive Partitioning Analysis Prognostic Index in Patients With Newly Diagnosed Brain Metastases

    SciTech Connect

    Niwinska, Anna; Murawska, Magdalena

    2012-04-01

    Purpose: The aim of the study was to present a new breast cancer recursive partitioning analysis (RPA) prognostic index for patients with newly diagnosed brain metastases as a guide in clinical decision making. Methods and Materials: A prospectively collected group of 441 consecutive patients with breast cancer and brain metastases treated between the years 2003 and 2009 was assessed. Prognostic factors significant for univariate analysis were included into RPA. Results: Three prognostic classes of a new breast cancer RPA prognostic index were selected. The median survival of patients within prognostic Classes I, II, and III was 29, 9, and 2.4 months, respectively (p < 0.0001). Class I included patients with one or two brain metastases, without extracranial disease or with controlled extracranial disease, and with Karnofsky performance status (KPS) of 100. Class III included patients with multiple brain metastases with KPS of {<=}60. Class II included all other cases. Conclusions: The breast cancer RPA prognostic index is an easy and valuable tool for use in clinical practice. It can select patients who require aggressive treatment and those in whom whole-brain radiotherapy or symptomatic therapy is the most reasonable option. An individual approach is required for patients from prognostic Class II.

  14. Second cancer following cutaneous melanoma and cancers of the brain, thyroid, connective tissue, bone, and eye in Connecticut, 1935-82.

    PubMed

    Tucker, M A; Boice, J D; Hoffman, D A

    1985-12-01

    The risk of second primary cancers developing was evaluated in individuals with 6 rare tumors in Connecticut between 1935 and 1982. Small but significant excesses of all second cancers occurred in patients with cutaneous melanoma (42%), and cancers of the brain (59%), thyroid (49%), connective tissue (23%), bone (66%), and eye (40%). In individuals with cutaneous melanoma, the highest risks were for subsequent cutaneous melanomas [relative risk (RR) = 8.5] that persisted throughout all intervals of observation. The risk for second melanomas was higher in persons under age 40, consistent with a heritable component. Connective tissue tumors and breast cancers also occurred in excess. Among patients with brain cancer, an increase of melanoma was observed that may represent an underlying neural crest abnormality, although no excess of brain cancer was seen after melanoma. Reciprocal increases of bone cancer after connective tissue cancer and connective tissue cancer after bone cancer point to shared risk factors, such as high dose radiotherapy or genetic susceptibility states. An anticipated high risk of osteogenic sarcoma following Ewing's sarcoma was not seen. An excess of breast cancer (RR = 1.9) after thyroid cancer indicates common etiologic factors. Expected excesses of bilateral retinoblastoma and bone cancer after retinoblastoma were seen. Tumors commonly treated with alkylating agents or nitrosoureas (melanoma, brain, connective tissue) showed slightly elevated risks of acute nonlymphocytic leukemia. Prostate cancer was frequently found to be in excess, but this is likely an artifact due to ascertainment bias.

  15. Descriptive epidemiology and geographic variation of childhood brain cancer in the US

    SciTech Connect

    Bunin, G.R.

    1984-11-01

    The descriptive epidemiology and geographic variation of childhood brain cancer by cell type was studied. For each cell type, the study indicates time trends, sex ratios, geographic variation, racial differences, urban-rural differences, and socioeconomic differences. Since, in animals, one virus or chemical often causes tumors at several sites, the sex, race, age and socio-economic status of childhood brain cancer cases was compared to the epidemiologic profile of childhood leukemias. Similar epidemiological profiles would imply similar etiologies. 116 references, 18 figures, 71 tables.

  16. Micronucleus formation induced by dielectric barrier discharge plasma exposure in brain cancer cells

    NASA Astrophysics Data System (ADS)

    Kaushik, Nagendra K.; Uhm, Hansup; Ha Choi, Eun

    2012-02-01

    Induction of micronucleus formation (cytogenetic damage) in brain cancer cells upon exposure of dielectric barrier discharge plasma has been investigated. We have investigated the influence of exposure and incubation times on T98G brain cancer cells by using growth kinetic, clonogenic, and micronucleus formation assay. We found that micronucleus formation rate directly depends on the plasma exposure time. It is also shown that colony formation capacity of cells has been inhibited by the treatment of plasma at all doses. Cell death and micronucleus formation are shown to be significantly elevated by 120 and 240 s exposure of dielectric barrier discharge plasma.

  17. Chemotherapy Altered Brain Functional Connectivity in Women with Breast Cancer: A Pilot Study

    PubMed Central

    Dumas, Julie A.; Makarewicz, Jenna; Schaubhut, Geoffrey J.; Devins, Robert; Albert, Kimberly; Dittus, Kim; Newhouse, Paul A.

    2013-01-01

    Adjuvant chemotherapy is associated with improvements in long-term cancer survival. However, reports of cognitive impairment following treatment emphasize the importance of understanding the long-term effects of chemotherapy on brain functioning. Cognitive deficits found in chemotherapy patients suggest a change in brain functioning that affects specific cognitive domains such as attentional processing and executive functioning. This study examined the processes potentially underlying these changes in cognition by examining brain functional connectivity pre- and post-chemotherapy in women with breast cancer. Functional connectivity examines the temporal correlation between spatially remote brain regions in an effort to understand how brain networks support specific cognitive functions. Nine women diagnosed with breast cancer completed a functional magnetic resonance imaging (fMRI) session before chemotherapy, one month after, and one year after the completion of chemotherapy. Seed-based functional connectivity analyses were completed using seeds in the intraparietal sulcus (IPS) to examine connectivity in the dorsal anterior attention network and in the posterior cingulate cortex (PCC) to examine connectivity in the default mode network. Results showed decreased functional connectivity one month after chemotherapy that partially returned to baseline at one year in the dorsal attention network. Decreased connectivity was seen in the default mode network at one month and one year following chemotherapy. In addition, increased subjective memory complaints were noted at one month and one year post-chemotherapy. These findings suggest a detrimental effect of chemotherapy on brain functional connectivity that is potentially related to subjective cognitive assessment. PMID:23852814

  18. Systemic treatments for brain metastases from breast cancer, non-small cell lung cancer, melanoma and renal cell carcinoma: an overview of the literature.

    PubMed

    Lombardi, Giuseppe; Di Stefano, Anna Luisa; Farina, Patrizia; Zagonel, Vittorina; Tabouret, Emeline

    2014-09-01

    The frequency of metastatic brain tumors has increased over recent years; the primary tumors most involved are breast cancer, lung cancer, melanoma and renal cell carcinoma. While radiation therapy and surgery remain the mainstay treatment in selected patients, new molecular drugs have been developed for brain metastases. Studies so far report interesting results. This review focuses on systemic cytotoxic drugs and, in particular, on new targeted therapies and their clinically relevant activities in brain metastases from solid tumors in adults.

  19. 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 ...

  20. Memoirs of an amnesiac--two years with brain cancer, or the outer space of living with brain tumors.

    PubMed

    Dor-Ner, A D

    1991-11-01

    Alexandra Dane Dor-Ner ("Ali" to friends) was a photographer, writer, and a producer of programs on child development. In February 1989, at the age of 41, she was diagnosed with malignant brain cancer. During the following months she underwent brain surgery, radiation, and implant radiation. Throughout her treatment, she continued to work on a novel and write stores and literary criticism. A volunteer in hospitals before her illness, she now became very active in a support group of brain tumor patients and often served as a first resource and contact for others diagnosed with brain cancer. All was very accomplished; her award-winning photographs have been exhibited in the Smithsonian Institution in Washington, and her articles and pictures were published in books, periodicals, and newspapers around the world. A native of Boston, Ali lived for 17 years in Israel, where she joined a group of photographers documenting disappearing neighborhoods in Jerusalem. She was awarded first prize in the "Israel Through the Camera's Eye" competition in 1977. She also taught English and photography in Israeli high schools. Ali traveled extensively on photographic assignments. Early in their 22-year marriage, she and her husband circumnavigated the globe on a freighter, producing a documentary film of the voyage. "Memoirs of an Amnesiac" was written while Ali was a student at the Warren Wilson College Writers' Program in North Carolina; she intended to explore the compensatory aspects of her disease. In February 1991, within days of completing the piece, Ali had a third brain operation to remove a regrowth of cancerous tumor cells, as well as necrotic tissue. Two days later, she was again operated on to remove blood clots resulting from the previous surgery. For the next 12 weeks she fought to regain her ability to walk, talk, and write. In May, she underwent a fifth operation to relieve pressure in the brain. She was still in the hospital when she learned, to her great pleasure

  1. Memoirs of an amnesiac--two years with brain cancer, or the outer space of living with brain tumors.

    PubMed Central

    Dor-Ner, A. D.

    1991-01-01

    Alexandra Dane Dor-Ner ("Ali" to friends) was a photographer, writer, and a producer of programs on child development. In February 1989, at the age of 41, she was diagnosed with malignant brain cancer. During the following months she underwent brain surgery, radiation, and implant radiation. Throughout her treatment, she continued to work on a novel and write stores and literary criticism. A volunteer in hospitals before her illness, she now became very active in a support group of brain tumor patients and often served as a first resource and contact for others diagnosed with brain cancer. All was very accomplished; her award-winning photographs have been exhibited in the Smithsonian Institution in Washington, and her articles and pictures were published in books, periodicals, and newspapers around the world. A native of Boston, Ali lived for 17 years in Israel, where she joined a group of photographers documenting disappearing neighborhoods in Jerusalem. She was awarded first prize in the "Israel Through the Camera's Eye" competition in 1977. She also taught English and photography in Israeli high schools. Ali traveled extensively on photographic assignments. Early in their 22-year marriage, she and her husband circumnavigated the globe on a freighter, producing a documentary film of the voyage. "Memoirs of an Amnesiac" was written while Ali was a student at the Warren Wilson College Writers' Program in North Carolina; she intended to explore the compensatory aspects of her disease. In February 1991, within days of completing the piece, Ali had a third brain operation to remove a regrowth of cancerous tumor cells, as well as necrotic tissue. Two days later, she was again operated on to remove blood clots resulting from the previous surgery. For the next 12 weeks she fought to regain her ability to walk, talk, and write. In May, she underwent a fifth operation to relieve pressure in the brain. She was still in the hospital when she learned, to her great pleasure

  2. Radio-frequency radiation exposure from AM radio transmitters and childhood leukemia and brain cancer.

    PubMed

    Ha, Mina; Im, Hyoungjune; Lee, Mihye; Kim, Hyun Joo; Kim, Byung-Chan; Gimm, Yoon-Myoung; Pack, Jeong-Ki

    2007-08-01

    Leukemia and brain cancer patients under age 15 years, along with controls with respiratory illnesses who were matched to cases on age, sex, and year of diagnosis (1993-1999), were selected from 14 South Korean hospitals using the South Korean Medical Insurance Data System. Diagnoses were confirmed through the South Korean National Cancer Registry. Residential addresses were obtained from medical records. A newly developed prediction program incorporating a geographic information system that was modified by the results of actual measurements was used to estimate radio-frequency radiation (RFR) exposure from 31 amplitude modulation (AM) radio transmitters with a power of 20 kW or more. A total of 1,928 leukemia patients, 956 brain cancer patients, and 3,082 controls were analyzed. Cancer risks were estimated using conditional logistic regression adjusted for residential area, socioeconomic status, and community population density. The odds ratio for all types of leukemia was 2.15 (95% confidence interval (CI): 1.00, 4.67) among children who resided within 2 km of the nearest AM radio transmitter as compared with those resided more than 20 km from it. For total RFR exposure from all transmitters, odds ratios for lymphocytic leukemia were 1.39 (95% CI: 1.04, 1.86) and 1.59 (95% CI: 1.19, 2.11) for children in the second and third quartiles, respectively, versus the lowest quartile. Brain cancer and infantile cancer were not associated with AM RFR.

  3. 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.

  4. Multi-study Integration of Brain Cancer Transcriptomes Reveals Organ-Level Molecular Signatures

    PubMed Central

    Sung, Jaeyun; Kim, Pan-Jun; Ma, Shuyi; Funk, Cory C.; Magis, Andrew T.; Wang, Yuliang; Hood, Leroy; Geman, Donald; Price, Nathan D.

    2013-01-01

    We utilized abundant transcriptomic data for the primary classes of brain cancers to study the feasibility of separating all of these diseases simultaneously based on molecular data alone. These signatures were based on a new method reported herein – Identification of Structured Signatures and Classifiers (ISSAC) – that resulted in a brain cancer marker panel of 44 unique genes. Many of these genes have established relevance to the brain cancers examined herein, with others having known roles in cancer biology. Analyses on large-scale data from multiple sources must deal with significant challenges associated with heterogeneity between different published studies, for it was observed that the variation among individual studies often had a larger effect on the transcriptome than did phenotype differences, as is typical. For this reason, we restricted ourselves to studying only cases where we had at least two independent studies performed for each phenotype, and also reprocessed all the raw data from the studies using a unified pre-processing pipeline. We found that learning signatures across multiple datasets greatly enhanced reproducibility and accuracy in predictive performance on truly independent validation sets, even when keeping the size of the training set the same. This was most likely due to the meta-signature encompassing more of the heterogeneity across different sources and conditions, while amplifying signal from the repeated global characteristics of the phenotype. When molecular signatures of brain cancers were constructed from all currently available microarray data, 90% phenotype prediction accuracy, or the accuracy of identifying a particular brain cancer from the background of all phenotypes, was found. Looking forward, we discuss our approach in the context of the eventual development of organ-specific molecular signatures from peripheral fluids such as the blood. PMID:23935471

  5. Cancer and non-cancer brain and eye effects of chronic low-dose ionizing radiation exposure

    PubMed Central

    2012-01-01

    Background According to a fundamental law of radiobiology (“Law of Bergonié and Tribondeau”, 1906), the brain is a paradigm of a highly differentiated organ with low mitotic activity, and is thus radio-resistant. This assumption has been challenged by recent evidence discussed in the present review. Results Ionizing radiation is an established environmental cause of brain cancer. Although direct evidence is lacking in contemporary fluoroscopy due to obvious sample size limitation, limited follow-up time and lack of focused research, anecdotal reports of clusters have appeared in the literature, raising the suspicion that brain cancer may be a professional disease of interventional cardiologists. In addition, although terminally differentiated neurons have reduced or mild proliferative capacity, and are therefore not regarded as critical radiation targets, adult neurogenesis occurs in the dentate gyrus of the hippocampus and the olfactory bulb, and is important for mood, learning/memory and normal olfactory function, whose impairment is a recognized early biomarker of neurodegenerative diseases. The head doses involved in radiotherapy are high, usually above 2 Sv, whereas the low-dose range of professional exposure typically involves lifetime cumulative whole-body exposure in the low-dose range of < 200 mSv, but with head exposure which may (in absence of protection) arrive at a head equivalent dose of 1 to 3 Sv after a professional lifetime (corresponding to a brain equivalent dose around 500 mSv). Conclusions At this point, a systematic assessment of brain (cancer and non-cancer) effects of chronic low-dose radiation exposure in interventional cardiologists and staff is needed. PMID:22540409

  6. Deciphering the Finger Prints of Brain Cancer Glioblastoma Multiforme from Four Different Patients by Using Near Infrared Raman Spectroscopy

    PubMed Central

    Banerjee, Hirendra Nath; Banerji, Arnold; Banerjee, Arunendra Nath; Riddick, Eilena; Petis, Jenae; Evans, Shavonda; Patel, Megha; Parson, Carl; Smith, Valerie; Gwebu, E.; Voisin, Sarah

    2015-01-01

    To explore the effectiveness of Raman spectra to diagnose brain cancer glioblastoma multiforme (GBM), we investigated the Raman spectra of single cell from four different GBM cell lines developed from four different patients and analyzed the spectra. The Raman spectra of brain cancer (GBM) cells were similar in all these cell lines. The results indicate that Raman spectra can offer the experimental basis for the cancer diagnosis and treatment. PMID:25937869

  7. 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.

  8. Systematic review of wireless phone use and brain cancer and other head tumors.

    PubMed

    Repacholi, Michael H; Lerchl, Alexander; Röösli, Martin; Sienkiewicz, Zenon; Auvinen, Anssi; Breckenkamp, Jürgen; d'Inzeo, Guglielmo; Elliott, Paul; Frei, Patrizia; Heinrich, Sabine; Lagroye, Isabelle; Lahkola, Anna; McCormick, David L; Thomas, Silke; Vecchia, Paolo

    2012-04-01

    We conducted a systematic review of scientific studies to evaluate whether the use of wireless phones is linked to an increased incidence of the brain cancer glioma or other tumors of the head (meningioma, acoustic neuroma, and parotid gland), originating in the areas of the head that most absorb radiofrequency (RF) energy from wireless phones. Epidemiology and in vivo studies were evaluated according to an agreed protocol; quality criteria were used to evaluate the studies for narrative synthesis but not for meta-analyses or pooling of results. The epidemiology study results were heterogeneous, with sparse data on long-term use (≥ 10 years). Meta-analyses of the epidemiology studies showed no statistically significant increase in risk (defined as P < 0.05) for adult brain cancer or other head tumors from wireless phone use. Analyses of the in vivo oncogenicity, tumor promotion, and genotoxicity studies also showed no statistically significant relationship between exposure to RF fields and genotoxic damage to brain cells, or the incidence of brain cancers or other tumors of the head. Assessment of the review results using the Hill criteria did not support a causal relationship between wireless phone use and the incidence of adult cancers in the areas of the head that most absorb RF energy from the use of wireless phones. There are insufficient data to make any determinations about longer-term use (≥ 10 years).

  9. Association of brain cancer with residential exposure to petrochemical air pollution in Taiwan.

    PubMed

    Liu, Chia-Chia; Chen, Chih-Cheng; Wu, Trong-Neng; Yang, Chun-Yuh

    2008-01-01

    To investigate the relationship between petrochemical air pollution and brain cancer (29 yr of age or younger), the authors conducted a matched case-control study using deaths that occurred in Taiwan from 1995 through 2005. Data on all eligible brain cancer deaths were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. The control group consisted of subjects who died from causes other than neoplasms or diseases that were not associated with respiratory problems. The controls were pair matched to the cases by sex, year of birth, and year of death. Each matched control was selected randomly from the set of possible controls for each case. The proportion of a municipality's total population employed in the petrochemical industry in a municipality was used as an indicator of a resident's exposure to air emissions from the petrochemical industry. The subjects were divided into tertiles according to the levels of the index just described. Subjects who lived in the group of municipalities characterized by the highest levels of petrochemical air pollution had a statistically significant higher risk of developing brain cancer than the group that lived in municipalities with the lowest petrochemical air pollution levels after controlling for possible confounders (OR = 1.65, 95% CI = 1.00-2.73). The findings of this study warrant further investigation of the role of petrochemical air pollution in the etiology of brain cancer. PMID:18214804

  10. Exercise Improves Physical Function and Mental Health of Brain Cancer Survivors: Two Exploratory Case Studies.

    PubMed

    Levin, Gregory T; Greenwood, Kenneth M; Singh, Favil; Tsoi, Daphne; Newton, Robert U

    2016-06-01

    Background Malignant brain tumors are unpredictable and incurable, with 5-year survival rates less than 30%. The poor prognosis combined with intensive treatment necessitates the inclusion of complementary and supportive therapies that optimize quality of life and reduce treatment-related declines in health. Exercise therapy has been shown to be beneficial in other cancer populations, but no evidence is available for brain cancer survivors. Therefore, we report results from 2 preliminary cases. Methods Two female patients diagnosed with glioblastoma multiforme and oligodendroglioma participated in a structured and supervised 12-week exercise program. The program consisted of two 1-hour resistance and aerobic exercise sessions per week and additional self-managed aerobic sessions. Outcome measures of strength, cardiovascular fitness, and several psychological indicators (depression, anxiety, and quality of life) were recorded at baseline, after 6 weeks and at the conclusion of the intervention. Results Exercise was well tolerated; both participants completed all 24 sessions and the home-based component with no adverse effects. Objective outcome measures displayed positive responses relating to reduced morbidity. Similar positive responses were found for psychological outcomes. Scores on the Hospital Anxiety and Depression Scale showed clinically meaningful improvements in depression and total distress. Conclusion These findings provide initial evidence that, despite the difficulties associated with brain cancer treatment and survivorship, exercise may be safe and beneficial and should be considered in the overall management of patients with brain cancer.

  11. Environmental effects on molecular biomarkers expression in pancreatic and brain cancer

    NASA Astrophysics Data System (ADS)

    Mensah, Lawrence; Mallidi, Srivalleesha; Massodi, Iqbal; Anbil, Sriram; Mai, Zhiming; Hasan, Tayyaba

    2013-03-01

    A complete understanding of the biological mechanisms regulating devastating disease such as cancer remains elusive. Pancreatic and brain cancers are primary among the cancer types with poor prognosis. Molecular biomarkers have emerged as group of proteins that are preferentially overexpressed in cancers and with a key role in driving disease progression and resistance to chemotherapy. The epidermal growth factor receptor (EGFR), a cell proliferative biomarker is particularly highly expressed in most cancers including brain and pancreatic cancers. The ability of EGFR to sustain prolong cell proliferation is augmented by biomarkers such as Bax, Bcl-XL and Bcl-2, proteins regulating the apoptotic process. To better understand the role and effect of the microenvironment on these biomarkers in pancreatic cancer (PaCa); we analysed two pancreatic tumor lines (AsPc-1 and MiaPaCa-2) in 2D, 3D in-vitro cultures and in orthotopic tumors at different growth stages. We also investigated in patient derived glioblastoma (GBM) tumor cultures, the ability to utilize the EGFR expression to specifically deliver photosensitizer to the cells for photodynamic therapy. Overall, our results suggest that (1) microenvironment changes affect biomarker expression; thereby it is critical to understand these effects prior to designing combination therapies and (2) EGFR expression in tumor cells indeed could serve as a reliable and a robust biomarker that could be used to design targeted and image-guided photodynamic therapy.

  12. Nitrates in drinking water and the risk of death from brain cancer: does hardness in drinking water matter?

    PubMed

    Ho, Chi-Kung; Yang, Ya-Hui; Yang, Chun-Yuh

    2011-01-01

    The objectives of this study were to (1) examine the relationship between nitrate levels in public water supplies and risk of death from brain cancer and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water might modify the influence of nitrates on development of brain cancer. A matched cancer case-control study was used to investigate the relationship between the risk of death from brain cancer and exposure to nitrates in drinking water in Taiwan. All brain cancer deaths of Taiwan residents from 2003 through 2008 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Controls were deaths from other causes and were pair-matched to cancer cases by gender, year of birth, and year of death. Information on the levels of nitrate-nitrogen (NO₃-N), Ca, and Mg in drinking water was obtained from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases and controls was presumed to be the source of the subject's NO₃-N, Ca, and Mg exposure via drinking water. Relative to individuals whose NO₃-N exposure level was <0.38 ppm, the adjusted OR (95% CI) for brain cancer occurrence was 1.04 (0.85-1.27) for individuals who resided in municipalities served by drinking water with a NO₃-N exposure ≥ 0.38 ppm. No marked effect modification was observed due to Ca and Mg intake via drinking water on brain cancer occurrence.

  13. [Brain metastases in breast cancer. Epidemiology and natural history. The Institut Curie experience].

    PubMed

    Gachet, Julie; Giroux, Julie; Girre, Véronique; Brain, Étienne; Kirova, Youlia; Mignot, Laurent; Mazeron, Jean-Jacques; Dutertre, Guillaume; Pouit, Bernard; Mosseri, Véronique; Falcou, Marie-Christine; Cottu, Paul H

    2011-04-01

    Breast cancer is the second cause for brain metastases. Their incidence is rising, partly due to the therapeutic improvements which alter the natural history of breast cancer. Predictive factors for brain metastases have been identified: HER2 oncogene overexpression, lack of expression of hormone receptors, young age and triple negative status. Brain metastases prognosis remains poor with a median survival shorter than 1 year, except for solitary lesions treated by surgery or radiosurgery. We have analysed two series of data from Institut Curie (Paris and Saint-Cloud). In women younger than 65 years, with HER2 negative breast carcinoma, median survival was 7.1 months. In women older than 65 years, median survival was 4 months.

  14. Some Brain Cancer Patients Have Radiation Options: Study

    MedlinePlus

    ... The report was published July 26 in the Journal of the American Medical Association . In the past, whole brain radiation was ... New Hyde Park, N.Y.; July 26, 2016, Journal of the American Medical Association HealthDay Copyright (c) 2016 HealthDay . All rights ...

  15. Brain MRI Findings in Neurological Complications of Cancer Treatment.

    PubMed

    Cabaj, Astra; Bekiesińska-Figatowska, Monika; Duczkowska, Agnieszka; Duczkowski, Marek

    2016-01-01

    The amount of people living with cancer is increasing; they live longer and have thus a higher risk of developing neurological complications. Magnetic resonance as a diagnostic procedure of choice in detecting the reasons of neurological/psychiatric symptoms in oncological patients is nowadays relatively easily accessible. Early diagnosis established by radiologists familiar with neurological entities that may follow cancer treatment allow clinicians to provide proper treatment, even if the diagnosis seems unbelievable. The review of MR images of acute and chronic neurological complications of cancer treatment from the authors' own archive is the focus of this report. Neurological complications of cancer can be metastatic and non-metastatic; the first cannot be considered as a treatment complication, the latter can be chemoor radiotherapy-induced, acute, chronic and delayed. In our material we dealt with complications with dramatic course (stroke, PRES, acute leukoencephalopathy, Wernicke's encephalopathy) and with cases with milder and/or longer course (neuro-infections, chronic leukoencephalopathy, telangiectasias and/or cavernous hemangiomas, second tumors: glioma and meningioma after irradiation). The central nervous system is very susceptible to complications of systemic cancer and its treatment. Even though the first thought of clinicians and radiologists after a patient's first neurological/psychiatric symptoms appears concerns the metastatic spread of the disease, they need to have an understanding that there are a number of other causes of such symptoms. The knowledge of entities which can be expected and diagnostic experience prevent clinicians from making wrong diagnosis. PMID:27629856

  16. Immunotherapy of Brain Cancers: The Past, the Present, and Future Directions

    PubMed Central

    Ge, Lisheng; Hoa, Neil; Bota, Daniela A.; Natividad, Josephine; Howat, Andrew; Jadus, Martin R.

    2010-01-01

    Treatment of brain cancers, especially high grade gliomas (WHO stage III and IV) is slowly making progress, but not as fast as medical researchers and the patients would like. Immunotherapy offers the opportunity to allow the patient's own immune system a chance to help eliminate the cancer. Immunotherapy's strength is that it efficiently treats relatively small tumors in experimental animal models. For some patients, immunotherapy has worked for them while not showing long-term toxicity. In this paper, we will trace the history of immunotherapy for brain cancers. We will also highlight some of the possible directions that this field may be taking in the immediate future for improving this therapeutic option. PMID:21437175

  17. Delayed leukoencephalopathy of non-small cell lung cancer patients with brain metastases underwent whole brain radiation therapy.

    PubMed

    Zhong, Xiaoling; Huang, Biao; Feng, Jieying; Yang, Wanqun; Liu, Hongjun

    2015-10-01

    To explore the incidence, MR imaging findings, dynamic developing process of delayed leukoencephalopathy (DLE) in non-small cell lung cancer (NSCLC) patients with brain metastases patients who undergone whole brain radiation (WBRT) therapy, we retrospectively reviewed 48 NSCLC patients who underwent WBRT for brain metastases from January 2010 through June 2015 and had evaluable magnetic resonance imaging after treatment. The DLE were graded using a scale to evaluate T2-FLAIR (fluid attenuated image recovery) images: grade 1 = little or no white matter hyperintensity, grade 2 = limited periventricular hyperintensity and grade 3 = diffuse white matter hyperintensity. 48 NSCLC patients with brain metastases were enrolled. The median age of these patients was 55.7 years (range 33-75 years). The median follow-up was 12 months. The characteristic MR imaging of DLE in those patients was bilaterally diffuse white matter T2 hyperintensity around the periventricular areas without enhancement, sparing from U-fiber, callosum and gray matter structure. The incidence of DLE developed 6.25% (3/48), 30.00% (12/40), 48.39% (15/31), 61.90% (13/21), 85.71% (6/7), 100% (3/3) in those patients who were followed up for 3, 6, 9, 12, 24, 36 months, respectively. Through increased understanding of it, it may be possible to help clinicians develop further therapeutic strategies to maximize benefit while limiting potential long term toxicities. These data supplement existing reports regarding the late effects of WBRT in NSCLC patients with brain metastasis.

  18. Transmigration characteristics of breast cancer and melanoma cells through the brain endothelium: Role of Rac and PI3K.

    PubMed

    Molnár, Judit; Fazakas, Csilla; Haskó, János; Sipos, Orsolya; Nagy, Krisztina; Nyúl-Tóth, Ádám; Farkas, Attila E; Végh, Attila G; Váró, György; Galajda, Péter; Krizbai, István A; Wilhelm, Imola

    2016-05-01

    Brain metastases are common and devastating complications of both breast cancer and melanoma. Although mammary carcinoma brain metastases are more frequent than those originating from melanoma, this latter has the highest tropism to the brain. Using static and dynamic in vitro approaches, here we show that melanoma cells have increased adhesion to the brain endothelium in comparison to breast cancer cells. Moreover, melanoma cells can transmigrate more rapidly and in a higher number through brain endothelial monolayers than breast cancer cells. In addition, melanoma cells have increased ability to impair tight junctions of cerebral endothelial cells. We also show that inhibition of Rac or PI3K impedes adhesion of breast cancer cells and melanoma cells to the brain endothelium. In addition, inhibition of Rac or PI3K inhibits the late phase of transmigration of breast cancer cells and the early phase of transmigration of melanoma cells. On the other hand, the Rac inhibitor EHT1864 impairs the junctional integrity of the brain endothelium, while the PI3K inhibitor LY294002 has no damaging effect on interendothelial junctions. We suggest that targeting the PI3K/Akt pathway may represent a novel opportunity in preventing the formation of brain metastases of melanoma and breast cancer.

  19. [Whole Brain Irradiation and Hypo-fractionation Radiotherapy for the Metastases in Non-small Cell Lung Cancer].

    PubMed

    Gu, Xingting; Zhao, Yaqin; Xu, Feng

    2016-04-20

    Up to 40% non-small cell lung cancer patients developed brain metastasis during progression. Multiple brain metastases are common in non-small cell lung cancer. The prognosis of brain metastasis is poor with median survival of less than 1 year. Radio therapy for brain metastases has gradually developed from whole brain radiotherapy (WBRT) to various radiation strategies. WBRT, surgery+WBRT, stereotactic radiotherapy+WBRT or WBRT with simultaneous integrated boost (SIB), etc. have better overall survival than those untreated patients. The damage of the cognitive function from WBRT has been realized recently, however, options of radiation strategies for long expected survival patients remain controversial. This paper will discuss different WBRT strategies and treatment side effects of non-small cell lung cancer with brain metastases. PMID:27118651

  20. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.

    PubMed

    Zhang, Isabella; Zaorsky, Nicholas G; Palmer, Joshua D; Mehra, Ranee; Lu, Bo

    2015-10-01

    The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

  1. Novel Brain Cancer Treatment Taps into Sound Waves

    MedlinePlus

    ... report was published June 15 in the journal Science Translational Medicine . SOURCES: Frederic Sottilini, CEO, CarThera, Paris, France; Ekokobe ... Cancer Treatment Center, Temple, Texas; June 15, 2016, Science Translational Medicine HealthDay Copyright (c) 2016 HealthDay . All rights reserved. ...

  2. 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.

  3. Dead of night.

    PubMed

    Balter, Leon

    2010-07-01

    Dead of Night, the first psychoanalytic horror film, was produced in England in 1945, immediately after the end of World War II--that is, after the English population had suffered systematic Nazi terror from imminent invasion, incessant aerial bombing, and rocket-bombs. This film continued the prewar format of horror films based on themes of the supernatural and the hubris and excesses of science. However, it introduced psychoanalysis as the science in question. The film is structured on two levels: a genteel English country weekend to which witty and urbane guests have been invited; and five horror stories told by the guests. Psychoanalytic insights into this film structure are used here to explain how the film induces horror in the audience.

  4. Dead of night.

    PubMed

    Balter, Leon

    2010-07-01

    Dead of Night, the first psychoanalytic horror film, was produced in England in 1945, immediately after the end of World War II--that is, after the English population had suffered systematic Nazi terror from imminent invasion, incessant aerial bombing, and rocket-bombs. This film continued the prewar format of horror films based on themes of the supernatural and the hubris and excesses of science. However, it introduced psychoanalysis as the science in question. The film is structured on two levels: a genteel English country weekend to which witty and urbane guests have been invited; and five horror stories told by the guests. Psychoanalytic insights into this film structure are used here to explain how the film induces horror in the audience. PMID:20726184

  5. Diagnosis of Brain Metastases from Lung Cancer Using a Modified Electromagnetism like Mechanism Algorithm.

    PubMed

    Chen, Kun-Huang; Wang, Kung-Jeng; Adrian, Angelia Melani; Wang, Kung-Min; Teng, Nai-Chia

    2016-01-01

    Brain metastases are commonly found in patients that are diagnosed with primary malignancy on their lung. Lung cancer patients with brain metastasis tend to have a poor survivability, which is less than 6 months in median. Therefore, an early and effective detection system for such disease is needed to help prolong the patients' survivability and improved their quality of life. A modified electromagnetism-like mechanism (EM) algorithm, MEM-SVM, is proposed by combining EM algorithm with support vector machine (SVM) as the classifier and opposite sign test (OST) as the local search technique. The proposed method is applied to 44 UCI and IDA datasets, and 5 cancers microarray datasets as preliminary experiment. In addition, this method is tested on 4 lung cancer microarray public dataset. Further, we tested our method on a nationwide dataset of brain metastasis from lung cancer (BMLC) in Taiwan. Since the nature of real medical dataset to be highly imbalanced, the synthetic minority over-sampling technique (SMOTE) is utilized to handle this problem. The proposed method is compared against another 8 popular benchmark classifiers and feature selection methods. The performance evaluation is based on the accuracy and Kappa index. For the 44 UCI and IDA datasets and 5 cancer microarray datasets, a non-parametric statistical test confirmed that MEM-SVM outperformed the other methods. For the 4 lung cancer public microarray datasets, MEM-SVM still achieved the highest mean value for accuracy and Kappa index. Due to the imbalanced property on the real case of BMLC dataset, all methods achieve good accuracy without significance difference among the methods. However, on the balanced BMLC dataset, MEM-SVM appears to be the best method with higher accuracy and Kappa index. We successfully developed MEM-SVM to predict the occurrence of brain metastasis from lung cancer with the combination of SMOTE technique to handle the class imbalance properties. The results confirmed that MEM

  6. Engineering a Brain Cancer Chip for High-throughput Drug Screening.

    PubMed

    Fan, Yantao; Nguyen, Duong Thanh; Akay, Yasemin; Xu, Feng; Akay, Metin

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant of all human primary brain cancers, in which drug treatment is still one of the most effective treatments. However, existing drug discovery and development methods rely on the use of conventional two-dimensional (2D) cell cultures, which have been proven to be poor representatives of native physiology. Here, we developed a novel three-dimensional (3D) brain cancer chip composed of photo-polymerizable poly(ethylene) glycol diacrylate (PEGDA) hydrogel for drug screening. This chip can be produced after a few seconds of photolithography and requires no silicon wafer, replica molding, and plasma bonding like microfluidic devices made of poly(dimethylsiloxane) (PDMS). We then cultured glioblastoma cells (U87), which formed 3D brain cancer tissues on the chip, and used the GBM chip to perform combinatorial treatment of Pitavastatin and Irinotecan. The results indicate that this chip is capable of high-throughput GBM cancer spheroids formation, multiple-simultaneous drug administration, and a massive parallel testing of drug response. Our approach is easily reproducible, and this chip has the potential to be a powerful platform in cases such as high-throughput drug screening and prolonged drug release. The chip is also commercially promising for other clinical applications, including 3D cell culture and micro-scale tissue engineering. PMID:27151082

  7. Engineering a Brain Cancer Chip for High-throughput Drug Screening.

    PubMed

    Fan, Yantao; Nguyen, Duong Thanh; Akay, Yasemin; Xu, Feng; Akay, Metin

    2016-05-06

    Glioblastoma multiforme (GBM) is the most common and malignant of all human primary brain cancers, in which drug treatment is still one of the most effective treatments. However, existing drug discovery and development methods rely on the use of conventional two-dimensional (2D) cell cultures, which have been proven to be poor representatives of native physiology. Here, we developed a novel three-dimensional (3D) brain cancer chip composed of photo-polymerizable poly(ethylene) glycol diacrylate (PEGDA) hydrogel for drug screening. This chip can be produced after a few seconds of photolithography and requires no silicon wafer, replica molding, and plasma bonding like microfluidic devices made of poly(dimethylsiloxane) (PDMS). We then cultured glioblastoma cells (U87), which formed 3D brain cancer tissues on the chip, and used the GBM chip to perform combinatorial treatment of Pitavastatin and Irinotecan. The results indicate that this chip is capable of high-throughput GBM cancer spheroids formation, multiple-simultaneous drug administration, and a massive parallel testing of drug response. Our approach is easily reproducible, and this chip has the potential to be a powerful platform in cases such as high-throughput drug screening and prolonged drug release. The chip is also commercially promising for other clinical applications, including 3D cell culture and micro-scale tissue engineering.

  8. Engineering a Brain Cancer Chip for High-throughput Drug Screening

    PubMed Central

    Fan, Yantao; Nguyen, Duong Thanh; Akay, Yasemin; Xu, Feng; Akay, Metin

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and malignant of all human primary brain cancers, in which drug treatment is still one of the most effective treatments. However, existing drug discovery and development methods rely on the use of conventional two-dimensional (2D) cell cultures, which have been proven to be poor representatives of native physiology. Here, we developed a novel three-dimensional (3D) brain cancer chip composed of photo-polymerizable poly(ethylene) glycol diacrylate (PEGDA) hydrogel for drug screening. This chip can be produced after a few seconds of photolithography and requires no silicon wafer, replica molding, and plasma bonding like microfluidic devices made of poly(dimethylsiloxane) (PDMS). We then cultured glioblastoma cells (U87), which formed 3D brain cancer tissues on the chip, and used the GBM chip to perform combinatorial treatment of Pitavastatin and Irinotecan. The results indicate that this chip is capable of high-throughput GBM cancer spheroids formation, multiple-simultaneous drug administration, and a massive parallel testing of drug response. Our approach is easily reproducible, and this chip has the potential to be a powerful platform in cases such as high-throughput drug screening and prolonged drug release. The chip is also commercially promising for other clinical applications, including 3D cell culture and micro-scale tissue engineering. PMID:27151082

  9. [Interest of biological documentation on brain metastatic disease in breast cancer: A case report].

    PubMed

    Boissonneau, S; Faguer, R; Joubert, C; Fuentes, S; Metellus, P

    2015-08-01

    Breast cancer, after lung cancer, is the second major cause of brain metastases. In breast cancer, the prognosis is closely linked to the molecular subtype of the primary tumor. Targeted therapies, with or without cytotoxic treatment, have significantly modified overall survival in these patients. We report, the case of a patient suffering from breast cancer with brain metastasis in whom the biological documentation of the metastatic disease permitted to tailor the systemic treatment. Analysis of the surgical specimen revealed an immunohistochemical HER2 positive staining, which was not found in the primary tumor and therefore warranted trastuzumab administration. Another interesting insight based on this case report was to underline the phenotypic heterogeneity of the metastatic disease and its potential dynamic course as illustrated by the dissociated response to trastuzumab on body TEP-TDM in this particular patient. This case report also highlights the new place of the neurosurgeon in brain metastases management, not only as a participant in local treatment but also as a physician who is in fact involved in the delineation of the global oncological strategy in these patients as well as medical oncologists and radiation oncologists.

  10. Chemotherapy altered brain functional connectivity in women with breast cancer: a pilot study.

    PubMed

    Dumas, Julie A; Makarewicz, Jenna; Schaubhut, Geoffrey J; Devins, Robert; Albert, Kimberly; Dittus, Kim; Newhouse, Paul A

    2013-12-01

    Adjuvant chemotherapy is associated with improvements in long-term cancer survival. However, reports of cognitive impairment following treatment emphasize the importance of understanding the long-term effects of chemotherapy on brain functioning. Cognitive deficits found in chemotherapy patients suggest a change in brain functioning that affects specific cognitive domains such as attentional processing and executive functioning. This study examined the processes potentially underlying these changes in cognition by examining brain functional connectivity pre- and post-chemotherapy in women with breast cancer. Functional connectivity examines the temporal correlation between spatially remote brain regions in an effort to understand how brain networks support specific cognitive functions. Nine women diagnosed with breast cancer completed a functional magnetic resonance imaging (fMRI) session before chemotherapy, 1 month after, and 1 year after the completion of chemotherapy. Seed-based functional connectivity analyses were completed using seeds in the intraparietal sulcus (IPS) to examine connectivity in the dorsal anterior attention network and in the posterior cingulate cortex (PCC) to examine connectivity in the default mode network. Results showed decreased functional connectivity 1 month after chemotherapy that partially returned to baseline at 1 year in the dorsal attention network. Decreased connectivity was seen in the default mode network at 1 month and 1 year following chemotherapy. In addition, increased subjective memory complaints were noted at 1 month and 1 year post-chemotherapy. These findings suggest a detrimental effect of chemotherapy on brain functional connectivity that is potentially related to subjective cognitive assessment.

  11. New Life From Dead Trees

    ERIC Educational Resources Information Center

    DeGraaf, Richard M.

    1978-01-01

    There are numerous bird species that will nest only in dead or dying trees. Current forestry practices include clearing forests of these snags, or dead trees. This practice is driving many species out of the forests. An illustrated example of bird succession in and on a tree is given. (MA)

  12. A Multidisciplinary Breast Cancer Brain Metastases Clinic: The University of North Carolina Experience

    PubMed Central

    McKee, Megan J.; Keith, Kevin; Deal, Allison M.; Garrett, Amy L.; Wheless, Amy A.; Green, Rebecca L.; Benbow, Julie M.; Dees, E. Claire; Carey, Lisa A.; Ewend, Matthew G.; Zagar, Timothy M.

    2016-01-01

    Background. Breast cancer brain metastasis (BCBM) confers a poor prognosis and is unusual in requiring multidisciplinary care in the metastatic setting. The University of North Carolina at Chapel Hill (UNC-CH) has created a BCBM clinic to provide medical and radiation oncology, neurosurgical, and supportive services to this complex patient population. We describe organization and design of the clinic as well as characteristics, treatments, and outcomes of the patients seen in its first 3 years. Methods. Clinical and demographic data were collected from patients in a prospectively maintained database. Descriptive statistics are reported as percentages and means. The Kaplan-Meier method was used to estimate time-to-event outcomes. Results. Sixty-five patients were seen between January 2012 and January 2015. At the time of presentation to the BCBM clinic, most patients (74%) had multiple (≥2) brain metastases and had received prior systemic (77%) and whole-brain radiation therapy and/or central nervous system stereotactic radiosurgery (65%) in the metastatic setting. Seventy-eight percent returned for a follow-up visit; 32% were enrolled in a clinical trial. Median time from diagnosis of brain metastasis to death was 2.11 years (95% confidence interval [CI] 1.31–2.47) for all patients, 1.15 years (95% CI 0.4–2.43) for triple-negative breast cancer, 1.31 years (95% CI 0.51–2.52) for hormone receptor-positive/HER2− breast cancer, and 3.03 years (95% CI lower limit 1.94, upper limit not estimable) for HER2+ breast cancer (p = .0037). Conclusion. Patients with BCBM have unique and complex needs that require input from several oncologic disciplines. The development of the UNC-CH multidisciplinary BCBM clinic is a model that can be adapted at other centers to provide coordinated care for patients with a challenging and complex disease. Implications for Practice: Patients with breast cancer brain metastases often require unique multidisciplinary care to meet the

  13. 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.

  14. The Horse Is Dead.

    ERIC Educational Resources Information Center

    Hart, Leslie A.

    1989-01-01

    Educational restructuring demands come from all quarters except school administrators resistant to change. Restructuring requires scrapping the screening type of school and sweeping out the frozen, ritualized, instructional methods that produce poor results. Brain-based education calls for numerous changes, including working from theory and…

  15. A High Performance Nano-Bio Photocatalyst for Targeted Brain Cancer Therapy

    PubMed Central

    Rozhkova, Elena A.; Ulasov, Ilya; Lai, Barry; Dimitrijevic, Nada M.; Lesniak, Maciej; Rajh, Tijana

    2014-01-01

    We report pronounced and specific anti-glioblastoma cell phototoxicity of 5 nm TiO2 particles covalently tethered to an antibody via dihydroxybenzene bivalent linker. The linker application enables absorption of a visible part of solar spectrum by the nanobio hybrid. The phototoxicity is mediated by reactive oxygen species (ROS) that initiate cancer cell programmed cell death. Synchrotron X-Ray Fluorescence Microscopy (XFM) was applied for direct visualization of the nanobioconjugate distribution through a single brain cancer cell at the sub-micrometer scale. PMID:19640002

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

    ClinicalTrials.gov

    2016-05-26

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

  17. How Long Has Grandpa Been Dead and Other Forensic Mysteries

    ScienceCinema

    Baden, Michael [MD, New York Police, New York, New York, United States

    2016-07-12

    Was the baby born alive? Can a child's brain really be shaken hard enough to cause death? Was the body dead before going into the water? Does a lightening strike cause any unique changes in the body? Why are hair and maggots becoming so important to the forensic scientist? Let's talk.

  18. How Long Has Grandpa Been Dead and Other Forensic Mysteries

    SciTech Connect

    Baden, Michael

    2006-05-17

    Was the baby born alive? Can a child's brain really be shaken hard enough to cause death? Was the body dead before going into the water? Does a lightening strike cause any unique changes in the body? Why are hair and maggots becoming so important to the forensic scientist? Let's talk.

  19. Cancer-associated fibroblast promote transmigration through endothelial brain cells in three-dimensional in vitro models.

    PubMed

    Choi, Yoon Pyo; Lee, Joo Hyun; Gao, Ming-Qing; Kim, Baek Gil; Kang, Suki; Kim, Se Hoon; Cho, Nam Hoon

    2014-11-01

    Brain metastases are associated with high morbidity as well as with poor prognosis and survival in breast cancer patients. Despite its clinical importance, metastasis of breast cancer cells through the blood-brain barrier (BBB) is poorly understood. The objective of our study was to investigate whether cancer-associated fibroblasts (CAFs) play crucial roles in breast cancer brain metastasis. Using a cell adhesion assays, in vitro BBB permeability and transmigration assays and soft agar colony formation assays, we investigated the physical roles of CAFs in breast cancer brain metastasis. We also performed immunofluorescence, flow cytometric analysis, Droplet Digital PCR and Simon™ Simple Western System to confirm changes in expression levels. We established two novel three-dimensional (3D) culture systems using a perpendicular slide chamber and applying 3D embedded culture method to reflect brain metastasis conditions. With a newly developed device, CAFs was proven to promote cell adhesion to human brain microvascular endothelial cells, in vitro BBB permeability and transmigration and colony formation of breast cancer cells. Furthermore, CAFs enhanced the invasive migration of breast cancer cells in two kinds of 3D cultures. These 3D models also reliably recapitulate the initial steps of BBB transmigration, micro-metastasis and colonization. Expression of integrin α5β1 and αvβ3, c-MET and α2,6-siayltransferase was increased in breast cancer cells that migrated through the BBB. In conclusion, based on our in vitro BBB and co-culture models, our data suggest that CAFs may play a role in breast cancer brain metastasis.

  20. The activity of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in the sera of patients with brain cancer.

    PubMed

    Jelski, Wojciech; Laniewska-Dunaj, Magdalena; Orywal, Karolina; Kochanowicz, Jan; Rutkowski, Robert; Szmitkowski, Maciej

    2014-12-01

    Human brain tissue contains various alcohol dehydrogenase (ADH) isoenzymes and possess also aldehyde dehydrogenase (ALDH) activity. In our last experiments we have shown that ADH and ALDH are present also in the brain tumour cells. Moreover the activities of total ADH and class I isoenzymes were significantly higher in cancer tissue than healthy cells. It can suggests that these changes may be reflected by enzyme activity in the serum of patients with brain cancer. Serum samples were taken for routine biochemical investigation from 62 patients suffering from brain cancer (36 glioblastoma, 26 meningioma). For the measurement of the activity of class I and II ADH isoenzymes and ALDH activity, the fluorometric methods were used. The total ADH activity and activity of class III and IV isoenzymes were measured by the photometric method. A statistically significant increase of class I alcohol dehydrogenase isoenzymes was found in the sera of patients with brain cancer. The median activity of this class isoenzyme in the patients group increased about 24 % in the comparison to the control level. The total alcohol dehydrogenase activity was also significantly higher (26 %) among patients with brain tumour than healthy ones. The activities of other tested ADH isoenzymes and total ALDH were unchanged. The increase of the activity of total ADH and class I alcohol dehydrogenase isoenzyme in the sera of patients with brain cancer seems to be caused by the release of this isoenzyme from tumour's cells.

  1. Decoding brain cancer dynamics: a quantitative histogram-based approach using temporal MRI

    NASA Astrophysics Data System (ADS)

    Zhou, Mu; Hall, Lawrence O.; Goldgof, Dmitry B.; Russo, Robin; Gillies, Robert J.; Gatenby, Robert A.

    2015-03-01

    Brain tumor heterogeneity remains a challenge for probing brain cancer evolutionary dynamics. In light of evolution, it is a priority to inspect the cancer system from a time-domain perspective since it explicitly tracks the dynamics of cancer variations. In this paper, we study the problem of exploring brain tumor heterogeneity from temporal clinical magnetic resonance imaging (MRI) data. Our goal is to discover evidence-based knowledge from such temporal imaging data, where multiple clinical MRI scans from Glioblastoma multiforme (GBM) patients are generated during therapy. In particular, we propose a quantitative histogram-based approach that builds a prediction model to measure the difference in histograms obtained from pre- and post-treatment. The study could significantly assist radiologists by providing a metric to identify distinctive patterns within each tumor, which is crucial for the goal of providing patient-specific treatments. We examine the proposed approach for a practical application - clinical survival group prediction. Experimental results show that our approach achieved 90.91% accuracy.

  2. 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

  3. Limited value of CT brain scans in the staging of small cell lung cancer

    SciTech Connect

    Johnson, D.H.; Windham, W.W.; Allen, J.H.; Greco, F.A.

    1983-01-01

    Computed tomography of the brain was performed as part of the initial staging evaluation of 84 patients with small cell lung cancer. Brain scans indicative of metastatic disease were obtained in 12 (14%) patients, two of whom had no neurologic signs or symptoms. One of these had no other extrathoracic disease. Brainscans without evidence of metastatic disease were obtained in 72 patients, 58 (80.5%) of whom had no signs or symptoms suggestive of metastatic intracranial disease. In the 14 patients with neurologic symptoms but negative computed tomographic scans, other explanations than brain metastases were found. It was concluded that head scanning is a sensitive and accurate method of detecting central nervous system metastases in patients with small cell lung cancer. However, head computed tomography should not be included as part of the initial staging evaluation of the neurologically asymptomatic patients. In only one of 60 such patients did the brain scan change the initial clinical staging, which included chest films, liver and bone scans, and bone marrow biopsy.

  4. Incidence of adult brain cancers is higher in countries where the protozoan parasite Toxoplasma gondii is common

    USGS Publications Warehouse

    Thomas, Frédéric; Lafferty, Kevin D.; Brodeur, Jacques; Elguero, Eric; Gauthier-Clerc, Michel; Missé, Dorothée

    2012-01-01

    We explored associations between the common protozoan parasite Toxoplasma gondii and brain cancers in human populations. We predicted that T. gondii could increase the risk of brain cancer because it is a long-lived parasite that encysts in the brain, where it provokes inflammation and inhibits apoptosis. We used a medical geography approach based on the national incidence of brain cancers and seroprevalence of T. gondii. We corrected reports of incidence for national gross domestic product because wealth probably increases the ability to detect cancer. We also included gender, cell phone use and latitude as variables in our initial models. Prevalence of T. gondii explained 19 per cent of the residual variance in brain cancer incidence after controlling for the positive effects of gross domestic product and latitude among nations. Infection with T. gondii was associated with a 1.8-fold increase in the risk of brain cancers across the range of T. gondii prevalence in our dataset (4–67%). These results, though correlational, suggest that T. gondii should be investigated further as a possible oncogenic pathogen of humans.

  5. S100B and S100B autoantibody as biomarkers for early detection of brain metastases in lung cancer

    PubMed Central

    Puvenna, Vikram; Brennan, Chanda; Mahmoud, Shamseldeen; Wang, Xiao-Feng; Phillips, Michael; Janigro, Damir; Mazzone, Peter

    2016-01-01

    Background S100B is an astrocytic protein that enters the blood stream when there is disruption of the blood-brain barrier (BBB). Over time, antibodies against S100B develop in the sera of patients who experience persistent or repeated BBB disruptions. We explored the use of serum S100B protein and S100B autoantibodies for the detection of brain metastasis in patients with lung cancer. Methods One hundred and twenty eight untreated patients with lung cancer who had brain imaging performed as part of their routine evaluation, participated. Serum S100B protein levels were measured by direct ELISA and S100B autoantibody levels by reverse ELISA. These levels in patients with brain metastases were compared alone and in combination to those without brain metastases. Results Eighteen (14%) patients had brain metastasis at the time of lung cancer diagnosis. An S100B cutoff of 0.058 ng/mL had a sensitivity of 89% and specificity of 43% for brain metastasis. When an autoantibody threshold of <2.00 absorbance units was used in conjunction with S100B, the sensitivity remained at 89%, and the specificity increased to 58%. The overall accuracy was 51% with S100B alone, improving to 62.5% when combined with autoantibodies. Conclusions Serum S100B and S100B autoantibody levels may help to identify which lung cancer patients have brain metastases. PMID:27652205

  6. Brain metastases as site of first and isolated recurrence of breast cancer: the role of systemic therapy after local treatment.

    PubMed

    Niwińska, Anna

    2016-10-01

    The role of systemic treatment was assessed after local therapy for breast cancer patients who developed central nervous system (CNS) metastases as a first and isolated recurrence. Subjects were 128 breast cancer patients with brain metastases as the first and isolated site of recurrence that were selected from 673 consecutive breast cancer patients with brain metastases treated at the same institution. Median survival from brain metastases in patients with and without systemic treatment after local therapy was respectively 15 and 4 months (p < 0.001). In patients with a Karnofsky Performance Status ≥70 and those <70, survival was respectively 16 and 5.5 months (p < 0.001). The median survival from brain metastasis in patients with solitary brain metastasis, with and without systemic treatment after local therapy, was respectively 22 and 7 months (p = 0.003). Cox multivariate analysis demonstrated that good performance status, solitary brain metastasis and systemic therapy undertaken after local treatment were factors which prolonged survival. However patient survival was adversely affected by those having leptomeningeal metastasis associated with brain parenchymal lesions. Systemic therapy, undertaken after local treatment improved survival in those patients with breast cancer and brain metastases as the site of first and isolated recurrence. Further study is required in order to fully establish the role of systemic treatment for this patient group.

  7. S100B and S100B autoantibody as biomarkers for early detection of brain metastases in lung cancer

    PubMed Central

    Puvenna, Vikram; Brennan, Chanda; Mahmoud, Shamseldeen; Wang, Xiao-Feng; Phillips, Michael; Janigro, Damir; Mazzone, Peter

    2016-01-01

    Background S100B is an astrocytic protein that enters the blood stream when there is disruption of the blood-brain barrier (BBB). Over time, antibodies against S100B develop in the sera of patients who experience persistent or repeated BBB disruptions. We explored the use of serum S100B protein and S100B autoantibodies for the detection of brain metastasis in patients with lung cancer. Methods One hundred and twenty eight untreated patients with lung cancer who had brain imaging performed as part of their routine evaluation, participated. Serum S100B protein levels were measured by direct ELISA and S100B autoantibody levels by reverse ELISA. These levels in patients with brain metastases were compared alone and in combination to those without brain metastases. Results Eighteen (14%) patients had brain metastasis at the time of lung cancer diagnosis. An S100B cutoff of 0.058 ng/mL had a sensitivity of 89% and specificity of 43% for brain metastasis. When an autoantibody threshold of <2.00 absorbance units was used in conjunction with S100B, the sensitivity remained at 89%, and the specificity increased to 58%. The overall accuracy was 51% with S100B alone, improving to 62.5% when combined with autoantibodies. Conclusions Serum S100B and S100B autoantibody levels may help to identify which lung cancer patients have brain metastases.

  8. Brain radiation - discharge

    MedlinePlus

    Radiation - brain - discharge; Cancer-brain radiation; Lymphoma - brain radiation; Leukemia - brain radiation ... Decadron) while you are getting radiation to the brain. It may make you hungrier, cause leg swelling ...

  9. Over Expression of BCL2 and Low Expression of Caspase 8 Related to TRAIL Resistance in Brain Cancer Stem Cells.

    PubMed

    Qi, Ling; Ren, Kuang; Fang, Fang; Zhao, Dong-Hai; Yang, Ning-Jiang; Li, Yan

    2015-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been investigated as an effective agent to treat various cancers. Cancer stem cells are resistant to TRAIL treatment, but the mechanism of TRAIL resistance remains unknown. In this study, brain cancer stem cells were isolated by CD133 magnetic sorting, and the number of CD133 positive cells detected by flow cytometry. The self-renewing capacity of brain cancer stem cells was examined by a neurosphere formation assay, and the percentage of cell death after TRAIL treatment was examined by an MTS assay. Expression of DR5, FADD, caspase 8 and BCL2 proteins was detected by western blot. The amount of CD133 positive cells was enriched to 71% after CD133 magnetic sorting. Brain cancer stem cell neurosphere formation was significantly increased after TRAIL treatment. TRAIL treatment also reduced the amount of viable cells and this decrease was inhibited by a caspase 8 inhibitor or by the pan-caspase inhibitor z-VAD (P<0.05). Brain cancer stem cells expressed lower levels caspase 8 protein and higher levels of BCL2 protein when compared with CD133 negative cells (P<0.05). Our data suggest that TRAIL resistance is related to overexpression of BCL2 and low expression of caspase 8 which limit activation of caspase 8 in brain cancer stem cells.

  10. Effect of Lapatinib on the Outgrowth of Metastatic Breast Cancer Cells to the Brain

    PubMed Central

    Gril, Brunilde; Palmieri, Diane; Bronder, Julie L.; Herring, Jeanne M.; Vega-Valle, Eleazar; Feigenbaum, Lionel; Liewehr, David J.; Steinberg, Seth M.; Merino, Maria J.; Rubin, Stephen D.

    2008-01-01

    Background The brain is increasingly being recognized as a sanctuary site for metastatic tumor cells in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy, and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis. Methods EGFR-overexpressing MDA-MB-231-BR (231-BR) brain-seeking breast cancer cells were transfected with an expression vector that contained or lacked the HER2 cDNA and used to examine the effect of lapatinib on the activation (ie, phosphorylation) of cell signaling proteins by immunoblotting, on cell growth by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and on cell migration using a Boyden chamber assay. The outgrowth of large (ie, >50 μm2) and micrometastases was counted in brain sections from nude mice that had been injected into the left cardiac ventricle with 231-BR cells and, beginning 5 days later, treated by oral gavage with lapatinib or vehicle (n = 22–26 mice per treatment group). All statistical tests were two-sided. Results In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream signaling proteins; cell proliferation; and migration in 231-BR cells (both with and without HER2). Among mice injected with 231-BR-vector cells, those treated with 100 mg lapatinib/kg body weight had 54% fewer large metastases 24 days after starting treatment than those treated with vehicle (mean number of large metastases per brain section: 1.56 vs 3.36, difference = 1.80, 95% confidence interval [CI] = 0.92 to 2.68, P < .001), whereas treatment with 30 mg lapatinib/kg body weight had no effect. Among mice injected with 231-BR-HER2 cells, those treated with

  11. Impact of Triple-Negative Phenotype on Prognosis of Patients With Breast Cancer Brain Metastases

    SciTech Connect

    Xu Zhiyuan; Schlesinger, David; Toulmin, Sushila; Rich, Tyvin; Sheehan, Jason

    2012-11-01

    Purpose: To elucidate survival times and identify potential prognostic factors in patients with triple-negative (TN) phenotype who harbored brain metastases arising from breast cancer and who underwent stereotactic radiosurgery (SRS). Methods and Materials: A total of 103 breast cancer patients with brain metastases were treated with SRS and then studied retrospectively. Twenty-four patients (23.3%) were TN. Survival times were estimated using the Kaplan-Meier method, with a log-rank test computing the survival time difference between groups. Univariate and multivariate analyses to predict potential prognostic factors were performed using a Cox proportional hazard regression model. Results: The presence of TN phenotype was associated with worse survival times, including overall survival after the diagnosis of primary breast cancer (43 months vs. 82 months), neurologic survival after the diagnosis of intracranial metastases, and radiosurgical survival after SRS, with median survival times being 13 months vs. 25 months and 6 months vs. 16 months, respectively (p < 0.002 in all three comparisons). On multivariate analysis, radiosurgical survival benefit was associated with non-TN status and lower recursive partitioning analysis class at the initial SRS. Conclusion: The TN phenotype represents a significant adverse prognostic factor with respect to overall survival, neurologic survival, and radiosurgical survival in breast cancer patients with intracranial metastasis. Recursive partitioning analysis class also served as an important and independent prognostic factor.

  12. Restoration of Brain Acid Soluble Protein 1 Inhibits Proliferation and Migration of Thyroid Cancer Cells

    PubMed Central

    Guo, Run-Sheng; Yu, Yue; Chen, Jun; Chen, Yue-Yu; Shen, Na; Qiu, Ming

    2016-01-01

    Background: Brain acid soluble protein 1 (BASP1) is identified as a novel potential tumor suppressor in several cancers. However, its role in thyroid cancer has not been investigated yet. In the present study, the antitumor activities of BASP1 against the growth and migration of thyroid cancer cells were evaluated. Methods: BASP1 expression in thyroid cancer tissues and normal tissues were examined by immunohistochemical staining and the association between its expression and prognosis was analyzed. pcDNA-BASP1 carrying full length of BASP1 cDNA was constructed to restore the expression of BASP1 in thyroid cancer cell lines (BHT-101 and KMH-2). The cell proliferation in vitro and in vivo was evaluated by WST-1 assay and xenograft tumor models, respectively. Cell cycle distribution after transfection was analyzed using flow cytometry. Cell apoptosis after transfection was examined by annexin V/propidium iodide assay. The migration was examined using transwell assay. Results: BASP1 expression was abundant in normal tissues while it is significantly decreased in cancer tissues (P = 0.000). pcDNA-BASP1 restored the expression of BASP1 and significantly inhibited the growth of BHT-101 and KMH-2 cells as well as xenograft tumors in nude mice (P = 0.000). pcDNA-BASP1 induced G1 arrest and apoptosis in BHT-101 and KMH-2 cells. In addition, pcDNA-BASP1 significantly inhibited the cell migration. Conclusions: Downregulation of BASP1 expression may play a role in the tumorigenesis of thyroid cancer. Restoration of BASP1 expression exerted extensive antitumor activities against growth and migration of thyroid cancer cells, which suggested that BASP1 gene might act as a potential therapeutic agent for the treatment of thyroid cancer. PMID:27270539

  13. Pediatric Cancers and Brain Tumors in Adolescents and Young Adults.

    PubMed

    McCabe, Martin G; Valteau-Couanet, Dominique

    2016-01-01

    Embryonal tumors classically occur in young children, some principally within the first year of life. Prospective national and international clinical trials during recent decades have brought about progressive improvements in survival, and associated biological studies have advanced our understanding of tumor biology, in some cases allowing biological tumor characteristics to be harnessed for therapeutic benefit. Embryonal tumors continue to occur, albeit less commonly, during childhood, adolescence and throughout adulthood. These tumors are less well understood, usually not managed according to standardized protocols and rarely included in clinical trials. Survival outcomes are generally poorer than their childhood equivalents. We present here a summary of the published literature on embryonal tumors that present ectopically during adolescence and adulthood. We show that for some tumors protocol-driven treatment, supported by accurate and complete diagnostics and staging, can result in equivalent outcomes to those seen during childhood. We make the case that clinical trial eligibility criteria should be disease-based rather than age-based, and support improvements in dialogue between children's and adults' cancer clinicians to improve outcomes for these rare tumors. PMID:27595358

  14. 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.

  15. Is Piaget's Epistemic Subject Dead?

    ERIC Educational Resources Information Center

    Lawson, Anton E.

    1991-01-01

    Argues that the Piaget's epistemic subject is not supported by evidence and contains weaknesses. Concludes that the epistemic subject is dead and that continued acceptance of this aspect of Piagetian theory would be counterproductive. (PR)

  16. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy

    PubMed Central

    Miller, Bryan W; Morton, Jennifer P; Pinese, Mark; Saturno, Grazia; Jamieson, Nigel B; McGhee, Ewan; Timpson, Paul; Leach, Joshua; McGarry, Lynn; Shanks, Emma; Bailey, Peter; Chang, David; Oien, Karin; Karim, Saadia; Au, Amy; Steele, Colin; Carter, Christopher Ross; McKay, Colin; Anderson, Kurt; Evans, Thomas R Jeffry; Marais, Richard; Springer, Caroline; Biankin, Andrew; Erler, Janine T; Sansom, Owen J

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1-Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor-free survival in KPC mice with early-stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease. PMID:26077591

  17. Brain and central nervous system cancer incidence in navarre (Spain), 1973-2008 and projections for 2014.

    PubMed

    Etxeberria, J; Román, E San; Burgui, R; Guevara, M; Moreno-Iribas, C; Urbina, M J; Ardanaz, E

    2015-01-01

    Different studies have pointed out Navarre as one of the regions of Spain with the highest incidence rates of brain and other central nervous system (CNS) cancer. Trend analysis for cancer incidence rates for long periods of time, might help determining risk factors as well as, assessing prevention actions involved in this disease. The objective of this study was to describe the incidence of brain and CNS cancer using data from the population-based cancer registry of Navarre, (Spain) during the period 1973-2008 and provide forecast figures up to-2014. Crude and age-standardized (world population) incidence rates of brain cancer per 100,000 person-years were calculated by the direct method separately by gender, area (Pamplona and others), and age-groups. Penalized splines for smoothing rates in the temporal dimensions were applied in order to estimate and forecast cancer incidence rates. Age-adjusted incidence rates showed an increase over the study and forecast periods in both sexes more marked in women than in men. Higher incidence rates were observed in men compared with women but the differences became smaller with time. The increase was due to the rise of rates in the oldest age groups since the rates for younger age groups remained stable or decreased over time. As the entire aetiology of brain and other CNS cancer is not still clear, keep promoting healthful lifestyles for cancer primary prevention among the whole population is necessary.

  18. Climate change and dead zones.

    PubMed

    Altieri, Andrew H; Gedan, Keryn B

    2015-04-01

    Estuaries and coastal seas provide valuable ecosystem services but are particularly vulnerable to the co-occurring threats of climate change and oxygen-depleted dead zones. We analyzed the severity of climate change predicted for existing dead zones, and found that 94% of dead zones are in regions that will experience at least a 2 °C temperature increase by the end of the century. We then reviewed how climate change will exacerbate hypoxic conditions through oceanographic, ecological, and physiological processes. We found evidence that suggests numerous climate variables including temperature, ocean acidification, sea-level rise, precipitation, wind, and storm patterns will affect dead zones, and that each of those factors has the potential to act through multiple pathways on both oxygen availability and ecological responses to hypoxia. Given the variety and strength of the mechanisms by which climate change exacerbates hypoxia, and the rates at which climate is changing, we posit that climate change variables are contributing to the dead zone epidemic by acting synergistically with one another and with recognized anthropogenic triggers of hypoxia including eutrophication. This suggests that a multidisciplinary, integrated approach that considers the full range of climate variables is needed to track and potentially reverse the spread of dead zones.

  19. Climate change and dead zones.

    PubMed

    Altieri, Andrew H; Gedan, Keryn B

    2015-04-01

    Estuaries and coastal seas provide valuable ecosystem services but are particularly vulnerable to the co-occurring threats of climate change and oxygen-depleted dead zones. We analyzed the severity of climate change predicted for existing dead zones, and found that 94% of dead zones are in regions that will experience at least a 2 °C temperature increase by the end of the century. We then reviewed how climate change will exacerbate hypoxic conditions through oceanographic, ecological, and physiological processes. We found evidence that suggests numerous climate variables including temperature, ocean acidification, sea-level rise, precipitation, wind, and storm patterns will affect dead zones, and that each of those factors has the potential to act through multiple pathways on both oxygen availability and ecological responses to hypoxia. Given the variety and strength of the mechanisms by which climate change exacerbates hypoxia, and the rates at which climate is changing, we posit that climate change variables are contributing to the dead zone epidemic by acting synergistically with one another and with recognized anthropogenic triggers of hypoxia including eutrophication. This suggests that a multidisciplinary, integrated approach that considers the full range of climate variables is needed to track and potentially reverse the spread of dead zones. PMID:25385668

  20. Dead Star Rumbles

    NASA Technical Reports Server (NTRS)

    2005-01-01

    [figure removed for brevity, see original site] Composite of Supernova Remnant Cassiopeia A This Spitzer Space Telescope composite shows the supernova remnant Cassiopeia A (white ball) and surrounding clouds of dust (gray, orange and blue). It consists of two processed images taken one year apart. Dust features that have not changed over time appear gray, while those that have changed are colored blue or orange. Blue represents an earlier time and orange, a later time.

    These observations illustrate that a blast of light from Cassiopeia A is waltzing outward through the dusty skies. This dance, called an 'infrared echo,' began when the remnant erupted about 50 years ago.

    Cassiopeia A is the remnant of a once massive star that died in a violent supernova explosion 325 years ago. It consists of a dead star, called a neutron star, and a surrounding shell of material that was blasted off as the star died. This remnant is located 10,000 light-years away in the northern constellation Cassiopeia.

    An infrared echo is created when a star explodes or erupts, flashing light into surrounding clumps of dust. As the light zips through the dust clumps, it heats them up, causing them to glow successively in infrared, like a chain of Christmas bulbs lighting up one by one. The result is an optical illusion, in which the dust appears to be flying outward at the speed of light. This apparent motion can be seen here by the shift in colored dust clumps.

    Echoes are distinct from supernova shockwaves, which are made up material that is swept up and hurled outward by exploding stars.

    This infrared echo is the largest ever seen, stretching more than 50 light-years away from Cassiopeia A. If viewed from Earth, the entire movie frame would take up the same amount of space as two full moons.

    Hints of an older infrared echo from Cassiopeia A's supernova explosion hundreds of years ago can also be seen.

    The earlier Spitzer image was taken on November 30

  1. Isolated brain metastases as first site of recurrence in prostate cancer: case report and review of the literature

    PubMed Central

    Craig, J.; Woulfe, J.; Sinclair, J.; Malone, S.

    2015-01-01

    Fewer than 2% of patients with metastatic prostate cancer (pca) develop brain metastases. Autopsy series have confirmed the rarity of brain metastases. When present, brain metastases occur in end stage, once the pca is castrate-resistant and spread to other sites is extensive. Here, we present a rare case of a patient with pca who developed a solitary parenchymal brain metastasis as first site of relapse 9 years after radical therapy. The patient underwent craniotomy and excision of the tumour. A second recurrence was also isolated to the brain. In the literature, pca patients with brain metastases have a poor mean survival of 1–7.6 months. The patient in our case report experienced a relatively favourable outcome, surviving 19 months after his initial brain relapse. PMID:26715888

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

    PubMed

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

    2015-10-01

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

  3. 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.

  4. Brain-derived neurotrophic factor regulates cell motility in human colon cancer.

    PubMed

    Huang, Ssu-Ming; Lin, Chingju; Lin, Hsiao-Yun; Chiu, Chien-Ming; Fang, Chia-Wei; Liao, Kuan-Fu; Chen, Dar-Ren; Yeh, Wei-Lan

    2015-06-01

    Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominant-negative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.

  5. Correlation of neurocognitive function and brain parenchyma volumes in children surviving cancer

    NASA Astrophysics Data System (ADS)

    Reddick, Wilburn E.; White, Holly A.; Glass, John O.; Mulhern, Raymond K.

    2002-04-01

    This research builds on our hypothesis that white matter damage and associated neurocognitive symptoms, in children treated for cancer with cranial spinal irradiation, spans a continuum of severity that can be reliably probed using non-invasive MR technology. Quantitative volumetric assessments of MR imaging and psychological assessments were obtained in 40 long-term survivors of malignant brain tumors treated with cranial irradiation. Neurocognitive assessments included a test of intellect (Wechsler Intelligence Test for Children, Wechsler Adult Intelligence Scale), attention (Conner's Continuous Performance Test), and memory (California Verbal Learning Test). One-sample t-tests were conducted to evaluate test performance of survivors against age-adjusted scores from the test norms; these analyses revealed significant impairments in all apriori selected measures of intelligence, attention, and memory. Partial correlation analyses were performed to assess the relationships between brain tissues volumes (normal appearing white matter (NAWM), gray matter, and CSF) and neurocognitive function. Global intelligence (r = 0.32, p = 0.05) and global attentional (r = 0.49, p < 0.01) were significantly positively correlated with NAWM volumes, whereas global memory was significantly positively correlated with overall brain parenchyma (r = 0.38, p = 0.04). We conclude that quantitative assessment of MR examinations in survivors of childhood cancer treated with cranial irradiation reveal that loss of NAWM is associated with decreased intellectual and attentional deficits, whereas overall parenchyma loss, as reflected by increased CSF and decreased white matter, is associated with memory-related deficits.

  6. Pre-Adult MRI of Brain Cancer and Neurological Injury: Multivariate Analyses

    PubMed Central

    Levman, Jacob; Takahashi, Emi

    2016-01-01

    Brain cancer and neurological injuries, such as stroke, are life-threatening conditions for which further research is needed to overcome the many challenges associated with providing optimal patient care. Multivariate analysis (MVA) is a class of pattern recognition technique involving the processing of data that contains multiple measurements per sample. MVA can be used to address a wide variety of neuroimaging challenges, including identifying variables associated with patient outcomes; understanding an injury’s etiology, development, and progression; creating diagnostic tests; assisting in treatment monitoring; and more. Compared to adults, imaging of the developing brain has attracted less attention from MVA researchers, however, remarkable MVA growth has occurred in recent years. This paper presents the results of a systematic review of the literature focusing on MVA technologies applied to brain injury and cancer in neurological fetal, neonatal, and pediatric magnetic resonance imaging (MRI). With a wide variety of MRI modalities providing physiologically meaningful biomarkers and new biomarker measurements constantly under development, MVA techniques hold enormous potential toward combining available measurements toward improving basic research and the creation of technologies that contribute to improving patient care. PMID:27446888

  7. Pre-Adult MRI of Brain Cancer and Neurological Injury: Multivariate Analyses.

    PubMed

    Levman, Jacob; Takahashi, Emi

    2016-01-01

    Brain cancer and neurological injuries, such as stroke, are life-threatening conditions for which further research is needed to overcome the many challenges associated with providing optimal patient care. Multivariate analysis (MVA) is a class of pattern recognition technique involving the processing of data that contains multiple measurements per sample. MVA can be used to address a wide variety of neuroimaging challenges, including identifying variables associated with patient outcomes; understanding an injury's etiology, development, and progression; creating diagnostic tests; assisting in treatment monitoring; and more. Compared to adults, imaging of the developing brain has attracted less attention from MVA researchers, however, remarkable MVA growth has occurred in recent years. This paper presents the results of a systematic review of the literature focusing on MVA technologies applied to brain injury and cancer in neurological fetal, neonatal, and pediatric magnetic resonance imaging (MRI). With a wide variety of MRI modalities providing physiologically meaningful biomarkers and new biomarker measurements constantly under development, MVA techniques hold enormous potential toward combining available measurements toward improving basic research and the creation of technologies that contribute to improving patient care. PMID:27446888

  8. Breast cancer brain metastases responding to lapatinib plus capecitabine as second-line primary systemic therapy.

    PubMed

    Bergen, Elisabeth S; Berghoff, Anna S; Rudas, Margaretha; Preusser, Matthias; Bartsch, Rupert

    2015-06-01

    Brain metastases (BM) are diagnosed in up to 40% of HER2-positive breast cancer patients. Standard treatment includes local approaches such as whole-brain radiotherapy (WBRT), radiosurgery, and neurosurgery. The landscape trial established primary systemic therapy as an effective and safe alternative to WBRT in selected patients with Her2-positive BM. We aim to further focus on the role of systemic therapy in oligosymptomatic patients by presenting this case report. We report on a 50-year-old patient diagnosed with multiple BM 5 years after early breast cancer diagnosis. As the patient was asymptomatic and had a favorable diagnosis-specific GPA score, she received primary systemic treatment with T-DM1. She achieved partial remission within the brain for eight treatment cycles and then progressed despite stable extracranial disease. As the patient remained asymptomatic and refused WBRT, we decided upon trastuzumab, lapatinib plus capecitabine as second-line therapy. Another partial remission of BM was observed; to date, she has received 11 treatment cycles without any sign of disease progression. In this case, WBRT was delayed by at least 14 months, again indicating the activity of systemic treatment in BM. Apparently, in selected patients, BM can be controlled with multiple lines of systemic therapy similar to extracranial disease. Further investigation of systemic treatment approaches is therefore warranted.

  9. Environmental exposure to xenoestrogens and oestrogen related cancers: reproductive system, breast, lung, kidney, pancreas, and brain

    PubMed Central

    2012-01-01

    The role of steroids in carcinogenesis has become a major concern in environmental protection, biomonitoring, and clinical research. Although historically oestrogen has been related to development of reproductive system, research over the last decade has confirmed its crucial role in the development and homeostasis of other organ systems. As a number of anthropogenic agents are xenoestrogens, environmental health research has focused on oestrogen receptor level disturbances and of aromatase polymorphisms. Oestrogen and xenoestrogens mediate critical points in carcinogenesis by binding to oestrogen receptors, whose distribution is age-, gender-, and tissue-specific. This review brings data about cancer types whose eatiology may be found in environmental exposure to xenoestrogens. Cancer types that have been well documented in literature to be related with environmental exposure include the reproductive system, breast, lung, kidney, pancreas, and brain. The results of our data mining show (a) a significant correlation between exposure to xenoestrogens and increased, gender-related, cancer risk and (b) a need to re-evaluate agents so far defined as endocrine disruptors, as they are also key molecules in carcinogenesis. This revision may be used to further research of cancer aetiology and to improvement of related legislation. Investigation of cancers caused by xenoestrogens may elucidate yet unknown mechanisms also valuable for oncology and the development of new therapies. PMID:22759508

  10. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer

    PubMed Central

    Okugawa, Y; Tanaka, K; Inoue, Y; Kawamura, M; Kawamoto, A; Hiro, J; Saigusa, S; Toiyama, Y; Ohi, M; Uchida, K; Mohri, Y; Kusunoki, M

    2013-01-01

    Background: Brain-derived neutrophic factor (BDNF) is a member of the neutrophin family that is known to activate the high-affinity tropomyosin-related receptor kinase B (TrkB). This study aimed to clarify the clinical and biological significance of the BDNF/TrkB pathway in gastric cancer. Methods: We analysed BDNF and TrkB expression in gastric cancer samples by real-time reverse transcription PCR and immunohistochemistry. To investigate the biological role of BDNF/TrkB axis, recombinant human BDNF (rhBDNF) and the Trk antagonist K252a were used for in vitro and in vivo analysis. Results: The BDNF expression at the invasive front of primary tumours was significantly elevated compared with that in the tumour core and adjacent normal mucosa. Increased BDNF expression at the invasive front was significantly correlated with factors reflecting disease progression, and poor prognosis. Increased co-expression of the BDNF/TrkB axis was significantly correlated with poor prognosis. Gastric cancer cells expressed BDNF, and administration of rhBDNF promoted proliferation, migration, invasion, and inhibition of anoikis. These effects were generally inhibited by K252a. In an in vivo assay, BDNF(+)/TrkB(+) gastric cancer cells injected into nude mice established peritoneal dissemination, whereas K252a inhibited tumour growth. Conclusion: The BDNF/TrkB pathway might be deeply involved in gastric cancer disease progression. PMID:23175149

  11. A critical role for HER3 in HER2-amplified and non-amplified breast cancers: function of a kinase-dead RTK

    PubMed Central

    Dey, Nandini; Williams, Casey; Leyland-Jones, Brain; De, Pradip

    2015-01-01

    ERBB3/HER3 is the most intriguing RTK by virtue of its ability to transduce multiple cytosolic signals for the proliferation and growth of tumor cells in spite of being a “kinase dead” receptor that binds to its true ligand, heregulin. Although other members of the HER3 family like EGFR and HER2 have long been recognized to be associated with breast tumorigenesis and studied because of their predictive and prognostic value, the significance of HER3 as an irrefutable component of HER family signalosome is a relatively new development. The recent understanding of signals originating from the oncogenic partnership of HER3 with HER2 in the context of HER2 amplification/overexpression showed the critical clinical value for the treatment of HER2+BC. The downstream signaling cascade (included but not limited to the PI3K signaling) associated with signals originating from HER2:HER3 dimers play a vital role in the tumorigenesis, drug-resistance and tumor progression of HER2+BC. The upregulation of HER3 activity provides an alternate “escape route” via which tumor cells bypass either the inhibition of the HER family RTKs or the inhibition of the downstream PI3K-AKT-mTOR signaling pathway. By understanding the signaling that provides this “escape route” for these tumor cells treated with a targeted therapy (HER2 inhibitors or inhibitors of downstream PI3K-AKT-mTOR signaling pathway), we are just beginning to appreciate the prognostic value of HER3 in breast cancer. In this review, we will discuss the relevance of HER3 signaling in the context of, (1) downstream oncogenic signals and (2) therapeutic options in HER2 amplified BC. PMID:26064441

  12. Toward intracellular targeted delivery of cancer therapeutics: progress and clinical outlook for brain tumor therapy.

    PubMed

    Pandya, Hetal; Debinski, Waldemar

    2012-08-01

    A number of anti-cancer drugs have their targets localized to particular intracellular compartments. These drugs reach the targets mainly through diffusion, dependent on biophysical and biochemical forces that allow cell penetration. This means that both cancer cells and normal cells will be subjected to such diffusion; hence many of these drugs, like chemotherapeutics, are potentially toxic and the concentration achieved at the site of their action is often suboptimal. The same relates to radiation that indiscriminately affects normal and diseased cells. However, nature-designed systems enable compounds present in the extracellular environment to end up inside the cell and even travel to more specific intracellular compartments. For example, viruses and bacterial toxins can more or less specifically recognize eukaryotic cells, enter these cells, and direct some protein portions to designated intracellular areas. These phenomena have led to creative thinking, such as employing viruses or bacterial toxins for cargo delivery to cells and, more specifically, to cancer cells. Proteins can be genetically engineered in order to not only mimic what viruses and bacterial toxins can do, but also to add new functions, extending or changing the intracellular routes. It is possible to make conjugates or, more preferably, single-chain proteins that recognize cancer cells and deliver cargo inside the cells, even to the desired subcellular compartment. These findings offer new opportunities to deliver drugs/labels only to cancer cells and only to their site of action within the cells. The development of such dual-specificity vectors for targeting cancer cells is an attractive and potentially safer and more efficacious way of delivering drugs. We provide examples of this approach for delivering brain cancer therapeutics, using a specific biomarker on glioblastoma tumor cells.

  13. Brain Metastases from Breast Cancer and Response to Treatment with Eribulin: A Case Series.

    PubMed

    Chang, Alex Y; Ying, Xu Xiao

    2015-01-01

    Brain metastases are common in patients with advanced breast cancer (BC), causing considerable morbidity and mortality. Eribulin is a microtubule dynamics inhibitor approved for treating certain patients with metastatic BC, previously treated with an anthracycline and a taxane. In the 301 phase 3 study in 1102 women with advanced BC, eribulin and capecitabine treatments did not differ for co-primary endpoints (overall survival [OS]: 15.9 vs 14.5 months, P = 0.056; progression-free survival [PFS]: 4.1 vs 4.2 months, P = 0.30). Here, we report outcomes for six patients (eribulin, n = 3; capecitabine, n = 3) who had received treatment for brain metastases from BC (BCBM) at baseline. All eribulin-treated patients experienced brain lesion shrinkage at some point during treatment, compared with one capecitabine-treated patient. Fewer patients in study 301 developed new BCBM with eribulin (13/544, 2.4%) compared with capecitabine (25/546, 4.6%). Eribulin does not cross the healthy blood-brain barrier (BBB), but could have the potential to do so after cranial radiation therapy. Capecitabine may cross the BBB and has demonstrated activity in BCBM. Data from these patients and previous cases suggest that further investigation of eribulin for BCBM may be warranted. PMID:26052228

  14. Frontiers of X-ray spectromicroscopy in biology and medicine: Gadolinium in brain cancer

    NASA Astrophysics Data System (ADS)

    De Stasio, Gelsomina; Gilbert, B.; Perfetti, P.; Margaritondo, G.; Mercanti, D.; Ciotti, M. T.; Casalbore, P.; Larocca, L. M.; Rinelli, A.; Pallini, R.

    2000-02-01

    We present the first feasibility test of spectromicroscopy on the microlocalization of gadolinium in brain cancer tissue. A gadolinium compound was injected to the patients before the brain tumor was extracted with surgery, and we looked for Gd in the tumor tissue. The goal of the experiment was to understand if Gd Neutron Capture Therapy (GdNCT) is viable for clinical tests, i.e. if there is enough Gd, and it is localized near the nuclei of tumor cells. The experiments were performed using the MEPHISTO X-ray PhotoElectron Emission Microscope (X-PEEM) at the Wisconsin Synchrotron Radiation Center. The present results demonstrate the feasibility of the experiment, and suggest how to improve the sample preparation and data acquisition to achieve the goal.

  15. More Complete Removal of Malignant Brain Tumors by Fluorescence-Guided Surgery

    ClinicalTrials.gov

    2016-05-13

    Benign Neoplasms, Brain; Brain Cancer; Brain Neoplasms, Benign; Brain Neoplasms, Malignant; Brain Tumor, Primary; Brain Tumor, Recurrent; Brain Tumors; Intracranial Neoplasms; Neoplasms, Brain; Neoplasms, Intracranial; Primary Brain Neoplasms; Primary Malignant Brain Neoplasms; Primary Malignant Brain Tumors; Gliomas; Glioblastoma

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-07-01

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

  18. [Parasitic dead-end: update].

    PubMed

    Magnaval, J F

    2006-08-01

    Parasitic dead-ends occur when a parasite is unable to establish a permanent interaction in an unnatural host. Although the likelihood of successful reproduction by the pathogenic agent is nul, parasitic dead-end heralds capture of new parasites and therefore expansion of the host range. Angiostrongyliasis due to A. cantonensis or A. costaricensis, anisakiasis, Ancylostoma caninum infection, gnathostomiasis and sparganosis are undoubtedly emerging zoonoses of particular medical interest. Prevention of these diseases relies on abstinence from eating raw meat from invertebrates or cold-blooded (poikilotherm) vertebrates (e.g. used in exotic dishes). These guidelines must be included in recommendations to travelers. PMID:16999036

  19. Dead space closure with quilting suture versus conventional closure with drainage for the prevention of seroma after mastectomy for breast cancer (QUISERMAS): protocol for a multicentre randomised controlled trial

    PubMed Central

    Ouldamer, Lobna; Bonastre, Julia; Brunet-Houdard, Solène; Body, Gilles; Giraudeau, Bruno; Caille, Agnès

    2016-01-01

    Introduction Postoperative wound seroma is common after mastectomy. This complication is associated with significant impact on patient outcomes and healthcare costs. The optimal closure approach for seroma prevention remains unknown but some evidence suggests that quilting suture of the dead space could lower the incidence of seroma. The aim of this trial is to compare seroma formation using quilting suture versus conventional closure with drainage in patients undergoing mastectomy. Methods and analysis This is a multicentre, superiority, randomised controlled trial in women undergoing mastectomy with or without axillary involvement. Exclusion criteria include indication of bilateral mastectomy or immediate reconstruction and any physical or psychiatric condition that could impair patient's ability to cooperate with postoperative data collection or that do not allow an informed consent. 320 participants will be randomised in a 1:1 ratio to receive either quilting suture or conventional wound closure with drain. The primary outcome is seroma requiring either aspiration or surgical intervention within 21 days following mastectomy. Secondary outcomes include seroma regardless of whether or not it requires an intervention, surgical site infection, pain score, cosmetic result, patient's quality of life, costs and cost-effectiveness. The primary analysis will be an intention-to treat analysis performed with a χ2 test (or Fisher's exact test). Ethics and dissemination Written informed consent will be obtained from all participants. This study was approved by Tours Research ethics committee (CPP TOURS—Region Centre—Ouest 1, 2014-R20, 16 December 2014). Study findings will be published in peer-reviewed journals and presented at relevant national and international breast cancer conferences. Trial registration number NCT02263651. PMID:27044574

  20. Alterations in brain structure related to breast cancer and its treatment: Chemotherapy and other considerations

    PubMed Central

    McDonald, Brenna C.; Saykin, Andrew J.

    2013-01-01

    Cognitive effects of cancer and its treatment have been a topic of increasing investigation over the past ∼30 years. Recent studies have focused on better understanding the neural correlates of these effects, with an emphasis on post-chemotherapy effects in breast cancer patients. Structural MRI studies have utilized both automated and manual approaches to quantify gray and white matter characteristics (e.g., regional volume and density) in breast cancer patients treated with chemotherapy relative to patients who did not receive chemotherapy and/or healthy controls. While most work to date has been retrospective, a small number of baseline (pre-systemic therapy) and prospective longitudinal studies have been conducted. Data have consistently shown lower gray and white matter volume and density in patients treated with chemotherapy, particularly in frontal and temporal brain regions. Host factors and/or the cancer disease process and other therapies (e.g., antiestrogen treatment) also seem likely to contribute to the observed differences, though the relative contributions of these effects have not yet been investigated in detail. These structural abnormalities have been shown to relate to subjective and objective cognitive functioning, as well as to biological factors that may help to elucidate the underlying mechanism(s). This review examines the currently available published observations and discusses the major themes and promising directions for future studies. PMID:23996156

  1. Pre-Exposure of Human Adipose Mesenchymal Stem Cells to Soluble Factors Enhances Their Homing to Brain Cancer

    PubMed Central

    Smith, Chris L.; Chaichana, Kaisorn L.; Lee, Young M.; Lin, Benjamin; Stanko, Kevin M.; O’Donnell, Thomas; Gupta, Saksham; Shah, Sagar R.; Wang, Joanne; Wijesekera, Olindi; Delannoy, Michael

    2015-01-01

    Recent research advances have established mesenchymal stem cells (MSCs) as a promising vehicle for therapeutic delivery. Their intrinsic tropism for brain injury and brain tumors, their lack of immunogenicity, and their ability to breach the blood-brain barrier make these cells an attractive potential treatment of brain disorders, including brain cancer. Despite these advantages, the efficiency of MSC homing to the brain has been limited in commonly used protocols, hindering the feasibility of such therapies. In the present study, we report a reproducible, comprehensive, cell culture-based approach to enhance human adipose-derived MSC (hAMSC) engraftment to brain tumors. We used micro- and nanotechnological tools to systematically model several steps in the putative homing process. By pre-exposing hAMSCs to glioma-conditioned media and the extracellular matrix proteins fibronectin and laminin, we achieved significant enhancements of the individual homing steps in vitro. This homing was confirmed in an in vivo rodent model of brain cancer. This comprehensive, cell-conditioning approach provides a novel method to enhance stem cell homing to gliomas and, potentially, other neurological disorders. PMID:25646527

  2. Pre-exposure of human adipose mesenchymal stem cells to soluble factors enhances their homing to brain cancer.

    PubMed

    Smith, Chris L; Chaichana, Kaisorn L; Lee, Young M; Lin, Benjamin; Stanko, Kevin M; O'Donnell, Thomas; Gupta, Saksham; Shah, Sagar R; Wang, Joanne; Wijesekera, Olindi; Delannoy, Michael; Levchenko, Andre; Quiñones-Hinojosa, Alfredo

    2015-03-01

    Recent research advances have established mesenchymal stem cells (MSCs) as a promising vehicle for therapeutic delivery. Their intrinsic tropism for brain injury and brain tumors, their lack of immunogenicity, and their ability to breach the blood-brain barrier make these cells an attractive potential treatment of brain disorders, including brain cancer. Despite these advantages, the efficiency of MSC homing to the brain has been limited in commonly used protocols, hindering the feasibility of such therapies. In the present study, we report a reproducible, comprehensive, cell culture-based approach to enhance human adipose-derived MSC (hAMSC) engraftment to brain tumors. We used micro- and nanotechnological tools to systematically model several steps in the putative homing process. By pre-exposing hAMSCs to glioma-conditioned media and the extracellular matrix proteins fibronectin and laminin, we achieved significant enhancements of the individual homing steps in vitro. This homing was confirmed in an in vivo rodent model of brain cancer. This comprehensive, cell-conditioning approach provides a novel method to enhance stem cell homing to gliomas and, potentially, other neurological disorders.

  3. ST6GALNAC5 Expression Decreases the Interactions between Breast Cancer Cells and the Human Blood-Brain Barrier

    PubMed Central

    Drolez, Aurore; Vandenhaute, Elodie; Delannoy, Clément Philippe; Dewald, Justine Hélène; Gosselet, Fabien; Cecchelli, Romeo; Julien, Sylvain; Dehouck, Marie-Pierre; Delannoy, Philippe; Mysiorek, Caroline

    2016-01-01

    The ST6GALNAC5 gene that encodes an α2,6-sialyltransferase involved in the biosynthesis of α-series gangliosides, was previously identified as one of the genes that mediate breast cancer metastasis to the brain. We have shown that the expression of ST6GALNAC5 in MDA-MB-231 breast cancer cells resulted in the expression of GD1α ganglioside at the cell surface. By using a human blood-brain barrier in vitro model recently developed, consisting in CD34+ derived endothelial cells co-cultivated with pericytes, we show that ST6GALNAC5 expression decreased the interactions between the breast cancer cells and the human blood-brain barrier. PMID:27529215

  4. ST6GALNAC5 Expression Decreases the Interactions between Breast Cancer Cells and the Human Blood-Brain Barrier.

    PubMed

    Drolez, Aurore; Vandenhaute, Elodie; Delannoy, Clément Philippe; Dewald, Justine Hélène; Gosselet, Fabien; Cecchelli, Romeo; Julien, Sylvain; Dehouck, Marie-Pierre; Delannoy, Philippe; Mysiorek, Caroline

    2016-08-11

    The ST6GALNAC5 gene that encodes an α2,6-sialyltransferase involved in the biosynthesis of α-series gangliosides, was previously identified as one of the genes that mediate breast cancer metastasis to the brain. We have shown that the expression of ST6GALNAC5 in MDA-MB-231 breast cancer cells resulted in the expression of GD1α ganglioside at the cell surface. By using a human blood-brain barrier in vitro model recently developed, consisting in CD34⁺ derived endothelial cells co-cultivated with pericytes, we show that ST6GALNAC5 expression decreased the interactions between the breast cancer cells and the human blood-brain barrier.

  5. Exploring the Support Needs of Family Caregivers of Patients with Brain Cancer Using the CSNAT: A Comparative Study with Other Cancer Groups.

    PubMed

    Aoun, Samar M; Deas, Kathleen; Howting, Denise; Lee, Gabriel

    2015-01-01

    A substantial burden is placed on family caregivers of patients diagnosed with brain cancers. Despite this, the support needs of the caregivers are often under-recognised and not addressed adequately in current routine and patient centred clinical care. The Carer Support Needs Assessment Tool (CSNAT) is a validated instrument designed to systematically identify and address caregiver needs [corrected]. It has been trialled in an Australian palliative care community setting using a stepped wedge cluster design involving 322 family carers of terminally ill patients. The current article reports on a subset from this trial, 29 caregivers of patients with primary brain cancer, and compares their profile and outcomes to those of other cancer groups. Caregiver strain was assessed using the Family Appraisal of Caregiving Questionnaire, caregiver physical and mental wellbeing using SF12 and caregiver workload using a questionnaire on support with activities of daily living (ADL). In comparison to caregivers of patients with all other cancers, the primary brain cancer group had significantly higher levels of caregiver strain, lower levels of mental wellbeing and a higher level of ADL workload. Their physical wellness also deteriorated significantly over time. An action plan approach led to practical solutions for addressing highlighted concerns. Four themes evolved from the family caregivers' feedback interviews: The extremely challenging caregiver experience with brain cancer; the systematic and practical approach of the CSNAT during rapid changes; connection with health professionals, feeling acknowledged and empowered; and timely advice and assurance of support during the caregiving journey. This preliminary study has demonstrated that the CSNAT provides a practical and useful tool for assessing the support needs of family caregivers of patients with brain cancer and has provided the basis for a larger scale, longitudinal study that allows a more detailed characterisation

  6. Exploring the Support Needs of Family Caregivers of Patients with Brain Cancer Using the CSNAT: A Comparative Study with Other Cancer Groups

    PubMed Central

    Aoun, Samar M.; Deas, Kathleen; Howting, Denise; Lee, Gabriel

    2015-01-01

    A substantial burden is placed on family caregivers of patients diagnosed with brain cancers. Despite this, the support needs of the caregivers are often under-recognised and not addressed adequately in current routine and patient centred clinical care. The Care Support Needs Assessment Tool (CSNAT) is a validated instrument designed to systematically identify and address caregiver needs. It has been trialled in an Australian palliative care community setting using a stepped wedge cluster design involving 322 family carers of terminally ill patients. The current article reports on a subset from this trial, 29 caregivers of patients with primary brain cancer, and compares their profile and outcomes to those of other cancer groups. Caregiver strain was assessed using the Family Appraisal of Caregiving Questionnaire, caregiver physical and mental wellbeing using SF12 and caregiver workload using a questionnaire on support with activities of daily living (ADL). In comparison to caregivers of patients with all other cancers, the primary brain cancer group had significantly higher levels of caregiver strain, lower levels of mental wellbeing and a higher level of ADL workload. Their physical wellness also deteriorated significantly over time. An action plan approach led to practical solutions for addressing highlighted concerns. Four themes evolved from the family caregivers’ feedback interviews: The extremely challenging caregiver experience with brain cancer; the systematic and practical approach of the CSNAT during rapid changes; connection with health professionals, feeling acknowledged and empowered; and timely advice and assurance of support during the caregiving journey. This preliminary study has demonstrated that the CSNAT provides a practical and useful tool for assessing the support needs of family caregivers of patients with brain cancer and has provided the basis for a larger scale, longitudinal study that allows a more detailed characterisation of the

  7. Exploring the Support Needs of Family Caregivers of Patients with Brain Cancer Using the CSNAT: A Comparative Study with Other Cancer Groups.

    PubMed

    Aoun, Samar M; Deas, Kathleen; Howting, Denise; Lee, Gabriel

    2015-01-01

    A substantial burden is placed on family caregivers of patients diagnosed with brain cancers. Despite this, the support needs of the caregivers are often under-recognised and not addressed adequately in current routine and patient centred clinical care. The Carer Support Needs Assessment Tool (CSNAT) is a validated instrument designed to systematically identify and address caregiver needs [corrected]. It has been trialled in an Australian palliative care community setting using a stepped wedge cluster design involving 322 family carers of terminally ill patients. The current article reports on a subset from this trial, 29 caregivers of patients with primary brain cancer, and compares their profile and outcomes to those of other cancer groups. Caregiver strain was assessed using the Family Appraisal of Caregiving Questionnaire, caregiver physical and mental wellbeing using SF12 and caregiver workload using a questionnaire on support with activities of daily living (ADL). In comparison to caregivers of patients with all other cancers, the primary brain cancer group had significantly higher levels of caregiver strain, lower levels of mental wellbeing and a higher level of ADL workload. Their physical wellness also deteriorated significantly over time. An action plan approach led to practical solutions for addressing highlighted concerns. Four themes evolved from the family caregivers' feedback interviews: The extremely challenging caregiver experience with brain cancer; the systematic and practical approach of the CSNAT during rapid changes; connection with health professionals, feeling acknowledged and empowered; and timely advice and assurance of support during the caregiving journey. This preliminary study has demonstrated that the CSNAT provides a practical and useful tool for assessing the support needs of family caregivers of patients with brain cancer and has provided the basis for a larger scale, longitudinal study that allows a more detailed characterisation

  8. Cancer-related multiple brain infarctions caused by Trousseau syndrome in a patient with metastatic colon cancer: a case report.

    PubMed

    Akiyama, Takahiko; Miyamoto, Yuji; Sakamoto, Yasuo; Tokunaga, Ryuma; Kosumi, Keisuke; Shigaki, Hironobu; Kurashige, Junji; Iwatsuki, Masaaki; Baba, Yoshifumi; Yoshida, Naoya; Baba, Hideo

    2016-12-01

    Thromboembolism that occurs in association with a malignant tumor is known as Trousseau syndrome. We herein present a case of Trousseau syndrome during systemic chemotherapy for metastatic colon cancer. A 65-year-old man with multiple liver metastases underwent primary tumor resection and systemic chemotherapy. Multiple brain infarctions were detected by magnetic resonance imaging immediately after first-line chemotherapy, which was deemed ineffective. There was no evidence of cardioembolic stroke or carotid atherosclerosis. Although the patient was initially asymptomatic, he subsequently developed paralysis. Despite anticoagulant treatment, he developed repeated recurrences of the infarction, and the area of the infarction spread as the liver metastases progressed. The patient's condition showed no response to an alternative treatment regimen for advanced colon carcinoma. He died approximately 11 months after tumor discovery. PMID:27595586

  9. Diffuse optical tomography and spectroscopy of breast cancer and fetal brain

    NASA Astrophysics Data System (ADS)

    Choe, Regine

    Diffuse optical techniques utilize light in the near infrared spectral range to measure tissue physiology non-invasively. Based on these measurements, either on average or a three-dimensional spatial map of tissue properties such as total hemoglobin concentration, blood oxygen saturation and scattering can be obtained using model-based reconstruction algorithms. In this thesis, diffuse optical techniques were applied for in vivo breast cancer imaging and trans-abdominal fetal brain oxygenation monitoring. For in vivo breast cancer imaging, clinical diffuse optical tomography and related instrumentation was developed and used in several contexts. Bulk physiological properties were quantified for fifty-two healthy subjects in the parallel-plate transmission geometry. Three-dimensional images of breast were reconstructed for subjects with breast tumors and, tumor contrast with respect to normal tissue was found in total hemoglobin concentration and scattering and was quantified for twenty-two breast carcinomas. Tumor contrast and tumor volume changes during neoadjuvant chemotherapy were tracked for one subject and compared to the dynamic contrast-enhanced MRI. Finally, the feasibility for measuring blood flow of breast tumors using optical methods was demonstrated for seven subjects. In a qualitatively different set of experiments, the feasibility for trans-abdominal fetal brain oxygenation monitoring was demonstrated on pregnant ewes with induced fetal hypoxia. Preliminary clinical experiences were discussed to identify future directions. In total, this research has translated diffuse optical tomography techniques into clinical research environment.

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

    PubMed

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

    2015-10-01

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

  11. Performance Evaluation: A Deadly Disease?

    ERIC Educational Resources Information Center

    Aluri, Rao; Reichel, Mary

    1994-01-01

    W. Edwards Deming condemned performance evaluations as a deadly disease afflicting American management. He argued that performance evaluations nourish fear, encourage short-term thinking, stifle teamwork, and are no better than lotteries. This article examines library literature from Deming's perspective. Although that literature accepts…

  12. Who are the Unclaimed Dead?

    PubMed

    Quinet, Kenna; Nunn, Samuel; Ballew, Alfarena

    2016-01-01

    Unclaimed dead are deceased persons with no known next of kin (NoK) or NoK was located but did not claim the deceased. Unclaimed dead in Marion County, Indiana, 2004-2011, are examined. Comparisons are provided of the unclaimed to the claimed dead population and county death patterns. Race, gender, marital status, age, location, manner and cause of death, NoK, and days to disposition are analyzed. The unclaimed dead were disproportionately male, slightly more likely to be Black, younger at death, died from natural causes, had unknown marital status, were equally likely as not to have NoK, did not die in a hospital, and were subject to autopsy. Nearly half the unclaimed had NoK who did not claim the body; the other half had no identifiable NoK. Unclaimed were more likely to have an autopsy and to die from external causes. Most unclaimed were identified by means outside fingerprints or DNA. PMID:26524620

  13. Brain cancer and nonoccupational risk factors: a case-control study among workers at two nuclear facilities.

    PubMed Central

    Carpenter, A V; Flanders, W D; Frome, E L; Cole, P; Fry, S A

    1987-01-01

    In a nested case-control study of nuclear workers, 82 brain cancer cases were compared with 328 matched controls to investigate the possible association with nonoccupational risk factors such as histories of epilepsy or head injury. We observed a moderately strong association between brain cancer occurrence and history of epilepsy (OR = 5.7, 95 per cent CI: 1.0, 32.1), but did not find a positive association with previous head injury (OR = 0.9, 95 per cent CI: 0.2, 4.2). PMID:3618849

  14. Brain cancer and nonoccupational risk factors: a case-control study among workers at two nuclear facilities

    SciTech Connect

    Carpenter, A.V.; Flanders, W.D.; Frome, E.L.; Cole, P.; Fry, S.A.

    1987-09-01

    In a nested case-control study of nuclear workers, 82 brain cancer cases were compared with 328 matched controls to investigate the possible association with nonoccupational risk factors such as histories of epilepsy or head injury. We observed a moderately strong association between brain cancer occurrence and history of epilepsy (OR = 5.7, 95 per cent CI: 1.0, 32.1), but did not find a positive association with previous head injury (OR = 0.9, 95 per cent CI: 0.2, 4.2).

  15. Narciclasine as well as other Amaryllidaceae isocarbostyrils are promising GTP-ase targeting agents against brain cancers.

    PubMed

    Van Goietsenoven, Gwendoline; Mathieu, Véronique; Lefranc, Florence; Kornienko, Alexander; Evidente, Antonio; Kiss, Robert

    2013-03-01

    The anticancer activity of Amaryllidaceae isocarbostyrils is well documented. At pharmacological concentrations, that is, approximately 1 μM in vitro and approximately 10 mg/kg in vivo, narciclasine displays marked proapoptotic and cytotoxic activity, as does pancratistatin, and significant in vivo anticancer effects in various experimental models, but it is also associated with severe toxic side effects. At physiological doses, that is, approximately 50 nM in vitro and approximately 1 mg/kg in vivo, narciclasine is not cytotoxic but cytostatic and displays marked anticancer activity in vivo in experimental models of brain cancer (including gliomas and brain metastases), but it is not associated with toxic side effects. The cytostatic activity of narciclasine involves the impairment of actin cytoskeleton organization by targeting GTPases, including RhoA and the elongation factor eEF1A. We have demonstrated that chronic treatments of narciclasine (1 mg/kg) significantly increased the survival of immunodeficient mice orthotopically xenografted with highly invasive human glioblastomas and apoptosis-resistant brain metastases, including melanoma- and non-small-cell-lung cancer- (NSCLC) related brain metastases. Thus, narciclasine is a potentially promising agent for the treatment of primary brain cancers and various brain metastases. To date, efforts to develop synthetic analogs with anticancer properties superior to those of narciclasine have failed; thus, research efforts are now focused on narciclasine prodrugs.

  16. Occupational risk factors for brain cancer: a population-based case-control study in Iowa.

    PubMed

    Zheng, T; Cantor, K P; Zhang, Y; Keim, S; Lynch, C F

    2001-04-01

    A number of occupations and industries have been inconsistently associated with the risk of brain cancer. To further explore possible relationships, we conducted a population-based case-control study of brain glioma in the state of Iowa, involving 375 histologically confirmed incident cases and 2434 population-based controls. Among men, the industries and/or occupations that had a significantly increased risk for employment of more than 10 years included roofing, siding, and sheet metalworking; newspaper work; rubber and plastics products, particularly tires and inner tubes; miscellaneous manufacturing industries; wholesale trade of durable goods, grain, and field beans; cleaning and building service occupations; miscellaneous mechanics and repairers; and janitors and cleaners. Subjects who worked in plumbing, heating, and air conditioning; electrical services; gasoline service stations; and military occupations also experienced a significantly increased risk. Among women, significant excess risk was observed for occupations in agricultural services and farming, apparel and textile products, electrical and electronic equipment manufacturing, various retail sales, record-keeping, and restaurant service. Workers in industries with a potential for gasoline or motor exhaust exposures experienced a non-significant excess risk of brain glioma.

  17. Self-Targeting Fluorescent Carbon Dots for Diagnosis of Brain Cancer Cells.

    PubMed

    Zheng, Min; Ruan, Shaobo; Liu, Shi; Sun, Tingting; Qu, Dan; Zhao, Haifeng; Xie, Zhigang; Gao, Huile; Jing, Xiabin; Sun, Zaicheng

    2015-11-24

    A new type of carbon dots (CD-Asp) with targeting function toward brain cancer glioma was synthesized via a straightforward pyrolysis route by using D-glucose and L-aspartic acid as starting materials. The as-prepared CD-Asp exhibits not only excellent biocompatibility and tunable full-color emission, but also significant capability of targeting C6 glioma cells without the aid of any extra targeting molecules. In vivo fluorescence images showed high-contrast biodistribution of CD-Asp 15 min after tail vein injection. A much stronger fluorescent signal was detected in the glioma site than that in normal brain, indicating their ability to freely penetrate the blood-brain barrier and precisely targeting glioma tissue. However, its counterparts, the CDs synthesized from D-glucose (CD-G), L-asparic acid (CD-A), or D-glucose and L-glutamic acid (CD-Glu) have no or low selectivity for glioma. Therefore, CD-Asp could act as a fluorescence imaging and targeting agent for noninvasive glioma diagnosis. This work highlights the potential application of CDs for constructing an intelligent nanomedicine with integration of diagnostic, targeting, and therapeutic functions.

  18. Pemetrexed/cisplatin as first-line chemotherapy for advanced lung cancer with brain metastases

    PubMed Central

    He, Guangzhao; Xiao, Xiaoguang; Zou, Man; Zhang, Chengliang; Xia, Shu

    2016-01-01

    Abstract Background: Brain metastases (BMs) are a common and serious complication of non-small cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT), surgery, and molecular targeted therapy are usually used to treat NSCLC with BM. Chemotherapeutic options for BM are limited by tumor resistance, ineffective agents, and the blood–brain barrier. Pemetrexed/cisplatin is the preferred chemotherapy in nonsquamous NSCLC, but the efficacy of this treatment for nonsquamous NSCLC with BM is uncertain. Methods: We present a case of nonsquamous NSCLC with asymptomatic BM presenting with irritating cough and right shoulder back pain (unknown sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase). Results: He benefited from administration of first-line chemotherapy of pemetrexed/cisplatin. Partial remission was achieved in the primary lesion of the lungs and BM lesion. He was further given 3 cycles of pemetrexed monotherapy and WBRT. Complete remission was further achieved in BM lesion. Conclusion: The findings of clinical trials and theoretical studies about the current pemetrexed/cisplatin in the treatment of nonsquamous NSCLC with BM are also summarized to provide a reference for the application of pemetrexed/cisplatin in nonsquamous NSCLC with BM. Whether or not pemetrexed/cisplatin is definitely effective in nonsquamous NSCLC with BM must be proven by subsequent phase III clinical trials. PMID:27512852

  19. Stereotactic Radiosurgery for Patients With Brain Metastases From Small Cell Lung Cancer

    SciTech Connect

    Wegner, Rodney E.; Olson, Adam C.; Kondziolka, Douglas; Niranjan, Ajay; Lundsford, L. Dade; Flickinger, John C.

    2011-11-01

    Background: Patients with small-cell lung cancer have a high likelihood of developing brain metastases. Many of these patients will have prophylactic cranial irradiation (PCI) or eventually undergo whole brain radiation therapy (WBRT). Despite these treatments, a large number of these patients will have progression of their intracranial disease and require additional local therapy. Stereotactic radiosurgery (SRS) is an important treatment option for such patients. Methods: We retrospectively reviewed the charts of 44 patients with brain metastases from small-cell lung cancer treated with gamma knife SRS. Multivariate analysis was used to determine significant prognostic factors influencing survival. Results: The median follow-up from SRS in this patient population was 9 months (1-49 months). The median overall survival (OS) was 9 months after SRS. Karnofsky performance status (KPS) and combined treatment involving WBRT and SRS within 4 weeks were the two factors identified as being significant predictors of increased OS (p = 0.033 and 0.040, respectively). When comparing all patients, patients treated with a combined approach had a median OS of 14 months compared to 6 months if SRS was delivered alone. We also compared the OS times from the first definitive radiation: WBRT, WBRT and SRS if combined therapy was used, and SRS if the patient never received WBRT. The median survival for those groups was 12, 14, and 13 months, respectively, p = 0.19. Seventy percent of patients had follow-up magnetic resonance imaging available for review. Actuarial local control at 6 months and 12 months was 90% and 86%, respectively. Only 1 patient (2.2%) had symptomatic intracranial swelling related to treatment, which responded to a short course of steroids. New brain metastases outside of the treated area developed in 61% of patients at a median time of 7 months; 81% of these patients had received previous WBRT. Conclusions: Stereotactic radiosurgery for small-cell lung carcinoma

  20. Understanding Brain Tumors

    MedlinePlus

    ... to Know About Brain Tumors . What is a Brain Tumor? A brain tumor is an abnormal growth
 ... Tumors” from Frankly Speaking Frankly Speaking About Cancer: Brain Tumors Download the full book Questions to ask ...

  1. Postoperative Structural Brain Changes and Cognitive Dysfunction in Patients with Breast Cancer

    PubMed Central

    Kawai, Masaaki; Kotozaki, Yuka; Nouchi, Rui; Tada, Hiroshi; Takeuchi, Hikaru; Ishida, Takanori; Taki, Yasuyuki; Kawashima, Ryuta; Ohuchi, Noriaki

    2015-01-01

    Objective The primary purpose of this study was to clarify the influence of the early response to surgery on brain structure and cognitive function in patients with breast cancer. It was hypothesized that the structure of the thalamus would change during the early response after surgery due to the effects of anesthesia and would represent one aspect of an intermediate phenotype of postoperative cognitive dysfunction (POCD). Methods We examined 32 postmenopausal females with breast cancer and 20 age-matched controls. We assessed their cognitive function (attention, memory, and executive function), and performed brain structural MRI 1.5 ± 0.5 days before and 5.6 ± 1.2 days after surgery. Results We found a significant interaction between regional grey matter volume (rGMV) in the thalamus (P < 0.05, familywise error (FWE), small volume correction (SVC)) and one attention domain subtest (P = 0.001, Bonferroni correction) after surgery in the patient group compared with the control group. Furthermore, the changes in attention were significantly associated with sevoflurane anesthetic dose (r2 = 0.247, β = ‒0.471, P = 0.032) and marginally associated with rGMV changes in the thalamus (P = 0.07, FWE, SVC) in the Pt group. Conclusion Our findings suggest that alterations in brain structure, particularly in the thalamus, may occur shortly after surgery and may be associated with attentional dysfunction. This early postoperative response to anesthesia may represent an intermediate phenotype of POCD. It was assumed that patients experiencing other risk factors of POCD, such as the severity of surgery, the occurrence of complications, and pre-existing cognitive impairments, would develop clinical POCD with broad and multiple types of cognitive dysfunction. PMID:26536672

  2. Unexpected detection of brain metastases by 18F-NaF PET/CT in a patient with lung cancer.

    PubMed

    Wu, Jiang; Zhu, Hong; Ji, Hengshan

    2013-11-01

    In recent years, the inconsistent supply of (99m)Tc and the increasingly widespread use of PET/CT have led to a renewed interest in PET/CT bone scans using (18)F-NaF. Recently, a 64-year-old man with biopsy-proven lung cancer underwent an (18)F-NaF PET/CT bone scan due to a shortage of (99m)Tc. Unexpectedly, multiple nodular foci of increased tracer uptake were present in the brain, whereas there were no definitive bone metastases detected. Subsequently, brain MRI confirmed the presence of brain metastases.

  3. 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.

  4. 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.

  5. White matter changes in breast cancer brain metastases patients who undergo radiosurgery alone compared to whole brain radiation therapy plus radiosurgery.

    PubMed

    Stokes, Timothy B; Niranjan, Ajay; Kano, Hideyuki; Choi, Phillip A; Kondziolka, Douglas; Dade Lunsford, L; Monaco, Edward A

    2015-02-01

    Delayed toxicity after whole brain radiation therapy (WBRT) is of increasing concern in patients who survive more than one year with brain metastases from breast cancer. Radiation-related white matter toxicity is detected by magnetic resonance imaging (MRI) and has been correlated with neurocognitive dysfunction. This study assessed the risk of developing white matter changes (WMC) in breast cancer patients who underwent either WBRT plus stereotactic radiosurgery (SRS) or SRS alone. We retrospectively compared 35 patients with breast cancer brain metastases who received WBRT and SRS to 30 patients who only received SRS. All patients had evaluable imaging at a median of one year after their initial management. The development of white matter T2 prolongation as detected by T2 or FLAIR imaging was graded: grade 1 = little or no white matter T2 hyperintensity; grade 2 = limited periventricular hyperintensity; and grade 3 = diffuse white matter hyperintensity. After WBRT plus SRS, patients demonstrated a significantly higher incidence of WMC (p < 0.0001). After one year, 71.5 % of patients whose treatment included WBRT demonstrated WMC (42.9 % grade 2; 28.6 % grade 3). Only one patient receiving only SRS developed WMC. In long-term survivors of breast cancer, the risk of WMC was significantly reduced when SRS alone was used for management. Further prospective studies are necessary to determine how these findings correlate with neurocognitive toxicity. WBRT usage as initial management of limited brain disease should be replaced by SRS alone to reduce the risk of delayed white matter toxicity.

  6. FAQ: West Nile Virus and Dead Birds

    MedlinePlus

    ... Education Public Service Videos West Nile Virus & Dead Birds Recommend on Facebook Tweet Share Compartir On this ... dead bird sightings to local authorities. How do birds get infected with West Nile virus? West Nile ...

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

    PubMed

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

    2006-11-01

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

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

    PubMed

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

    2015-09-24

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

  9. 7 CFR 322.29 - Dead bees.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 7 Agriculture 5 2013-01-01 2013-01-01 false Dead bees. 322.29 Section 322.29 Agriculture..., DEPARTMENT OF AGRICULTURE BEES, BEEKEEPING BYPRODUCTS, AND BEEKEEPING EQUIPMENT Importation and Transit of Restricted Articles § 322.29 Dead bees. (a) Dead bees imported into or transiting the United States must...

  10. 7 CFR 322.29 - Dead bees.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 5 2014-01-01 2014-01-01 false Dead bees. 322.29 Section 322.29 Agriculture..., DEPARTMENT OF AGRICULTURE BEES, BEEKEEPING BYPRODUCTS, AND BEEKEEPING EQUIPMENT Importation and Transit of Restricted Articles § 322.29 Dead bees. (a) Dead bees imported into or transiting the United States must...

  11. 7 CFR 322.29 - Dead bees.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 5 2012-01-01 2012-01-01 false Dead bees. 322.29 Section 322.29 Agriculture..., DEPARTMENT OF AGRICULTURE BEES, BEEKEEPING BYPRODUCTS, AND BEEKEEPING EQUIPMENT Importation and Transit of Restricted Articles § 322.29 Dead bees. (a) Dead bees imported into or transiting the United States must...

  12. 7 CFR 322.29 - Dead bees.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 5 2011-01-01 2011-01-01 false Dead bees. 322.29 Section 322.29 Agriculture..., DEPARTMENT OF AGRICULTURE BEES, BEEKEEPING BYPRODUCTS, AND BEEKEEPING EQUIPMENT Importation and Transit of Restricted Articles § 322.29 Dead bees. (a) Dead bees imported into or transiting the United States must...

  13. 7 CFR 322.29 - Dead bees.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 5 2010-01-01 2010-01-01 false Dead bees. 322.29 Section 322.29 Agriculture..., DEPARTMENT OF AGRICULTURE BEES, BEEKEEPING BYPRODUCTS, AND BEEKEEPING EQUIPMENT Importation and Transit of Restricted Articles § 322.29 Dead bees. (a) Dead bees imported into or transiting the United States must...

  14. Brain responses to erotic and other emotional stimuli in breast cancer survivors with and without distress about low sexual desire: a preliminary fMRI study.

    PubMed

    Versace, Francesco; Engelmann, Jeffrey M; Jackson, Edward F; Slapin, Aurelija; Cortese, Kristin M; Bevers, Therese B; Schover, Leslie R

    2013-12-01

    Many breast cancer survivors report a loss of sexual desire and arousability, consonant with the new DSM-V category of female sexual interest/arousal disorder. The cause of decreased sexual desire and pleasure after treatment for cancer is unknown. One possibility is that cancer, or treatment for cancer, damages brain circuits that are involved in reward-seeking. To test the hypothesis that brain reward systems are involved in decreased sexual desire in breast cancer survivors, we used functional magnetic resonance imaging (fMRI) to compare brain responses to erotica and other emotional stimuli in two groups of women previously treated for breast cancer with chemotherapy: those who were distressed about a perceived loss of sexual desire and those who may have had low desire, but were not distressed about it. Women distressed about their desire had reduced brain responses to erotica in the anterior cingulate and dorsolateral prefrontal cortex, which are part of the brain reward system. This study is the first to demonstrate, in cancer survivors, that problems with sexual desire/arousability are associated with blunted brain responses to erotica in reward systems. Future research is necessary to determine whether brain responses differ as a result of chemotherapy, hormone therapy, and menopausal status. This may contribute to the development of new, evidence-based interventions for one of the most prevalent and enduring side effects of cancer treatment. PMID:23955492

  15. Predictive Risk of Radiation Induced Cerebral Necrosis in Pediatric Brain Cancer Patients after VMAT Versus Proton Therapy

    PubMed Central

    Freund, Derek; Zhang, Rui; Sanders, Mary; Newhauser, Wayne

    2015-01-01

    Cancer of the brain and central nervous system (CNS) is the second most common of all pediatric cancers. Treatment of many of these cancers includes radiation therapy of which radiation induced cerebral necrosis (RICN) can be a severe and potentially devastating side effect. Risk factors for RICN include brain volume irradiated, the dose given per fraction and total dose. Thirteen pediatric patients were selected for this study to determine the difference in predicted risk of RICN when treating with volumetric modulated arc therapy (VMAT) compared to passively scattered proton therapy (PSPT) and intensity modulated proton therapy (IMPT). Plans were compared on the basis of dosimetric endpoints in the planned treatment volume (PTV) and brain and a radiobiological endpoint of RICN calculated using the Lyman-Kutcher-Burman probit model. Uncertainty tests were performed to determine if the predicted risk of necrosis was sensitive to positional errors, proton range errors and selection of risk models. Both PSPT and IMPT plans resulted in a significant increase in the maximum dose to the brain, a significant reduction in the total brain volume irradiated to low doses, and a significant lower predicted risk of necrosis compared with the VMAT plans. The findings of this study were upheld by the uncertainty analysis. PMID:25866999

  16. Normative seeds for deadly martyrdoms.

    PubMed

    Tobeña, Adolf; Vilarroya, Oscar

    2014-08-01

    Even if Lankford's biographical examination of perpetrators of suicidal attacks serves to alert us on the role played by individual factors in their recruitment, psychological frailties, distress, or coercion do not exhaust the causal pathways to deadly martyrdom. Normative personality attributes must be explored further in order to ascertain plausible roots of murderous sacrifice. We have advanced (Tobeña 2004b; 2009; 2011) a template of normative temperamental traits that could lead activists to the threshold of volunteering for murderous missions.

  17. Relationship Between HER2 Status and Prognosis in Women With Brain Metastases From Breast Cancer

    SciTech Connect

    Xu Zhiyuan; Marko, Nicholas F.; Chao, Sam T.; Angelov, Lilyana; Vogelbaum, Michael A.; Suh, John H.; Barnett, Gene H.; Weil, Robert J.

    2012-04-01

    Purpose: To analyze factors affecting outcomes in breast cancer patients with brain metastases (BM) and characterize the role of HER2 status. Methods and Materials: We identified 264 breast cancer patients treated between 1999 and 2008 for BM. HER2 status was known definitively for 172 patients and was used to define cohorts in which survival and risk factors were analyzed. Results: Kaplan-Meier survival analysis demonstrated improved mean overall survival (105.7 vs. 74.3 months, p < 0.02), survival after diagnosis of BM (neurologic survival, NS) (32.2 vs. 18.9 months, p < 0.01), and survival after treatment with stereotactic radiosurgery (RS) (31.3 vs. 14.1, p < 0.01) in HER2+ patients relative to those with HER2- breast cancer. HER2+ status was an independent, positive prognostic factor for survival on univariate and multivariate hazard analysis (hazard ratio: overall survival = 0.66, 0.18; NS = 0.50, 0.34). Additionally, subgroup analysis suggests that stereotactic radiosurgery may be of particular benefit in patients with HER2+ tumors. Conclusions: Overall survival, NS, and RS are improved in patients with HER2+ tumors, relative to those with HER2- lesions, and HER2 amplification is independently associated with increased survival in patients with BM from breast cancer. Our findings suggest that the prognosis of HER2+ patients may be better than that of otherwise similar patients who are HER2- and that stereotactic radiosurgery may be beneficial for some patients with HER2+ lesions.

  18. Surface engineered polymeric nanocarriers mediate the delivery of transferrin-methotrexate conjugates for an improved understanding of brain cancer.

    PubMed

    Jain, Atul; Jain, Ashay; Garg, Neeraj K; Tyagi, Rajeev K; Singh, Bhupinder; Katare, Om Prakash; Webster, Thomas J; Soni, Vandana

    2015-09-01

    The objective of present study was to enhance permeation of bioactive molecules across blood brain barrier (BBB) through polysorbate 80 coated poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) loaded with methotrexate-transferrin (Tw-Mtx-Tf-NP) conjugates (Mtx-Tf). The easy trans-BBB migration of developed formulations through endocytosis, and inhibition of P-gp efflux pump present in brain were established by Pluronic F-68 and/or polysorbate 80 (Tween 80/Tw). The over-expression of transferrin (Tf) receptors on cancer cell surface allowed targeted and sustained delivery of Mtx-Tf conjugated to brain cancer cells by receptor mediated endocytosis. The developed formulations showed improved penetration in comparison to non-targeting experimental NP controls. The transportation potential and bio-distribution studies of such nanosized polymeric carriers showing successful migration and trans-BBB passage was carried out by administering FITC labeled drug loaded NPs to albino rats through intravenous route. We have validated anti-tumor efficiency of newly formulated and drug loaded NPs compared to controls in experimentally induced tumor-harboring rat model. The present study suggests greater compatibility, less organ toxicity and higher anti-tumor activity of developed formulations due to their targeting and sustained delivery potential in cancer therapeutic interventions. In conclusion, our findings of targeted and sustained drug delivery potential of NPs for are corroborated with in vitro and in vivo evidence, and formulated novel delivery vehicle shows its value in developing new tools for treating brain cancer.

  19. Development of a Patient-Derived Xenograft Model Using Brain Tumor Stem Cell Systems to Study Cancer.

    PubMed

    Chokshi, Chirayu; Dhillon, Manvir; McFarlane, Nicole; Venugopal, Chitra; Singh, Sheila K

    2016-01-01

    Patient-derived xenograft (PDX) models provide an excellent platform to understand cancer initiation and development in vivo. In the context of brain tumor initiating cells (BTICs), PDX models allow for characterization of tumor formation, growth, and recurrence, in a clinically relevant in vivo system. Here, we detail procedures to harvest, culture, characterize, and orthotopically inject human BTICs derived from patient samples.

  20. Brain Injury After Proton Therapy or Carbon Ion Therapy for Head-and-Neck Cancer and Skull Base Tumors

    SciTech Connect

    Miyawaki, Daisuke Murakami, Masao; Demizu, Yusuke; Sasaki, Ryohei; Niwa, Yasue; Terashima, Kazuki; Nishimura, Hideki; Hishikawa, Yoshio; Sugimura, Kazuro

    2009-10-01

    Purpose: To assess the incidence of early delayed or late morbidity of Brain after particle therapy for skull base tumors and head-and-neck cancers. Methods and Materials: Between May 2001 and December 2005, 59 patients with cancerous invasion of the skull base were treated with proton or carbon ion therapy at the Hyogo Ion Beam Medical Center. Adverse events were assessed according to the magnetic resonance imaging findings (late effects of normal tissue-subjective, objective, management, analytic [LENT-SOMA]) and symptoms (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0). Dose-volume histograms were used to analyze the relationship between the dose and volume of the irradiated brain and the occurrence of brain injury. The median follow-up time was 33 months. Results: Of the 48 patients treated with proton therapy and 11 patients treated with carbon ion radiotherapy, 8 (17%) and 7 (64%), respectively, developed radiation-induced brain changes (RIBCs) on magnetic resonance imaging (LENT-SOMA Grade 1-3). Four patients (7%) had some clinical symptoms, such as vertigo and headache (CTCAE Grade 2) or epilepsy (CTCAE Grade 3). The actuarial occurrence rate of RIBCs at 2 and 3 years was 20% and 39%, respectively, with a significant difference in the incidence between the proton and carbon ion radiotherapy groups. The dose-volume histogram analyses revealed significant differences between Brain lobes with and without RIBCs in the actuarial volume of brain lobes receiving high doses. Conclusion: Particle therapies produced minimal symptomatic brain toxicities, but sequential evaluation with magnetic resonance imaging detected a greater incidence of RIBCs. Significant differences were observed in the irradiated brain volume between Brain lobes with and without RIBCs.

  1. Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer.

    PubMed

    Adkins, Chris E; Mohammad, Afroz S; Terrell-Hall, Tori B; Dolan, Emma L; Shah, Neal; Sechrest, Emily; Griffith, Jessica; Lockman, Paul R

    2016-04-01

    The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases. PMID:26944053

  2. Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer.

    PubMed

    Adkins, Chris E; Mohammad, Afroz S; Terrell-Hall, Tori B; Dolan, Emma L; Shah, Neal; Sechrest, Emily; Griffith, Jessica; Lockman, Paul R

    2016-04-01

    The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.

  3. Computed tomography of the brain, chest, and abdomen in the preoperative assessment of non-small cell lung cancer.

    PubMed Central

    Grant, D; Edwards, D; Goldstraw, P

    1988-01-01

    The benefit to be gained from carrying out computed tomography of brain and abdomen in addition to the chest has been evaluated retrospectively in 114 consecutive patients with non-small cell lung cancer who, on the basis of history, clinical examination, chest radiography, and bronchoscopy had been considered potentially operable. Computed tomography of the chest showed potentially inoperable tumour in 37 patients, of whom 25 had tumour confined to the chest. Three patients were shown to have malignant disease within the mediastinum and abdomen; five within the mediastinum and brain; and four within the mediastinum, abdomen, and brain. Computed tomography of the abdomen disclosed deposits in nine patients, but in only two were the abnormalities restricted to the abdomen. Computed tomography of the brain showed metastases in 10 patients, of whom only one had metastatic disease confined to the brain. Thus three patients had isolated deposits in the abdomen and brain. In 12 patients the identification of metastases in the abdomen and brain removed the need for mediastinoscopy. Preoperative computed tomography of the abdomen and brain detected occult metastases in 15 patients (13%) in this study. In three patients the extrathoracic abnormality proved the only contraindication to surgery, but in the other 12 it provided valuable corroborative evidence of incurability and facilitated the assessment of the mediastinal abnormality. PMID:2851880

  4. Human neural stem cells expressing carboxyl esterase target and inhibit tumor growth of lung cancer brain metastases.

    PubMed

    Hong, S H; Lee, H J; An, J; Lim, I; Borlongan, C; Aboody, K S; Kim, S U

    2013-12-01

    Neural stem cells (NSCs) led to the development of a novel strategy for delivering therapeutic genes to brain tumors. Human NSCs expressing rabbit carboxyl esterase (F3.CE), which activates CPT-11, significantly inhibit the growth of A549 human non-small cell lung adenocarcinoma cells in the presence of CPT-11 in vitro and in vivo. F3.CE cells migrated selectively into the brain metastases located in the opposite hemisphere. The treatment also significantly decreased tumor volume in immune-deficient mice bearing lung cancer when F3.CE cells were transplanted into the contralateral hemisphere. The survival of tumor-bearing animals was significantly prolonged by the treatment with F3.CE and CPT-11. This strategy could be considered as an effective treatment regimen for lung cancer brain metastases.

  5. Metastatic brain cancer: prediction of response to whole-brain helical tomotherapy with simultaneous intralesional boost for metastatic disease using quantitative MR imaging features

    NASA Astrophysics Data System (ADS)

    Sharma, Harish; Bauman, Glenn; Rodrigues, George; Bartha, Robert; Ward, Aaron

    2014-03-01

    The sequential application of whole brain radiotherapy (WBRT) and more targeted stereotactic radiosurgery (SRS) is frequently used to treat metastatic brain tumors. However, SRS has side effects related to necrosis and edema, and requires separate and relatively invasive localization procedures. Helical tomotherapy (HT) allows for a SRS-type simultaneous infield boost (SIB) of multiple brain metastases, synchronously with WBRT and without separate stereotactic procedures. However, some patients' tumors may not respond to HT+SIB, and would be more appropriately treated with radiosurgery or conventional surgery despite the additional risks and side effects. As a first step toward a broader objective of developing a means for response prediction to HT+SIB, the goal of this study was to investigate whether quantitative measurements of tumor size and appearance (including first- and second-order texture features) on a magnetic resonance imaging (MRI) scan acquired prior to treatment could be used to differentiate responder and nonresponder patient groups after HT+SIB treatment of metastatic disease of the brain. Our results demonstrated that smaller lesions may respond better to this form of therapy; measures of appearance provided limited added value over measures of size for response prediction. With further validation on a larger data set, this approach may lead to a means for prediction of individual patient response based on pre-treatment MRI, supporting appropriate therapy selection for patients with metastatic brain cancer.

  6. Activity of T-DM1 in Her2-positive breast cancer brain metastases.

    PubMed

    Bartsch, Rupert; Berghoff, Anna S; Vogl, Ursula; Rudas, Margaretha; Bergen, Elisabeth; Dubsky, Peter; Dieckmann, Karin; Pinker, Katja; Bago-Horvath, Zsuzsanna; Galid, Arik; Oehler, Leopold; Zielinski, Christoph C; Gnant, Michael; Steger, Guenther G; Preusser, Matthias

    2015-10-01

    Brain metastases (BM) are frequently diagnosed in metastatic Her2-positive breast cancer. Local treatment remains the standard of care but lapatinib plus capecitabine was recently established as systemic therapy option. Due to a disruption of the blood-brain/tumour-barrier at metastatic sites, even large molecules may penetrate into the central nervous system (CNS). Here, we report on the activity of T-DM1 in Her2-positive breast cancer BM. T-DM1 was administered at a dose of 3.6 mg once every 3 weeks as primary systemic therapy for BM or upon documented CNS progression after initial local treatment. Thus, this study allowed for the appraisal of T-DM1 activity in BM. Restaging was conducted every 12 weeks with MRI or whenever symptoms of disease progression occurred. Ten patients were included; in two asymptomatic subjects, T-DM1 was administered as primary therapy, while eight had progressive BM. All patients had received prior treatment with trastuzumab, six had already received lapatinib, and three pertuzumab as well. Three patients had partial remission of BM, and two patient had stable disease lasting for ≥6 months; two further patients had stable disease for <6 months while three progressed despite treatment. At 8.5 months median follow-up, intracranial PFS was 5 months, and median OS from initiation of T-DM1 was not reached. Local treatment of BM remains the standard of care; lapatinib plus capecitabine is currently the best established systemic therapy option. Still, T-DM1 apparently offers relevant clinical activity in BM and further investigation is warranted.

  7. Occupational exposure to magnetic fields in relation to mortality from brain cancer among electricity generation and transmission workers.

    PubMed Central

    Harrington, J M; McBride, D I; Sorahan, T; Paddle, G M; van Tongeren, M

    1997-01-01

    OBJECTIVE: To investigate whether the risks of mortality from brain cancer are related to occupational exposure to magnetic fields. METHODS: A total of 112 cases of primary brain cancer (1972-91) were identified from a cohort of 84,018 male and female employees of the (then) Central Electricity Generating Board and its privatised successor companies. Individual cumulative occupational exposures to magnetic fields were estimated by linking available computerised job history data with magnetic field measurements collected over 675 person-workshifts. Estimated exposure histories of the case workers were compared with those of 654 control workers drawn from the cohort (nested case-control study), by means of conditional logistic regression. RESULTS: For exposure assessments based on arithmetic means, the risk of mortality from brain cancer for subjects with an estimated cumulative exposure to magnetic fields of 5.4-13.4 microT.y v subjects with lower exposures (0.0-5.3 microT.y) was 1.04 (95% confidence interval (95% CI) 0.60 to 1.80). The corresponding relative risk in subjects with higher exposures (> or = 13.5 microT.y) was 0.95 (95% CI 0.54 to 1.69). There was no indication of a positive trend for cumulative exposure and risk of mortality from brain cancer either when the analysis used exposure assessments based on geometric means or when the analysis was restricted to exposures received within five years of the case diagnosis (or corresponding period for controls). CONCLUSIONS: Although the exposure categorisation was based solely on recent observations, the study findings do not support the hypothesis that the risk of brain cancer is associated with occupational exposure to magnetic fields. PMID:9072027

  8. Effects of Chemotherapy on the Brain in Women With Newly Diagnosed Early-Stage Breast Cancer

    ClinicalTrials.gov

    2016-05-12

    Breast Cancer; Chemotherapeutic Agent Toxicity; Cognitive/Functional Effects; Fatigue; Long-term Effects Secondary to Cancer Therapy in Adults; Neurotoxicity; Psychosocial Effects of Cancer and Its Treatment

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  11. Time-Frequency Analysis of Peptide Microarray Data: Application to Brain Cancer Immunosignatures

    PubMed Central

    O’Donnell, Brian; Maurer, Alexander; Papandreou-Suppappola, Antonia; Stafford, Phillip

    2015-01-01

    One of the gravest dangers facing cancer patients is an extended symptom-free lull between tumor initiation and the first diagnosis. Detection of tumors is critical for effective intervention. Using the body’s immune system to detect and amplify tumor-specific signals may enable detection of cancer using an inexpensive immunoassay. Immunosignatures are one such assay: they provide a map of antibody interactions with random-sequence peptides. They enable detection of disease-specific patterns using classic train/test methods. However, to date, very little effort has gone into extracting information from the sequence of peptides that interact with disease-specific antibodies. Because it is difficult to represent all possible antigen peptides in a microarray format, we chose to synthesize only 330,000 peptides on a single immunosignature microarray. The 330,000 random-sequence peptides on the microarray represent 83% of all tetramers and 27% of all pentamers, creating an unbiased but substantial gap in the coverage of total sequence space. We therefore chose to examine many relatively short motifs from these random-sequence peptides. Time-variant analysis of recurrent subsequences provided a means to dissect amino acid sequences from the peptides while simultaneously retaining the antibody–peptide binding intensities. We first used a simple experiment in which monoclonal antibodies with known linear epitopes were exposed to these random-sequence peptides, and their binding intensities were used to create our algorithm. We then demonstrated the performance of the proposed algorithm by examining immunosignatures from patients with Glioblastoma multiformae (GBM), an aggressive form of brain cancer. Eight different frameshift targets were identified from the random-sequence peptides using this technique. If immune-reactive antigens can be identified using a relatively simple immune assay, it might enable a diagnostic test with sufficient sensitivity to detect tumors

  12. Longitudinal MRI Evaluation of Intracranial Development and Vascular Characteristics of Breast Cancer Brain Metastases in a Mouse Model

    PubMed Central

    Zhou, Heling; Chen, Min; Zhao, Dawen

    2013-01-01

    Longitudinal MRI was applied to monitor intracranial initiation and development of brain metastases and assess tumor vascular volume and permeability in a mouse model of breast cancer brain metastases. Using a 9.4T system, high resolution anatomic MRI and dynamic susceptibility contrast (DSC) perfusion MRI were acquired at different time points after an intracardiac injection of brain-tropic breast cancer MDA-MB231BR-EGFP cells. Three weeks post injection, multifocal brain metastases were first observed with hyperintensity on T2-weighted images, but isointensity on T1-weighted post contrast images, indicating that blood-tumor-barrier (BTB) at early stage of brain metastases was impermeable. Follow-up MRI revealed intracranial tumor growth and increased number of metastases that distributed throughout the whole brain. At the last scan on week 5, T1-weighted post contrast images detected BTB disruption in 160 (34%) of a total of 464 brain metastases. Enhancement in some of the metastases was only seen in partial regions of the tumor, suggesting intratumoral heterogeneity of BTB disruption. DSC MRI measurements of relative cerebral blood volume (rCBV) showed that rCBV of brain metastases was significantly lower (mean  = 0.89±0.03) than that of contralateral normal brain (mean  = 1.00±0.03; p<0.005). Intriguingly, longitudinal measurements revealed that rCBV of individual metastases at early stage was similar to, but became significantly lower than that of contralateral normal brain with tumor growth (p<0.05). The rCBV data were concordant with histological analysis of microvascular density (MVD). Moreover, comprehensive analysis suggested no significant correlation among tumor size, rCBV and BTB permeability. In conclusion, longitudinal MRI provides non-invasive in vivo assessments of spatial and temporal development of brain metastases and their vascular volume and permeability. The characteristic rCBV of brain metastases may have a diagnostic value. PMID

  13. Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors

    PubMed Central

    Wollmann, Guido; Drokhlyansky, Eugene; Davis, John N.; Cepko, Connie

    2015-01-01

    tested a series of chimeric viruses containing genes coding for VSV, together with a gene coding for the glycoprotein from other viruses, including Ebola virus, Lassa virus, LCMV, rabies virus, and Marburg virus, which was substituted for the VSV glycoprotein gene. Ebola and Lassa chimeric viruses were safe in the brain and targeted brain tumors. Lassa-VSV was particularly effective, showed no adverse side effects even when injected directly into the brain, and targeted and destroyed two different types of deadly brain cancer, including glioblastoma and melanoma. PMID:25878115

  14. Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer

    PubMed Central

    Fu, Bo; Long, Wei; Zhang, Ying; Zhang, Aifeng; Miao, Fengqin; Shen, Yuqing; Pan, Ning; Gan, Guangming; Nie, Fang; He, Youji; Zhang, Jianqiong; Teng, Gaojun

    2015-01-01

    Novel molecularly targeted agents that block the development and metastasis of human brain metastatic breast cancer hold great promise for their translational value. In this study, we constructed a novel targeting composite peptide BRBP1-TAT-KLA comprising of three elements: a brain metastatic breast carcinoma cell (231-BR)-binding peptide BRBP1, a cell penetrating peptide TAT, and a proapoptotic peptide KLA. This composite peptide efficiently internalized in 231-BR cells and consequently induced mitochondrial damage and cellular apoptosis. Exposure of 231-BR cells to BRBP1-TAT-KLA significantly decreased cell viability and increased apoptosis compared with the cells treated with the control peptides. In vivo relevance of these findings was further corroborated in the 231-BR tumor-bearing mice that demonstrated significantly delayed tumor development and metastasis following administration of BRBP1-TAT-KLA compared with those treated with TAT-KLA alone. Interestingly, BRBP1-TAT-KLA inhibited the formation of both large and micro-metastases, while TAT-KLA alone failed to significantly reduce micro-metastases in the breast cancer brain metastasis mice. BRBP1-TAT-KLA selectively homed to the tumors in vivo where it induced cellular apoptosis without significant toxicity on non-tumor tissues. Our findings therefore demonstrated the enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA, providing insights toward development of a potential therapeutic strategy for brain metastatic breast cancer. PMID:25619721

  15. Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer.

    PubMed

    Fu, Bo; Long, Wei; Zhang, Ying; Zhang, Aifeng; Miao, Fengqin; Shen, Yuqing; Pan, Ning; Gan, Guangming; Nie, Fang; He, Youji; Zhang, Jianqiong; Teng, Gaojun

    2015-01-26

    Novel molecularly targeted agents that block the development and metastasis of human brain metastatic breast cancer hold great promise for their translational value. In this study, we constructed a novel targeting composite peptide BRBP1-TAT-KLA comprising of three elements: a brain metastatic breast carcinoma cell (231-BR)-binding peptide BRBP1, a cell penetrating peptide TAT, and a proapoptotic peptide KLA. This composite peptide efficiently internalized in 231-BR cells and consequently induced mitochondrial damage and cellular apoptosis. Exposure of 231-BR cells to BRBP1-TAT-KLA significantly decreased cell viability and increased apoptosis compared with the cells treated with the control peptides. In vivo relevance of these findings was further corroborated in the 231-BR tumor-bearing mice that demonstrated significantly delayed tumor development and metastasis following administration of BRBP1-TAT-KLA compared with those treated with TAT-KLA alone. Interestingly, BRBP1-TAT-KLA inhibited the formation of both large and micro-metastases, while TAT-KLA alone failed to significantly reduce micro-metastases in the breast cancer brain metastasis mice. BRBP1-TAT-KLA selectively homed to the tumors in vivo where it induced cellular apoptosis without significant toxicity on non-tumor tissues. Our findings therefore demonstrated the enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA, providing insights toward development of a potential therapeutic strategy for brain metastatic breast cancer.

  16. Compact point-detection fluorescence spectroscopy system for quantifying intrinsic fluorescence redox ratio in brain cancer diagnostics

    NASA Astrophysics Data System (ADS)

    Liu, Quan; Grant, Gerald; Li, Jianjun; Zhang, Yan; Hu, Fangyao; Li, Shuqin; Wilson, Christy; Chen, Kui; Bigner, Darell; Vo-Dinh, Tuan

    2011-03-01

    We report the development of a compact point-detection fluorescence spectroscopy system and two data analysis methods to quantify the intrinsic fluorescence redox ratio and diagnose brain cancer in an orthotopic brain tumor rat model. Our system employs one compact cw diode laser (407 nm) to excite two primary endogenous fluorophores, reduced nicotinamide adenine dinucleotide, and flavin adenine dinucleotide. The spectra were first analyzed using a spectral filtering modulation method developed previously to derive the intrinsic fluorescence redox ratio, which has the advantages of insensitivty to optical coupling and rapid data acquisition and analysis. This method represents a convenient and rapid alternative for achieving intrinsic fluorescence-based redox measurements as compared to those complicated model-based methods. It is worth noting that the method can also extract total hemoglobin concentration at the same time but only if the emission path length of fluorescence light, which depends on the illumination and collection geometry of the optical probe, is long enough so that the effect of absorption on fluorescence intensity due to hemoglobin is significant. Then a multivariate method was used to statistically classify normal tissues and tumors. Although the first method offers quantitative tissue metabolism information, the second method provides high overall classification accuracy. The two methods provide complementary capabilities for understanding cancer development and noninvasively diagnosing brain cancer. The results of our study suggest that this portable system can be potentially used to demarcate the elusive boundary between a brain tumor and the surrounding normal tissue during surgical resection.

  17. Ultrasound Imaging-guided Intracardiac Injection to Develop a Mouse Model of Breast Cancer Brain Metastases Followed by Longitudinal MRI

    PubMed Central

    Zhou, Heling; Zhao, Dawen

    2014-01-01

    Breast cancer brain metastasis, occurring in 30% of breast cancer patients at stage IV, is associated with high mortality. The median survival is only 6 months. It is critical to have suitable animal models to mimic the hemodynamic spread of the metastatic cells in the clinical scenario. Here, we are introducing the use of small animal ultrasound imaging to guide an accurate injection of brain tropical breast cancer cells into the left ventricle of athymic nude mice. Longitudinal MRI is used to assessing intracranial initiation and growth of brain metastases. Ultrasound-guided intracardiac injection ensures not only an accurate injection and hereby a higher successful rate but also significantly decreased mortality rate, as compared to our previous manual procedure. In vivo high resolution MRI allows the visualization of hyperintense multifocal lesions, as small as 310 µm in diameter on T2-weighted images at 3 weeks post injection. Follow-up MRI reveals intracranial tumor growth and increased number of metastases that distribute throughout the whole brain. PMID:24637963

  18. Is Piaget's epistemic subject dead?

    NASA Astrophysics Data System (ADS)

    Lawson, Anton E.

    Niaz (1990) presents arguments in favor of the retention of Piaget's epistemic subject as a theoretical construct to guide research and practice in science education and psychology. The intent of this article is to point out the weaknesses of those arguments and to suggest that the weight of evidence argues against the existence of the logical thinker postulated by Piaget. Therefore, contrary to Niaz's conclusion that the acceptance of Piaget's epistemic subject will facilitate the development of cognitive theories with greater explanatory power, the conclusion is reached that Piaget's epistemic subject is dead and that continued acceptance of this aspect of Piagetian theory would be counterproductive.

  19. "Dead quasars" in nearby galaxies?

    PubMed

    Rees, M J

    1990-02-16

    The nuclei of some galaxies undergo violent activity, quasars being the most extreme instances of this phenomenon. Such activity is probably short-lived compared to galactic lifetimes, and was most prevalent when the universe was only about one-fifth of its present age. A massive black hole seems the inevitable end point of such activity, and dead quasars should greatly outnumber active ones. In recent years, studies of stellar motions in the cores of several nearby galaxies indicate the presence of central dark masses which could be black holes. This article discusses how such evidence might be corroborated, and the potential implications for our understanding of active galaxies and black holes.

  20. Importance of Extracranial Disease Status and Tumor Subtype for Patients Undergoing Radiosurgery for Breast Cancer Brain Metastases

    SciTech Connect

    Dyer, Michael A.; Kelly, Paul J.; Chen, Yu-Hui; Pinnell, Nancy E.; Lee, Eudocia Q.; Arvold, Nils D.; Lin, Nancy U.

    2012-07-15

    Purpose: In this retrospective study, we report on outcomes and prognostic factors for patients treated with stereotactic radiosurgery (SRS) for breast cancer brain metastases. Methods and Materials: We identified 132 consecutive patients with breast cancer who were treated with SRS for brain metastases from January 2000 through June 2010. We retrospectively reviewed records of the 51 patients with adequate follow-up data who received SRS as part of the initial management of their brain metastases. Overall survival (OS) and time to central nervous system (CNS) progression from the date of SRS were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results: Triple negative subtype was associated with CNS progression on univariate analysis (hazard ratio [HR] = 5.0, p = 0.008). On multivariate analysis, triple negative subtype (HR = 8.6, p = 0.001), Luminal B subtype (HR = 4.3, p = 0.03), and omission of whole-brain radiation therapy (HR = 3.7, p = 0.02) were associated with CNS progression. With respect to OS, Karnofsky Performance Status (KPS) {<=} 80% (HR = 2.0, p = 0.04) and progressive extracranial disease (HR = 3.1, p = 0.002) were significant on univariate analysis; KPS {<=} 80% (HR = 4.1, p = 0.0004), progressive extracranial disease (HR = 6.4, p < 0.0001), and triple negative subtype (HR = 2.9, p = 0.04) were significant on multivariate analysis. Although median survival times were consistent with those predicted by the breast cancer-specific Graded Prognostic Assessment (Breast-GPA) score, the addition of extracranial disease status further separated patient outcomes. Conclusions: Tumor subtype is associated with risk of CNS progression after SRS for breast cancer brain metastases. In addition to tumor subtype and KPS, which are incorporated into the Breast-GPA, progressive extracranial disease may be an important prognostic factor for OS.

  1. Eating the dead in Madagascar.

    PubMed

    Campbell, Gwyn

    2013-12-01

    Cannibalism has been poorly understood and has seldom been studied, since it was often suppressed by missionaries and colonial administrators, and very few societies still practise it. Cannibalistic practices are more complex than was originally thought. They may be supported in societies under stress or in times of famine, to reflect aggression and antisocial behaviour (in cases where the bodies of enemies killed in battle or people who have harmed the family are eaten), or to honour a dead kinsman. It was, for example, noted in Madagascar during the imperial campaigns of Ranavalona I in the period 1829 - 1853. Two types of cannibalism have been described: exocannibalism, where enemies were consumed, and endocannibalism, where dead relatives were eaten to assist their passing to the world of the ancestors, or to prolong contact with beloved and admired family members and absorb their good qualities. This article reviews some of the beliefs and motivations that surrounded the cannibalistic practices of the people of Madagascar in the 19th century.  PMID:24300654

  2. [Serotonin dysfunctions in the background of the seven deadly sins].

    PubMed

    Janka, Zoltán

    2003-11-20

    The symbolic characters of the Seven Deadly Sins can be traced from time to time in the cultural history of human mankind, being directly specified in certain artistic products. Such are, among others, the painting entitled "The Seven Deadly Sins and the Four Lost Things" by Hieronymus Bosch and the poems Divina Commedia and The Foerie Queene by Dante Alighieri and Edmund Spenser, respectively. However, there are several paragraphs referring to these behaviours of the Seven Deadly Sins in the Bible and in the dramas of William Shakespeare. The objective of the present review is to propose that dysfunctions in the central serotonergic system might be involved in the neurobiology of these 'sinful' behaviour patterns. Evidences indicate that behaviour traits such as Accidia (Sloth), Luxuria (Lust, Lechery), Superbia (Pride), Ira (Wrath, Anger), Invidia (Envy), Avaritia (Greed, Avarice), and Gula (Gluttony) can relate to the functional alterations of serotonin in the brain. Results of biochemical and molecular genetic (polymorphism) studies on the human serotonergic system (receptor, transporter, enzyme), findings of functional imaging techniques, effects of depletion (or supplementation) of the serotonin precursor tryptophan, data of challenge probe investigations directed to testing central serotonergic functions, alterations in the peripheral serotonin measures (platelet), and the changes in the CSF 5-hydroxy-indoleacetic acid content indicate such serotonergic involvement. Furthermore, results of animal experiments on behaviour change (aggressive, dominant or submissive, appetite, alcohol preference) attributed to serotonin status modification and the clinically evidenced therapeutic efficacy of pharmacological interventions, based on the modulation and perturbation of the serotonergic system (e.g. selective serotonin reuptake inhibitors), in treating the 'sinful' behaviour forms and analogous pathological states reaching the severity of psychiatric disorders

  3. [Serotonin dysfunctions in the background of the seven deadly sins].

    PubMed

    Janka, Zoltán

    2003-11-20

    The symbolic characters of the Seven Deadly Sins can be traced from time to time in the cultural history of human mankind, being directly specified in certain artistic products. Such are, among others, the painting entitled "The Seven Deadly Sins and the Four Lost Things" by Hieronymus Bosch and the poems Divina Commedia and The Foerie Queene by Dante Alighieri and Edmund Spenser, respectively. However, there are several paragraphs referring to these behaviours of the Seven Deadly Sins in the Bible and in the dramas of William Shakespeare. The objective of the present review is to propose that dysfunctions in the central serotonergic system might be involved in the neurobiology of these 'sinful' behaviour patterns. Evidences indicate that behaviour traits such as Accidia (Sloth), Luxuria (Lust, Lechery), Superbia (Pride), Ira (Wrath, Anger), Invidia (Envy), Avaritia (Greed, Avarice), and Gula (Gluttony) can relate to the functional alterations of serotonin in the brain. Results of biochemical and molecular genetic (polymorphism) studies on the human serotonergic system (receptor, transporter, enzyme), findings of functional imaging techniques, effects of depletion (or supplementation) of the serotonin precursor tryptophan, data of challenge probe investigations directed to testing central serotonergic functions, alterations in the peripheral serotonin measures (platelet), and the changes in the CSF 5-hydroxy-indoleacetic acid content indicate such serotonergic involvement. Furthermore, results of animal experiments on behaviour change (aggressive, dominant or submissive, appetite, alcohol preference) attributed to serotonin status modification and the clinically evidenced therapeutic efficacy of pharmacological interventions, based on the modulation and perturbation of the serotonergic system (e.g. selective serotonin reuptake inhibitors), in treating the 'sinful' behaviour forms and analogous pathological states reaching the severity of psychiatric disorders

  4. Temporal Change in Brain Natriuretic Peptide After Radiotherapy for Thoracic Esophageal Cancer

    SciTech Connect

    Jingu, Keiichi Nemoto, Kenji; Kaneta, Tomohiro; Oikawa, Minako; Ogawa, Yoshihiro; Ariga, Hisanori; Takeda, Ken; Sakayauchi, Toru; Fujimoto, Keisuke; Narazaki, Kakutaro; Takai, Yoshihiro; Nakata, Eiko; Fukuda, Hiroshi; Takahashi, Shoki; Yamada, Shogo

    2007-12-01

    Purpose: To investigate the relationships of plasma levels of brain natriuretic peptide (BNP) with abnormal {sup 18}F-fluorodeoxyglucose (FDG) accumulation in the myocardium corresponding to irradiated fields and temporal changes in BNP, which is used as an index of heart remodeling, after radiotherapy for the mediastinum. Materials and Methods: Brain natriuretic peptide concentrations were measured before and after radiotherapy for thoracic esophageal cancer, and the change in BNP concentration after radiotherapy was investigated. Moreover, FDG accumulation in the myocardium was investigated in patients who had undergone FDG positron emission tomography less than 14 days before or after measurement of BNP concentration, and the Mann-Whitney U test was used to detect significant difference between BNP concentrations in patients with and without abnormal FDG accumulation corresponding to the irradiated field. Results: There was significant difference between the levels of BNP in patients without abnormal FDG accumulation in the irradiated myocardium and in patients with abnormal FDG accumulation (p < 0.001). The levels of BNP in the 9-24 months after radiotherapy group and in the >24 months after radiotherapy group were significantly higher than the levels in the before radiotherapy group, immediately after radiotherapy group, 1-2 months after radiotherapy group, and control group. Conclusions: The level of BNP was significantly increased more than 9 months after the start of radiotherapy and was significantly higher in patients who had high FDG accumulation corresponding to the irradiated field. The results of this study indicate that BNP concentration might be an early indicator of radiation-induced myocardial damage.

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

    PubMed Central

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

    2015-01-01

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

  6. Experts and 'knowledge that counts': a study into the world of brain cancer diagnosis.

    PubMed

    Gross, Sky

    2009-12-01

    This paper provides a close, in situ look into the life of a neuro-oncology (brain cancer) clinic of a large hospital in Israel, based on a six-month participant observation. It points to the many challenges involved in the solidification of brain tumour diagnoses by different experts, and presents these epistemological and practical complexities as they uncover in daily routine. The paper's task is two-fold: first, to underline the technological and epistemological grounds of 'expertise' in the medicoscientific practice of diagnosis, and their roles in the assertion of expert authoritativeness; and second, to provide analytical tools to approach the complexity of diagnostic processes, the potential frictions it may create, and the related mechanisms of resolution. These mechanisms include Hierarchisation: ranking the relative validity and reliability of the different sources of information, eventually prioritising reports from more authoritative expertises (e.g. imaging reports would be considered more reliable than patients' accounts); Sequencing: relying upon the temporal dimension, and defining the discrepancy itself as a diagnostic sign (e.g. the degradation or amelioration of the disease); Negotiation: adjusting diagnoses via a preliminary exchange between experts and a consequent "fine tuning" of the reports (e.g. radiologists being aware of clinical evaluations before finalising their reports); Peripheralising: turning to other expertises to "explain away" symptoms that do not fit with a well established initial diagnosis (e.g. asserting that a symptom's source was orthopaedic rather than neurological); and pragmatism: using information only as far as it provided sufficient grounds for treatment decisions, leaving ambiguities unresolved. These five mechanisms are presented here in the context of the daily work of the clinic.

  7. Comparison of computed tomography and radionuclide scanning for detection of brain metastases in small cell lung cancer

    SciTech Connect

    Crane, J.M.; Nelson, M.J.; Ihde, D.C.; Makuch, R.W.; Glatstein, E.; Zabell, A.; Johnston-Early, A.; Bates, H.R.; Saini, N.; Cohen, M.H.

    1984-09-01

    Neurologic history and examination, radionuclide brain scans (RN), and computed tomographic brain scans (CT) were performed at diagnosis and sequentially in 153 consecutive patients with small cell lung cancer (SCLC) to assess the sensitivity and accuracy of these screening methods and to determine whether the early detection of brain metastases influences survival. CT scans (sensitivity, 98%; positive predictive accuracy, 98%) were superior to RN scans (sensitivity, 71%; positive predictive accuracy, 86%) in patients with or without neurologic signs or symptoms. However, CT scans were positive in only 6% of asymptomatic patients at diagnosis and 13% of asymptomatic patients after systemic therapy. Brain metastases detected by CT scan were the sole site of extensive-stage disease in 6% of patients at diagnosis. Despite the enhanced ability of CT scans to detect asymptomatic lesions, survival after therapeutic cranial irradiation was similar for asymptomatic and symptomatic patients. The results suggest that CT brain scans should be used routinely in SCLC patients with neurologic signs or symptoms, at diagnosis (when treatment decisions are based on stage), and at six-month intervals in patients with prior brain metastases and in whom erratic follow-up is likely.

  8. "Dead quasars" in nearby galaxies?

    PubMed

    Rees, M J

    1990-02-16

    The nuclei of some galaxies undergo violent activity, quasars being the most extreme instances of this phenomenon. Such activity is probably short-lived compared to galactic lifetimes, and was most prevalent when the universe was only about one-fifth of its present age. A massive black hole seems the inevitable end point of such activity, and dead quasars should greatly outnumber active ones. In recent years, studies of stellar motions in the cores of several nearby galaxies indicate the presence of central dark masses which could be black holes. This article discusses how such evidence might be corroborated, and the potential implications for our understanding of active galaxies and black holes. PMID:17746076

  9. Role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae

    SciTech Connect

    Laukkanen, E.; Klonoff, H.; Allan, B.; Graeb, D.; Murray, N.

    1988-06-01

    Ninety-four patients with limited stage small cell lung cancer treated between 1981 and 1985 with a regimen including prophylactic brain irradiation (PBI) after combination chemotherapy were assessed for compliance with PBI, brain relapse, and neurologic morbidity. Seventy-seven percent of patients had PBI and of these, 22% developed brain metastases after a median time of 11 months post treatment. The brain was the apparent unique initial site of relapse in 10% of PBI cases but more commonly brain relapse was preceded or accompanied by failure at other sites, especially the chest. Brain metastases were the greatest cause of morbidity in 50% of PBI failures. Twelve of 14 PBI patients alive 2 years after treatment had oncologic, neurologic, and neuropsychological evaluation, and brain CT. All long-term survivors were capable of self care and none fulfilled diagnostic criteria for dementia, with three borderline cases. One third had pretreatment neurologic dysfunction and two thirds post treatment neurologic symptoms, most commonly recent memory loss. Fifty percent had subtle motor findings. Intellectual functioning was at the 38th percentile with most patients having an unskilled occupational history. Neuropsychologic impairment ratings were borderline in three cases and definitely impaired in seven cases. CT scans showed brain atrophy in all cases with mild progression in those having a pre-treatment baseline. Periventricular and subcortical low density lesions identical to the CT appearance of subcortical arteriosclerotic encephalopathy were seen in 82% of posttreatment CT studies, and lacunar infarcts in 54%. Neuropsychologic impairment scores and the extent of CT periventricular low density lesions were strongly associated.

  10. Annual Report to the Nation on the Status of Cancer, 1975–2007, Featuring Tumors of the Brain and Other Nervous System

    PubMed Central

    Ward, Elizabeth; McCarthy, Bridget J.; Schymura, Maria J.; Eheman, Christie; Jemal, Ahmedin; Anderson, Robert N.; Ajani, Umed A.; Edwards, Brenda K.

    2011-01-01

    Background The American Cancer Society, the Centers for Disease Control and Prevention (CDC), the National Cancer Institute, and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updated information on cancer occurrence and trends in the United States. This year’s report highlights brain and other nervous system (ONS) tumors, including nonmalignant brain tumors, which became reportable on a national level in 2004. Methods Cancer incidence data were obtained from the National Cancer Institute, CDC, and NAACCR, and information on deaths was obtained from the CDC’s National Center for Health Statistics. The annual percentage changes in age-standardized incidence and death rates (2000 US population standard) for all cancers combined and for the top 15 cancers for men and for women were estimated by joinpoint analysis of long-term (1992–2007 for incidence; 1975–2007 for mortality) trends and short-term fixed interval (1998–2007) trends. Analyses of malignant neuroepithelial brain and ONS tumors were based on data from 1980–2007; data on nonmalignant tumors were available for 2004–2007. All statistical tests were two-sided. Results Overall cancer incidence rates decreased by approximately 1% per year; the decrease was statistically significant (P < .05) in women, but not in men, because of a recent increase in prostate cancer incidence. The death rates continued to decrease for both sexes. Childhood cancer incidence rates continued to increase, whereas death rates continued to decrease. Lung cancer death rates decreased in women for the first time during 2003–2007, more than a decade after decreasing in men. During 2004–2007, more than 213 500 primary brain and ONS tumors were diagnosed, and 35.8% were malignant. From 1987–2007, the incidence of neuroepithelial malignant brain and ONS tumors decreased by 0.4% per year in men and women combined. Conclusions The decrease in cancer incidence and

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

    PubMed Central

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

    2014-01-01

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

  12. Analyzing collaboration networks and developmental patterns of nano-enabled drug delivery (NEDD) for brain cancer.

    PubMed

    Huang, Ying; Ma, Jing; Porter, Alan L; Kwon, Seokbeom; Zhu, Donghua

    2015-01-01

    The rapid development of new and emerging science & technologies (NESTs) brings unprecedented challenges, but also opportunities. In this paper, we use bibliometric and social network analyses, at country, institution, and individual levels, to explore the patterns of scientific networking for a key nano area - nano-enabled drug delivery (NEDD). NEDD has successfully been used clinically to modulate drug release and to target particular diseased tissues. The data for this research come from a global compilation of research publication information on NEDD directed at brain cancer. We derive a family of indicators that address multiple facets of research collaboration and knowledge transfer patterns. Results show that: (1) international cooperation is increasing, but networking characteristics change over time; (2) highly productive institutions also lead in influence, as measured by citation to their work, with American institutes leading; (3) research collaboration is dominated by local relationships, with interesting information available from authorship patterns that go well beyond journal impact factors. Results offer useful technical intelligence to help researchers identify potential collaborators and to help inform R&D management and science & innovation policy for such nanotechnologies.

  13. Analyzing collaboration networks and developmental patterns of nano-enabled drug delivery (NEDD) for brain cancer

    PubMed Central

    Huang, Ying; Ma, Jing; Kwon, Seokbeom; Zhu, Donghua

    2015-01-01

    Summary The rapid development of new and emerging science & technologies (NESTs) brings unprecedented challenges, but also opportunities. In this paper, we use bibliometric and social network analyses, at country, institution, and individual levels, to explore the patterns of scientific networking for a key nano area – nano-enabled drug delivery (NEDD). NEDD has successfully been used clinically to modulate drug release and to target particular diseased tissues. The data for this research come from a global compilation of research publication information on NEDD directed at brain cancer. We derive a family of indicators that address multiple facets of research collaboration and knowledge transfer patterns. Results show that: (1) international cooperation is increasing, but networking characteristics change over time; (2) highly productive institutions also lead in influence, as measured by citation to their work, with American institutes leading; (3) research collaboration is dominated by local relationships, with interesting information available from authorship patterns that go well beyond journal impact factors. Results offer useful technical intelligence to help researchers identify potential collaborators and to help inform R&D management and science & innovation policy for such nanotechnologies. PMID:26425417

  14. Analyzing collaboration networks and developmental patterns of nano-enabled drug delivery (NEDD) for brain cancer.

    PubMed

    Huang, Ying; Ma, Jing; Porter, Alan L; Kwon, Seokbeom; Zhu, Donghua

    2015-01-01

    The rapid development of new and emerging science & technologies (NESTs) brings unprecedented challenges, but also opportunities. In this paper, we use bibliometric and social network analyses, at country, institution, and individual levels, to explore the patterns of scientific networking for a key nano area - nano-enabled drug delivery (NEDD). NEDD has successfully been used clinically to modulate drug release and to target particular diseased tissues. The data for this research come from a global compilation of research publication information on NEDD directed at brain cancer. We derive a family of indicators that address multiple facets of research collaboration and knowledge transfer patterns. Results show that: (1) international cooperation is increasing, but networking characteristics change over time; (2) highly productive institutions also lead in influence, as measured by citation to their work, with American institutes leading; (3) research collaboration is dominated by local relationships, with interesting information available from authorship patterns that go well beyond journal impact factors. Results offer useful technical intelligence to help researchers identify potential collaborators and to help inform R&D management and science & innovation policy for such nanotechnologies. PMID:26425417

  15. Gene Tied to Breast Cancer Raises Uterine Cancer Risk Too

    MedlinePlus

    ... news/fullstory_159652.html Gene Tied to Breast Cancer Raises Uterine Cancer Risk Too Women with BRCA1 may want to ... increased risk for a deadly form of uterine cancer, a new study finds. The BRCA1 gene mutation ...

  16. More Dead than Dead: Perceptions of Persons in the Persistent Vegetative State

    ERIC Educational Resources Information Center

    Gray, Kurt; Knickman, T. Anne; Wegner, Daniel M.

    2011-01-01

    Patients in persistent vegetative state (PVS) may be biologically alive, but these experiments indicate that people see PVS as a state curiously more dead than dead. Experiment 1 found that PVS patients were perceived to have less mental capacity than the dead. Experiment 2 explained this effect as an outgrowth of afterlife beliefs, and the…

  17. A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases.

    PubMed

    Lin, Nancy U; Freedman, Rachel A; Ramakrishna, Naren; Younger, Jerry; Storniolo, Anna Maria; Bellon, Jennifer R; Come, Steven E; Gelman, Rebecca S; Harris, Gordon J; Henderson, Mark A; Macdonald, Shannon M; Mahadevan, Anand; Eisenberg, Emily; Ligibel, Jennifer A; Mayer, Erica L; Moy, Beverly; Eichler, April F; Winer, Eric P

    2013-11-01

    Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1-8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash (n = 2), diarrhea (n = 2), hypoxia (n = 1), and grade 4 pulmonary embolus (n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59-92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring.

  18. Respect for the dead and dying.

    PubMed

    Preus, A

    1984-11-01

    Against the thesis that permanently unconscious persons cannot be harmed, and thus are not owed moral deference, it is argued that even the dead can be harmed and are owed moral respect, so a fortiori those dubiously or not quite dead deserve some moral deference.

  19. There's Life in Those Dead Logs!

    ERIC Educational Resources Information Center

    Biggs, Devin; Miller, Todd; Hall, Dee

    2006-01-01

    Although it is unspectacular in appearance, dead wood is one of the most ecologically important resources in forests. Fallen logs, dead standing trees, stumps, and even cavities in live trees fulfill a wide range of roles. Prominent among these is that they provide habitat for many organisms, especially insects. Fourth-grade students at Fox…

  20. Erlotinib plus concurrent whole-brain radiation therapy for non-small cell lung cancers patients with multiple brain metastases

    PubMed Central

    Ulahannan, Danny

    2016-01-01

    Sequencing of the epidermal growth factor receptor (EGFR) gene to identify mutations in lung adenocarcinomas is routine in clinical practice. The use of tyrosine kinase inhibitors (TKIs) has transformed the management of patients with brain metastases harboring EGFR mutations, with improved response rates (RR) and survival. We evaluate the role of concurrent TKI therapy and radiotherapy in this group of patients, considering this data in the context of emerging concepts in this advancing field. PMID:27186518

  1. EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases

    PubMed Central

    2012-01-01

    Background The presence of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) is associated with increased radiosensitivity in vitro. However, the results from clinical studies regarding the radiosensitivity in NSCLC with mutant EGFR are inconclusive. We retrospectively analyzed our NSCLC patients who had been regularly followed up by imaging studies after irradiation for brain metastases, and investigated the impact of EGFR mutations on radiotherapy (RT). Methods Forty-three patients with brain metastases treated with RT, together with EGFR mutation status, demographics, smoking history, performance status, recursive partitioning analysis (RPA) class, tumor characteristics, and treatment modalities, were included. Radiological images were taken at 1 to 3 months after RT, and 3 to 6 months thereafter. Radiographic response was evaluated by RECIST criteria version 1.1 according to the intracranial images before and after RT. Log-rank test and Cox regression model were used to correlate EGFR mutation status and other clinical features with intracranial radiological progression-free survival (RPFS) and overall survival (OS). Results The median follow-up duration was 15 months. Patients with mutant EGFR had higher response rates to brain RT than those with wild-type EGFR (80% vs. 46%; p = 0.037). Logistic regression analysis showed that EGFR mutation status is the only predictor for treatment response (p = 0.032). The median intracranial RPFS was 18 months (95% CI = 8.33-27.68 months). In Cox regression analysis, mutant EGFR (p = 0.025) and lower RPA class (p = 0.026) were associated with longer intracranial RPFS. EGFR mutation status (p = 0.061) and performance status (p = 0.076) had a trend to predict OS. Conclusions Mutant EGFR in NSCLC patients is an independent prognostic factor for better treatment response and longer intracranial RPFS following RT for brain metastases. PMID:23110940

  2. Inhibition of β2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative β-blockade.

    PubMed

    Choy, Cecilia; Raytis, John L; Smith, David D; Duenas, Matthew; Neman, Josh; Jandial, Rahul; Lew, Michael W

    2016-06-01

    In response to recent studies, we investigated an association between perioperative β-blockade and breast cancer metastases. First, a retrospective study examining perioperative β-blocker use and cancer recurrence and metastases was conducted on 1,029 patients who underwent breast cancer surgery at the City of Hope Cancer Center between 2000 and 2010. We followed the clinical study and examined proliferation, migration, and invasion in vitro of primary and brain-metastatic breast cancer cells in response to β2-activation and inhibition. We also investigated in vivo the metastatic potential of propranolol-treated metastatic cells. For stage II breast cancer patients, perioperative β-blockade was associated with decreased cancer recurrence using Cox regression analysis (hazard's ratio =0.51; 95% CI: 0.23-0.97; p=0.041). Triple-negative (TN) brain-metastatic cells were found to have increased β2-adrenergic receptor mRNA and protein expression relative to TN primary cells. In response to β2-adrenergic receptor activation, TN brain-metastatic cells also exhibited increased cell proliferation and migration relative to the control. These effects were abrogated by propranolol. Propranolol decreased β2-adrenergic receptor-activated invasion. In vivo, propranolol treatment of TN brain-metastatic cells decreased establishment of brain metastases. Our results suggest that stress and corresponding β2-activation may promote the establishment of brain metastases of TN breast cancer cells. In addition, our data suggest a benefit to perioperative β-blockade during surgery-induced stress with respect to breast cancer recurrence and metastases.

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

    PubMed

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

    2015-09-01

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

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

    PubMed Central

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

    2015-01-01

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

  5. Durable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain

    PubMed Central

    Koumarianou, Anna; Kontopoulou, Christina; Kouloulias, Vassilis; Tsionou, Christina

    2016-01-01

    Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases. PMID:27195161

  6. The activity of class I, II, III and IV of alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) in brain cancer.

    PubMed

    Laniewska-Dunaj, Magdalena; Jelski, Wojciech; Orywal, Karolina; Kochanowicz, Jan; Rutkowski, Robert; Szmitkowski, Maciej

    2013-07-01

    The brain being highly sensitive to the action of alcohol is potentially susceptible to its carcinogenic effects. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the main enzymes involved in ethanol metabolism, which leads to the generation of carcinogenic acetaldehyde. Human brain tissue contains various ADH isoenzymes and possess also ALDH activity. The purpose of this study was to compare the capacity for ethanol metabolism measured by ADH isoenzymes and ALDH activity in cancer tissues and healthy brain cells. The samples were taken from 62 brain cancer patients (36 glioblastoma, 26 meningioma). For the measurement of the activity of class I and II ADH isoenzymes and ALDH activity, the fluorometric methods were used. The total ADH activity and activity of class III and IV isoenzymes were measured by the photometric method. The total activity of ADH, and activity of class I ADH were significantly higher in cancer cells than in healthy tissues. The other tested classes of ADH and ALDH did not show statistically significant differences of activity in cancer and in normal cells. Analysis of the enzymes activity did not show significant differences depending on the location of the tumor. The differences in the activity of total alcohol dehydrogenase, and class I isoenzyme between cancer tissues and healthy brain cells might be a factor for metabolic changes and disturbances in low mature cancer cells and additionally might be a reason for higher level of acetaldehyde which can intensify the carcinogenesis.

  7. The Effect of Early Detection of Occult Brain Metastases in HER2-Positive Breast Cancer Patients on Survival and Cause of Death

    SciTech Connect

    Niwinska, Anna; Tacikowska, Malgorzata; Murawska, Magdalena

    2010-07-15

    Purpose: The aim of the study is to evaluate disease-free survival, survival from the detection of brain metastases, overall survival, and cause of death in patients with occult brain metastases (Group I) vs. patients with symptomatic brain metastases (Group II). Methods and Materials: In 80 HER2-positive breast cancer patients, treated with trastuzumab and cytostatic agents for metastatic disease, magnetic resonance imaging screening of the brain was performed, and in 29 patients (36%) occult brain metastasis was detected (Group I). Whole-brain radiotherapy was delivered to Group I. This first group was compared with 52 patients who had symptomatic brain metastases (Group II) and was treated the same way, at the same clinic, during the same time period. Results: Median disease-free survival was 17 months in Group I and 19.9 months in Group II (p = 0.58). The median time interval between the dissemination of the disease and the detection of occult or symptomatic brain metastases was 9 and 15 months, respectively (p = 0.11). When the brain metastases were detected, the median survival was 9 and 8.78 months, respectively (p = 0.80). The median overall survival was 53 and 51 months, respectively (p = 0.94). In the group with occult brain metastases (Group I) 16% of patients died because of progression within the brain. In the group with symptomatic brain metastases (Group II) the rate of cerebral death was 48% (p = 0.009). Conclusions: Whole-brain radiotherapy of occult brain metastases in HER2-positive breast cancer patients with visceral dissemination produces a three-fold decrease in cerebral deaths but does not prolong survival.

  8. Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism.

    PubMed

    Sartorius, C A; Hanna, C T; Gril, B; Cruz, H; Serkova, N J; Huber, K M; Kabos, P; Schedin, T B; Borges, V F; Steeg, P S; Cittelly, D M

    2016-06-01

    Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40±0.02-fold, P<0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These

  9. Validity of Three Recently Proposed Prognostic Grading Indexes for Breast Cancer Patients With Radiosurgically Treated Brain Metastases

    SciTech Connect

    Yamamoto, Masaaki; Kawabe, Takuya; Higuchi, Yoshinori; Sato, Yasunori; Barfod, Bierta E.; Kasuya, Hidetoshi; Urakawa, Yoichi

    2012-12-01

    Purpose: We tested the validity of 3 recently proposed prognostic indexes for breast cancer patients with brain metastases (METs) treated radiosurgically. The 3 indexes are Diagnosis-Specific Graded Prognostic Assessment (DS-GPA), New Breast Cancer (NBC)-Recursive Partitioning Analysis (RPA), and our index, sub-classification of RPA class II patients into 3 sub-classes (RPA class II-a, II-b and II-c) based on Karnofsky performance status, tumor number, original tumor status, and non-brain METs. Methods and Materials: This was an institutional review board-approved, retrospective cohort study using our database of 269 consecutive female breast cancer patients (mean age, 55 years; range, 26-86 years) who underwent Gamma Knife radiosurgery (GKRS) alone, without whole-brain radiation therapy, for brain METs during the 15-year period between 1996 and 2011. The Kaplan-Meier method was used to estimate the absolute risk of each event. Results: Kaplan-Meier plots of our patient series showed statistically significant survival differences among patients stratified into 3, 4, or 5 groups based on the 3 systems (P<.001). However, the mean survival time (MST) differences between some pairs of groups failed to reach statistical significance with all 3 systems. Thus, we attempted to regrade our 269 breast cancer patients into 3 groups by modifying our aforementioned index along with the original RPA class I and III, (ie, RPA I+II-a, II-b, and II-c+III). There were statistically significant MST differences among these 3 groups without overlap of 95% confidence intervals (CIs) between any 2 pairs of groups: 18.4 (95% CI = 14.0-29.5) months in I+II-a, 9.2 in II-b (95% CI = 6.8-12.9, P<.001 vs I+II-a) and 5.0 in II-c+III (95% CI = 4.2-6.8, P<.001 vs II-b). Conclusions: As none of the new grading systems, DS-GPS, BC-RPA and our system, was applicable to our set of radiosurgically treated patients for comparing survivals after GKRS, we slightly modified our system for breast cancer

  10. [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.

  11. Links between private habits, psychological stress and brain cancer: a case-control pilot study in France.

    PubMed

    Cabaniols, Cécilia; Giorgi, Roch; Chinot, Olivier; Ferahta, Nabila; Spinelli, Valérie; Alla, Philippe; Barrie, Maryline; Lehucher-Michel, Marie-Pascale

    2011-06-01

    Numerous studies have increasingly suggested that medical history and lifestyle factors could be involved in the increase of cancer risk in adults. The issue whether psychological factors can influence the development of cancer has been discussed for many years. In the field of brain cancer, psychological stress has not so far been investigated. We conducted a French case-control pilot study with 122 adult incident cases and 122 controls free of any cancer diagnosis, matched for age and gender, to investigate links between malignant primitive brain tumours (MPBT) and medical history, private habits and psychological stress. Data were collected through self-administered questionnaires, and person-to-person interviews. To complete the psychological stress assessment, 100-mm visual analog scales were used. After adjustment for confounders, we found no significant effect of head trauma, aspartame, tobacco or alcohol consumption, place (rural or urban) of residence, sociodemographic data, and experience of psychological stress at work/home. Our results showed a significant association between MPBT risk and major life events over the past 5 years before diagnosis (OR = 1.90, 95% CI 1.13-3.20), family histories of cancer (OR = 1.90, 95% CI 1.12-3.22), fresh vegetable and fruit intake (OR = 0.29, 95% CI 0.09-0.95), and skipped meals several times per week (OR = 0.35, 95% CI 0.16-0.77). The present study suggests the role of genetic factors in glioma risk, and also suggests that an acute and sudden psychological stress might influence MPBT appearance. Additional large clinical studies are needed to confirm these findings.

  12. The dead spot of a tennis racket

    NASA Astrophysics Data System (ADS)

    Cross, Rod

    1997-08-01

    It is shown that a tennis racket has a dead spot, but it does not have a well-defined sweet spot, when measured in terms of the rebound of a tennis ball. A ball dropped onto the center of the strings bounces to about 30% its original height. The bounce is much weaker near the tip of the racket, being almost zero at the dead spot. These effects are explained in terms of the effective mass and rotational inertia of the racket, and by reference to the behavior of other cantilevered beams. It is concluded, somewhat paradoxically, that the best place to hit a serve or smash is at the dead spot.

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

    PubMed

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

    2014-04-01

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

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

    PubMed

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

    2014-04-01

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

  15. Selection of a Relevant In Vitro Blood-Brain Barrier Model to Investigate Pro-Metastatic Features of Human Breast Cancer Cell Lines

    PubMed Central

    Drolez, Aurore; Vandenhaute, Elodie; Julien, Sylvain; Gosselet, Fabien; Burchell, Joy; Cecchelli, Roméo; Delannoy, Philippe; Dehouck, Marie-Pierre; Mysiorek, Caroline

    2016-01-01

    Around 7–17% of metastatic breast cancer patients will develop brain metastases, associated with a poor prognosis. To reach the brain parenchyma, cancer cells need to cross the highly restrictive endothelium of the Blood-Brain Barrier (BBB). As treatments for brain metastases are mostly inefficient, preventing cancer cells to reach the brain could provide a relevant and important strategy. For that purpose an in vitro approach is required to identify cellular and molecular interaction mechanisms between breast cancer cells and BBB endothelium, notably at the early steps of the interaction. However, while numerous studies are performed with in vitro models, the heterogeneity and the quality of BBB models used is a limitation to the extrapolation of the obtained results to in vivo context, showing that the choice of a model that fulfills the biological BBB characteristics is essential. Therefore, we compared pre-established and currently used in vitro models from different origins (bovine, mice, human) in order to define the most appropriate tool to study interactions between breast cancer cells and the BBB. On each model, the BBB properties and the adhesion capacities of breast cancer cell lines were evaluated. As endothelial cells represent the physical restriction site of the BBB, all the models consisted of endothelial cells from animal or human origins. Among these models, only the in vitro BBB model derived from human stem cells both displayed BBB properties and allowed measurement of meaningful different interaction capacities of the cancer cell lines. Importantly, the measured adhesion and transmigration were found to be in accordance with the cancer cell lines molecular subtypes. In addition, at a molecular level, the inhibition of ganglioside biosynthesis highlights the potential role of glycosylation in breast cancer cells adhesion capacities. PMID:26958843

  16. Selection of a Relevant In Vitro Blood-Brain Barrier Model to Investigate Pro-Metastatic Features of Human Breast Cancer Cell Lines.

    PubMed

    Drolez, Aurore; Vandenhaute, Elodie; Julien, Sylvain; Gosselet, Fabien; Burchell, Joy; Cecchelli, Roméo; Delannoy, Philippe; Dehouck, Marie-Pierre; Mysiorek, Caroline

    2016-01-01

    Around 7-17% of metastatic breast cancer patients will develop brain metastases, associated with a poor prognosis. To reach the brain parenchyma, cancer cells need to cross the highly restrictive endothelium of the Blood-Brain Barrier (BBB). As treatments for brain metastases are mostly inefficient, preventing cancer cells to reach the brain could provide a relevant and important strategy. For that purpose an in vitro approach is required to identify cellular and molecular interaction mechanisms between breast cancer cells and BBB endothelium, notably at the early steps of the interaction. However, while numerous studies are performed with in vitro models, the heterogeneity and the quality of BBB models used is a limitation to the extrapolation of the obtained results to in vivo context, showing that the choice of a model that fulfills the biological BBB characteristics is essential. Therefore, we compared pre-established and currently used in vitro models from different origins (bovine, mice, human) in order to define the most appropriate tool to study interactions between breast cancer cells and the BBB. On each model, the BBB properties and the adhesion capacities of breast cancer cell lines were evaluated. As endothelial cells represent the physical restriction site of the BBB, all the models consisted of endothelial cells from animal or human origins. Among these models, only the in vitro BBB model derived from human stem cells both displayed BBB properties and allowed measurement of meaningful different interaction capacities of the cancer cell lines. Importantly, the measured adhesion and transmigration were found to be in accordance with the cancer cell lines molecular subtypes. In addition, at a molecular level, the inhibition of ganglioside biosynthesis highlights the potential role of glycosylation in breast cancer cells adhesion capacities.

  17. The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer.

    PubMed

    Pruessmeyer, Jessica; Ludwig, Andreas

    2009-04-01

    Various surface molecules undergo regulated cleavage by the disintegrin and metalloproteinases ADAM10 and ADAM17. The list of substrates includes molecules involved in brain pathology, inflammation and cancer. In the brain both proteases mediate neuroprotective cleavage events such as inactivation of amyloid precursor protein. In inflammatory settings signaling of cytokines including TNFalpha and IL-6 is triggered by proteolytic release of soluble agonists and leukocyte recruitment is controlled by the cleavage of adhesion molecules. Moreover, in tumors, ADAM10- and ADAM17-mediated shedding events trigger proliferative signaling via activation of growth factors including ErbB family members. Concepts of either increasing ADAM10- or ADAM17-activity to limit neurodegeneration or suppressing their activity to block inflammation or tumor growth have to be carefully scrutinized for their potential side effects in various tissues and pathologies. PMID:18951988

  18. Nanotube x-ray for cancer therapy: a compact microbeam radiation therapy system for brain tumor treatment

    PubMed Central

    Zhang, Lei; Yuan, Hong; Inscoe, Christina; Chtcheprov, Pavel; Hadsell, Michael; Lee, Yueh; Lu, Jianping; Chang, Sha; Zhou, Otto

    2014-01-01

    Microbeam radiation therapy (MRT) is a promising preclinical modality for cancer treatment, with remarkable preferential tumoricidal effects, that is, tumor eradication without damaging normal tissue functions. Significant lifespan extension has been demonstrated in brain tumor-bearing small animals treated with MRT. So far, MRT experiments can only be performed in a few synchrotron facilities around the world. Limited access to MRT facilities prevents this enormously promising radiotherapy technology from reaching the broader biomedical research community and hinders its potential clinical translation. We recently demonstrated, for the first time, the feasibility of generating microbeam radiation in a laboratory environment using a carbon nanotube x-ray source array and performed initial small animal studies with various brain tumor models. This new nanotechnology-enabled microbeam delivery method, although still in its infancy, has shown promise for achieving comparable therapeutic effects to synchrotron MRT and has offered a potential pathway for clinical translation. PMID:25417729

  19. Scale-free brain dynamics under physical and psychological distress: pre-treatment effects in women diagnosed with breast cancer.

    PubMed

    Churchill, Nathan W; Cimprich, Bernadine; Askren, Mary K; Reuter-Lorenz, Patricia A; Jung, Mi Sook; Peltier, Scott; Berman, Marc G

    2015-03-01

    Stressful life events are related to negative outcomes, including physical and psychological manifestations of distress, and behavioral deficits. Patients diagnosed with breast cancer report impaired attention and working memory prior to adjuvant therapy, which may be induced by distress. In this article, we examine whether brain dynamics show systematic changes due to the distress associated with cancer diagnosis. We hypothesized that impaired working memory is associated with suppression of "long-memory" neuronal dynamics; we tested this by measuring scale-free ("fractal") brain dynamics, quantified by the Hurst exponent (H). Fractal scaling refers to signals that do not occur at a specific time-scale, possessing a spectral power curve P(f)∝ f(-β); they are "long-memory" processes, with significant autocorrelations. In a BOLD functional magnetic resonance imaging study, we scanned three groups during a working memory task: women scheduled to receive chemotherapy or radiotherapy and aged-matched controls. Surprisingly, patients' BOLD signal exhibited greater H with increasing intensity of anticipated treatment. However, an analysis of H and functional connectivity against self-reported measures of psychological distress (Worry, Anxiety, Depression) and physical distress (Fatigue, Sleep problems) revealed significant interactions. The modulation of (Worry, Anxiety) versus (Fatigue, Sleep Problems, Depression) showed the strongest effect, where higher worry and lower fatigue was related to reduced H in regions involved in visuospatial search, attention, and memory processing. This is also linked to decreased functional connectivity in these brain regions. Our results indicate that the distress associated with cancer diagnosis alters BOLD scaling, and H is a sensitive measure of the interaction between psychological versus physical distress. PMID:25388082

  20. Scale-free brain dynamics under physical and psychological distress: pre-treatment effects in women diagnosed with breast cancer.

    PubMed

    Churchill, Nathan W; Cimprich, Bernadine; Askren, Mary K; Reuter-Lorenz, Patricia A; Jung, Mi Sook; Peltier, Scott; Berman, Marc G

    2015-03-01

    Stressful life events are related to negative outcomes, including physical and psychological manifestations of distress, and behavioral deficits. Patients diagnosed with breast cancer report impaired attention and working memory prior to adjuvant therapy, which may be induced by distress. In this article, we examine whether brain dynamics show systematic changes due to the distress associated with cancer diagnosis. We hypothesized that impaired working memory is associated with suppression of "long-memory" neuronal dynamics; we tested this by measuring scale-free ("fractal") brain dynamics, quantified by the Hurst exponent (H). Fractal scaling refers to signals that do not occur at a specific time-scale, possessing a spectral power curve P(f)∝ f(-β); they are "long-memory" processes, with significant autocorrelations. In a BOLD functional magnetic resonance imaging study, we scanned three groups during a working memory task: women scheduled to receive chemotherapy or radiotherapy and aged-matched controls. Surprisingly, patients' BOLD signal exhibited greater H with increasing intensity of anticipated treatment. However, an analysis of H and functional connectivity against self-reported measures of psychological distress (Worry, Anxiety, Depression) and physical distress (Fatigue, Sleep problems) revealed significant interactions. The modulation of (Worry, Anxiety) versus (Fatigue, Sleep Problems, Depression) showed the strongest effect, where higher worry and lower fatigue was related to reduced H in regions involved in visuospatial search, attention, and memory processing. This is also linked to decreased functional connectivity in these brain regions. Our results indicate that the distress associated with cancer diagnosis alters BOLD scaling, and H is a sensitive measure of the interaction between psychological versus physical distress.

  1. Regular Exercise: Antidote for Deadly Diseases?

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_160326.html Regular Exercise: Antidote for Deadly Diseases? High levels of physical ... Aug. 9, 2016 (HealthDay News) -- Getting lots of exercise may reduce your risk for five common diseases, ...

  2. Surviving Sepsis: Taming a Deadly Immune Response

    MedlinePlus

    ... disclaimer . Subscribe Surviving Sepsis Taming a Deadly Immune Response Many people have never heard of sepsis, or ... tract infection) and then a powerful and harmful response by your body’s own immune system . “With sepsis, ...

  3. Dead pixel replacement in LWIR microgrid polarimeters.

    PubMed

    Ratliff, Bradley M; Tyo, J Scott; Boger, James K; Black, Wiley T; Bowers, David L; Fetrow, Matthew P

    2007-06-11

    LWIR imaging arrays are often affected by nonresponsive pixels, or "dead pixels." These dead pixels can severely degrade the quality of imagery and often have to be replaced before subsequent image processing and display of the imagery data. For LWIR arrays that are integrated with arrays of micropolarizers, the problem of dead pixels is amplified. Conventional dead pixel replacement (DPR) strategies cannot be employed since neighboring pixels are of different polarizations. In this paper we present two DPR schemes. The first is a modified nearest-neighbor replacement method. The second is a method based on redundancy in the polarization measurements.We find that the redundancy-based DPR scheme provides an order-of-magnitude better performance for typical LWIR polarimetric data. PMID:19547086

  4. Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines.

    PubMed

    Momeny, Majid; Saunus, Jodi M; Marturana, Flavia; McCart Reed, Amy E; Black, Debra; Sala, Gianluca; Iacobelli, Stefano; Holland, Jane D; Yu, Dihua; Da Silva, Leonard; Simpson, Peter T; Khanna, Kum Kum; Chenevix-Trench, Georgia; Lakhani, Sunil R

    2015-02-28

    HER2-positive breast tumors are associated with a high risk of brain relapse. HER3 is thought to be an indispensible signaling substrate for HER2 (encoded by ERBB2) and is induced in breast cancer-brain metastases, though the molecular mechanisms by which this oncogenic dimer promotes the development of brain metastases are still elusive. We studied the effects of the HER3-HER2 ligand, heregulin (neuregulin-1, broadly expressed in the brain), on luminal breast cancer cell lines in vitro. Treatment of SKBr3 (ERBB2-amplified), MDA-MB-361 (ERBB2-amplified, metastatic brain tumor-derived) and MCF7 (HER2-positive, not ERBB2-amplified) cells with exogenous heregulin increased proliferation and adhesive potential, concomitant with induction of cyclin D1 and ICAM-1, and suppression of p27. All three cell lines invaded through matrigel toward a heregulin chemotactic signal in transwell experiments, associated with activation of extracellular cathepsin B and matrix metalloproteinase-9 (MMP-9). Moreover, heregulin induced breast cancer cell transmigration across a tight barrier of primary human brain microvascular endothelia. This was dependent on the activity of HER2, HER3 and MMPs, and was completely abrogated by combination HER2-HER3 blockade using Herceptin® and the humanized HER3 monoclonal antibody, EV20. Collectively these data suggest mechanisms by which the HER3-HER2 dimer promotes development of metastatic tumors in the heregulin-rich brain microenvironment.

  5. 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.

  6. 42 CFR 71.55 - Dead bodies.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Dead bodies. 71.55 Section 71.55 Public Health... QUARANTINE Importations § 71.55 Dead bodies. The remains of a person who died of a communicable disease listed in § 71.32(b) may not be brought into a U.S. port unless the body is (a) properly embalmed...

  7. 42 CFR 71.55 - Dead bodies.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Dead bodies. 71.55 Section 71.55 Public Health... QUARANTINE Importations § 71.55 Dead bodies. The remains of a person who died of a communicable disease listed in § 71.32(b) may not be brought into a U.S. port unless the body is (a) properly embalmed...

  8. Dead zones and extrasolar planetary properties

    NASA Astrophysics Data System (ADS)

    Matsumura, Soko; Pudritz, Ralph E.

    2006-01-01

    Most low-mass protostellar discs evolve in clustered environments where they are affected by external radiation fields, while others evolve in more isolated star-forming regions. Assuming that the magnetorotational instability (MRI) is the main source of viscosity, we calculate the size of a poorly ionized, MRI inactive and hence low viscosity region - the `dead zone'- in these protostellar discs. We include disc ionization by X-rays, cosmic rays, radioactive elements and thermal collisions, recombination by molecules, metals and grains, as well as the effect of turbulence stimulation in the dead zone by the active layers lying above it. We also calculate the gap-opening masses of planets, which are determined by a disc's viscosity and a disc aspect ratio, for discs in these environments and compare them with each other. We find that the dead zone is a robust feature of the protostellar discs that is largely independent of their environment, typically stretching out to ~15 au. We analyse the possible effects of dead zones on planet formation, migration and eccentricity evolution. We show that the gap-opening mass inside the dead zone is expected to be of the order of terrestrial and ice giant mass planets while that outside the dead zone is Jovian or super-Jovian mass planets, largely independent of the star-forming environment. We show that dead zones can significantly slow down both type I and type II planetary migration due to their lower viscosity. We also find that the growth of eccentricity of massive extrasolar planets is particularly favourable through the planet-disc interaction inside the dead zones due to the large gaps expected to be opened by planets.

  9. Is the Aluminum Hypothesis Dead?

    PubMed Central

    2014-01-01

    The Aluminum Hypothesis, the idea that aluminum exposure is involved in the etiology of Alzheimer disease, dates back to a 1965 demonstration that aluminum causes neurofibrillary tangles in the brains of rabbits. Initially the focus of intensive research, the Aluminum Hypothesis has gradually been abandoned by most researchers. Yet, despite this current indifference, the Aluminum Hypothesis continues to attract the attention of a small group of scientists and aluminum continues to be viewed with concern by some of the public. This review article discusses reasons that mainstream science has largely abandoned the Aluminum Hypothesis and explores a possible reason for some in the general public continuing to view aluminum with mistrust. PMID:24806729

  10. Is the Aluminum Hypothesis dead?

    PubMed

    Lidsky, Theodore I

    2014-05-01

    The Aluminum Hypothesis, the idea that aluminum exposure is involved in the etiology of Alzheimer disease, dates back to a 1965 demonstration that aluminum causes neurofibrillary tangles in the brains of rabbits. Initially the focus of intensive research, the Aluminum Hypothesis has gradually been abandoned by most researchers. Yet, despite this current indifference, the Aluminum Hypothesis continues to attract the attention of a small group of scientists and aluminum continues to be viewed with concern by some of the public. This review article discusses reasons that mainstream science has largely abandoned the Aluminum Hypothesis and explores a possible reason for some in the general public continuing to view aluminum with mistrust.

  11. Neurobehavioral radiation mitigation to standard brain cancer therapy regimens by Mn(III) n-butoxyethylpyridylporphyrin-based redox modifier.

    PubMed

    Weitzel, Douglas H; Tovmasyan, Artak; Ashcraft, Kathleen A; Boico, Alina; Birer, Samuel R; Roy Choudhury, Kingshuk; Herndon, James; Rodriguiz, Ramona M; Wetsel, William C; Peters, Katherine B; Spasojevic, Ivan; Batinic-Haberle, Ines; Dewhirst, Mark W

    2016-06-01

    Combinations of radiotherapy (RT) and chemotherapy have shown efficacy toward brain tumors. However, therapy-induced oxidative stress can damage normal brain tissue, resulting in both progressive neurocognitive loss and diminished quality of life. We have recently shown that MnTnBuOE-2-PyP(5+) (Mn(III)meso-tetrakis(N-n-butoxyethylpyridinium -2-yl)porphyrin) rescued RT-induced white matter damage in cranially-irradiated mice. Radiotherapy is not used in isolation for treatment of brain tumors; temozolomide is the standard-of-care for adult glioblastoma, whereas cisplatin is often used for treatment of pediatric brain tumors. Therefore, we evaluated the brain radiation mitigation ability of MnTnBuOE-2-PyP(5+) after either temozolomide or cisplatin was used singly or in combination with 10 Gy RT. MnTnBuOE-2-PyP(5+) accumulated in brains at low nanomolar levels. Histological and neurobehavioral testing showed a drastic decrease (1) of axon density in the corpus callosum and (2) rotorod and running wheel performance in the RT only treatment group, respectively. MnTnBuOE-2-PyP(5+) completely rescued this phenotype in irradiated animals. In the temozolomide groups, temozolomide/ RT treatment resulted in further decreased rotorod responses over RT alone. Again, MnTnBuOE-2-PyP(5+) treatment rescued the negative effects of both temozolomide ± RT on rotorod performance. While the cisplatin-treated groups did not give similar results as the temozolomide groups, inclusion of MnTnBuOE-2-PyP(5+) did not negatively affect rotorod performance. Additionally, MnTnBuOE-2-PyP(5+) sensitized glioblastomas to either RT ± temozolomide in flank tumor models. Mice treated with both MnTnBuOE-2-PyP(5+) and radio-/chemo-therapy herein demonstrated brain radiation mitigation. MnTnBuOE-2-PyP(5+) may well serve as a normal tissue radio-/chemo-mitigator adjuvant therapy to standard brain cancer treatment regimens. Environ. Mol. Mutagen. 57:372-381, 2016. © 2016 Wiley Periodicals, Inc.

  12. Preclinical Characterization of Signal Transducer and Activator of Transcription 3 Small Molecule Inhibitors for Primary and Metastatic Brain Cancer Therapy

    PubMed Central

    Assi, Hikmat H.; Paran, Chris; VanderVeen, Nathan; Savakus, Jonathan; Doherty, Robert; Petruzzella, Emanuele; Hoeschele, James D.; Appelman, Henry; Raptis, Leda; Mikkelsen, Tom; Lowenstein, Pedro R.

    2014-01-01

    Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds (CPA-7 [trichloronitritodiammineplatinum(IV)], WP1066 [(S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, C17H14BrN3O], and ML116 [4-benzyl-1-{thieno[2,3-d]pyrimidin-4-yl}piperidine, C18H19N3S]) in cultured rodent and human glioma cells, including GBM cancer stem cells. Our results demonstrate a potent induction of growth arrest in GBM cells after drug treatment with a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor κ light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7–derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors. PMID:24696041

  13. Preventive sparing of spinal cord and brain stem in the initial irradiation of locally advanced head and neck cancers.

    PubMed

    Farace, Paolo; Piras, Sara; Porru, Sergio; Massazza, Federica; Fadda, Giuseppina; Solla, Ignazio; Piras, Denise; Deidda, Maria Assunta; Amichetti, Maurizio; Possanzini, Marco

    2014-01-01

    Since reirradiation in recurrent head and neck patients is limited by previous treatment, a marked reduction of maximum doses to spinal cord and brain stem was investigated in the initial irradiation of stage III/IV head and neck cancers. Eighteen patients were planned by simultaneous integrated boost, prescribing 69.3 Gy to PTV1 and 56.1 Gy to PTV2. Nine 6 MV coplanar photon beams at equispaced gantry angles were chosen for each patient. Step-and-shoot IMRT was calculated by direct machine parameter optimization, with the maximum number of segments limited to 80. In the standard plan, optimization considered organs at risk (OAR), dose conformity, maximum dose < 45 Gy to spinal cord and < 50 Gy to brain stem. In the sparing plans, a marked reduction to spinal cord and brain stem were investigated, with/without changes in dose conformity. In the sparing plans, the maximum doses to spinal cord and brain stem were reduced from the initial values (43.5 ± 2.2 Gy and 36.7 ± 14.0 Gy), without significant changes on the other OARs. A marked difference (-15.9 ± 1.9 Gy and -10.1 ± 5.7 Gy) was obtained at the expense of a small difference (-1.3% ± 0.9%) from initial PTV195% coverage (96.6% ± 0.9%). Similar difference (-15.7 ± 2.2 Gy and -10.2 ± 6.1 Gy) was obtained compromising dose conformity, but unaffecting PTV195% and with negligible decrease in PTV295% (-0.3% ± 0.3% from the initial 98.3% ± 0.8%). A marked spinal cord and brain stem preventive sparing was feasible at the expense of a decrease in dose conformity or slightly compromising target coverage. A sparing should be recommended in highly recurrent tumors, to make potential reirradiation safer. PMID:24423836

  14. A novel PET protocol for visualization of breast cancer resistance protein function at the blood–brain barrier

    PubMed Central

    Wanek, Thomas; Kuntner, Claudia; Bankstahl, Jens P; Mairinger, Severin; Bankstahl, Marion; Stanek, Johann; Sauberer, Michael; Filip, Thomas; Erker, Thomas; Müller, Markus; Löscher, Wolfgang; Langer, Oliver

    2012-01-01

    Breast cancer resistance protein (BCRP) is the most abundant multidrug efflux transporter at the human blood–brain barrier (BBB), restricting brain distribution of various drugs. In this study, we developed a positron emission tomography (PET) protocol to visualize Bcrp function at the murine BBB, based on the dual P-glycoprotein (P-gp)/Bcrp substrate radiotracer [11C]tariquidar in combination with the Bcrp inhibitor Ko143. To eliminate the contribution of P-gp efflux to [11C]tariquidar brain distribution, we studied mice in which P-gp was genetically knocked out (Mdr1a/b(−/−) mice) or chemically knocked out by pretreatment with cold tariquidar. We found that [11C]tariquidar brain uptake increased dose dependently after administration of escalating doses of Ko143, both in Mdr1a/b(−/−) mice and in tariquidar pretreated wild-type mice. After 15 mg/kg Ko143, the maximum increase in [11C]tariquidar brain uptake relative to baseline scans was 6.3-fold in Mdr1a/b(−/−) mice with a half-maximum effect dose of 4.98 mg/kg and 3.6-fold in tariquidar (8 mg/kg) pretreated wild-type mice, suggesting that the presented protocol is sensitive to visualize a range of different functional Bcrp activities at the murine BBB. We expect that this protocol can be translated to the clinic, because tariquidar can be safely administered to humans at doses that completely inhibit cerebral P-gp. PMID:22828996

  15. Changes of Brain Glucose Metabolism in the Pretreatment Patients with Non-Small Cell Lung Cancer: A Retrospective PET/CT Study

    PubMed Central

    Zhang, Weishan; Ning, Ning; Li, Xianjun; Niu, Gang; Bai, Lijun; Guo, Youmin; Yang, Jian

    2016-01-01

    Objective The tumor-to-brain communication has been emphasized by recent converging evidences. This study aimed to compare the difference of brain glucose metabolism between patients with non-small cell lung cancer (NSCLC) and control subjects. Methods NSCLC patients prior to oncotherapy and control subjects without malignancy confirmed by 6 months follow-up were collected and underwent the resting state 18F-fluoro-D-glucose (FDG) PET/CT. Normalized FDG metabolism was calculated by a signal intensity ratio of each brain region to whole brain. Brain glucose metabolism was compared between NSCLC patients and control group using two samples t-test and multivariate test by statistical parametric maps (SPM) software. Results Compared with the control subjects (n = 76), both brain glucose hyper- and hypometabolism regions with significant statistical differences (P<0.01) were found in the NSCLC patients (n = 83). The hypermetabolism regions (bilateral insula, putamen, pallidum, thalamus, hippocampus and amygdala, the right side of cerebellum, orbital part of right inferior frontal gyrus and vermis) were component parts of visceral to brain signal transduction pathways, and the hypometabolism regions (the left superior parietal lobule, bilateral inferior parietal lobule and left fusiform gyrus) lied in dorsal attention network and visuospatial function areas. Conclusions The changes of brain glucose metabolism exist in NSCLC patients prior to oncotherapy, which might be attributed to lung-cancer related visceral sympathetic activation and decrease of dorsal attention network function. PMID:27529342

  16. Brain cancer mortality in an agricultural and a metropolitan region of Rio de Janeiro, Brazil: a population-based, age-period-cohort study, 1996–2010

    PubMed Central

    2014-01-01

    Background Individuals who live in rural areas are at greater risk for brain cancer, and pesticide exposure may contribute to this increased risk. The aims of this research were to analyze the mortality trends and to estimate the age-period-cohort effects on mortality rates from brain cancer in two regions in Rio de Janeiro, Brazil. Methods This descriptive study examined brain cancer mortality patterns in individuals of both sexes, >19 years of age, who died between 1996 and 2010. They were residents of a rural (Serrana) or a non-rural (Metropolitan) area of Rio de Janeiro, Brazil. We estimated mortality trends using Joinpoint Regression analysis. Age-period-cohort models were estimated using Poisson regression analysis. Results The estimated annual percentage change in mortality caused by brain cancer was 3.8% in the Serrana Region (95% confidence interval (CI): 0.8–5.6) and -0.2% (95% CI: -1.2–0.7) in the Metropolitan Region. The results indicated that the relative risk was higher in the rural region for the more recent birth cohorts (1954 and later). Compared with the reference birth cohort (1945–49, Serrana Region), the relative risk was four times higher for individuals born between 1985 and 1989. Conclusions The results of this study indicate that there is an increasing trend in brain cancer mortality rates in the rural Serrana Region in Brazil. A cohort effect occurred in the birth cohorts born in this rural area after 1954. At the ecological level, different environmental factors, especially the use of pesticides, may explain regional disparities in the mortality patterns from brain cancers. PMID:24884498

  17. Analyses of Resected Human Brain Metastases of Breast Cancer Reveal the Association between Up-regulation of Hexokinase 2 and Poor Prognosis

    PubMed Central

    Palmieri, Diane; Fitzgerald, Daniel; Shreeve, S. Martin; Hua, Emily; Bronder, Julie L.; Weil, Robert J.; Davis, Sean; Stark, Andreas M.; Merino, Maria J.; Kurek, Raffael; Mehdorn, H. Maximilian; Davis, Gary; Steinberg, Seth M.; Meltzer, Paul S.; Aldape, Kenneth; Steeg, Patricia S.

    2009-01-01

    Brain metastases of breast cancer appear to be increasing in incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser captured epithelial cells from resected human brain metastases of breast cancer compared to unlinked primary breast tumors. The tumors were matched for histology, TNM stage and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases which included, surprisingly, many genes associated with metastasis. Q-PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMγ3, SIAH, STHMN3 and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P), in vitro. Knockdown of HK2 expression in 231-BR cells using shRNA reduced cell proliferation when cultures were maintained in glucose limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival post-craniotomy (P=0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. PMID:19723875

  18. Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis.

    PubMed

    Palmieri, Diane; Fitzgerald, Daniel; Shreeve, S Martin; Hua, Emily; Bronder, Julie L; Weil, Robert J; Davis, Sean; Stark, Andreas M; Merino, Maria J; Kurek, Raffael; Mehdorn, H Maximilian; Davis, Gary; Steinberg, Seth M; Meltzer, Paul S; Aldape, Kenneth; Steeg, Patricia S

    2009-09-01

    Brain metastases of breast cancer seem to be increasingin incidence as systemic therapy improves. Metastatic disease in the brain is associated with high morbidity and mortality. We present the first gene expression analysis of laser-captured epithelial cells from resected human brain metastases of breast cancer compared with unlinked primary breast tumors. The tumors were matched for histology, tumor-node-metastasis stage, and hormone receptor status. Most differentially expressed genes were down-regulated in the brain metastases, which included, surprisingly, many genes associated with metastasis. Quantitative real-time PCR analysis confirmed statistically significant differences or strong trends in the expression of six genes: BMP1, PEDF, LAMgamma3, SIAH, STHMN3, and TSPD2. Hexokinase 2 (HK2) was also of interest because of its increased expression in brain metastases. HK2 is important in glucose metabolism and apoptosis. In agreement with our microarray results, HK2 levels (both mRNA and protein) were elevated in a brain metastatic derivative (231-BR) of the human breast carcinoma cell line MDA-MB-231 relative to the parental cell line (231-P) in vitro. Knockdown of HK2 expression in 231-BR cells using short hairpin RNA reduced cell proliferation when cultures were maintained in glucose-limiting conditions. Finally, HK2 expression was analyzed in a cohort of 123 resected brain metastases of breast cancer. High HK2 expression was significantly associated with poor patient survival after craniotomy (P = 0.028). The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target. PMID:19723875

  19. Incidental 11C-choline PET/CT brain uptake due to meningioma in a patient studied for prostate cancer: correlation with MRI and imaging fusion.

    PubMed

    Bertagna, Francesco; Bosio, Giovanni; Pinelli, Lorenzo; Treglia, Giorgio; Giubbini, Raffaele

    2013-11-01

    We report a case of a 75-year-old male patient treated with radiotherapy in 1999 for prostate cancer. Due to a rise in prostate-specific antigen, he underwent (11)C-choline PET/CT. The study was negative for secondary lesions but revealed an incidental pathologic focal brain uptake. A subsequent magnetic resonance examination confirmed the presence of a brain lesion typical for meningioma.

  20. A Chaplain-led Spiritual Life Review Pilot Study for Patients with Brain Cancers and Other Degenerative Neurologic Diseases

    PubMed Central

    Piderman, Katherine M.; Breitkopf, Carmen Radecki; Jenkins, Sarah M.; Euerle, Terin T.; Lovejoy, Laura A.; Kwete, Gracia M.; Jatoi, Aminah

    2015-01-01

    Objective: This pilot study was designed to describe changes in spiritual well-being (SWB), spiritual coping, and quality of life (QOL) in patients with brain cancer or other neurodegenerative diseases participating in a chaplain-led spiritual life review interview and development of a spiritual legacy document (SLD). Methods: Eligible participants were enrolled and completed baseline questionnaires. They were interviewed by a board-certified chaplain about spiritual influences, beliefs, practices, values, and spiritual struggles. An SLD was prepared for each participant, and one month follow-up questionnaires were completed. Two cases are summarized, and spiritual development themes are illustrated within a spiritual development framework. Results: A total of 27 patients completed baseline questionnaires and the interview; 24 completed the SLD, and 15 completed the follow-up questionnaire. Increases in SWB, religious coping, and QOL were detected. The majority maintained the highest (best) scores of negative religious coping, demonstrating minimal spiritual struggle. Conclusions: Despite the challenges of brain cancers and other neurodegenerative diseases, participants demonstrated improvements in SWB, positive religious coping, and QOL. Patient comments indicate that benefit is related to the opportunity to reflect on and integrate spiritual experiences and to preserve them for others. Research with a larger, more diverse sample is needed, as well as clinical applications for those too vulnerable to participate in longitudinal follow-up. PMID:25973267

  1. Childhood CT scans linked to leukemia and brain cancer later in life

    Cancer.gov

    Children and young adults scanned multiple times by computed tomography (CT), a commonly used diagnostic tool, have a small increased risk of leukemia and brain tumors in the decade following their first scan.

  2. [Improving the management of rare brain cancers with the POLA network].

    PubMed

    Terziev, Robert; Ravin, Mylène; Carpentier, Catherine; Dehais, Caroline

    2014-04-01

    The national POLA network is dedicated to the management of certain rare brain tumours, mainly anaplastic oligodendrogliomas, anaplastic oligoastrocytomas and glioblastomas with oligodendroglioma component. The nursing team and the patient are at the heart of the organisation.

  3. Effect of Tumor Subtype on Survival and the Graded Prognostic Assessment for Patients With Breast Cancer and Brain Metastases

    SciTech Connect

    Sperduto, Paul W.; Kased, Norbert; Roberge, David; Xu Zhiyuan; Shanley, Ryan; Luo, Xianghua; Sneed, Penny K.; Chao, Samuel T.; Weil, Robert J.; Suh, John; Bhatt, Amit; Jensen, Ashley W.; Brown, Paul D.; Shih, Helen A.; Kirkpatrick, John; Gaspar, Laurie E.; Fiveash, John B.; and others

    2012-04-01

    Purpose: The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype. Methods and Materials: A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index. Results: Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype. Conclusions: The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone.

  4. Can the dead be brought into disrepute?

    PubMed

    Masterton, Malin; Hansson, Mats G; Höglund, Anna T; Helgesson, Gert

    2007-01-01

    Queen Christina of Sweden was unconventional in her time, leading to hypotheses on her gender and possible hermaphroditic nature. If genetic analysis can substantiate the latter claim, could this bring the queen into disrepute 300 years after her death? Joan C. Callahan has argued that if a reputation changes, this constitutes a change only in the group of people changing their views and not in the person whose reputation it is. Is this so? This paper analyses what constitutes change and draws out the implications to the reputation of the dead. It is argued that a reputation is a relational property which can go through changes. The change is "real" for the group changing their views on Queen Christina and of a Cambridge kind for the long dead queen herself. Cambridge changes result in new properties being acquired, some of which can be of significance. Although the dead cannot go through any non-relational changes, it is possible for the dead to change properties through Cambridge changes. In this sense changes in reputation do affect the dead, and thus Queen Christina can acquire a new property, in this case possibly a worse reputation. PMID:17549606

  5. Improved Treatment of MT-3 Breast Cancer and Brain Metastases in a Mouse Xenograft by LRP-Targeted Oxaliplatin Liposomes.

    PubMed

    Orthmann, Andrea; Peiker, Lisa; Fichtner, Iduna; Hoffmann, Annika; Hilger, Ralf Axel; Zeisig, Reiner

    2016-01-01

    The anti-cancer drug oxaliplatin (OxP) has rarely been used to treat breast carcinoma, as it cannot cross the BBB to treat the frequently subsequent brain metastases. Here, we encapsulated OxP in liposomes prepared to reduce side effects and to simultaneously treat primary tumor and brain metastasis. The angiopep LRP-receptor ligand was bound to the vesicular surface for targeting. Targeted and non-targeted OxP liposomes were tested in vitro (binding, uptake, and transcytosis) and in vivo. Liposomes contained 0.65 mg OxP/mL, their mean diameter was 165 nm, and they released 50% of OxP within 8 days at 4 degrees C and within 22 h at 36 degrees C. MDCK cells were used for uptake and transcytosis quantification. Compared to non-targeted liposomes, targeted liposomes showed 12-fold greater uptake, and 2.25-fold higher transcytosis. In vivo efficacy was tested using human MT-3 breast cancer cells transplanted subcutaneously and intracerebrally into female nude mice, and tumor growth inhibition was measured. OxP was injected (6 mg OxP/kg) four times. The best results were obtained with targeted liposomes (T/C: 21% for subcutaneous and 50% for intracerebral). OxP liposomes with a fluid membrane all inhibited MT-3 tumors significantly better than free OxP, with no significant difference between targeted and non-targeted liposomes. The therapeutic effect was accompanied with strong leukopenia and mild thrombocytopenia with all formulations. The newly developed OxP liposomes significantly improved the treatment of subcutaneously and intracerebrally growing breast cancer, but the targeted angiopep-equipped liposomes showed no superior effect in vivo.

  6. Bevacizumab in Reducing CNS Side Effects in Patients Who Have Undergone Radiation Therapy to the Brain for Primary Brain Tumor, Meningioma, or Head and Neck Cancer

    ClinicalTrials.gov

    2014-04-21

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Central Nervous System Germ Cell Tumor; Adult Choroid Plexus Tumor; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Grade III Meningioma; Adult Malignant Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pineocytoma; Malignant Neoplasm; Meningeal Melanocytoma; Radiation Toxicity; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Brain Tumor; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage I Adenoid Cystic Carcinoma of the Oral Cavity; Stage I Basal Cell Carcinoma of the Lip; Stage I Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage I Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage I Lymphoepithelioma of the Nasopharynx; Stage I Lymphoepithelioma of the Oropharynx; Stage I Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage I Mucoepidermoid Carcinoma of the Oral Cavity; Stage I Salivary Gland Cancer; Stage I Squamous Cell Carcinoma

  7. Use of Stereotactic Radiosurgery for Brain Metastases From Non-Small Cell Lung Cancer in the United States

    SciTech Connect

    Halasz, Lia M.; Weeks, Jane C.; Neville, Bridget A.; Taback, Nathan; Punglia, Rinaa S.

    2013-02-01

    Purpose: The indications for treatment of brain metastases from non-small cell lung cancer (NSCLC) with stereotactic radiosurgery (SRS) remain controversial. We studied patterns, predictors, and cost of SRS use in elderly patients with NSCLC. Methods and Materials: Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we identified patients with NSCLC who were diagnosed with brain metastases between 2000 and 2007. Our cohort included patients treated with radiation therapy and not surgical resection as initial treatment for brain metastases. Results: We identified 7684 patients treated with radiation therapy within 2 months after brain metastases diagnosis, of whom 469 (6.1%) cases had billing codes for SRS. Annual SRS use increased from 3.0% in 2000 to 8.2% in 2005 and varied from 3.4% to 12.5% by specific SEER registry site. After controlling for clinical and sociodemographic characteristics, we found SRS use was significantly associated with increasing year of diagnosis, specific SEER registry, higher socioeconomic status, admission to a teaching hospital, no history of participation in low-income state buy-in programs (a proxy for Medicaid eligibility), no extracranial metastases, and longer intervals from NSCLC diagnosis. The average cost per patient associated with radiation therapy was 2.19 times greater for those who received SRS than for those who did not. Conclusions: The use of SRS in patients with metastatic NSCLC increased almost 3-fold from 2000 to 2005. In addition, we found significant variations in SRS use across SEER registries and socioeconomic quartiles. National practice patterns in this study suggested both a lack of consensus and an overall limited use of the approach among elderly patients before 2008.

  8. Controlling micro- and nano-environment of tumor and stem cells for novel research and therapy of brain cancer

    NASA Astrophysics Data System (ADS)

    Smith, Christopher Lloyd

    The use of modern technologies in cancer research has engendered a great deal of excitement. Many of these advanced approaches involve in-depth mathematical analyses of the inner working of cells, via genomic and proteomic analyses. However these techniques may not be ideal for the study of complex cell phenotypes and behaviors. This dissertation explores cancer and potential therapies through phenotypic analysis of cell behaviors, an alternative approach. We employ this experimental framework to study brain cancer (glioma), a particularly formidable example of this diverse ailment. Through the application of micro- and nanotechnology, we carefully control the surrounding environments of cells to understand their responses to various cues and to manipulate their behaviors. Subsequently we obtain clinically relevant information that allows better understanding of glioma, and enhancement of potential therapies. We first aim to address brain tumor dispersal, through analysis of cell migration. Utilizing nanometer-scale topographic models of the extracellular matrix, we study the migratory response of glioma cells to various stimuli in vitro. Second, we implement knowledge gained from these investigations to define characteristics of tumor progression in patients, and to develop treatments inhibiting cell migration. Next we use microfluidic and nanotopographic models to study the behaviors of stem cells in vitro. Here we attempt to improve their abilities to deliver therapeutic proteins to cancer, an innovative treatment approach. We analyze the multi-step process by which adipose-derived stem cells naturally home to tumor sites, and identify numerous environmental perturbations to enhance this behavior. Finally, we attempt to demonstrate that these cell culture-based manipulations can enhance the localization of adipose stem cells to glioma in vivo using animal models. Throughout this work we utilize environmental cues to analyze and induce particular behaviors in

  9. Dead Zone Accretion Flows in Protostellar Disks

    NASA Technical Reports Server (NTRS)

    Turner, Neal; Sano, T.

    2008-01-01

    Planets form inside protostellar disks in a dead zone where the electrical resistivity of the gas is too high for magnetic forces to drive turbulence. We show that much of the dead zone nevertheless is active and flows toward the star while smooth, large-scale magnetic fields transfer the orbital angular momentum radially outward. Stellar X-ray and radionuclide ionization sustain a weak coupling of the dead zone gas to the magnetic fields, despite the rapid recombination of free charges on dust grains. Net radial magnetic fields are generated in the magnetorotational turbulence in the electrically conducting top and bottom surface layers of the disk, and reach the midplane by ohmic diffusion. A toroidal component to the fields is produced near the midplane by the orbital shear. The process is similar to the magnetization of the solar tachocline. The result is a laminar, magnetically driven accretion flow in the region where the planets form.

  10. Effect of dead material in a calorimeter

    SciTech Connect

    Green, D.

    1995-10-01

    The existence of dead material in any practical calorimeter system is simply a fact of life. The task for the designer, then, is to understand the impact on the Physics in question, and strive to minimize it. The aim of this note is to use the ``Hanging File`` test data, which has fined grained individual readout of about 100 depth segments, to explore impact of dead material on the mean and r.m.s. of the hadronic distribution. The amount and location of the dead material is varied. It important to remember that the Hanging File data was calibrated, EM to HCAL compartment, so as to minimize the electron to pion energy dependence. In practical terms e/pie was made = 1.0 at an incident energy of about 100 GeV. Note that the PB(EM) + FE(HCAL) calorimeter was not a compensating device.

  11. Minimizing the Non-specific Binding of Nanoparticles to the Brain Enables Active Targeting of Fn14-positive Glioblastoma Cells

    PubMed Central

    Schneider, Craig S.; Perez, Jimena G.; Cheng, Emily; Zhang, Clark; Mastorakos, Panagiotis; Hanes, Justin; Winkles, Jeffrey A.; Woodworth, Graeme F.; Kim, Anthony J.

    2014-01-01

    A major limitation in the treatment of glioblastoma (GBM), the most common and deadly primary brain cancer, is delivery of therapeutics to invading tumor cells outside of the area that is safe for surgical removal. A promising way to target invading GBM cells is via drug-loaded nanoparticles that bind to fibroblast growth factor-inducible 14 (Fn14), thereby potentially improving efficacy and reducing toxicity. However, achieving broad particle distribution and nanoparticle targeting within the brain remains a significant challenge due to the adhesive extracellular matrix (ECM) and clearance mechanisms in the brain. In this work, we developed Fn14 monoclonal antibody-decorated nanoparticles that can efficiently penetrate brain tissue. We show these Fn14-targeted brain tissue penetrating nanoparticles are able to (i) selectively bind to recombinant Fn14 but not brain ECM proteins, (ii) associate with and be internalized by Fn14-positive GBM cells, and (iii) diffuse within brain tissue in a manner similar to non-targeted brain penetrating nanoparticles. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved tumor cell co-localization in mice bearing human GBM xenografts compared to non-targeted nanoparticles. Minimizing non-specific binding of targeted nanoparticles in the brain may greatly improve the access of particulate delivery systems to remote brain tumor cells and other brain targets. PMID:25542792

  12. Symptoms and Quality of Life in Cancer Patients With Brain Metastases Following Palliative Radiotherapy

    SciTech Connect

    Wong, Jennifer; Hird, Amanda; Zhang Liying; Tsao, May; Sinclair, Emily; Barnes, Elizabeth; Danjoux, Cyril; Chow, Edward

    2009-11-15

    Purpose: To examine prospectively patient self-rated symptoms and quality of life (QOL) indicators in patients with brain metastases following whole brain radiotherapy (WBRT). Methods and Materials: Consecutive patients with brain metastases referred for WBRT were approached for this study. Patients were asked to rate their symptoms and QOL using the Spitzer Quality of Life Index questionnaire. Follow-up was at 1, 2, and 3 months following WBRT. Linear regression analysis was used to determine the change in symptom severity over time. Results: Between August 2005 to October 2007, 129 patients with brain metastases were enrolled. The majority of patients (88%) received 20 Gy in five fractions. Median age was 64 years, and median Karnofsky Performance Status at baseline was 70. The most commonly experienced symptoms at baseline were headaches, weakness, balance problems, and fatigue. Thirty-five percent of patients rated neurological functional (NF) status as 1, indicating moderate neurological symptoms and need for assistance. Forty-three percent of patients had stable or decreased fatigue, and 47% had a stable or improved NF status over time (p = 0.0040). Although certain QOL domains improved over time, all other QOL domains and symptom items did not change significantly following WBRT. Conclusion: WBRT may have contributed to symptom stabilization in our study. An alternative goal of WBRT may be the prevention of symptom progression and QOL deterioration. Further research is required to select the most appropriate group of patients with brain metastases who would benefit most from WBRT.

  13. Continuous Time Random Walk and Migration-Proliferation Dichotomy of Brain Cancer

    NASA Astrophysics Data System (ADS)

    Iomin, A.

    A theory of fractional kinetics of glial cancer cells is presented. A role of the migration-proliferation dichotomy in the fractional cancer cell dynamics in the outer-invasive zone is discussed and explained in the framework of a continuous time random walk. The main suggested model is based on a construction of a 3D comb model, where the migration-proliferation dichotomy becomes naturally apparent and the outer-invasive zone of glioma cancer is considered as a fractal composite with a fractal dimension Dfr < 3.

  14. Continuous Time Random Walk and Migration-Proliferation Dichotomy of Brain Cancer

    NASA Astrophysics Data System (ADS)

    Iomin, A.

    2015-10-01

    A theory of fractional kinetics of glial cancer cells is presented. A role of the migration-proliferation dichotomy in the fractional cancer cell dynamics in the outer-invasive zone is discussed and explained in the framework of a continuous time random walk. The main suggested model is based on a construction of a 3D comb model, where the migration-proliferation dichotomy becomes naturally apparent and the outer-invasive zone of glioma cancer is considered as a fractal composite with a fractal dimension Dfr < 3.

  15. Childhood Brain Tumors

    MedlinePlus

    Brain tumors are abnormal growths inside the skull. They are among the most common types of childhood ... still be serious. Malignant tumors are cancerous. Childhood brain and spinal cord tumors can cause headaches and ...

  16. Dead-time Corrected Disdrometer Data

    DOE Data Explorer

    Bartholomew, Mary Jane

    2008-03-05

    Original and dead-time corrected disdrometer results for observations made at SGP and TWP. The correction is based on the technique discussed in Sheppard and Joe, 1994. In addition, these files contain calculated radar reflectivity factor, mean Doppler velocity and attenuation for every measurement for both the original and dead-time corrected data at the following wavelengths: 0.316, 0.856, 3.2, 5, and 10cm (W,K,X,C,S bands). Pavlos Kollias provided the code to do these calculations.

  17. Quantitative Perfusion and Permeability Biomarkers in Brain Cancer from Tomographic CT and MR Images

    PubMed Central

    Eilaghi, Armin; Yeung, Timothy; d’Esterre, Christopher; Bauman, Glenn; Yartsev, Slav; Easaw, Jay; Fainardi, Enrico; Lee, Ting-Yim; Frayne, Richard

    2016-01-01

    Dynamic contrast-enhanced perfusion and permeability imaging, using computed tomography and magnetic resonance systems, are important techniques for assessing the vascular supply and hemodynamics of healthy brain parenchyma and tumors. These techniques can measure blood flow, blood volume, and blood–brain barrier permeability surface area product and, thus, may provide information complementary to clinical and pathological assessments. These have been used as biomarkers to enhance the treatment planning process, to optimize treatment decision-making, and to enable monitoring of the treatment noninvasively. In this review, the principles of magnetic resonance and computed tomography dynamic contrast-enhanced perfusion and permeability imaging are described (with an emphasis on their commonalities), and the potential values of these techniques for differentiating high-grade gliomas from other brain lesions, distinguishing true progression from posttreatment effects, and predicting survival after radiotherapy, chemotherapy, and antiangiogenic treatments are presented. PMID:27398030

  18. Public perception of cancer survival rankings.

    PubMed

    Jensen, Jakob D; Scherr, Courtney L; Brown, Natasha; Jones, Christina; Christy, Katheryn

    2013-12-01

    Past research has observed that certain subgroups (e.g., individuals who are overweight/obese) have inaccurate estimates of survival rates for particular cancers (e.g., colon cancer). However, no study has examined whether the lay public can accurately rank cancer survival rates in comparison with one another (i.e., rank cancers from most deadly to least deadly). A sample of 400 Indiana adults aged 18 to 89 years (M = 33.88 years) completed a survey with questions regarding perceived cancer survival rates. Most cancers were ranked accurately; however, breast and stomach cancer survival rankings were highly distorted such that breast cancer was perceived to be significantly more deadly and stomach cancer significantly less deadly than reality. Younger participants also overestimated the survival rate for pancreatic cancer. These distortions mirror past content analytic work demonstrating that breast, stomach, and pancreatic cancers are misrepresented in the news. PMID:23463791

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

    PubMed

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

    1989-02-01

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

  20. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases

    PubMed Central

    Zhang, Jianying; Chen, Charlie; Chen, Luxi; Wang, Youwei; Wang, Hongwei; Yi, Long; Elder, J. Bradley; Wang, Qi-En; He, Xiaoming; Kaur, Balveen; Chiocca, E. Antonio; Yu, Jianhua

    2016-01-01

    Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs. PMID:27050072

  1. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases.

    PubMed

    Chen, Xilin; Han, Jianfeng; Chu, Jianhong; Zhang, Lingling; Zhang, Jianying; Chen, Charlie; Chen, Luxi; Wang, Youwei; Wang, Hongwei; Yi, Long; Elder, J Bradley; Wang, Qi-En; He, Xiaoming; Kaur, Balveen; Chiocca, E Antonio; Yu, Jianhua

    2016-05-10

    Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs.

  2. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases.

    PubMed

    Chen, Xilin; Han, Jianfeng; Chu, Jianhong; Zhang, Lingling; Zhang, Jianying; Chen, Charlie; Chen, Luxi; Wang, Youwei; Wang, Hongwei; Yi, Long; Elder, J Bradley; Wang, Qi-En; He, Xiaoming; Kaur, Balveen; Chiocca, E Antonio; Yu, Jianhua

    2016-05-10

    Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs. PMID:27050072

  3. Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases.

    PubMed

    Kanojia, Deepak; Balyasnikova, Irina V; Morshed, Ramin A; Frank, Richard T; Yu, Dou; Zhang, Lingjiao; Spencer, Drew A; Kim, Julius W; Han, Yu; Yu, Dihua; Ahmed, Atique U; Aboody, Karen S; Lesniak, Maciej S

    2015-10-01

    The treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer has been revolutionized by trastuzumab. However, longer survival of these patients now predisposes them to forming HER2 positive brain metastases, as the therapeutic antibodies cannot cross the blood brain barrier. The current oncologic repertoire does not offer a rational, nontoxic targeted therapy for brain metastases. In this study, we used an established human neural stem cell line, HB1.F3 NSCs and generated a stable pool of cells secreting a high amount of functional full-length anti-HER2 antibody, equivalent to trastuzumab. Anti-HER2Ab secreted by the NSCs (HER2Ab-NSCs) specifically binds to HER2 overexpressing human breast cancer cells and inhibits PI3K-Akt signaling. This translates to HER2Ab-NSC inhibition of breast cancer cell growth in vitro. Preclinical in vivo experiments using HER2Ab overexpressing NSCs in a breast cancer brain metastases (BCBM) mouse model demonstrate that intracranial injection of HER2Ab-NSCs significantly improves survival. In effect, these NSCs provide tumor localized production of HER2Ab, minimizing any potential off-target side effects. Our results establish HER2Ab-NSCs as a novel, nontoxic, and rational therapeutic approach for the successful treatment of HER2 overexpressing BCBM, which now warrants further preclinical and clinical investigation.

  4. Serum Biomarkers Associated with Clinical Outcomes Fail to Predict Brain Metastases in Patients with Stage IV Non-Small Cell Lung Cancers

    PubMed Central

    Li, Bob T.; Lou, Emil; Hsu, Meier; Yu, Helena A.; Naidoo, Jarushka; Zauderer, Marjorie G.; Sima, Camelia; Johnson, Melissa L.; Daras, Mariza; DeAngelis, Lisa M.; Fleisher, Martin; Kris, Mark G.; Azzoli, Christopher G.

    2016-01-01

    Background Lung cancers account for the majority of brain metastases which pose major therapeutic challenges. Biomarkers prognosticating for the development of brain metastases in patients with non-small cell lung cancers (NSCLC) may improve personalized care. Six serum proteomic biomarkers were previously investigated at Memorial Sloan Kettering but their associations with brain metastases were unknown. Methods Serum NSE, CYFRA 21–1, ProGRP, SCC-Ag, TIMP1, and HE4 by ELISA-based proteomic assays were prospectively collected from consecutive patients with stage IV NSCLC. Pre-treatment serum biomarker levels as well as age, histology, and epidermal growth factor receptor (EGFR) mutation status were evaluated for association with the baseline presence of brain metastases using logistic regression and multivariable analysis. For patients without brain metastases at baseline, the cumulative incidence of subsequent brain metastases were compared according to baseline biomarkers and clinical factors using Gray’s test. Results A total of 118 patients were enrolled, 31 (26%; 95% CI 0.19–0.35) had brain metastases at baseline and a further 26 (22%; 95% CI 0.15–0.30) developed brain metastases subsequently. Pre-treatment serum biomarker levels were available in 104 patients. There was no significant association between the six serum biomarkers and the baseline presence or subsequent development of brain metastases. Age younger than 65 years was the only clinical factor significantly associated with brain metastasis at baseline (OR 3.00; 95% CI 1.22–7.34, P = 0.02) by multivariable analysis. A trend toward increased cumulative incidence of subsequent brain metastases was observed in patients with EGFR mutation (p = 0.2), but this was not statistically significant possibly due to small sample size. Conclusions Serum NSE, CYFRA 21–1, Pro-GRP, SCC-Ag, TIMP1, and HE4 are not significantly associated with brain metastases. Our methods taking into account follow-up time

  5. Centralized databases available for describing primary brain tumor incidence, survival, and treatment: Central Brain Tumor Registry of the United States; Surveillance, Epidemiology, and End Results; and National Cancer Data Base.

    PubMed Central

    Davis, F. G.; McCarthy, B. J.; Berger, M. S.

    1999-01-01

    Characteristics of three databases--the Central Brain Tumor Registry of the United States (CBTRUS) database; the Surveillance, Epidemiology and End Results (SEER) database; and the National Cancer Data Base (NCDB)--containing information on primary brain tumors are discussed. The recently developed population-based CBTRUS database comprises incidence data on all primary brain tumors from 11 collaborating state registries; however, follow-up data are not available. SEER, the population-based gold standard for cancer data, collects incidence and follow-up data on malignant brain tumors only. While not population-based, the NCDB identifies newly diagnosed cases and conducts follow-up on all primary brain tumors from hospitals accredited by the American College of Surgeons. The NCDB is the largest of the three databases and also contains more complete information regarding treatment of these tumors than either the SEER or CBTRUS databases. Additional strengths and limitations of each of these are described, and their judicious use for supporting research, education, and health care planning is encouraged. PMID:11554389

  6. Hydrocarbon potential of Dead Sea Rift valley

    SciTech Connect

    Wilson, J.E.; Kashai, E.L.; Croker, P.F.

    1983-03-01

    The Dead Sea Rift is one of the world's unique geologic and topographic features, whose petroleum potential has not yet been evaluated. The sector of the Dead Sea is an asymmetric graben 20 km (12 mi) from rim to rim and over 120 km (75 mi) long. The total throw from the west rim, where the Upper Cretaceous crops out to the deeper portion of the grabens, is more than 8 km (26,200 ft). Throw on the eastern side is considerably greater as the valley wall is largely Precambrian. The level of the Dead Sea is -400 m (-1300 ft) - the lowest place on earth. Asphalt blocks floating from the Dead Sea, along with asphalt and heavy oil seeps in the valley, have been known since biblical times. These are suggestive of leaks from deeper accumulations. Although some exploration drilling has been done, no test has yet reached objectives in the deeper sunken block where the Miocene is figured to be at a depth of at least 7 km (23,000 ft.)

  7. Unethical and Deadly Symbiosis in Higher Education

    ERIC Educational Resources Information Center

    Crumbley, D. Larry; Flinn, Ronald; Reichelt, Kenneth J.

    2012-01-01

    As administrators are pressured to increase retention rates in accounting departments, and higher education in general, a deadly symbiosis is occurring. Most students and parents only wish for high grades, so year after year many educators engage in unethical grade inflation and course work deflation. Since administrators use the students to audit…

  8. Cheatgrass Dead Zones in Northern Nevada

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Reports of areas of cheatgrass die-off are becoming more frequent. In 2009, we investigated cheatgrass die-off in north-central Nevada. Dead zones ranged from several to hundreds of acres in size and were largely unvegetated and covered by cheatgrass litter with a distinct gray cast. We collected re...

  9. ON HYDRODYNAMIC MOTIONS IN DEAD ZONES

    SciTech Connect

    Oishi, Jeffrey S.; Mac Low, Mordecai-Mark E-mail: mordecai@amnh.or

    2009-10-20

    We investigate fluid motions near the midplane of vertically stratified accretion disks with highly resistive midplanes. In such disks, the magnetorotational instability drives turbulence in thin layers surrounding a resistive, stable dead zone. The turbulent layers in turn drive motions in the dead zone. We examine the properties of these motions using three-dimensional, stratified, local, shearing-box, non-ideal, magnetohydrodynamical simulations. Although the turbulence in the active zones provides a source of vorticity to the midplane, no evidence for coherent vortices is found in our simulations. It appears that this is because of strong vertical oscillations in the dead zone. By analyzing time series of azimuthally averaged flow quantities, we identify an axisymmetric wave mode particular to models with dead zones. This mode is reduced in amplitude, but not suppressed entirely, by changing the equation of state from isothermal to ideal. These waves are too low frequency to affect sedimentation of dust to the midplane, but may have significance for the gravitational stability of the resulting midplane dust layers.

  10. 32 CFR 632.4 - Deadly force.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... and standards for protection of nuclear weapons (paragraph (c) of this section AR 50-5-1) and for... weapon). Use it only in extreme need, when all lesser means have failed or cannot reasonably be used. Use... property (such as operable weapons or ammunition) which could cause deadly harm to others in the hands...

  11. 32 CFR 632.4 - Deadly force.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... and standards for protection of nuclear weapons (paragraph (c) of this section AR 50-5-1) and for... weapon). Use it only in extreme need, when all lesser means have failed or cannot reasonably be used. Use... property (such as operable weapons or ammunition) which could cause deadly harm to others in the hands...

  12. 32 CFR 632.4 - Deadly force.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... and standards for protection of nuclear weapons (paragraph (c) of this section AR 50-5-1) and for... weapon). Use it only in extreme need, when all lesser means have failed or cannot reasonably be used. Use... property (such as operable weapons or ammunition) which could cause deadly harm to others in the hands...

  13. 32 CFR 632.4 - Deadly force.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... and standards for protection of nuclear weapons (paragraph (c) of this section AR 50-5-1) and for... weapon). Use it only in extreme need, when all lesser means have failed or cannot reasonably be used. Use... property (such as operable weapons or ammunition) which could cause deadly harm to others in the hands...

  14. 32 CFR 632.4 - Deadly force.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... and standards for protection of nuclear weapons (paragraph (c) of this section AR 50-5-1) and for... weapon). Use it only in extreme need, when all lesser means have failed or cannot reasonably be used. Use... property (such as operable weapons or ammunition) which could cause deadly harm to others in the hands...

  15. Effect of Dead Algae on Soil Permeability

    SciTech Connect

    Harvey, R.S.

    2003-02-21

    Since existing basins support heavy growths of unicellular green algae which may be killed by temperature variation or by inadvertent pH changes in waste and then deposited on the basin floor, information on the effects of dead algae on soil permeability was needed. This study was designed to show the effects of successive algal kills on the permeability of laboratory soil columns.

  16. Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin

    PubMed Central

    Kafka, Anja; Tomas, Davor; Beroš, Vili; Pećina, Hrvoje Ivan; Zeljko, Martina; Pećina-Šlaus, Nives

    2014-01-01

    The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p = 0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p = 0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain. PMID:24933634

  17. Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin.

    PubMed

    Kafka, Anja; Tomas, Davor; Beroš, Vili; Pećina, Hrvoje Ivan; Zeljko, Martina; Pećina-Šlaus, Nives

    2014-06-13

    The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p=0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p=0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain.

  18. SU-E-J-90: MRI-Based Treatment Simulation and Patient Setup for Radiation Therapy of Brain Cancer

    SciTech Connect

    Yang, Y; Cao, M; Han, F; Santhanam, A; Neylon, J; Gomez, C; Kaprealian, T; Sheng, K; Agazaryan, N; Low, D; Hu, P

    2014-06-01

    Purpose: Traditional radiation therapy of cancer is heavily dependent on CT. CT provides excellent depiction of the bones but lacks good soft tissue contrast, which makes contouring difficult. Often, MRIs are fused with CT to take advantage of its superior soft tissue contrast. Such an approach has drawbacks. It is desirable to perform treatment simulation entirely based on MRI. To achieve MR-based simulation for radiation therapy, bone imaging is an important challenge because of the low MR signal intensity from bone due to its ultra-short T2 and T1, which presents difficulty for both dose calculation and patient setup in terms of digitally reconstructed radiograph (DRR) generation. Current solutions will either require manual bone contouring or multiple MR scans. We present a technique to generate DRR using MRI with an Ultra Short Echo Time (UTE) sequence which is applicable to both OBI and ExacTrac 2D patient setup. Methods: Seven brain cancer patients were scanned at 1.5 Tesla using a radial UTE sequence. The sequence acquires two images at two different echo times. The two images were processed using in-house software. The resultant bone images were subsequently loaded into commercial systems to generate DRRs. Simulation and patient clinical on-board images were used to evaluate 2D patient setup with MRI-DRRs. Results: The majority bones are well visualized in all patients. The fused image of patient CT with the MR bone image demonstrates the accuracy of automatic bone identification using our technique. The generated DRR is of good quality. Accuracy of 2D patient setup by using MRI-DRR is comparable to CT-based 2D patient setup. Conclusion: This study shows the potential of DRR generation with single MR sequence. Further work will be needed on MR sequence development and post-processing procedure to achieve robust MR bone imaging for other human sites in addition to brain.

  19. Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases

    PubMed Central

    Iorio, Anna Lisa; da Ros, Martina; Fantappiè, Ornella; Lucchesi, Maurizio; Facchini, Ludovica; Stival, Alessia; Becciani, Sabrina; Guidi, Milena; Favre, Claudio; de Martino, Maurizio; Genitori, Lorenzo; Sardi, Iacopo

    2016-01-01

    The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies. The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS. In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases. PMID:26584727

  20. Using the theory of planned behavior to understand the determinants of exercise intention in patients diagnosed with primary brain cancer.

    PubMed

    Jones, Lee W; Guill, Bebe; Keir, Stephen T; Carter, Karen; Friedman, Henry S; Bigner, Darell D; Reardon, David A

    2007-03-01

    The purpose of the present study was to examine the demographic, medical, and social cognitive determinants of exercise intentions in a institution-based cohort of primary brain tumor patients. Using a cross-sectional survey, 100 primary brain tumor patients completed a mailed survey that assessed medical and demographic characteristics, past exercise behavior using the Godin Leisure Time Exercise Questionnaire (GLTEQ), and social cognitive beliefs towards exercise using Aizen's theory of planned behavior (TPB; i.e. intention, perceived behavioral control, subjective norm, affective and instrumental attitude). Descriptive statistics indicated that participants had positive social cognitive beliefs towards exercise. In support of the tenets of the TPB, we found moderate to large (>0.40) positive correlations between the majority of TPB constructs. Moreover, the TPB constructs combined to explain 32% of the variance in exercise intentions with affective attitude (beta = 0.24; p = 0.020) and perceived behavioral control (beta = 0.36; p<0.001) being the most important determinants. Except past exercise behavior, medical and demographic variables were not consistently correlated with any TPB constructs. Finally, participant's gender and body mass index influenced the association between instrumental attitude and exercise intention with male and overweight/obese patients (> or =25 kg/m(2)) considering the health benefits of exercise to be more important than their female and normal weight (<25 kg/m(2)) counterparts. Information gained from this study suggests that the TPB is a useful framework to design and implement theoretically based interventions to promote exercise in primary brain cancer patients.

  1. More dead than dead: perceptions of persons in the persistent vegetative state.

    PubMed

    Gray, Kurt; Knickman, T Anne; Wegner, Daniel M

    2011-11-01

    Patients in persistent vegetative state (PVS) may be biologically alive, but these experiments indicate that people see PVS as a state curiously more dead than dead. Experiment 1 found that PVS patients were perceived to have less mental capacity than the dead. Experiment 2 explained this effect as an outgrowth of afterlife beliefs, and the tendency to focus on the bodies of PVS patients at the expense of their minds. Experiment 3 found that PVS is also perceived as "worse" than death: people deem early death better than being in PVS. These studies suggest that people perceive the minds of PVS patients as less valuable than those of the dead - ironically, this effect is especially robust for those high in religiosity. PMID:21798528

  2. Occupational and environmental risk factors of adult primary brain cancers: a systematic review.

    PubMed

    Gomes, J; Al Zayadi, A; Guzman, A

    2011-04-01

    The incidence of brain neoplasm has been progressively increasing in recent years in the industrialized countries. One of the reasons for this increased incidence could be better access to health care and improved diagnosis in the industrialized countries. It also appears that Caucasians have a higher incidence than blacks or Hispanics or Asians. A number of risk factors have been identified and described including the genetic, ethnic and age-based factors. Certain occupational and environmental factors are also believed to influence the risk of primary adult brain tumors. Potential occupational and environmental factors include exposure to diagnostic and therapeutic radiations, electromagnetic radiation from cellular phones and other wireless devices, infectious agents, air pollution and residence near landfills and high-voltage power lines and jobs as firefighters, farmers, physician, chemists and jobs in industries such as petrochemical, power generation, synthetic rubber manufacturing, agricultural chemicals manufacturing. The purpose of this systematic review is to examine occupational and environmental risk factors of brain neoplasm. A range of occupational and environmental exposures are evaluated for significance of their relationship with adult primary brain tumors. On the basis of this review we suggest a concurrent evaluation of multiple risk factors both within and beyond occupational and environmental domains. The concurrent approach needs to consider better exposure assessment techniques, lifetime occupational exposures, genotypic and phenotypic characteristics and lifestyle and dietary habits. This approach needs to be interdisciplinary with contributions from neurologists, oncologists, epidemiologists and molecular biologists. Conclusive evidence that has eluded multitude of studies with single focus and single exposure needs to multifaceted and multidisciplinary. PMID:23022824

  3. Abandoning the dead donor rule? A national survey of public views on death and organ donation.

    PubMed

    Nair-Collins, Michael; Green, Sydney R; Sutin, Angelina R

    2015-04-01

    Brain dead organ donors are the principal source of transplantable organs. However, it is controversial whether brain death is the same as biological death. Therefore, it is unclear whether organ removal in brain death is consistent with the 'dead donor rule', which states that organ removal must not cause death. Our aim was to evaluate the public's opinion about organ removal if explicitly described as causing the death of a donor in irreversible apneic coma. We conducted a cross-sectional internet survey of the American public (n=1096). Questionnaire domains included opinions about a hypothetical scenario of organ removal described as causing the death of a patient in irreversible coma, and items measuring willingness to donate organs after death. Some 71% of the sample agreed that it should be legal for patients to donate organs in the scenario described and 67% agreed that they would want to donate organs in a similar situation. Of the 85% of the sample who agreed that they were willing to donate organs after death, 76% agreed that they would donate in the scenario of irreversible coma with organ removal causing death. There appears to be public support for organ donation in a scenario explicitly described as violating the dead donor rule. Further, most but not all people who would agree to donate when organ removal is described as occurring after death would also agree to donate when organ removal is described as causing death in irreversible coma. PMID:25260779

  4. Abandoning the dead donor rule? A national survey of public views on death and organ donation.

    PubMed

    Nair-Collins, Michael; Green, Sydney R; Sutin, Angelina R

    2015-04-01

    Brain dead organ donors are the principal source of transplantable organs. However, it is controversial whether brain death is the same as biological death. Therefore, it is unclear whether organ removal in brain death is consistent with the 'dead donor rule', which states that organ removal must not cause death. Our aim was to evaluate the public's opinion about organ removal if explicitly described as causing the death of a donor in irreversible apneic coma. We conducted a cross-sectional internet survey of the American public (n=1096). Questionnaire domains included opinions about a hypothetical scenario of organ removal described as causing the death of a patient in irreversible coma, and items measuring willingness to donate organs after death. Some 71% of the sample agreed that it should be legal for patients to donate organs in the scenario described and 67% agreed that they would want to donate organs in a similar situation. Of the 85% of the sample who agreed that they were willing to donate organs after death, 76% agreed that they would donate in the scenario of irreversible coma with organ removal causing death. There appears to be public support for organ donation in a scenario explicitly described as violating the dead donor rule. Further, most but not all people who would agree to donate when organ removal is described as occurring after death would also agree to donate when organ removal is described as causing death in irreversible coma.

  5. Microwave beamforming for non-invasive patient-specific hyperthermia treatment of pediatric brain cancer

    NASA Astrophysics Data System (ADS)

    Burfeindt, Matthew J.; Zastrow, Earl; Hagness, Susan C.; Van Veen, Barry D.; Medow, Joshua E.

    2011-05-01

    We present a numerical study of an array-based microwave beamforming approach for non-invasive hyperthermia treatment of pediatric brain tumors. The transmit beamformer is designed to achieve localized heating—that is, to achieve constructive interference and selective absorption of the transmitted electromagnetic waves at the desired focus location in the brain while achieving destructive interference elsewhere. The design process takes into account patient-specific and target-specific propagation characteristics at 1 GHz. We evaluate the effectiveness of the beamforming approach using finite-difference time-domain simulations of two MRI-derived child head models from the Virtual Family (IT'IS Foundation). Microwave power deposition and the resulting steady-state thermal distribution are calculated for each of several randomly chosen focus locations. We also explore the robustness of the design to mismatch between the assumed and actual dielectric properties of the patient. Lastly, we demonstrate the ability of the beamformer to suppress hot spots caused by pockets of cerebrospinal fluid (CSF) in the brain. Our results show that microwave beamforming has the potential to create localized heating zones in the head models for focus locations that are not surrounded by large amounts of CSF. These promising results suggest that the technique warrants further investigation and development.

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

    PubMed Central

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

    2016-01-01

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

  7. 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.

  8. Prognostic Value of MR Imaging Texture Analysis in Brain Non-Small Cell Lung Cancer Oligo-Metastases Undergoing Stereotactic Irradiation

    PubMed Central

    Tini, Paolo; Biondi, Michelangelo; Sebaste, Lucio; Vanzi, Eleonora; De Otto, Gianmarco; Rubino, Giovanni; Carfagno, Tommaso; Battaglia, Giuseppe; Pastina, Pierpaolo; Cerase, Alfonso; Mazzoni, Lorenzo Nicola; Banci Buonamici, Fabrizio; Pirtoli, Luigi

    2016-01-01

    Background  Stereotactic irradiation is widely used in brain oligo-metastases treatment. The aim of this study is to evaluate the prognostic value of magnetic resonance imaging (MRI) texture analysis (TA) of brain metastases (BM) of non-small cell lung cancer (NSCLC). Materials and methods  This study included thirty-eight consecutive patients undergoing stereotactic irradiation, that is, stereotactic fractionated radiotherapy (SRT) or radiosurgery (SRS), from January 2011 to December 2014 for 1-2 brain BM from NSCLC. Whole-brain radiotherapy (WBRT) was not delivered. The diagnostic MRI DICOM (Digital Imaging and Communications in Medicine) images were collected and analyzed with a homemade ImageJ macro, and typical TA parameters (mean, standard deviation, skewness, kurtosis, entropy, and uniformity) were evaluated for: brain progression-free survival; modality of brain metastatic progression (local progression or/and new metastases); and overall survival, after SRT/SRS. Results After SRT/SRS 14 patients (36.8%) experienced recurrence in the brain, with a recurrence in the irradiated site (five patients, 13.2%), new metastases (11 patients, 28.9%), local recurrence and new metastases (two patients, 5.25%). Nineteen patients (50%) died of tumor progression or other causes. Entropy and uniformity were significantly associated with local progression, whereas kurtosis was significantly associated with both local progression and new brain metastases. Conclusions  These results appear promising, since the knowledge of factors correlated with the modality of brain progression after stereotactic irradiation of brain oligo-metastatic foci of NSCLC might help in driving the best treatment in these patients (association of SRT/SRS with WBRT? Increase of SRT/SRS dose?). Our preliminary data needs confirmation in large patient series. PMID:27226944

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

    PubMed Central

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

    2016-01-01

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

  10. Gulf of Mexico dead zone - the last 150 years

    USGS Publications Warehouse

    Osterman, Lisa; Swarzenski, P.W.; Poore, R.Z.

    2006-01-01

    'Gulf of Mexico Dead Zone-The Last 150 Years' discusses the dead zone that forms seasonally in the northern Gulf of Mexico when subsurface waters become depleted in dissolved oxygen and cannot support most life.

  11. Motexafin Gadolinium Combined With Prompt Whole Brain Radiotherapy Prolongs Time to Neurologic Progression in Non-Small-Cell Lung Cancer Patients With Brain Metastases: Results of a Phase III Trial

    SciTech Connect

    Mehta, Minesh P. Shapiro, William R.; Phan, See C.; Gervais, Radj; Carrie, Christian; Chabot, Pierre; Patchell, Roy A.; Glantz, Michael J.; Recht, Lawrence; Langer, Corey; Sur, Ranjan K.; Roa, Wilson H.; Mahe, Marc A.; Fortin, Andre; Nieder, Carsten; Meyers, Christina A.; Smith, Jennifer A.; Miller, Richard A.; Renschler, Markus F.

    2009-03-15

    Purpose: To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer. Methods and Materials: In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received. Results: Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed. Conclusion: In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

  12. Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study

    PubMed Central

    Siena, S.; Crinò, L.; Danova, M.; Del Prete, S.; Cascinu, S.; Salvagni, S.; Schiavetto, I.; Vitali, M.; Bajetta, E.

    2010-01-01

    Background: Brain metastases reduce survival because therapeutic options are limited. This phase II study evaluated the efficacy of single-agent therapy with alternating weekly, dose-dense temozolomide in pretreated patients with brain metastases prospectively stratified by primary tumor type. Methods: Eligible patients had bidimensionally measurable brain metastases from histologically/cytologically confirmed melanoma, breast cancer (BC), or non-small-cell lung cancer (NSCLC). Prior chemotherapy, radiotherapy, and whole-brain radiotherapy (WBRT) were allowed. Patients received temozolomide 150 mg/m2/day (days 1–7 and 15–21 every 28- or 35-day cycle). Results: In the intent-to-treat population (N = 157; 53 melanoma, 51 BC, and 53 NSCLC), one patient had complete response, nine (6%) had partial responses, and 31 (20%) had stable disease in the brain. Median progression-free survival was 56, 58, and 66 days for melanoma, BC, and NSCLC, respectively. Median overall survival was 100 days for melanoma, 172 days for NSCLC, and not evaluable in the BC group. Thrombocytopenia was the most common adverse event causing dose modification or treatment discontinuation. Grade 4 toxic effects were rare. Conclusions: This alternating weekly, dose-dense temozolomide regimen was well tolerated and clinically active in heavily pretreated patients with brain metastases, particularly in patients with melanoma. Combining temozolomide with WBRT or other agents may improve clinical outcomes. PMID:19767314

  13. Dieldrin and heptachlor residues in dead gray bats, Franklin County, Missouri--1976 versus 1977

    USGS Publications Warehouse

    Clark, D.R.; LaVal, R.K.; Krynitsky, A.J.

    1980-01-01

    Lethal dieldrin concentrations were found in the brains of dead gray bats (Myotis grisescens) collected during 1976 and 1977 beneath a maternity roost in a Missouri cave. In addition, residues of heptachlor epoxide, oxychlordane, cis-chlordane, and trans-nonachlor increased significantly in both brains and carcasses of bats collected during 1977. These increases appear to reflect a switch by local farmers from aldrin, dieldrin's parent compound, to heptachlor for the control of cutworms. They also constitute an additional threat to this colony of this endangered bat species.

  14. Risk Factors for Brain Metastases in Locally Advanced Non-Small Cell Lung Cancer With Definitive Chest Radiation

    SciTech Connect

    Ji, Zhe; Bi, Nan; Wang, Jingbo; Hui, Zhouguang; Xiao, Zefen; Feng, Qinfu; Zhou, Zongmei; Chen, Dongfu; Lv, Jima; Liang, Jun; Fan, Chengcheng; Liu, Lipin; Wang, Luhua

    2014-06-01

    Purpose: We intended to identify risk factors that affect brain metastases (BM) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving definitive radiation therapy, which may guide the choice of selective prevention strategies. Methods and Materials: The characteristics of 346 patients with stage III NSCLC treated with thoracic radiation therapy from January 2008 to December 2010 in our institution were retrospectively reviewed. BM rates were analyzed by the Kaplan-Meier method. Multivariate Cox regression analysis was performed to determine independent risk factors for BM. Results: The median follow-up time was 48.3 months in surviving patients. A total of 74 patients (21.4%) experienced BM at the time of analysis, and for 40 (11.7%) of them, the brain was the first site of failure. The 1-year and 3-year brain metastasis rates were 15% and 28.1%, respectively. In univariate analysis, female sex, age ≤60 years, non-squamous cell carcinoma, T3-4, N3, >3 areas of lymph node metastasis, high lactate dehydrogenase and serum levels of tumor markers (CEA, NSE, CA125) before treatment were significantly associated with BM (P<.05). In multivariate analysis, age ≤60 years (P=.004, hazard ratio [HR] = 0.491), non-squamous cell carcinoma (P=.000, HR=3.726), NSE >18 ng/mL (P=.008, HR=1.968) and CA125 ≥ 35 U/mL (P=.002, HR=2.129) were independent risk factors for BM. For patients with 0, 1, 2, and 3 to 4 risk factors, the 3-year BM rates were 7.3%, 18.9%, 35.8%, and 70.3%, respectively (P<.001). Conclusions: Age ≤60 years, non-squamous cell carcinoma, serum NSE >18 ng/mL, and CA125 ≥ 35 U/mL were independent risk factors for brain metastasis. The possibilities of selectively using prophylactic cranial irradiation in higher-risk patients with LA-NSCLC should be further explored in the future.

  15. Brain-stem auditory evoked potentials and brain death.

    PubMed

    Machado, C; Valdés, P; García-Tigera, J; Virues, T; Biscay, R; Miranda, J; Coutin, P; Román, J; García, O

    1991-01-01

    BAEP records were obtained from 30 brain-dead patients. Three BAEP patterns were observed: (1) no identifiable waves (73.34%), (2) an isolated bilateral wave I (16.66%), and (3) an isolated unilateral wave I (10%). When wave I was present, it was always significantly delayed. Significant augmentation of wave I amplitude was present bilaterally in one case and unilaterally in another. On the other hand, in serial records from 3 cases wave I latency tended to increase progressively until this component disappeared. During the same period, wave I amplitude fluctuations were observed. A significant negative correlation was found for wave I latency with heart rate and body temperature in 1 case. Two facts might explain the progressive delay and disappearance of wave I in brain-dead patients: a progressive hypoxic-ischaemic dysfunction of the cochlea and the eighth nerve plus hypothermia, often present in brain-dead patients. Then the incidence of wave I preservation reported by different authors in single BAEP records from brain-dead patients might depend on the moment at which the evoked potential study was done in relation to the onset of the clinical state. It is suggested that, although BAEPs provide an objective electrophysiological assessment of brain-stem function, essential for BD diagnosis, this technique could be of no value for this purpose when used in isolation.

  16. 9 CFR 314.8 - Dead animal carcasses.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Dead animal carcasses. 314.8 Section 314.8 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Dead animal carcasses. (a) With the exception of dead livestock which have died en route and...

  17. 9 CFR 314.8 - Dead animal carcasses.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Dead animal carcasses. 314.8 Section 314.8 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Dead animal carcasses. (a) With the exception of dead livestock which have died en route and...

  18. 9 CFR 314.8 - Dead animal carcasses.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Dead animal carcasses. 314.8 Section 314.8 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Dead animal carcasses. (a) With the exception of dead livestock which have died en route and...

  19. 9 CFR 314.8 - Dead animal carcasses.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Dead animal carcasses. 314.8 Section 314.8 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Dead animal carcasses. (a) With the exception of dead livestock which have died en route and...

  20. 9 CFR 314.8 - Dead animal carcasses.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Dead animal carcasses. 314.8 Section 314.8 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Dead animal carcasses. (a) With the exception of dead livestock which have died en route and...

  1. 14 CFR 1203b.106 - Use of deadly force.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 5 2011-01-01 2010-01-01 true Use of deadly force. 1203b.106 Section 1203b... AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.106 Use of deadly force. Deadly force shall be used only in those circumstances where the security force officer reasonably believes...

  2. 14 CFR 1203b.106 - Use of deadly force.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Use of deadly force. 1203b.106 Section... AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.106 Use of deadly force. Deadly force shall be used only in those circumstances where the security force officer reasonably believes...

  3. Preventing Deadly Conflict: Toward a World without War.

    ERIC Educational Resources Information Center

    Francis, Greg

    Although some people believed that the end of the Cold War would herald a new age of peace, the 1990s have seen more than five million people die in over 35 deadly conflicts. New technologies have made warfare ever more deadly. There is, however, a breadth of options available to prevent or control deadly conflict in the world. This curriculum…

  4. 14 CFR 1203b.106 - Use of deadly force.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 5 2012-01-01 2012-01-01 false Use of deadly force. 1203b.106 Section... AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.106 Use of deadly force. Deadly force shall be used only in those circumstances where the security force officer reasonably believes...

  5. 14 CFR § 1203b.106 - Use of deadly force.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 5 2014-01-01 2014-01-01 false Use of deadly force. § 1203b.106 Section Â... AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.106 Use of deadly force. NASA security force personnel may use deadly force only when necessary, that is, when the officer has a...

  6. 14 CFR 1203b.106 - Use of deadly force.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 5 2013-01-01 2013-01-01 false Use of deadly force. 1203b.106 Section... AUTHORITY AND USE OF FORCE BY NASA SECURITY FORCE PERSONNEL § 1203b.106 Use of deadly force. Deadly force shall be used only in those circumstances where the security force officer reasonably believes...

  7. Analysis of Cancer-Targeting Alkylphosphocholine Analogue Permeability Characteristics Using a Human Induced Pluripotent Stem Cell Blood-Brain Barrier Model.

    PubMed

    Clark, Paul A; Al-Ahmad, Abraham J; Qian, Tongcheng; Zhang, Ray R; Wilson, Hannah K; Weichert, Jamey P; Palecek, Sean P; Kuo, John S; Shusta, Eric V

    2016-09-01

    Cancer-targeting alkylphosphocholine (APC) analogues are being clinically developed for diagnostic imaging, intraoperative visualization, and therapeutic applications. These APC analogues derived from chemically synthesized phospholipid ethers were identified and optimized for cancer-targeting specificity using extensive structure-activity studies. While they strongly label human brain cancers associated with disrupted blood-brain barriers (BBB), APC permeability across intact BBB remains unknown. Three of our APC analogues, CLR1404 (PET radiotracer), CLR1501 (green fluorescence), and CLR1502 (near-infrared fluorescence), were tested for permeability across a BBB model composed of human induced pluripotent stem cell-derived brain microvascular endothelial cells (iPSC-derived BMECs). This in vitro BBB system has reproducibly consistent high barrier integrity marked by high transendothelial electrical resistance (TEER > 1500 Ω-cm(2)) and functional expression of drug efflux transporters. The radioiodinated and fluorescent APC analogues demonstrated fairly low permeability across the iPSC-BMEC (35 ± 5.7 (CLR1404), 54 ± 3.2 (CLR1501), and 26 ± 4.9 (CLR1502) × 10(-5) cm/min) compared with BBB-impermeable sucrose (13 ± 2.5) and BBB-permeable diazepam (170 ± 29). Only the fluorescent APC analogues (CLR1501, CLR1502) underwent BCRP and MRP polarized drug efflux transport in the brain-to-blood direction of the BBB model, and this efflux can be specifically blocked with pharmacological inhibition. None of the tested APC analogues appeared to undergo substantial P-gp transport. Limited permeability of the APC analogues across an intact BBB into normal brain likely contributes to the high tumor to background ratios observed in initial human trials. Moreover, addition of fluorescent moieties to APCs resulted in greater BMEC efflux via MRP and BCRP, and may affect fluorescence-guided applications. Overall, the characterization of APC analogue permeability across human BBB

  8. Analysis of Cancer-Targeting Alkylphosphocholine Analogue Permeability Characteristics Using a Human Induced Pluripotent Stem Cell Blood-Brain Barrier Model.

    PubMed

    Clark, Paul A; Al-Ahmad, Abraham J; Qian, Tongcheng; Zhang, Ray R; Wilson, Hannah K; Weichert, Jamey P; Palecek, Sean P; Kuo, John S; Shusta, Eric V

    2016-09-01

    Cancer-targeting alkylphosphocholine (APC) analogues are being clinically developed for diagnostic imaging, intraoperative visualization, and therapeutic applications. These APC analogues derived from chemically synthesized phospholipid ethers were identified and optimized for cancer-targeting specificity using extensive structure-activity studies. While they strongly label human brain cancers associated with disrupted blood-brain barriers (BBB), APC permeability across intact BBB remains unknown. Three of our APC analogues, CLR1404 (PET radiotracer), CLR1501 (green fluorescence), and CLR1502 (near-infrared fluorescence), were tested for permeability across a BBB model composed of human induced pluripotent stem cell-derived brain microvascular endothelial cells (iPSC-derived BMECs). This in vitro BBB system has reproducibly consistent high barrier integrity marked by high transendothelial electrical resistance (TEER > 1500 Ω-cm(2)) and functional expression of drug efflux transporters. The radioiodinated and fluorescent APC analogues demonstrated fairly low permeability across the iPSC-BMEC (35 ± 5.7 (CLR1404), 54 ± 3.2 (CLR1501), and 26 ± 4.9 (CLR1502) × 10(-5) cm/min) compared with BBB-impermeable sucrose (13 ± 2.5) and BBB-permeable diazepam (170 ± 29). Only the fluorescent APC analogues (CLR1501, CLR1502) underwent BCRP and MRP polarized drug efflux transport in the brain-to-blood direction of the BBB model, and this efflux can be specifically blocked with pharmacological inhibition. None of the tested APC analogues appeared to undergo substantial P-gp transport. Limited permeability of the APC analogues across an intact BBB into normal brain likely contributes to the high tumor to background ratios observed in initial human trials. Moreover, addition of fluorescent moieties to APCs resulted in greater BMEC efflux via MRP and BCRP, and may affect fluorescence-guided applications. Overall, the characterization of APC analogue permeability across human BBB

  9. Dead Sea Minerals loaded polymeric nanoparticles.

    PubMed

    Dessy, Alberto; Kubowicz, Stephan; Alderighi, Michele; Bartoli, Cristina; Piras, Anna Maria; Schmid, Ruth; Chiellini, Federica

    2011-10-15

    Therapeutic properties of Dead Sea Water (DSW) in the treatment of skin diseases such as atopic dermatitis, psoriasis and photo aging UV damaged skin have been well established. DSW is in fact rich in minerals such as calcium, magnesium, sodium, potassium, zinc and strontium which are known to exploit anti-inflammatory effects and to promote skin barrier recovery. In order to develop a Dead Sea Minerals (DSM) based drug delivery system for topical therapy of skin diseases, polymeric nanoparticles based on Poly (maleic anhydride-alt-butyl vinyl ether) 5% grafted with monomethoxy poly(ethyleneglycol) 2000 MW (PEG) and 95% grafted with 2-methoxyethanol (VAM41-PEG) loaded with DSM were prepared by means of a combined miniemulsion/solvent evaporation process. The resulting nanoparticles were characterized in terms of dimension, morphology, biocompatibility, salt content and release. Cytocompatible spherical nanoparticles possessing an average diameter of about 300 nm, a time controlled drug release profile and a high formulation yield were obtained.

  10. Potential Evaporite Biomarkers from the Dead Sea

    NASA Technical Reports Server (NTRS)

    Morris, Penny A.; Wentworth, Susan J.; Thomas-Keprta, Kathie; Allen, Carlton C.; McKay, David S.

    2001-01-01

    The Dead Sea is located on the northern branch of the African-Levant Rift systems. The rift system, according to one model, was formed by a series of strike slip faults, initially forming approximately two million years ago. The Dead Sea is an evaporite basin that receives freshwater from springs and from the Jordan River. The Dead Sea is different from other evaporite basins, such as the Great Salt Lake, in that it possesses high concentrations of magnesium and has an average pH of 6.1. The dominant cation in the Great Salt Lake is sodium, and the pH is 7.7. Calcium concentrations are also higher in the Dead Sea than in the Great Salt Lake. Both basins are similar in that the dominant anion is chlorine and the salinity levels are approximately 20 %. Other common cations that have been identified from the waters of the Dead Sea and the Great Salt Lake include sodium and potassium. A variety of Archea, Bacteria, and a single genus of a green algal, Dunaliella, has been described from the Dead Sea. Earlier studies concentrated on microbial identification and analysis of their unique physiology that allows them to survive in this type of extreme environment. Potential microbial fossilization processes, microbial fossils, and the metallic ions associated with fossilization have not been studied thoroughly. The present study is restricted to identifying probable microbial morphologies and associated metallic ions. XRD (X Ray Diffraction) analysis indicates the presence of halite, quartz, and orthoclase feldspar. In addition to these minerals, other workers have reported potassium chloride, magnesium bromide, magnesium chloride, calcium chloride, and calcium sulfate. Halite, calcium sulfate, and orthoclase were examined in this report for the presence of microbes, microbially induced deposits or microbial alteration. Neither the gypsum nor the orthoclase surfaces possesses any obvious indications of microbial life or fossilization. The sand-sized orthoclase particles are

  11. Perturbative search for dead-end CFTs

    NASA Astrophysics Data System (ADS)

    Nakayama, Yu

    2015-05-01

    To explore the possibility of self-organized criticality, we look for CFTs without any relevant scalar deformations (a.k.a. dead-end CFTs) within power-counting renormalizable quantum field theories with a weakly coupled Lagrangian description. In three dimensions, the only candidates are pure (Abelian) gauge theories, which may be further deformed by Chern-Simons terms. In four dimensions, we show that there are infinitely many non-trivial candidates based on chiral gauge theories. Using the three-loop beta functions, we compute the gap of scaling dimensions above the marginal value, and it can be as small as and robust against the perturbative corrections. These classes of candidates are very weakly coupled and our perturbative conclusion seems difficult to refute. Thus, the hypothesis that non-trivial dead-end CFTs do not exist is likely to be false in four dimensions.

  12. Zero dead volume tube to surface seal

    DOEpatents

    Benett, William J.; Folta, James A.

    2000-01-01

    A method and apparatus for connecting a tube to a surface that creates a dead volume seal. The apparatus is composed of three components, a body, a ferrule, and a threaded fitting. The ferrule is compressed onto a tube and a seal is formed between the tube and a device retained in the body by threading the fitting into the body which provides pressure that seals the face of the ferrule to a mating surface on the device. This seal can be used at elevated temperatures depending on the materials used. While the invention has been developed for use with micro-machined silicon wafers used in Capillary Gas Chromatograph (GC), it can be utilized anywhere for making a gas or fluid face seal to the surface of a device that has near zero dead volume.

  13. Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer.

    PubMed

    Fancy, Stephen P J; Harrington, Emily P; Baranzini, Sergio E; Silbereis, John C; Shiow, Lawrence R; Yuen, Tracy J; Huang, Eric J; Lomvardas, Stavros; Rowitch, David H

    2014-04-01

    In colon cancer, mutation of the Wnt repressor APC (encoding adenomatous polyposis coli) leads to a state of aberrant and unrestricted high-activity signaling. However, the relevance of high Wnt tone in non-genetic human disease is unknown. Here we demonstrate that distinct functional states of Wnt activity determine oligodendrocyte precursor cell (OPC) differentiation and myelination. Mouse OPCs with genetic Wnt dysregulation (high tone) express multiple genes in common with colon cancer, including Lef1, Sp5, Ets2, Rnf43 and Dusp4. Surprisingly, we found that OPCs in lesions of hypoxic human neonatal white matter injury upregulated markers of high Wnt activity and lacked expression of APC. We also found that lack of Wnt repressor tone promoted permanent white matter injury after mild hypoxic insult. These findings suggest a state of pathological high-activity Wnt signaling in human disease tissues that lack predisposing genetic mutation.

  14. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer

    PubMed Central

    Mansfield, A. S.; Aubry, M. C.; Moser, J. C.; Harrington, S. M.; Dronca, R. S.; Park, S. S.; Dong, H.

    2016-01-01

    Background The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD-L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases. Experimental design Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the χ2 or Fisher's exact test were used for analysis. Results We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, κ = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, κ = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009). Conclusions We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment. PMID:27502709

  15. Improving measurement of Chesapeake Bay's dead zone

    NASA Astrophysics Data System (ADS)

    Schultz, Colin

    2013-09-01

    In the 1930s, researchers first noticed that the Chesapeake Bay had a dead zone, an expanse of water with drastically reduced concentrations of oxygen. In the 1980s, hypoxia—low-oxygen conditions—gave way in some places to anoxia—a near-total depletion of dissolved oxygen. A lack of oxygen makes the water inhospitable for many marine organisms, and the Chesapeake Bay is the focus of major ecosystem rehabilitation efforts.

  16. Ultra-small gadolinium oxide nanoparticles to image brain cancer cells in vivo with MRI.

    PubMed

    Faucher, Luc; Guay-Bégin, Andrée-Anne; Lagueux, Jean; Côté, Marie-France; Petitclerc, Eric; Fortin, Marc-André

    2011-01-01

    The majority of contrast agents used in magnetic resonance imaging (MRI) is based on the rare-earth element gadolinium. Gadolinium-based nanoparticles could find promising applications in pre-clinical diagnostic procedures of certain types of cancer, such as glioblastoma multiforme. This is one of the most malignant, lethal and poorly accessible forms of cancer. Recent advances in colloidal nanocrystal synthesis have led to the development of ultra-small crystals of gadolinium oxide (US-Gd(2)O(3), 2-3 nm diameter). As of today, this is the smallest and the densest of all Gd-containing nanoparticles. Cancer cells labeled with a sufficient quantity of this compound appear bright in T(1)-weighted MRI images. Here we demonstrate that US-Gd(2)O(3) can be used to label GL-261 glioblastoma multiforme cells, followed by localization and visualization in vivo using MRI. Very high amounts of Gd are efficiently internalized and retained in cells, as confirmed with TEM and ICP-MS. Labeled cells were visualized in vivo at 1.5 T using the chicken embryo model. This is one more step toward the development of "positively contrasted" cell tracking procedures with MRI.

  17. Surviving deadness in the analytic experience.

    PubMed

    Koritar, Endre

    2014-12-01

    The transference/countertransference (third space) analysis is considered to be central in the therapeutic effectiveness of the analytic process. Less emphasis has been placed on the actual experiences of analyst and analysand in the conflictual reenactment of third space experience and its resolution. This paper recounts the shared experience of a patient who was silent throughout most of the analysis, and my reaction, in fantasy and enactment, to this disturbing experience-both for him and for myself. I argue that it is the affective re-experiencing of past repressed trauma in the analytic space that has a therapeutic impact, leading to growth in the patient and also the therapist. I contrast Freud's emphasis on insight, making the unconscious conscious, with Ferenczi's suggestion that the therapeutic impact lies in the repetition of past traumatic experience in the analysis but with the possibility of a different outcome with a more benign object, leading to symbolic representation of repressed trauma. Re-experiencing and symbolization, in the third space, of past traumatic experience can be an exit point from the endless repetition of trauma in internal and external object relations, leading to a new beginning in the patient's life. Immersed in the experience of deadness in the analysis, which had become a dead womb, the struggle to remain alive and thinking led to a rupture out of the dead womb, like the Caesura of birth, into aliveness and the ability to mentalize what had previously remained unmentalized. PMID:25434889

  18. In vivo visualization and ex vivo quantification of murine breast cancer cells in the mouse brain using MRI cell tracking and electron paramagnetic resonance.

    PubMed

    Danhier, Pierre; Magat, Julie; Levêque, Philippe; De Preter, Géraldine; Porporato, Paolo E; Bouzin, Caroline; Jordan, Bénédicte F; Demeur, Gladys; Haufroid, Vincent; Feron, Olivier; Sonveaux, Pierre; Gallez, Bernard

    2015-03-01

    Cell tracking could be useful to elucidate fundamental processes of cancer biology such as metastasis. The aim of this study was to visualize, using MRI, and to quantify, using electron paramagnetic resonance (EPR), the entrapment of murine breast cancer cells labeled with superparamagnetic iron oxide particles (SPIOs) in the mouse brain after intracardiac injection. For this purpose, luciferase-expressing murine 4 T1-luc breast cancer cells were labeled with fluorescent Molday ION Rhodamine B SPIOs. Following intracardiac injection, SPIO-labeled 4 T1-luc cells were imaged using multiple gradient-echo sequences. Ex vivo iron oxide quantification in the mouse brain was performed using EPR (9 GHz). The long-term fate of 4 T1-luc cells after injection was characterized using bioluminescence imaging (BLI), brain MRI and immunofluorescence. We observed hypointense spots due to SPIO-labeled cells in the mouse brain 4 h after injection on T2 *-weighted images. Histology studies showed that SPIO-labeled cancer cells were localized within blood vessels shortly after delivery. Ex vivo quantification of SPIOs showed that less than 1% of the injected cells were taken up by the mouse brain after injection. MRI experiments did not reveal the development of macrometastases in the mouse brain several days after injection, but immunofluorescence studies demonstrated that these cells found in the brain established micrometastases. Concerning the metastatic patterns of 4 T1-luc cells, an EPR biodistribution study demonstrated that SPIO-labeled 4 T1-luc cells were also entrapped in the lungs of mice after intracardiac injection. BLI performed 6 days after injection of 4 T1-luc cells showed that this cell line formed macrometastases in the lungs and in the bones. Conclusively, EPR and MRI were found to be complementary for cell tracking applications. MRI cell tracking at 11.7 T allowed sensitive detection of isolated SPIO-labeled cells in the mouse brain, whereas EPR

  19. In vivo visualization and ex vivo quantification of murine breast cancer cells in the mouse brain using MRI cell tracking and electron paramagnetic resonance.

    PubMed

    Danhier, Pierre; Magat, Julie; Levêque, Philippe; De Preter, Géraldine; Porporato, Paolo E; Bouzin, Caroline; Jordan, Bénédicte F; Demeur, Gladys; Haufroid, Vincent; Feron, Olivier; Sonveaux, Pierre; Gallez, Bernard

    2015-03-01

    Cell tracking could be useful to elucidate fundamental processes of cancer biology such as metastasis. The aim of this study was to visualize, using MRI, and to quantify, using electron paramagnetic resonance (EPR), the entrapment of murine breast cancer cells labeled with superparamagnetic iron oxide particles (SPIOs) in the mouse brain after intracardiac injection. For this purpose, luciferase-expressing murine 4 T1-luc breast cancer cells were labeled with fluorescent Molday ION Rhodamine B SPIOs. Following intracardiac injection, SPIO-labeled 4 T1-luc cells were imaged using multiple gradient-echo sequences. Ex vivo iron oxide quantification in the mouse brain was performed using EPR (9 GHz). The long-term fate of 4 T1-luc cells after injection was characterized using bioluminescence imaging (BLI), brain MRI and immunofluorescence. We observed hypointense spots due to SPIO-labeled cells in the mouse brain 4 h after injection on T2 *-weighted images. Histology studies showed that SPIO-labeled cancer cells were localized within blood vessels shortly after delivery. Ex vivo quantification of SPIOs showed that less than 1% of the injected cells were taken up by the mouse brain after injection. MRI experiments did not reveal the development of macrometastases in the mouse brain several days after injection, but immunofluorescence studies demonstrated that these cells found in the brain established micrometastases. Concerning the metastatic patterns of 4 T1-luc cells, an EPR biodistribution study demonstrated that SPIO-labeled 4 T1-luc cells were also entrapped in the lungs of mice after intracardiac injection. BLI performed 6 days after injection of 4 T1-luc cells showed that this cell line formed macrometastases in the lungs and in the bones. Conclusively, EPR and MRI were found to be complementary for cell tracking applications. MRI cell tracking at 11.7 T allowed sensitive detection of isolated SPIO-labeled cells in the mouse brain, whereas EPR

  20. Brain Stimulation in the Treatment of Chronic Neuropathic and Non-Cancerous Pain

    PubMed Central

    Plow, EB; Pascual-Leone, A; Machado, A

    2012-01-01

    Chronic neuropathic pain is one of the most prevalent and debilitating disorders. Conventional medical management, however, remains frustrating for both patients and clinicians owing to poor specificity of pharmacotherapy, delayed-onset of analgesia and extensive side-effects. Neuromodulation presents as a promising alternative, or at least an adjunct, as it is more specific in inducing analgesia without associated risks of pharmacotherapy. Here, we discuss common clinical and investigational methods of neuromodulation. Compared to clinical spinal cord stimulation (SCS), investigational techniques of cerebral neuromodulation, both invasive [deep brain stimulation (DBS) and motor cortical stimulation (MCS)] and noninvasive [repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)], may be more advantageous. By adaptively targeting the multi-dimensional experience of pain, subtended by integrative pain circuitry in the brain, including somatosensory and thalamocortical, limbic and cognitive, cerebral methods may modulate the sensory-discriminative, affective-emotional and evaluative-cognitive spheres of the pain neuromatrix. Despite promise, the current state of results alludes to the possibility that cerebral neuromodulation has thus far not been effective in producing analgesia as intended in patients with chronic pain disorders. These techniques, thus, remain investigational and off-label. We discuss issues implicated in inadequate efficacy, variability of responsiveness and poor retention of benefit, while recommending design and conceptual refinements for future trials of cerebral neuromodulation in management of chronic neuropathic pain. PMID:22484179

  1. Photo-activated Cancer Therapy: Potential for Treatment of Brain Tumors

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry

    The diffuse and infiltrative nature of high grade gliomas, such as glioblastoma multiforme (GBM), makes complete surgical resection virtually impossible. The propensity of glioma cells to migrate along white matter tracts suggests that a cure is possible only if these migratory cells can be eradicated. Approximately 80% of GBMs recur within 2 cm of the resection margin, suggesting that a reasonable approach for improving the prognosis of GBM patients would be the development of improved local therapies capable of eradicating glioma cells in the brain-adjacent-to-tumor (BAT). An additional complicating factor for the development of successful therapies is the presence of the blood-brain barrier (BBB) which is highly variable throughout the BAT—it is intact in some regions, while leaky in others. This variance in BBB patency has significant implications for the delivery of therapeutic agents. The results of a number of studies have shown that experimental light-based therapeutic modalities such as photochemical internalization (PCI) and photothermal therapy (PTT) may be useful in the treatment of gliomas. This chapter summarizes recent findings illustrating the potential of: (1) PCI for the delivery of therapeutic macromolecules such as chemotherapeutic agents and tumor suppressor genes, and (2) nanoshell-mediated PTT, including nanoparticle delivery approaches via macrophages.

  2. Gamma Knife Stereotactic Radiosurgery as Salvage Therapy After Failure of Whole-Brain Radiotherapy in Patients With Small-Cell Lung Cancer

    SciTech Connect

    Harris, Sunit; Chan, Michael D.; Lovato, James F.; Ellis, Thomas L.; Tatter, Stephen B.; Bourland, J. Daniel; Munley, Michael T.; Guzman, Allan F. de; Shaw, Edward G.; Urbanic, James J.; McMullen, Kevin P.

    2012-05-01

    Purpose: Radiosurgery has been successfully used in selected cases to avoid repeat whole-brain irradiation (WBI) in patients with multiple brain metastases of most solid tumor histological findings. Few data are available for the use of radiosurgery for small-cell lung cancer (SCLC). Methods and Materials: Between November 1999 and June 2009, 51 patients with SCLC and previous WBI and new brain metastases were treated with GammaKnife stereotactic radiosurgery (GKSRS). A median dose of 18 Gy (range, 10-24 Gy) was prescribed to the margin of each metastasis. Patients were followed with serial imaging. Patient electronic records were reviewed to determine disease-related factors and clinical outcomes after GKSRS. Local and distant brain failure rates, overall survival, and likelihood of neurologic death were determined based on imaging results. The Kaplan-Meier method was used to determine survival and local and distant brain control. Cox proportional hazard regression was performed to determine strength of association between disease-related factors and survival. Results: Median survival time for the entire cohort was 5.9 months. Local control rates at 1 and 2 years were 57% and 34%, respectively. Distant brain failure rates at 1 and 2 years were 58% and 75%, respectively. Fifty-three percent of patients ultimately died of neurologic death. On multivariate analysis, patients with stable (hazard ratio [HR] = 2.89) or progressive (HR = 6.98) extracranial disease (ECD) had worse overall survival than patients without evidence of ECD (p = 0.00002). Concurrent chemotherapy improved local control (HR = 89; p = 0.006). Conclusions: GKSRS represents a feasible salvage option in patients with SCLC and brain metastases for whom previous WBI has failed. The status of patients' ECD is a dominant factor predictive of overall survival. Local control may be inferior to that seen with other cancer histological results, although the use of concurrent chemotherapy may help to improve

  3. 9 CFR 82.6 - Interstate movement of dead birds and dead poultry from a quarantined area.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... dead poultry from a quarantined area. 82.6 Section 82.6 Animals and Animal Products ANIMAL AND PLANT... POULTRY) AND ANIMAL PRODUCTS EXOTIC NEWCASTLE DIS- EASE (END) AND CHLAMYDIOSIS Exotic Newcastle Disease (END) § 82.6 Interstate movement of dead birds and dead poultry from a quarantined area. (a) Except...

  4. 9 CFR 82.6 - Interstate movement of dead birds and dead poultry from a quarantined area.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... dead poultry from a quarantined area. 82.6 Section 82.6 Animals and Animal Products ANIMAL AND PLANT... POULTRY) AND ANIMAL PRODUCTS EXOTIC NEWCASTLE DIS- EASE (END) AND CHLAMYDIOSIS Exotic Newcastle Disease (END) § 82.6 Interstate movement of dead birds and dead poultry from a quarantined area. (a) Except...

  5. 9 CFR 82.6 - Interstate movement of dead birds and dead poultry from a quarantined area.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... dead poultry from a quarantined area. 82.6 Section 82.6 Animals and Animal Products ANIMAL AND PLANT... POULTRY) AND ANIMAL PRODUCTS EXOTIC NEWCASTLE DISEASE (END) AND CHLAMYDI-OSIS Exotic Newcastle Disease (END) § 82.6 Interstate movement of dead birds and dead poultry from a quarantined area. (a) Except...

  6. 9 CFR 82.6 - Interstate movement of dead birds and dead poultry from a quarantined area.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... dead poultry from a quarantined area. 82.6 Section 82.6 Animals and Animal Products ANIMAL AND PLANT... POULTRY) AND ANIMAL PRODUCTS NEWCASTLE DISEASE AND CHLAMYDIOSIS Newcastle Disease § 82.6 Interstate movement of dead birds and dead poultry from a quarantined area. (a) Except as provided in paragraph (b)...

  7. 9 CFR 82.6 - Interstate movement of dead birds and dead poultry from a quarantined area.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... dead poultry from a quarantined area. 82.6 Section 82.6 Animals and Animal Products ANIMAL AND PLANT... POULTRY) AND ANIMAL PRODUCTS EXOTIC NEWCASTLE DISEASE (END) AND CHLAMYDI-OSIS Exotic Newcastle Disease (END) § 82.6 Interstate movement of dead birds and dead poultry from a quarantined area. (a) Except...

  8. Vertical Mixing in the Dead Sea

    NASA Astrophysics Data System (ADS)

    Gertman, Isaac; Ozer, Tal; Katsenelson, Boris; Lensky, Nadav

    2015-04-01

    For hundreds of years, the Dead Sea was characterized by a stable haline stratification, supported by runoff. The penetration of the winter convection was limited to an upper mixed layer (UML) of about 30-50 m. Below the UML, a stable halocline prevented the mixing. As a result of the runoff reduction, the UML salinity increased and the gravitational stability diminished. During the winter of 1978-1979, the sea water overturned, ending the long-term stable hydrological regime. Since 1979, the haline stratification structure reoccurred twice after extremely rainy winters, in 1980-82 and 1992-1995. In other years, the sea was entirely mixed by winter thermal convection ( which occurs from November to March ) and had a seasonal pycnocline beneath the UML during summer. Profiles of temperature and quasi-salinity (density anomaly from 1000 kg/m3 for the chosen reference temperature of 32° C) during the last 19 years, show the formation of summer ``overturning halocline'' beneath the UML, and the thermocline that supports the stable stratification. Another warm and saline layer is formed also during the summer period near the bottom. This layer spreads from the southern part of the sea, where end-brine is discharged to the sea from the Israeli and Jordanian salt plants' evaporation ponds. The end-brine has extremely high salinity (˜ 350 g/kg) and, in spite of the high temperatures ( ˜ 45° C), high density (1350 kg/m^3), it therefore spreads as a gravitational current in the Dead Sea deep basin. Estimation of the density ratio (Rρ) for the Dead Sea water (where measurements of water salinity is quite difficult) was done using quasi-salinity (σ32) and potential temperature (θ): Rρ= [α(partialθ/partial z)]/[β(partial σ32/partial z)], where α and β are temperature expansion and quasi-salinity contraction coefficients respectively. The values of α and β for the Dead Sea water were defined from water samples collected during 2008. The Rρ values confirm that

  9. Quality of life in patients with primary and metastatic brain cancer as reported in the literature using the EORTC QLQ-BN20 and QLQ-C30.

    PubMed

    Chiu, Leonard; Chiu, Nicholas; Zeng, Liang; Zhang, Liying; Popovic, Marko; Chow, Ronald; Lam, Henry; Poon, Michael; Chow, Edward

    2012-12-01

    The objective of this study is to compare the differences in quality of life (QoL) as assessed by the QLQ-BN20 and QLQ-C30 in patients with primary and metastatic brain neoplasms. A systematic literature search was conducted over the OvidSP platform in MEDLINE (1980-2012) and EMBASE (1980-2012). Studies in which the QLQ-BN20 was used as a QoL assessment for patients with malignant brain tumors (either metastatic or primary) were included in the study. Articles were included if they reported scores of at least one subscale of the QLQ-C30 or QLQ-BN20. The weighted means of the QLQ-BN20 and QLQ-C30 subscales were calculated based on sample size for included studies. Weighted analysis of variance was conducted to compare these scores in primary and metastatic brain patients. A p-value of < 0.05 was considered statistically significant. A total of 14 studies (16 arms: three brain metastases and 13 primary brain tumors) were identified and included in the data analysis. Fifteen of the 16 arms included QLQ-C30 scores along with QLQ-BN20 scores. Performance status of patients in both cohorts was similar. Patients with primary brain tumors and brain metastases had the following findings: physical functioning (weighted mean: 79.18 vs 74.93), global QoL (61.88 vs 59.44), role functioning (67.37 vs 75.00) and emotional functioning (70.44 vs 71.86); but none of them were statistically significantly different. Only cognitive functioning from the QLQ-C30 was significantly worse in patients with primary brain tumors (p-value = 0.0199). Despite cognitive function being significantly worse in patients with primary brain tumors, patients with metastatic brain tumors and patients with primary brain tumors have very similar QoL profiles. The study is limited by the large discrepancy in cohort sizes (1260 patients with primary brain cancer vs 183 patients with brain metastases) and the lack of clinical data.

  10. Activity-dependent neuroprotective protein (ADNP): a case study for highly conserved chordata-specific genes shaping the brain and mutated in cancer.

    PubMed

    Gozes, Illana; Yeheskel, Adva; Pasmanik-Chor, Metsada

    2015-01-01

    The recent finding of activity-dependent neuroprotective protein (ADNP) as a protein decreased in serum of patients with Alzheimer's disease (AD) compared to controls, alongside with the discovery of ADNP mutations in autism and coupled with the original description of cancer mutations, ignited an interest for a comparative analysis of ADNP with other AD/autism/cancer-associated genes. We strive toward a better understanding of the molecular structure of key players in psychiatric/neurodegenerative diseases including autism, schizophrenia, and AD. This article includes data mining and bioinformatics analysis on the ADNP gene and protein, in addition to other related genes, with emphasis on recent literature. ADNP is discovered here as unique to chordata with specific autism mutations different from cancer-associated mutation. Furthermore, ADNP exhibits similarities to other cancer/autism-associated genes. We suggest that key genes, which shape and maintain our brain and are prone to mutations, are by in large unique to chordata. Furthermore, these brain-controlling genes, like ADNP, are linked to cell growth and differentiation, and under different stress conditions may mutate or exhibit expression changes leading to cancer propagation. Better understanding of these genes could lead to better therapeutics.

  11. In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.

    PubMed

    Nanjo, Shigeki; Nakagawa, Takayuki; Takeuchi, Shinji; Kita, Kenji; Fukuda, Koji; Nakada, Mitsutoshi; Uehara, Hisanori; Nishihara, Hiroshi; Hara, Eiji; Uramoto, Hidetaka; Tanaka, Fumihiro; Yano, Seiji

    2015-03-01

    EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.

  12. Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine.

    PubMed

    Kim, Sang-Soo; Harford, Joe B; Pirollo, Kathleen F; Chang, Esther H

    2015-12-18

    Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood-brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review.

  13. Differential role of P-glycoprotein and breast cancer resistance protein in drug distribution into brain, CSF and peripheral nerve tissues in rats.

    PubMed

    Huang, Liyue; Li, Xingwen; Roberts, Jonathan; Janosky, Brett; Lin, Min-Hwa Jasmine

    2015-01-01

    1. This study was designed to evaluate how the absence of P-glycoprotein (Pgp, Mdr1a), breast cancer-resistance protein (Bcrp, Abcg2) or both affects drug distribution into sciatic nerves, brain and cerebrospinal fluid (CSF) in rats. 2. Pgp substrate (loperamide), BCRP substrates (dantrolene and proprietary compound X) and dual substrates (imatinib and proprietary compound Y) were well distributed into sciatic nerves with comparable nerve to plasma concentration ratios between wild-type and knockout (KO) rats. 3. Brain exposure increased substantially in Mdr1a(-/-) rats for loperamide and in Mdr1a(-/-)/Abcg2(-/-) rats for imatinib and compound Y, but minimally to modestly in Abcg2(-/-) rats for dantrolene and compound X. The deletion of Mdr1a or Abcg2 alone had little effect on brain distribution of compound Y. 4. While CSF to unbound brain concentration ratio remained ≥3 in the KO animals for dantrolene, compounds X and Y, it was reduced to 1 in the Mdr1a(-/-)/Abcg2(-/-) rats for imatinib. 5. The data indicate that Pgp and Bcrp do not play significant roles in drug distribution into peripheral nerve tissues in rats, while working in concert to regulate brain penetration. Our results further support that CSF concentration may not be a good surrogate for unbound brain concentration of efflux substrates.

  14. Photodynamic characterization and optimization using multifunctional nanoparticles for brain cancer treatment

    NASA Astrophysics Data System (ADS)

    Herrmann, Kristen; Lee Koo, Yong-Eun; Orringer, Daniel A.; Sagher, Oren; Philbert, Martin; Kopelman, Raoul

    2013-03-01

    Photosensitizer-conjugated polyacrylamide nanoparticles were prepared for in vivo characterization of the minimally invasive and localized treatment of photodynamic therapy (PDT) on brain tumors. By incorporating a variety of nanoparticle matrixes, choosing methylene blue as a photosensitizer, and targeting the nanoparticle by the use of F3 peptide we have made nanoparticle-based PDT improvements to current PDT efficiency. Quantitative growth patterns were determined through visual observation of the tumorigenic response to various treatments by the use of an animal cranial window model. PDT treatments with methylene blue-polyacrylamide (MB-PAA) nanoparticles produced significant adjournment of tumor growth over control groups, clearly demonstrating the advantages of nanoparticle-based PDT agents for the eradication of local tumors, leading to the potential palliation of the advancing disease.

  15. Management of Brain Metastases in ALK-Positive Non-Small-Cell Lung Cancer.

    PubMed

    Rusthoven, Chad G; Doebele, Robert C

    2016-08-20

    The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.A 54-year-old man with a former 15-pack-year smoking history presents with cough and dyspnea. Initial work-up with imaging demonstrates a right suprahilar mass measuring 4.7 cm as well as several enlarged hilar and ipsilateral mediastinal lymph nodes. Bronchoscopy with biopsy reveals adenocarcinoma consistent with a lung primary. Staging with positron emission tomography/computed tomography (PET/CT) reidentifies the primary mass and lymph nodes and shows several PET-avid bone metastases. Brain magnetic resonance imaging (MRI) demonstrates a 1.6-cm right parietal mass with mild vasogenic edema and four additional brain metastases measuring 4 to 9 mm in size. Molecular testing is positive for an anaplastic lymphoma kinase (ALK) gene rearrangement using fluorescence in situ hybridization and negative for EGFR, ROS1, RET, BRAF, KRAS, and other oncogenes. The patient denies any neurologic symptoms and has no significant findings on neurologic exam. He is referred to you for management options for newly diagnosed stage IV (T2aN2M1b) lung adenocarcinoma. PMID:27298405

  16. Biological and clinical implications of cancer stem cells in primary brain tumors

    PubMed Central

    Maugeri-Saccà, Marcello; Di Martino, Simona; De Maria, Ruggero

    2013-01-01

    Despite therapeutic advances, glioblastoma multiforme (GBM) remains a lethal disease. The infiltrative nature of this disease and the presence of a cellular population resistant to current medical treatments account for the poor prognosis of these patients. Growing evidence indicates the existence of a fraction of cancer cells sharing the functional properties of adult stem cells, including self-renewal and a greater ability to escape chemo-radiotherapy-induced death stimuli. Therefore, these cells are commonly defined as cancer stem cells (GBM-SCs). The initial GBM-SC concept has been challenged, and refined according to the emerging molecular taxonomy of GBM. This allowed to postulate the existence of multiple CSC types, each one driving a given molecular entity. Furthermore, it is becoming increasingly clear that GBM-SCs thrive through a dynamic and bidirectional interaction with the surrounding microenvironment. In this article, we discuss recent advances in GBM-SC biology, mechanisms through which these cells adapt to hostile conditions, pharmacological strategies for selectively killing GBM-SCs, and how novel CSC-associated endpoints have been investigated in the clinical setting. PMID:23355974

  17. Changing the conversation about brain death.

    PubMed

    Truog, Robert D; Miller, Franklin G

    2014-01-01

    We seek to change the conversation about brain death by highlighting the distinction between brain death as a biological concept versus brain death as a legal status. The fact that brain death does not cohere with any biologically plausible definition of death has been known for decades. Nevertheless, this fact has not threatened the acceptance of brain death as a legal status that permits individuals to be treated as if they are dead. The similarities between "legally dead" and "legally blind" demonstrate how we may legitimately choose bright-line legal definitions that do not cohere with biological reality. Not only does this distinction bring conceptual coherence to the conversation about brain death, but it has practical implications as well. Once brain death is recognized as a social construction not grounded in biological reality, we create the possibility of changing the social construction in ways that may better serve both organ donors and recipients alike. PMID:25046286

  18. Predictors of Individual Tumor Local Control After Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases

    SciTech Connect

    Garsa, Adam A.; Badiyan, Shahed N.; DeWees, Todd; Simpson, Joseph R.; Huang, Jiayi; Drzymala, Robert E.; Barani, Igor J.; Dowling, Joshua L.; Rich, Keith M.; Chicoine, Michael R.; Kim, Albert H.; Leuthardt, Eric C.; Robinson, Clifford G.

    2014-10-01

    Purpose: To evaluate local control rates and predictors of individual tumor local control for brain metastases from non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS). Methods and Materials: Between June 1998 and May 2011, 401 brain metastases in 228 patients were treated with Gamma Knife single-fraction SRS. Local failure was defined as an increase in lesion size after SRS. Local control was estimated using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analysis. Receiver operating characteristic analysis was used to identify an optimal cutpoint for conformality index relative to local control. A P value <.05 was considered statistically significant. Results: Median age was 60 years (range, 27-84 years). There were 66 cerebellar metastases (16%) and 335 supratentorial metastases (84%). The median prescription dose was 20 Gy (range, 14-24 Gy). Median overall survival from time of SRS was 12.1 months. The estimated local control at 12 months was 74%. On multivariate analysis, cerebellar location (hazard ratio [HR] 1.94, P=.009), larger tumor volume (HR 1.09, P<.001), and lower conformality (HR 0.700, P=.044) were significant independent predictors of local failure. Conformality index cutpoints of 1.4-1.9 were predictive of local control, whereas a cutpoint of 1.75 was the most predictive (P=.001). The adjusted Kaplan-Meier 1-year local control for conformality index ≥1.75 was 84% versus 69% for conformality index <1.75, controlling for tumor volume and location. The 1-year adjusted local control for cerebellar lesions was 60%, compared with 77% for supratentorial lesions, controlling for tumor volume and conformality index. Conclusions: Cerebellar tumor location, lower conformality index, and larger tumor volume were significant independent predictors of local failure after SRS for brain metastases from NSCLC. These results warrant further investigation in a prospective

  19. Outcomes and Prognostic Factors in Women With 1 to 3 Breast Cancer Brain Metastases Treated With Definitive Stereotactic Radiosurgery

    SciTech Connect

    Yang, T. Jonathan; Oh, Jung Hun; Folkert, Michael R.; Gupta, Gaorav; Shi, Weiji; Zhang, Zhigang; Morikawa, Aki; Seidman, Andrew; Brennan, Cameron; Yamada, Yoshiya; Chan, Timothy A.; Beal, Kathryn

    2014-11-01

    Background: With the continuing increase in the use of definitive stereotactic radiosurgery (SRS) for patients with limited brain metastases (BM), clinicians need more specific prognostic tools. We investigated clinical predictors of outcomes in patients with limited breast cancer BM treated with SRS alone. Methods and Materials: We identified 136 patients with breast cancer and 1-3 BM who underwent definitive SRS for 186 BM between 2000 and 2012. The Kaplan-Meier method was used to assess overall survival (OS), regional failure (RF), and local failure (LF). Associations between clinical factors and outcomes were tested using Cox regression. A point scoring system was used to stratify patients based on OS, and the predictive power was tested with concordance probability estimate (CPE). Results: The median OS was 17.6 months. The 12-month RF and LF rates were 45% and 10%, respectively. On multivariate analysis, >1 lesion (hazard ratio [HR] = 1.6, P=.02), triple-negative (TN) disease (HR=2.0, P=.006), and active extracranial disease (ED) (HR=2.7, P<.0001) were significantly associated with worse OS. The point score system was defined using proportional simplification of the multivariate Cox proportional hazards regression function. The median OS for patients with 3.0-4.0 points (n=37), 4.5-5.5 points (n=28), 6.0-6.5 points (n=37), and 8-8.5 points (n=34) were 9.2, 15.6, 25.1, and 45.1 months, respectively (P<.0001, CPE = 0.72). Active ED (HR=2.4, P=.0007) was significantly associated with RF. Higher risk for LF was significantly associated with larger BM size (HR=3.1, P=.0001). Conclusion: Patients with >1 BM, active ED, and TN had the highest risk of death after SRS. Active ED is an important prognostic factor for OS and intracranial control.

  20. Susceptibility of juvenile and adult blood–brain barrier to endothelin-1: regulation of P-glycoprotein and breast cancer resistance protein expression and transport activity

    PubMed Central

    2012-01-01

    Background P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) play a critical role in keeping neurotoxic substances from entering the brain. We and others have previously reported an impact of inflammation on the regulation of adult blood–brain barrier (BBB) efflux transporters. However, studies in children have not been done. From the pediatric clinical perspective, it is important to understand how the central nervous system (CNS) and BBB drug efflux transporters differ in childhood from those of adults under normal and inflammatory conditions. Therefore, we examined and compared the regulation of P-gp and BCRP expression and transport activity in young and adult BBB and investigated the molecular mechanisms underlying inflammatory responses. Methods Rats at postnatal day (P) P21 and P84, corresponding to the juvenile and adult stages of human brain maturation, respectively, were treated with endothelin-1 (ET-1) given by the intracerebroventricular (icv) route. Twenty-four hours later, we measured P-gp and BCRP protein expression in isolated brain capillary by immunoblotting as well as by transport activity in vivo by measuring the unbound drug partitioning coefficient of the brain (Kp,uu,brain) of known efflux transporter substrates administered intravenously. Glial activation was measured by immunohistochemistry. The release of cytokines/chemokines (interleukins-1α, 1-β (IL-1β), -6 (IL-6), -10 (IL-10), monocyte chemoattractant protein (MCP-1/CCL2), fractalkine and tissue inhibitor of metalloproteinases-1 (TIMP-1)) were simultaneously measured in brain and serum samples using the Agilent Technology cytokine microarray. Results We found that juvenile and adult BBBs exhibited similar P-gp and BCRP transport activities in the normal physiological conditions. However, long-term exposure of the juvenile brain to low-dose of ET-1 did not change BBB P-gp transport activity but tended to decrease BCRP transport activity in the juvenile brain, while a

  1. In-line phase-contrast and grating-based phase-contrast synchrotron imaging study of brain micrometastasis of breast cancer

    NASA Astrophysics Data System (ADS)

    Huang, Sheng; Kou, Binquan; Chi, Yayun; Xi, Yan; Cao, Yixin; Cui, Wenli; Hu, Xin; Shao, Zhimin; Guo, Han; Fu, Yanan; Xiao, Tiqiao; Sun, Jianqi; Zhao, Jun; Wang, Yujie; Wu, Jiong

    2015-03-01

    Current bio-medical imaging researches aim to detect brain micrometastasis in early stage for its increasing incidence and high mortality rates. Synchrotron phase-contrast imaging techniques, such as in-line phase-contrast (IPC) and grating-based phase-contrast (GPC) imaging, could provide a high spatial and density imaging study of biological specimens' 3D structures. In this study, we demonstrated the detection efficiencies of these two imaging tools on breast cancer micrometastasis in an ex vivo mouse brain. We found that both IPC and GPC can differentiate abnormal brain structures induced by micrometastasis from the surrounding normal tissues. We also found that GPC was more sensitive in detecting the small metastasis as compared to IPC.

  2. Immune factors and viral interactions in brain cancer etiology and outcomes, The 2016 Brain Tumor Epidemiology Consortium Meeting report.

    PubMed

    Johnson, Kimberly J; Hainfellner, Johannes A; Lau, Ching C; Scheurer, Michael E; Woehrer, Adelheid; Wiemels, Joseph

    2016-01-01

    The Brain Tumor Epidemiology Consortium (BTEC) is an international consortium that aims to advance development of multicenter and interdisciplinary collaborations that focus on research related to the etiology, outcomes, and prevention of brain tumors. The 17th annual BTEC meeting was held in Barcelona, Spain on June 21 - 23, 2016. The meeting focused on immune and viral factors that influence brain tumor development. Fundamentals of innate and adaptive immunity were reviewed, the role of immune checkpoint inhibitors in primary and secondary brain tumors was addressed, vaccination strategies for glioma treatment were presented, and the potential contribution of immune dysfunction and viruses tropic for glial cells in gliomagenesis was discussed. Further contributions addressed the risk of non-ionizing radiation, molecular and birth characteristics on brain tumor induction/outcomes, and patterns of care and effects of different treatments on brain tumor survival in the real world setting. The next BTEC meeting will be held in June 2017 in Banff, Canada, and will focus on brain tumor epidemiology in the era of precision medicine.
. PMID:27546018

  3. P-glycoprotein (MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) restrict brain accumulation of the JAK1/2 inhibitor, CYT387.

    PubMed

    Durmus, S; Xu, N; Sparidans, R W; Wagenaar, E; Beijnen, J H; Schinkel, A H

    2013-10-01

    CYT387 is an orally bioavailable, small molecule inhibitor of Janus family of tyrosine kinases (JAK) 1 and 2. It is currently undergoing Phase I/II clinical trials for the treatment of myelofibrosis and myeloproliferative neoplasms. We aimed to establish whether the multidrug efflux transporters P-glycoprotein (P-gp; MDR1; ABCB1) and breast cancer resistance protein (BCRP;ABCG2) restrict oral availability and brain penetration of CYT387. In vitro, CYT387 was efficiently transported by both human MDR1 and BCRP, and very efficiently by mouse Bcrp1 and its transport could be inhibited by specific MDR1 inhibitor, zosuquidar and/or specific BCRP inhibitor, Ko143. CYT387 (10 mg/kg) was orally administered to wild-type (WT), Bcrp1(-/-), Mdr1a/1b(-/-) and Bcrp1;Mdr1a/1b(-/-) mice and plasma and brain concentrations were analyzed. Over 8h, systemic exposure of CYT387 was similar between all the strains, indicating that these transporters do not substantially limit oral availability of CYT387. Despite the similar systemic exposure, brain accumulation of CYT387 was increased 10.5- and 56-fold in the Bcrp1;Mdr1a/1b(-/-) mice compared to the WT strain at 2 and 8h after CYT387 administration, respectively. In single Bcrp1(-/-) mice, brain accumulation of CYT387 was more substantially increased than in Mdr1a/1b(-/-) mice, suggesting that CYT387 is a slightly better substrate of Bcrp1 than of Mdr1a at the blood-brain barrier. These results indicate a marked and additive role of Bcrp1 and Mdr1a/1b in restricting brain penetration of CYT387, potentially limiting efficacy of this compound against brain (micro) metastases positioned behind a functional blood-brain barrier.

  4. Comet 'Bites the Dust' Around Dead Star

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Infrared Spectrometer Graph

    This artist's concept illustrates a comet being torn to shreds around a dead star, or white dwarf, called G29-38. NASA's Spitzer Space Telescope observed a cloud of dust around this white dwarf that may have been generated from this type of comet disruption. The findings suggest that a host of other comet survivors may still orbit in this long-dead solar system.

    The white dwarf G29-38 began life as a star that was about three times as massive as our sun. Its death involved the same steps that the sun will ultimately undergo billions of years from now. According to theory, the G29-38 star became brighter and brighter as it aged, until it bloated up into a dying star called a red giant. This red giant was large enough to engulf and evaporate any terrestrial planets like Earth that happened to be in its way. Later, the red giant shed its outer atmosphere, leaving behind a shrunken skeleton of star, called a white dwarf. If the star did host a planetary system, outer planets akin to Jupiter and Neptune and a remote ring of icy comets would remain.

    The Spitzer observations provide observational evidence for this orbiting outpost of comet survivors. Astronomers speculate that one such comet was knocked into the inner regions of G29-38, possibly by an outer planet. As the comet approached very close to the white dwarf, it may have been torn apart by the star's tidal forces. Eventually, all that would be left of the comet is a disk of dust.

    This illustration shows a comet in the process of being pulverized: part of it still exists as a chain of small clumps, while the rest has already spread out into a dusty disk. Comet Shoemaker-Levy 9 broke apart in a similar fashion when it plunged into Jupiter in 1994. Evidence for Comets Found in Dead Star's Dust The graph of data, or spectrum, from NASA's Spitzer Space Telescope indicates that a dead star, or white dwarf, called G29

  5. Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry.

    PubMed

    Luo, Haiming; Hernandez, Reinier; Hong, Hao; Graves, Stephen A; Yang, Yunan; England, Christopher G; Theuer, Charles P; Nickles, Robert J; Cai, Weibo

    2015-10-13

    Early diagnosis remains a task of upmost importance for reducing cancer morbidity and mortality. Successful development of highly specific companion diagnostics targeting aberrant molecular pathways of cancer is needed for sensitive detection, accurate diagnosis, and opportune therapeutic intervention. Herein, we generated a bispecific immunoconjugate [denoted as Bs-F(ab)2] by linking two antibody Fab fragments, an anti-epidermal growth factor receptor (EGFR) Fab and an anti-CD105 Fab, via bioorthogonal "click" ligation of trans-cyclooctene and tetrazine. PET imaging of mice bearing U87MG (EGFR/CD105(+/+)) tumors with (64)Cu-labeled Bs-F(ab)2 revealed a significantly enhanced tumor uptake [42.9 ± 9.5 percentage injected dose per gram (%ID/g); n = 4] and tumor-to-background ratio (tumor/muscle ratio of 120.2 ± 44.4 at 36 h postinjection; n = 4) compared with each monospecific Fab tracer. Thus, we demonstrated that dual targeting of EGFR and CD105 provides a synergistic improvement on both affinity and specificity of (64)Cu-NOTA-Bs-F(ab)2. (64)Cu-NOTA-Bs-F(ab)2 was able to visualize small U87MG tumor nodules (<5 mm in diameter), owing to high tumor uptake (31.4 ± 10.8%ID/g at 36 h postinjection) and a tumor/muscle ratio of 76.4 ± 52.3, which provided excellent sensitivity for early detection. Finally, we successfully confirmed the feasibility of a ZW800-1-labeled Bs-F(ab)2 for near-infrared fluorescence imaging and image-guided surgical resection of U87MG tumors. More importantly, our rationale can be used in the construction of other disease-targeting bispecific antibody fragments for early detection and diagnosis of small malignant lesions. PMID:26417085

  6. Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry

    PubMed Central

    Luo, Haiming; Hernandez, Reinier; Hong, Hao; Graves, Stephen A.; Yang, Yunan; England, Christopher G.; Theuer, Charles P.; Nickles, Robert J.; Cai, Weibo

    2015-01-01

    Early diagnosis remains a task of upmost importance for reducing cancer morbidity and mortality. Successful development of highly specific companion diagnostics targeting aberrant molecular pathways of cancer is needed for sensitive detection, accurate diagnosis, and opportune therapeutic intervention. Herein, we generated a bispecific immunoconjugate [denoted as Bs-F(ab)2] by linking two antibody Fab fragments, an anti-epidermal growth factor receptor (EGFR) Fab and an anti-CD105 Fab, via bioorthogonal “click” ligation of trans-cyclooctene and tetrazine. PET imaging of mice bearing U87MG (EGFR/CD105+/+) tumors with 64Cu-labeled Bs-F(ab)2 revealed a significantly enhanced tumor uptake [42.9 ± 9.5 percentage injected dose per gram (%ID/g); n = 4] and tumor-to-background ratio (tumor/muscle ratio of 120.2 ± 44.4 at 36 h postinjection; n = 4) compared with each monospecific Fab tracer. Thus, we demonstrated that dual targeting of EGFR and CD105 provides a synergistic improvement on both affinity and specificity of 64Cu-NOTA-Bs-F(ab)2. 64Cu-NOTA-Bs-F(ab)2 was able to visualize small U87MG tumor nodules (<5 mm in diameter), owing to high tumor uptake (31.4 ± 10.8%ID/g at 36 h postinjection) and a tumor/muscle ratio of 76.4 ± 52.3, which provided excellent sensitivity for early detection. Finally, we successfully confirmed the feasibility of a ZW800-1–labeled Bs-F(ab)2 for near-infrared fluorescence imaging and image-guided surgical resection of U87MG tumors. More importantly, our rationale can be used in the construction of other disease-targeting bispecific antibody fragments for early detection and diagnosis of small malignant lesions. PMID:26417085

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

    PubMed

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

    1996-11-27

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

  8. Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases

    PubMed Central

    Hoenerhoff, Mark; Hixon, Julie A.; Durum, Scott K.; Qiu, Ting-hu; He, Siping; Burkett, Sandra; Liu, Zi-Yao; Swanson, Steven M.; Green, Jeffrey E.

    2016-01-01

    Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1)/SV40-T/t-antigen (C3(1)/Tag) mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice) that carry only one copy of the C3(1)/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1)/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1)/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice), but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1)/Tag tumor-derived M6 cell line or individual C3(1)/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1)/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment responses in

  9. The five deadly sins of science publishing

    PubMed Central

    Tracz, Vitek

    2015-01-01

    Science cannot progress without scientists reporting their findings. And yet researchers have given control of this central pillar of the scientific process to science publishers, who are in the business of serving the interests of their journals; these are not always the same as the interests of science. This editorial describes the problems with the process of preparing and publishing research findings, and with judging their veracity and significance, and then explains how we at Faculty of 1000 are starting to tackle the ‘deadly sins’ of science publishing. PMID:26097694

  10. [A case of lycanthropy with deadly violence].

    PubMed

    Bénézech, M; De Witte, J; Etchepare, J J; Bourgeois, M

    1989-01-01

    After a short historical review of the contemporary medical literature, the authors analyze a new and original observation of lycanthropy. He is a 28 years old man, imprisoned for deadly violence, who has been showing, for many years, the belief of being transformed into a werewolf during depersonalization episodes when he presents a lycanthropic behaviour. Our observation is closer to hysteria and mythomania on an antisocial personality, although it seems difficult to place the mental pathology of this alcoholic recidivist delinquent into a nosographical frame.

  11. Laser-Neuron Interaction with Femtosecond Beat-Modulated 800-1200 nm Photon Beams, as the Treatment of Brain Cancer Tissue. Laser Neurophysics

    NASA Astrophysics Data System (ADS)

    Stefan, V. Alexander

    2011-03-01

    I propose a novel mechanism for the brain cancer tissue treatment: nonlinear interaction of ultrashort pulses of beat-photon, (ω1 -- ω2) , or double-photon, (ω1 +ω2) , beams with the cancer tissue. The multiphoton scattering is described via photon diffusion equation. The open-scull cerebral tissue can be irradiated with the beat-modulated photon pulses with the laser irradiances in the range of a few mW/cm2 , and repetition rate of a few 100s Hz generated in the beat-wave driven free electron laser. V. Stefan, B. I. Cohen, and C. Joshi, Nonlinear Mixing of Electromagnetic Waves in PlasmasScience 27 January 1989: V. Alexander Stefan, Genomic Medical Physics: A New Physics in the Making, (S-U-Press, 2008).} This highly accurate cancer tissue ablation removal may prove to be an efficient method for the treatment of brain cancer. Work supported in part by Nikola Tesla Laboratories (Stefan University), La Jolla, CA.

  12. Ethics of Practicing Medical Procedures on Newly Dead and Nearly Dead Patients

    PubMed Central

    Berger, Jeffrey T; Rosner, Fred; Cassell, Eric J

    2002-01-01

    OBJECTIVE To examine the ethical issues raised by physicians performing, for skill development, medically nonindicated invasive medical procedures on newly dead and dying patients. DESIGN Literature review; issue analysis employing current normative ethical obligations, and evaluation against moral rules and utilitarian assessments manifest in other common perimortem practices. RESULTS Practicing medical procedures for training purposes is not uncommon among physicians in training. However, empiric information is limited or absent evaluating the effects of this practice on physician competence and ethics, assessing public attitudes toward practicing medical procedures and requirements for consent, and discerning the effects of a consent requirement on physicians' clinical competence. Despite these informational gaps, there is an obligation to secure consent for training activities on newly and nearly dead patients based on contemporary norms for informed consent and family respect. Paradigms of consent-dependent societal benefits elsewhere in health care support our determination that the benefits from physicians practicing procedures does not justify setting aside the informed consent requirement. CONCLUSION Current ethical norms do not support the practice of using newly and nearly dead patients for training in invasive medical procedures absent prior consent by the patient or contemporaneous surrogate consent. Performing an appropriately consented training procedure is ethically acceptable when done under competent supervision and with appropriate professional decorum. The ethics of training on the newly and nearly dead remains an insufficiently examined area of medical training. PMID:12390553

  13. Asteroid 'Bites the Dust' Around Dead Star

    NASA Technical Reports Server (NTRS)

    2009-01-01

    NASA's Spitzer Space Telescope set its infrared eyes upon the dusty remains of shredded asteroids around several dead stars. This artist's concept illustrates one such dead star, or 'white dwarf,' surrounded by the bits and pieces of a disintegrating asteroid. These observations help astronomers better understand what rocky planets are made of around other stars.

    Asteroids are leftover scraps of planetary material. They form early on in a star's history when planets are forming out of collisions between rocky bodies. When a star like our sun dies, shrinking down to a skeleton of its former self called a white dwarf, its asteroids get jostled about. If one of these asteroids gets too close to the white dwarf, the white dwarf's gravity will chew the asteroid up, leaving a cloud of dust.

    Spitzer's infrared detectors can see these dusty clouds and their various constituents. So far, the telescope has identified silicate minerals in the clouds polluting eight white dwarfs. Because silicates are common in our Earth's crust, the results suggest that planets similar to ours might be common around other stars.

  14. Whole brain radiotherapy plus simultaneous in-field boost with image guided intensity-modulated radiotherapy for brain metastases of non-small cell lung cancer

    PubMed Central

    2014-01-01

    Background Whole brain radiotherapy (WBRT) plus sequential focal radiation boost is a commonly used therapeutic strategy for patients with brain metastases. However, recent reports on WBRT plus simultaneous in-field boost (SIB) also showed promising outcomes. The objective of present study is to retrospectively evaluate the efficacy and toxicities of WBRT plus SIB with image guided intensity-modulated radiotherapy (IG-IMRT) for inoperable brain metastases of NSCLC. Methods Twenty-nine NSCLC patients with 87 inoperable brain metastases were included in this retrospective study. All patients received WBRT at a dose of 40 Gy/20 f, and SIB boost with IG-IMRT at a dose of 20 Gy/5 f concurrent with WBRT in the fourth week. Prior to each fraction of IG-IMRT boost, on-line positioning verification and correction were used to ensure that the set-up errors were within 2 mm by cone beam computed tomography in all patients. Results The one-year intracranial control rate, local brain failure rate, and distant brain failure rate were 62.9%, 13.8%, and 19.2%, respectively. The two-year intracranial control rate, local brain failure rate, and distant brain failure rate were 42.5%, 30.9%, and 36.4%, respectively. Both median intracranial progression-free survival and median survival were 10 months. Six-month, one-year, and two-year survival rates were 65.5%, 41.4%, and 13.8%, corresponding to 62.1%, 41.4%, and 10.3% of intracranial progression-free survival rates. Patients with Score Index for Radiosurgery in Brain Metastases (SIR) >5, number of intracranial lesions <3, and history of EGFR-TKI treatment had better survival. Three lesions (3.45%) demonstrated radiation necrosis after radiotherapy. Grades 2 and 3 cognitive impairment with grade 2 radiation leukoencephalopathy were observed in 4 (13.8%) and 4 (13.8%) patients. No dosimetric parameters were found to be associated with these late toxicities. Patients received EGFR-TKI treatment had higher incidence of grades 2–3

  15. Gender, Race, and Survival: A Study in Non-Small-Cell Lung Cancer Brain Metastases Patients Utilizing the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification

    SciTech Connect

    Videtic, Gregory M.M.; Reddy, Chandana A.; Chao, Samuel T.; Rice, Thomas W.; Adelstein, David J.; Barnett, Gene H.; Mekhail, Tarek M.; Vogelbaum, Michael A.; Suh, John H.

    2009-11-15

    Purpose: To explore whether gender and race influence survival in non-small-cell lung cancer (NSCLC) in patients with brain metastases, using our large single-institution brain tumor database and the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) brain metastases classification. Methods and materials: A retrospective review of a single-institution brain metastasis database for the interval January 1982 to September 2004 yielded 835 NSCLC patients with brain metastases for analysis. Patient subsets based on combinations of gender, race, and RPA class were then analyzed for survival differences. Results: Median follow-up was 5.4 months (range, 0-122.9 months). There were 485 male patients (M) (58.4%) and 346 female patients (F) (41.6%). Of the 828 evaluable patients (99%), 143 (17%) were black/African American (B) and 685 (83%) were white/Caucasian (W). Median survival time (MST) from time of brain metastasis diagnosis for all patients was 5.8 months. Median survival time by gender (F vs. M) and race (W vs. B) was 6.3 months vs. 5.5 months (p = 0.013) and 6.0 months vs. 5.2 months (p = 0.08), respectively. For patients stratified by RPA class, gender, and race, MST significantly favored BFs over BMs in Class II: 11.2 months vs. 4.6 months (p = 0.021). On multivariable analysis, significant variables were gender (p = 0.041, relative risk [RR] 0.83) and RPA class (p < 0.0001, RR 0.28 for I vs. III; p < 0.0001, RR 0.51 for II vs. III) but not race. Conclusions: Gender significantly influences NSCLC brain metastasis survival. Race trended to significance in overall survival but was not significant on multivariable analysis. Multivariable analysis identified gender and RPA classification as significant variables with respect to survival.

  16. Photographic Study Of A Dead-Pressed Explosive

    NASA Astrophysics Data System (ADS)

    Swallowe, G. M.; Field, J. E.

    1983-03-01

    High speed photography in conjunction with electron microscopy and a pressure measuring technique have been used to investigate the differences between dead-pressed and non-dead-pressed samples of the primary explosive Mercury Fulminate (Hg Ful). Photographs of reaction propagation were taken in transmitted light using a specially adapted drop-weight machine with transparent anvils. The results of these experiments suggested a mechanism for dead-pressing in Hg Ful based on the microscopic internal structure of the compacted explosive.

  17. Drugs Approved for Brain Tumors

    MedlinePlus

    ... Ask about Your Treatment Research Drugs Approved for Brain Tumors This page lists cancer drugs approved by ... that are not listed here. Drugs Approved for Brain Tumors Afinitor (Everolimus) Afinitor Disperz (Everolimus) Avastin (Bevacizumab) ...

  18. The proinflammatory peptide substance P promotes blood-brain barrier breaching by breast cancer cells through changes in microvascular endothelial cell tight junctions.

    PubMed

    Rodriguez, Pedro L; Jiang, Shuxian; Fu, Yigong; Avraham, Shalom; Avraham, Hava Karsenty

    2014-03-01

    Neuropeptide substance P (SP) has been implicated in inflammation, pain, depression and breast cancer cell (BCC) growth. Here, we examined the role of SP in trafficking of BCCs (human MDA-MB-231 and MDA-MB-231BrM2 cells) across the blood-brain barrier (BBB) and brain microvascular endothelial cells (BMECs) using in vitro and in vivo models. SP was secreted from BCCs and mediated adhesion and transmigration of BCCs across human BMECs (HBMECs) in vitro. SP induced activation of HBMECs, leading to secretion of Tumor Necrosis Factor alpha (TNF-α) and angiopoietin-2 (Ang-2) from HBMECs, resulting in changes in localization and distribution of tight junction (TJ) ZO-1 (tight junction protein zonula occludins-1) and claudin-5 structures as well as increased permeability of HBMECs. Using spontaneous breast cancer metastasis mouse model (syngeneic) of GFP-4T1-BrM5 mammary tumor cells administered into mammary fat pads of Balb/c mice, SP inhibitor spantide III inhibited in vivo changes in permeability of the BBB and BMEC-TJs ZO-1 and claudin-5 structures as well as decreased tumor cell colonization in brain. Thus, SP secreted from BCCs induces transmigration of BCCs across the BBB, leading to activation of BMECs and secretion of TNF-α and Ang-2, resulting in BBB impairment and colonization of tumor cells in brain. Therefore, therapies based on SP inhibition in combination with other therapies may prevent breaching of the BBB by BCCs and their colonization in brain.

  19. Brain derived metastatic prostate cancer DU-145 cells are effectively inhibited in vitro by guava (Psidium gujava L.) leaf extracts.

    PubMed

    Chen, Kuan-Chou; Hsieh, Chiu-Lan; Peng, Chiung-Chi; Hsieh-Li, Hsiu-Mei; Chiang, Han-Sun; Huang, Kuan-Dar; Peng, Robert Y

    2007-01-01

    The aqueous extract of Psidium guajava L. (PE) inhibited the cancer cell DU-145 in a dose- and time-dependent manner. At 1.0 mg/mL, PE reduced the viability of PCa DU-145 (the androgen independent PCa cells) to 36.1 and 3.59%, respectively after 48 h and 72 h of incubations. The absolute cell viability suppressing capability (VSC)(AC) could reach 262.5 cells-mL-h/mg on exposure to PE for 72 h, corresponding to the safe ranges, i.e. the percent viability suppressing rates (PVSR) of 2.72 and 2.41 folds for DU-145 comparing to PZ-HPV-7 cells when treated with PE at 0.5 and 1.0 mg/mL respectively for 72 h. In addition, the colony forming capability of DU-145 cells was apparently lowered. The suppressing rates of which reached 8.09 and 5.96 colony/mg/day for D-145 and PZ-HPV-7 cells, respectively within the concentration range of PE at 0.1 asymptotically equal to 0.25 mg/mL. Cell cycle arrests at G0/G1 phase in both cells were observed by TUNEL assay and flow cytometric analysis, yet more prominently evident in DU-145. In addition, suppression of the matrix metalloproteinases MMP-2 and MMP-9, and the upregulation of active caspase-3 at 0.10 to 1.0 mg/mL in DU-145 were also effected in a dose-dependent manner by PE at 0.25 to 1.0 mg/mL, implicating a potent anti-metastasis power of PE. Conclusively, we ascribe the anticancer activity of PE to its extraordinarily high polyphenolic (165.61 +/- 10.39 mg/g) and flavonoid (82.85 +/- 0.22 mg/g) contents. Furthermore, PE might be useful for treatment of brain derived metastatic cancers such as DU-145, acting simultaneously as both a chemopreventive and a chemotherapeutic.

  20. Turbulence, Transport, and Waves in Ohmic Dead Zones

    NASA Astrophysics Data System (ADS)

    Gole, Daniel; Simon, Jacob B.; Lubow, Stephen H.; Armitage, Philip J.

    2016-07-01

    We use local numerical simulations to study a vertically stratified accretion disk with a resistive mid-plane that damps magnetohydrodynamic (MHD) turbulence. This is an idealized model for the dead zones that may be present at some radii in protoplanetary and dwarf novae disks. We vary the relative thickness of the dead and active zones to quantify how forced fluid motions in the dead zone change. We find that the residual Reynolds stress near the mid-plane decreases with increasing dead zone thickness, becoming negligible in cases where the active to dead mass ratio is less than a few percent. This implies that purely Ohmic dead zones would be vulnerable to episodic accretion outbursts via the mechanism of Martin & Lubow. We show that even thick dead zones support a large amount of kinetic energy, but this energy is largely in fluid motions that are inefficient at angular momentum transport. Confirming results from Oishi & Mac Low, the perturbed velocity field in the dead zone is dominated by an oscillatory, vertically extended circulation pattern with a low frequency compared to the orbital frequency. This disturbance has the properties predicted for the lowest order r mode in a hydrodynamic disk. We suggest that in a global disk similar excitations would lead to propagating waves, whose properties would vary with the thickness of the dead zone and the nature of the perturbations (isothermal or adiabatic). Flows with similar amplitudes would buckle settled particle layers and could reduce the efficiency of pebble accretion.

  1. The ecosystem service value of living versus dead biogenic reef

    NASA Astrophysics Data System (ADS)

    Sheehan, E. V.; Bridger, D.; Attrill, M. J.

    2015-03-01

    Mixed maerl beds (corralline red algae) comprise dead thalli with varying amounts of live maerl fragments, but previously it was not known whether the presence of the live maerl increases the ecosystem service 'habitat provision' of the dead maerl for the associated epibenthos. A 'flying array' towed sled with high definition video was used to film transects of the epibenthos in dead maerl and mixed maerl beds in two locations to the north and south of the English Channel (Falmouth and Jersey). Mixed maerl beds supported greater number of taxa and abundance than dead beds in Falmouth, while in Jersey, mixed and dead beds supported similar number of taxa and dead beds had a greater abundance of epifauna. Scallops tended to be more abundant on mixed beds than dead beds. Tube worms were more abundant on mixed beds in Falmouth and dead beds in Jersey. An increasing percentage occurrence of live maerl thalli correlated with increasing number of taxa in Falmouth but not Jersey. It was concluded that while live thalli can increase the functional role of dead maerl beds for the epibenthos, this is dependent on location and response variable. As a result of this work, maerl habitat in SE Jersey has been protected from towed demersal fishing gear.

  2. A Phase 3 Trial of Whole Brain Radiation Therapy and Stereotactic Radiosurgery Alone Versus WBRT and SRS With Temozolomide or Erlotinib for Non-Small Cell Lung Cancer and 1 to 3 Brain Metastases: Radiation Therapy Oncology Group 0320

    SciTech Connect

    Sperduto, Paul W.; Wang, Meihua; Robins, H. Ian; Schell, Michael C.; Werner-Wasik, Maria; Komaki, Ritsuko; Souhami, Luis; Buyyounouski, Mark K.; Khuntia, Deepak; Demas, William; Shah, Sunjay A.; Nedzi, Lucien A.; Perry, Gad; Suh, John H.; Mehta, Minesh P.

    2013-04-01

    Background: A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS. Methods and Materials: NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy × 15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m{sup 2}/day × 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150-200 mg/m{sup 2}/day × 5 days/month) could be continued for as long as 6 months after WBRT + SRS. The primary endpoint was OS. Results: After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT + SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001). Conclusion: The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms.

  3. Cancer

    MedlinePlus

    ... your life Being exposed to chemicals that can cause cancer Being at risk for skin cancer Depending on ... than nonsmokers. Other forms of tobacco can also cause cancer, such as cigars, chewing tobacco and snuff. If ...

  4. Stacking denoising auto-encoders in a deep network to segment the brainstem on MRI in brain cancer patients: A clinical study.

    PubMed

    Dolz, Jose; Betrouni, Nacim; Quidet, Mathilde; Kharroubi, Dris; Leroy, Henri A; Reyns, Nicolas; Massoptier, Laurent; Vermandel, Maximilien

    2016-09-01

    Delineation of organs at risk (OARs) is a crucial step in surgical and treatment planning in brain cancer, where precise OARs volume delineation is required. However, this task is still often manually performed, which is time-consuming and prone to observer variability. To tackle these issues a deep learning approach based on stacking denoising auto-encoders has been proposed to segment the brainstem on magnetic resonance images in brain cancer context. Additionally to classical features used in machine learning to segment brain structures, two new features are suggested. Four experts participated in this study by segmenting the brainstem on 9 patients who underwent radiosurgery. Analysis of variance on shape and volume similarity metrics indicated that there were significant differences (p<0.05) between the groups of manual annotations and automatic segmentations. Experimental evaluation also showed an overlapping higher than 90% with respect to the ground truth. These results are comparable, and often higher, to those of the state of the art segmentation methods but with a considerably reduction of the segmentation time. PMID:27236370

  5. HIV and Tuberculosis: a Deadly Human Syndemic

    PubMed Central

    Kwan, Candice K.; Ernst, Joel D.

    2011-01-01

    Summary: A syndemic is defined as the convergence of two or more diseases that act synergistically to magnify the burden of disease. The intersection and syndemic interaction between the human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics have had deadly consequences around the world. Without adequate control of the TB-HIV syndemic, the long-term TB elimination target set for 2050 will not be reached. There is an urgent need for additional resources and novel approaches for the diagnosis, treatment, and prevention of both HIV and TB. Moreover, multidisciplinary approaches that consider HIV and TB together, rather than as separate problems and diseases, will be necessary to prevent further worsening of the HIV-TB syndemic. This review examines current knowledge of the state and impact of the HIV-TB syndemic and reviews the epidemiological, clinical, cellular, and molecular interactions between HIV and TB. PMID:21482729

  6. Lighting up a Dead Star's Layers

    NASA Technical Reports Server (NTRS)

    2006-01-01

    This image from NASA's Spitzer Space Telescope shows the scattered remains of an exploded star named Cassiopeia A. Spitzer's infrared detectors 'picked' through these remains and found that much of the star's original layering had been preserved.

    In this false-color image, the faint, blue glow surrounding the dead star is material that was energized by a shock wave, called the forward shock, which was created when the star blew up. The forward shock is now located at the outer edge of the blue glow. Stars are also seen in blue. Green, yellow and red primarily represent material that was ejected in the explosion and heated by a slower shock wave, called the reverse shock wave.

    The picture was taken by Spitzer's infrared array camera and is a composite of 3.6-micron light (blue); 4.5-micron light (green); and 8.0-micron light (red).

  7. N-Terminal Pro-Brain Natriuretic Peptide Is Associated with a Future Diagnosis of Cancer in Patients with Coronary Artery Disease

    PubMed Central

    Tarín, Nieves; Cristóbal, Carmen; Lorenzo, Óscar; Blanco-Colio, Luis; Martín-Ventura, José Luis; Huelmos, Ana; Alonso, Joaquín; Aceña, Álvaro; Pello, Ana; Carda, Rocío; Asensio, Dolores; Mahíllo-Fernández, Ignacio; López Bescós, Lorenzo; Egido, Jesús; Farré, Jerónimo

    2015-01-01

    Objective Several papers have reported elevated plasma levels of natriuretic peptides in patients with a previous diagnosis of cancer. We have explored whether N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels predict a future diagnosis of cancer in patients with coronary artery disease (CAD). Methods We studied 699 patients with CAD free of cancer. At baseline, NT-proBNP, galectin-3, monocyte chemoattractant protein-1, soluble tumor necrosis factor-like weak inducer of apoptosis, high-sensitivity C-reactive protein, and high-sensitivity cardiac troponin I plasma levels were assessed. The primary outcome was new cancer diagnosis. The secondary outcome was cancer diagnosis, heart failure requiring hospitalization, or death. Results After 2.15±0.98 years of follow-up, 24 patients developed cancer. They were older (68.5 [61.5, 75.8] vs 60.0 [52.0, 72.0] years; p=0.011), had higher NT-proBNP (302.0 [134.8, 919.8] vs 165.5 [87.4, 407.5] pg/ml; p=0.040) and high-sensitivity C-reactive protein (3.27 [1.33, 5.94] vs 1.92 [0.83, 4.00] mg/L; p=0.030), and lower triglyceride (92.5 [70.5, 132.8] vs 112.0 [82.0, 157.0] mg/dl; p=0.044) plasma levels than those without cancer. NT-proBNP (Hazard Ratio [HR]=1.030; 95% Confidence Interval [CI]=1.008-1.053; p=0.007) and triglyceride levels (HR=0.987; 95%CI=0.975-0.998; p=0.024) were independent predictors of a new cancer diagnosis (multivariate Cox regression analysis). When patients in whom the suspicion of cancer appeared in the first one-hundred days after blood extraction were excluded, NT-proBNP was the only predictor of cancer (HR=1.061; 95%CI=1.034-1.088; p<0.001). NT-proBNP was an independent predictor of cancer, heart failure, or death (HR=1.038; 95%CI=1.023-1.052; p<0.001) along with age, and use of insulin and acenocumarol. Conclusions NT-proBNP is an independent predictor of malignancies in patients with CAD. New studies in large populations are needed to confirm these findings. PMID:26046344

  8. Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke

    PubMed Central

    Van Kanegan, Michael J.; Dunn, Denise E.; Kaltenbach, Linda S.; Shah, Bijal; He, Dong Ning; McCoy, Daniel D.; Yang, Peiying; Peng, Jiangnan; Shen, Li; Du, Lin; Cichewicz, Robert H.; Newman, Robert A.; Lo, Donald C.

    2016-01-01

    We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0–4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0–4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer’s disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD. PMID:27172999

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2016-04-01

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