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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. Preservation of organs from brain dead donors with hyperbaric oxygen.

    PubMed

    Bayrakci, Benan

    2008-08-01

    Hyperbaric oxygen therapy is a technology that involves oxygen treatment at supra-atmospheric pressures in high concentrations, generating increased levels of physically dissolved oxygen in blood plasma. This form of transported oxygen, compared with oxygen chemically bound to hemoglobin, is able to enter tissues with minimal or almost no blood flow. Experimental studies have suggested that hyperoxemia provided by hyperbaric oxygen may be beneficial in the treatment of reperfusion injury. Organs procured from brain-dead hyperbaric oxygen-treated donors may have less cellular injury from ischemia, reperfusion, and no-reflow phenomenon, thus yielding organs in an optimized state for transplantation. This current report consists of a gratifying experience about hyperbaric oxygen treatment playing a possible role on preservation of donor organs in vivo. In the siblings reported here, improved organ function prior to transplantation and the successful organ functioning after transplantation suggests the possible beneficial effect of hyperbaric oxygen treatment on the ischemic insult generated from brain death and repetitive cardiac arrests. Hyperbaric oxygen seems to be a promising candidate as a bridge to transplantation, keeping the donated organs viable until the harvesting procedure can take place for potential brain dead donors. This experience may lead to further investigations on hyperbaric oxygen's role in donor organ preservation. PMID:18672481

  3. Role of brain death and the dead-donor rule in the ethics of organ transplantation.

    PubMed

    Truog, Robert D; Robinson, Walter M

    2003-09-01

    The "dead-donor rule" requires patients to be declared dead before the removal of life-sustaining organs for transplantation. The concept of brain death was developed, in part, to allow patients with devastating neurologic injury to be declared dead before the occurrence of cardiopulmonary arrest. Brain death is essential to current practices of organ retrieval because it legitimates organ removal from bodies that continue to have circulation and respiration, thereby avoiding ischemic injury to the organs. The concept of brain death has long been recognized, however, to be plagued with serious inconsistencies and contradictions. Indeed, the concept fails to correspond to any coherent biological or philosophical understanding of death. We review the evidence and arguments that expose these problems and present an alternative ethical framework to guide the procurement of transplantable organs. This alternative is based not on brain death and the dead-donor rule, but on the ethical principles of nonmaleficence (the duty not to harm, or primum non nocere) and respect for persons. We propose that individuals who desire to donate their organs and who are either neurologically devastated or imminently dying should be allowed to donate their organs, without first being declared dead. Advantages of this approach are that (unlike the dead-donor rule) it focuses on the most salient ethical issues at stake, and (unlike the concept of brain death) it avoids conceptual confusion and inconsistencies. Finally, we point out parallel developments, both domestically and abroad, that reflect both implicit and explicit support for our proposal. PMID:14501972

  4. 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

  5. Intensive care nurses' experiences of caring for brain dead organ donor patients.

    PubMed

    Pearson, A; Robertson-Malt, S; Walsh, K; Fitzgerald, M

    2001-01-01

    This study was designed to identify the feelings and experiences of critical care nurses who have been involved in nursing brain dead patients prior to organ donation. The purpose of the study was to generate knowledge which informs the discipline of nursing. A number of themes relating to nurses' experiences of caring for brain dead organ donor patients were uncovered in this interpretative study. Overall, caring for patients who are diagnosed as brain dead is a challenging experience for nurses and they are intensely involved in a search for meaning in each event. The interpretative analysis in this study has revealed a range of meanings articulated by the nurses involved. However, the primary focus of care--as identified by the participating nurses--was the donor family. PMID:11820230

  6. 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

  7. 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

  8. Changes in the organ procurement system in South Korea: effects on brain-dead donor numbers.

    PubMed

    Lee, S D; Kim, J H

    2009-11-01

    In Korea, the Organ Transplantation Act came into effect in 2000, establishing the Korean Network for Organ Sharing (KONOS) with centralized authority for organ procurement as well as for approval of donors and recipients to ensure fair organ allocation. However, the number of brain-dead donors decreased sharply, and the organ allocation system proved inefficient. The government revised the Organ Transplantation Act in August 2002, introducing an incentive system. If a transplantation hospital formed a Committee for Brain Death Evaluation and a Hospital Organ Procurement Organization, it could receive a kidney from a brain dead-donor as an incentive to foster organ procurement regardless of the KONOS wait list. The government also launched a pilot brain-dead donor registry program to strengthen Hospital Organ Procurement Organization activity. If local hospitals collaborated with specialized hospitals in organ procurement, local hospitals obtained financial incentives. But because the organ shortage problem has not been resolved, the government has proposed four initiatives: first, broadening the incentive system, which makes it possible to give each specialized hospital a choice of one of eight organs from each donor as an incentive; second, development of an Independent Organ Procurement Organization; third introduction of an opt-out system; and last, improvement of the Committee for Brain Death Evaluation system. It is uncertain which initiatives will be adopted, but changes in organ procurement systems are nonetheless considered a key to solve the organ shortage problem in Korea. PMID:19917342

  9. The Ethics of Continued Life-Sustaining Treatment for those Diagnosed as Brain-dead.

    PubMed

    du Toit, Jessica; Miller, Franklin

    2016-03-01

    Given the long-standing controversy about whether the brain-dead should be considered alive in an irreversible coma or dead despite displaying apparent signs of life, the ethical and policy issues posed when family members insist on continued treatment are not as simple as commentators have claimed. In this article, we consider the kind of policy that should be adopted to manage a family's insistence that their brain-dead loved one continues to receive supportive care. We argue that while it would be ethically inappropriate to continue to devote scarce acute care resources to such patients in a hospital setting, it may not be ethically inappropriate for patients to receive these resources in certain other settings. Thus, if a family insists on continuing to care for their brain-dead loved at their home, we should not, from a policy perspective, interfere with the family's wishes. We also argue that healthcare professionals should make some effort to facilitate the transfer of brain-dead patients to these other settings when families insist on continued treatment despite being informed about the lack of any potential for recovery of consciousness. Our arguments are strengthened by the fact that patients in a persistent vegetative state, who, when correctly diagnosed, also have no potential for recovery of consciousness, are routinely transferred from hospitals to nursing homes or long-term care facilities where they continue to be ventilated, tube fed and to receive other supportive care. We also briefly explore the question of who should be responsible for the costs of such treatment at the long-term care facility. PMID:26183857

  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. 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

  12. Cancer around the brain

    PubMed Central

    Grisold, Wolfgang; Grisold, Anna

    2014-01-01

    Background Neuro-oncologists are familiar with primary brain tumors, intracerebral metastases meningeal carcinomatosis and extracerebral intracranial tumors as meningeoma. For these conditions, and also some other rare tumor entities several treatment options exist. Cancer can also involve structures around the brain as the dura, the base of the skull, the cavities of the skull and tissue around the bony skull, the skin, the tissue of the neck. and either compress, invade or spread in the central or peripheral nervous system. Methods A systematic literature research was conducted determining symptoms and signs, tumor sites of nerve invasion, tumor types, diagnostic techniques, mechanisms of nerve invasion, and important differential diagnosis. Additional cases from own experience were added for illustration. Results The mechanisms of tumor invasion of cranial nerves is heterogenous and not only involves several types of invasion, but also spread along the cranial nerves in antero- and retrograde fashion and even spread into different nerve territories via anastomosis. In addition the concept of angiosomas may have an influence on the spread of metastases. Conclusion In addition to the well described tumor spread in meningeal carcinomatosis and base of the skull metastases, dural spread, lesions of the bony skull, the cavities of the skull and skin of the face and tissue of the neck region need to be considered, and have an impact on therapeutic decisions. PMID:26034610

  13. Thyroid hormone therapy and procurement of livers from brain-dead donors.

    PubMed

    Novitzky, Dimitri; Mi, Zhibao; Videla, Luis A; Collins, Joseph F; Cooper, David K C

    2016-08-01

    Hormonal therapy to brain-dead potential organ donors remains controversial. A retrospective study was carried out of hormonal therapy on procurement of organs in 63,593 donors in whom information on T3/T4 therapy was available. In 40,124 donors, T3/T4 and all other hormonal therapy was recorded. The percentages of all organs procured, except livers, were greater in T3/T4-treated donors. Nevertheless, if T3/T4 therapy had been administered to the donor, liver transplantation was associated with significantly increased graft and recipient survival at 1 month and 12 months. The potential reasons for the lack of effect of T3/T4 therapy on the number of livers procured are discussed. PMID:26853445

  14. Hemodynamic and metabolic efficacy of dopamine versus norepinephrine in a brain-dead swine model.

    PubMed

    Zaky, Ahmed; Pretto, Ernesto A; Earle, Steven A; Piraccini, Emanuele; Zuccarelli, Jennifer E; Arheart, Kristopher L; Proctor, Kenneth G

    2008-09-01

    We tested the hypothesis that hepatosplanchnic and systemic hemodynamics are improved with equi-effective doses of dopamine (DA) versus norepinephrine (NE) in a brain-dead swine model. Pigs (n = 18) were anesthetized and ventilated. Brain death was induced by epidural balloon inflation, hypoventilation, and hypoxia. After 30 minutes, mechanical ventilation was restored without anesthesia. During 60 and until 480 minutes, half received DA (10 microg/kg/minute) and half received NE (0.1 microg/kg/minute) titrated to a mean arterial pressure (MAP) > 60 mm Hg with supplemental fluid to maintain a central venous pressure > 8 mm Hg. Hemodynamics, hepatic laser Doppler blood flow, and hepatic and gastric tissue oxygenation with near-infrared spectroscopy were continuously monitored. Serial blood samples were analyzed for blood gases and electrolytes, coagulation changes, and serum chemistries. Balloon inflation caused brain death and autonomic storm, and 8 of 18 were nonsurvivors. After 30 minutes, the MAP, mixed venous O(2) saturation, and partial pressure of arterial oxygen values decreased to 37 +/- 2 mm Hg, 38 +/- 4, and 49 +/- 8 mm Hg, respectively. Serum lactate increased to 5.4 +/- 0.7 mM. Among survivors (n = 10), MAP stabilized with either pressor. Urine output was maintained (>1 mL/kg/hour), but creatinine increased >30% with respect to the baseline. Tachyphylaxis developed with NE but not with DA (P < 0.05). Cardiac index was higher with DA versus NE (P < 0.05). There were no differences in stroke volume, metabolic indices, or liver blood flow. Liver tissue O(2) was higher with DA versus NE at 8 hours (P < 0.05). Coagulation tests and liver enzymes were similar with NE versus DA (P > 0.05). In conclusion, after brain death, cardiac index and hepatic oxygenation were significantly improved with equi-effective doses of DA versus NE. PMID:18756452

  15. Inhalational anesthesia for organ procurement: potential indications for administering inhalational anesthesia in the brain-dead organ donor.

    PubMed

    Elkins, Laurie J

    2010-08-01

    Organs needed for transplantation far outweigh their availability. There is minimal research regarding perioperative care of the brain-dead organ donor during the procurement procedure. Current research attributes a great deal of organ damage to autonomic or sympathetic storm that occurs during brain death. Literature searches were performed with the terms brain death, organ donor, organ procurement, anesthesia and organ donor, anesthesia and brain death, anesthesia and organ procurement, inhalational anesthetics and organ procurement, and inhalational anesthetics and brain dead. Additional resources were obtained from reference lists of published articles. The literature review showed there is a lack of published studies researching the use of inhalational anesthetics in organ procurement. No studies have been published evaluating the effect of preconditioning with inhalational agents (administering 1.3 minimal alveolar concentration of an inhalational agent for the 20 minutes before periods of ischemia) in the brain-dead organ donor population. Further studies are required to determine if administration of inhalational anesthetics reduces catecholamine release occurring with surgical stimulation during the organ procurement procedure and whether this technique increases viability of transplanted organs. Anesthetic preconditioning before the ischemic period may reduce ischemia-reperfusion injury in transplanted organs, further increasing viability of transplanted organs. PMID:20879630

  16. 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

  17. 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

  18. 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

  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. Cardio-pulmonary resuscitation of brain-dead organ donors: a literature review and suggestions for practice.

    PubMed

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

    2016-01-01

    "Organ preserving cardiopulmonary resuscitation (OP-CPR)" is defined as the use of CPR in cases of cardiac arrest to preserve organs for transplantation, rather than to revive the patient. Is it ethical to provide OP-CPR in a brain-dead organ donor to save organs that would otherwise be lost? To answer this question, we review the literature on brain-dead organ donors, conduct an ethical analysis, and make recommendations. We conclude that OP-CPR can benefit patients and families by fulfilling the wish to donate. However, it is an aggressive procedure that can cause physical damage to patients, and risks psychological harm to families and healthcare professionals. In a brain-dead organ donor, OP-CPR is acceptable without specific informed consent to OP-CPR, although advance discussion with next of kin regarding this possibility is strongly advised. In a patient where brain death is yet to be determined, but there is known wish for organ donation, OP-CPR would only be acceptable with a specific informed consent from the next of kin. When futility of treatment has not been established or it is as yet unknown if the patient wished to be an organ donor then OP-CPR should be prohibited, in order to avoid any conflict of interest. PMID:26073934

  1. The effects of the hypothermic management of brain dead dogs on preserving graft viability in heart transplantation.

    PubMed

    Ichikawa, H; Sakata, K; Takahashi, T; Ogiwara, H; Otaki, A; Ishikawa, S; Morishita, Y

    1998-02-01

    The effect of hypothermic management for brain dead dogs on preserving graft viability was evaluated through preservation and transplantation. After the occurrence of brain death, 43 dogs were divided into two groups; the normothermic group (37.2+/-0.3 degrees C) and the hypothermic group (31.8+/-0.3 degrees C) according to the esophageal temperature. After the 6-hour management of brain dead donors, the heart beat was arrested using a cardioplegic solution followed by coronary vascular bed washout. The donor heart was then harvested and preserved for 12 hours with simple immersion into the University of Wisconsin solution. Following preservation, orthotopic transplantation was performed in six grafts randomly selected from each group. During the 6-hour management of brain dead dogs; 1) heart rates, rate-pressure products, and the total amount of catecholamine were significantly (p<0.05) lower in the hypothermic group than in the normothermic group, and 2) lactate contents collected from the coronary sinus blood and O2-extraction rates of the heart tended to be lower in the hypothermic group than in the normothermic group. During 12 hours of preservation, intracellular pH and creatine phosphate contents were higher in the hypothermic group than in the normothermic group. Following orthotopic transplantation, the animals in the hypothermic group showed a significantly (p<0.05) higher recovery rate of left ventricular (LV) pressure and the maximum rate of the rise of LV pressure compared with normothermic group animals. We conclude that the hypothermic management of brain dead dogs may be effective in preserving graft viability and may provide a clinical application for heart transplantation with acceptable outcomes. PMID:9537536

  2. Hormone resuscitation therapy for brain-dead donors - is insulin beneficial or detrimental?

    PubMed

    Novitzky, Dimitri; Mi, Zhibao; Videla, Luis A; Collins, Joseph F; Cooper, David K C

    2016-07-01

    Hormonal replacement therapy to brain-dead potential organ donors remains controversial. A retrospective study was carried out of hormonal therapy on procurement of organs in 63 593 donors in whom information on thyroid hormone therapy (triiodothyronine or levothyroxine [T3 /T4 ]) was available. In 40 124 donors, T3 /T4 and all other hormonal therapy were recorded. The percentage of all organs procured, except livers, was greater when T3 /T4 had been administered. An independent beneficial effect of antidiuretic hormone (ADH) was also clear. Corticosteroids were less consistently beneficial (most frequently when T3 /T4 had not been administered), although never detrimental. Insulin was almost never beneficial and at times was associated with a reduced yield of organs, particularly of the pancreas and intestine, an observation that does not appear to have been reported previously. In addition, there was reduced survival at 12 months of recipients of pancreases from T3 /T4 -treated donors, but not of pancreas grafts. The possibly detrimental effect observed following insulin therapy is discussed. PMID:27037748

  3. 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

  4. 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

  5. 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

  6. DNA From Dead Cancer Cells Induces TLR9-Mediated Invasion and Inflammation In Living Cancer Cells

    PubMed Central

    Tuomela, Johanna; Sandholm, Jouko; Kaakinen, Mika; Patel, Ankita; Kauppila, Joonas H.; Ilvesaro, Joanna; Chen, Dongquan; Harris, Kevin W.; Graves, David; Selander, Katri S.

    2014-01-01

    TLR9 is a cellular DNA-receptor, which is widely expressed in breast and other cancers. Although synthetic TLR9-ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology has remained unclear. We show here that living cancer cells uptake DNA from chemotherapy-killed cancer cells. We discovered that such DNA induces TLR9- and cathepsin-mediated invasion in living cancer cells. To study whether this phenomenon contributes to treatment responses, triple negative, human MDA-MB-231 breast cancer cells stably expressing control or TLR9 siRNA were inoculated orthotopically into nude mice. The mice were treated with vehicle or doxorubicin. The tumor groups exhibited equal decreases in size in response to doxorubicin. However, while the weights of vehicle-treated mice were similar, mice bearing control siRNA tumors became significantly more cachectic in response to doxorubicin, as compared with similarly treated mice bearing TLR9 siRNA tumors, suggesting a TLR9-mediated inflammation at the site of the tumor. In conclusion, our findings propose that DNA released from chemotherapy-killed cancer cells has significant influence on TLR9-mediated biological effects in living cancer cells. Through these mechanisms, tumor TLR9 expression may affect treatment responses to chemotherapy. PMID:24212717

  7. Distributions of ethanol and intubation-related lidocaine in the brain of a trauma patient who was brain dead for about 5 days.

    PubMed

    Moriya, Fumio; Hashimoto, Yoshiaki; Nakanishi, Akinori

    2003-03-01

    A 48-year-old intoxicated man was admitted to a hospital with an acute subarachnoid hemorrhage from a blow to the head following a drinking session. Lidocaine jelly was used to facilitate intubation during cardiopulmonary resuscitation. While his heart resumed beating, he was classified as brain dead and his heart stopped 114 h after admission. His brain was soft and weighed 1.7 kg at autopsy. A small rupture (0.5 by 0.3 cm) of the left vertebral artery and diffuse subarachnoid hemorrhage were observed. Ethanol was detected only in the cerebrum, cerebellum and clotted blood in the superior sagittal sinus at 0.29, 0.15 and 0.12 mg/g, respectively. Lidocaine was also found in these areas at levels of 28, 24 and 7 ng/g, respectively. Significant amounts of ethanol were present in his brain because blood flow stopped after the injury. Smaller amounts of intubation-related lidocaine were probably distributed to the brain by limited cerebral circulation and remained there after circulation ceased. Toxicological analysis of the brain after death was useful for evaluating his state during treatment. PMID:12935567

  8. Treatment of Brain Metastasis from Lung Cancer

    PubMed Central

    Chi, Alexander; Komaki, Ritsuko

    2010-01-01

    Brain metastases are not only the most common intracranial neoplasm in adults but also very prevalent in patients with lung cancer. Patients have been grouped into different classes based on the presence of prognostic factors such as control of the primary tumor, functional performance status, age, and number of brain metastases. Patients with good prognosis may benefit from more aggressive treatment because of the potential for prolonged survival for some of them. In this review, we will comprehensively discuss the therapeutic options for treating brain metastases, which arise mostly from a lung cancer primary. In particular, we will focus on the patient selection for combined modality treatment of brain metastases, such as surgical resection or stereotactic radiosurgery (SRS) combined with whole brain irradiation; the use of radiosensitizers; and the neurocognitive deficits after whole brain irradiation with or without SRS. The benefit of prophylactic cranial irradiation (PCI) and its potentially associated neuro-toxicity for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are also discussed, along with the combined treatment of intrathoracic primary disease and solitary brain metastasis. The roles of SRS to the surgical bed, fractionated stereotactic radiotherapy, WBRT with an integrated boost to the gross brain metastases, as well as combining WBRT with epidermal growth factor receptor (EGFR) inhibitors, are explored as well. PMID:24281220

  9. Gliotoxin-induced swelling of astrocytes hinders diffusion in brain extracellular space via formation of dead-space microdomains

    PubMed Central

    SHERPA, ANG DOMA; VAN DE NES, PAULA; XIAO, FANRONG; WEEDON, JEREMY; HRABETOVA, SABINA

    2014-01-01

    One of the hallmarks of numerous life-threatening and debilitating brain diseases is cellular swelling that negatively impacts extracellular space (ECS) structure. The ECS structure is determined by two macroscopic parameters, namely tortuosity (λ) and volume fraction (α). Tortuosity represents hindrance imposed on the diffusing molecules by the tissue in comparison with an obstacle-free medium. Volume fraction is the proportion of tissue volume occupied by the ECS. From a clinical perspective, it is essential to recognize which factors determine the ECS parameters and how these factors change in brain diseases. Previous studies demonstrated that dead-space (DS) microdomains increased λ during ischemia and hypotonic stress, as these pocket-like structures transiently trapped diffusing molecules. We hypothesize that astrocytes play a key role in the formation of DS microdomains because their thin processes have concave shapes that may elongate as astrocytes swell in these pathologies. Here we selectively swelled astrocytes in the somatosensory neocortex of rat brain slices with a gliotoxin DL-α-Aminoadipic Acid (DL-AA), and we quantified the ECS parameters using Integrative Optical Imaging (IOI) and Real-Time Iontophoretic (RTI) diffusion methods. We found that α decreased and λ increased during DL-AA application. During recovery, α was restored whereas λ remained elevated. Increase in λ during astrocytic swelling and recovery is consistent with the formation of DS microdomains. Our data attribute to the astrocytes an important role in determining the ECS parameters, and indicate that extracellular diffusion can be improved not only by reducing the swelling but also by disrupting the DS microdomains. PMID:24687699

  10. First brain dead donor heart transplantation under new legislation in Japan.

    PubMed

    Matsuda, H; Fukushima, N; Sawa, Y; Nishimura, M; Matsumiya, G; Shirakura, R

    1999-10-01

    The first heart transplantation was carried out in Japan successfully, after the brain death and organ transplantation law was settled in 1997. The recipient patient was a 47-year-old man with the dilated phase of hypertrophic cardiomyopathy who had been on a Novacor implantable left ventricular assist system for the previous 4 months. Since the donor hospital was about 200 km from the recipient hospital which took approximately 2 hours for transportation, the total ischemic time was 3 hours and 24 minutes. The post-transplant course was smooth, and the patient was discharged on postoperative day 75. PMID:10554420

  11. Novel Brain Cancer Treatment Taps into Sound Waves

    MedlinePlus

    ... nih.gov/medlineplus/news/fullstory_159386.html Novel Brain Cancer Treatment Taps Into Sound Waves Experimental device ... 15, 2016 WEDNESDAY, June 15, 2016 (HealthDay News) -- Brain cancer patients might benefit from an implantable ultrasound ...

  12. Some Brain Cancer Patients Have Radiation Options: Study

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_160082.html Some Brain Cancer Patients Have Radiation Options: Study Targeted approach ... TUESDAY, July 26, 2016 (HealthDay News) -- For some brain cancer patients, pinpoint radiation of tumors, known as ...

  13. Researchers Find 8 Immune Genes in Aggressive Brain Cancer

    MedlinePlus

    ... 159031.html Researchers Find 8 Immune Genes in Aggressive Brain Cancer Discovery might eventually lead to better ... tissue samples from 170 people with a less aggressive type of brain tumor. This led to the ...

  14. Extensive Surgery Best for an Aggressive Brain Cancer

    MedlinePlus

    ... 159415.html Extensive Surgery Best for an Aggressive Brain Cancer: Study Although larger procedure carries more risk, ... comes to battling a particularly aggressive form of brain tumor, more extensive surgeries may be best to ...

  15. Chemo May Prolong Lives of Some Brain Cancer Patients

    MedlinePlus

    ... 158167.html Chemo May Prolong Lives of Some Brain Cancer Patients: Study Those with slow-growing gliomas ... the lives of people with certain slow-growing brain tumors, a new study finds. The findings come ...

  16. 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 ...

  17. Overturning refusal of a hospital to terminate life support for a brain-dead mother until the fetus was born: What is the law in South Africa?

    PubMed

    McQuoid-Mason, David Jan

    2014-08-01

    In a Texas case the court granted a husband an order for the removal of life support from his brain-dead pregnant wife after a hospital tried to keep her on it until the fetus was born. In South Africa the court would have issued a similar order, but for different reasons. Here, unlawfully and intentionally subjecting a pregnant corpse to life-support measures to keep a fetus alive against the wishes of the family would amount to the crime of violating a corpse. PMID:25213843

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

    PubMed

    Shin, Eun Myoung; Hay, Hui Sin; 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

    2014-09-01

    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

  19. [Treatment of brain metastasis from ovarian cancer].

    PubMed

    Bondiau, P-Y; Largillier, R; Foa, C; Rasendrarijao, D; Frenay, M; Gérard, J-P

    2003-06-01

    Systemic metastases from ovarian carcinoma are frequent, but they seldom affect the central nervous system. We present here the case of a patient treated for an ovarian cancer by surgery and chemotherapy. Three months after the end of chemotherapy, the patient developed cerebral metastases from ovarian carcinoma (CMOC) treated by iterative surgery and and whole brain irradiation. As the frequency of solitary cerebral metastasis of ovarian cancer is higher than with other cancers, it is likely that they behave slightly differently. Literature analysis reveals an increase in the incidence of CMOC since the middle of the nineties. CMOC can occur during or after adjuvant chemotherapy and the best management strategies to better define determinants of survival for patients are not well known. It appears that a better outcome of CMOC may be obtained by an aggressive treatment, if possible, including surgery, radiotherapy, and chemotherapy. Taking into account the increase in the incidence of the CMOC and their early occurrence, some authors have proposed a prophylactic brain radiotherapy in patients who receive adjuvant chemotherapy. PMID:12834774

  20. 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

  1. The La antigen is over-expressed in lung cancer and is a selective dead cancer cell target for radioimmunotherapy using the La-specific antibody APOMAB®

    PubMed Central

    2014-01-01

    Background The lupus-associated (La)-specific murine monoclonal antibody DAB4 (APOMAB®) specifically binds dead cancer cells. Using DAB4, we examined La expression in human lung cancer samples to assess its suitability as a cancer-selective therapeutic target. We evaluated the safety and effectiveness of radioimmunotherapy (RIT) using DAB4 radiolabeled with Lutetium-177 (177Lu) in the murine Lewis Lung (LL2) carcinoma model, and determined whether combining RIT with DNA-damaging cisplatin-based chemotherapy, a PARP inhibitor (PARPi), or both alters treatment responses. Methods The expression of La mRNA in human lung cancer samples was analysed using the online database Oncomine, and the protein expression of La was examined using a TissueFocus Cancer Survey Tissue Microarray. The binding of DAB4 to cisplatin-treated LL2 cells was assessed in vitro. LL2 tumour-bearing mice were administered escalating doses of 177Lu-DAB4 alone or in combination with chemotherapy, and tumour growth and survival measured. Biodistribution analysis was used to determine tissue uptake of 177Lu-DAB4 or its isotype control (177Lu-Sal5), when delivered alone or after chemotherapy. PARPi (rucaparib; AG-014699) was combined with chemotherapy and the effects of combined treatment on tumour growth, tumour cell DNA damage and death, and intratumoural DAB4 binding were also analysed. The effect of the triple combination of PARPi, chemotherapy and 177Lu-DAB4 on tumour growth and survival of LL2 tumour-bearing mice was tested. Results La was over-expressed at both mRNA and protein levels in surgical specimens of human lung cancer and the over-expression of La mRNA conferred a poorer prognosis. DAB4 bound specifically to cisplatin-induced dead LL2 cells in vitro. An anti-tumour dose response was observed when escalating doses of 177Lu-DAB4 were delivered in vivo, with supra-additive responses observed when chemotherapy was combined with 177Lu-DAB4. Combining PARPi with chemotherapy was more

  2. The immune system and hormone-receptor positive breast cancer: Is it really a dead end?

    PubMed

    Dieci, Maria Vittoria; Griguolo, Gaia; Miglietta, Federica; Guarneri, Valentina

    2016-05-01

    Even if breast cancer has not been traditionally considered an immunogenic tumor, recent data suggest that immunity, and its interaction with tumor cells and tumor microenvironment, might play an important role in this malignancy, in particular in triple negative and HER2+ subtypes. As no consistent data on the potential clinical relevance of tumor infiltrating lymphocytes have been produced in hormone receptor positive (HR+) HER2- breast cancer, the interest in studying immune aspects in this subtype has become less appealing. Nevertheless, some scattered evidence indicates that immunity and inflammation may be implicated in the biology of this subtype as well. In HR+ breast cancer, the interaction between tumor cells and the immune milieu might rely on different mechanisms than in other BC subtypes, involving the modulation of the tumor microenvironment by mutual interplays of endocrine factors, pro-inflammatory status and immune cells. These subtle mechanisms may require more refined methods of evaluation, such as the assessment of tumor infiltrating lymphocytes subpopulations or gene signatures. In this paper we aim to perform a comprehensive review of pre-clinical and clinical data on the interplay between the immune system and breast cancer in the HR+ subtype, to guide further research in the field. PMID:27055087

  3. 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

  4. Androgen deprivation of prostate cancer: Leading to a therapeutic dead end.

    PubMed

    Katzenwadel, Arndt; Wolf, Philipp

    2015-10-10

    Androgen deprivation therapy (ADT) is considered as the standard therapy for men with de novo or recurrent metastatic prostate cancer. ADT commonly leads to initial biochemical and clinical responses. However, several months after the beginning of treatment, tumors become castration-resistant and virtually all patients show disease progression. At this stage, tumors are no longer curable and cancer treatment options are only palliative. In this review, we describe molecular alterations in tumor cells during ADT, which lead to deregulation of different signaling pathways and castration-resistance, and how they might interfere with the clinical outcome of different second-line therapeutics. A recent breakthrough finding that early chemotherapy is associated with a significant survival benefit in metastatic hormone-sensitive disease highlights the fact that there is time for a fundamental paradigm shift in the treatment of advanced prostate cancer. Therapeutic intervention seems to be indicated before a castration-resistant stage is reached to improve therapeutic outcome and to reduce undesirable side effects. PMID:26185001

  5. 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 ...

  6. 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.

  7. Emerging strategies for treating brain metastases from breast cancer

    PubMed Central

    Kodack, David P.; Askoxylakis, Vasileios; Ferraro, Gino B.; Fukumura, Dai; Jain, Rakesh K.

    2015-01-01

    Summary Brain metastasis is an end stage in breast cancer progression. Traditional treatment options have minimal efficacy, and overall survival is on the order of months. The incidence of brain metastatic disease is increasing with the improved management of systemic disease and prolongation of survival. Unfortunately, the targeted therapies that control systemic disease have diminished efficacy against brain lesions. There are reasons to be optimistic, however, as emerging therapies have shown promise in preclinical and early clinical settings. This review discusses recent advances in breast cancer brain metastasis therapy and potential approaches for successful treatment. PMID:25670078

  8. 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. PMID:26709907

  9. Brain cancer survival in Kentucky: 1996-2000.

    PubMed

    Aldrich, Tim E; Freitas, Samantha J; Ling, Lan; McKinney, Paul

    2008-10-01

    This is a report of brain cancer survival patterns in certain Area Development Districts (ADDs) in Kentucky, the state, and the nation. Brain cancer is of national and regional concern as it is a disease of high case fatality rates and relatively short survival. Comparisons for survival were made between the U.S.A. and the state. Kentucky has higher brain cancer mortality rates than the U.S.A., but significantly better cause-specific survival (p < 0.05). In order to examine within state variations for brain cancer survival, data organized for the fifteen ADDs from the state's central cancer registry were used. The analytic focus of this analysis were three regions expressly: the Purchase ADD (location of the Paducah Gaseous Diffusion Plant), the Green River ADD (the location of elevated brain cancer mortality rates), and the Kentucky River ADD (comprising counties that each have significantly more than the state average of persons living below the national poverty level). We found no evidence of lower survival for brain cancer among the poorer region of the state. The western districts were found to have lower cause-specific survival than the state (p < 0.05) and the U.S.A. Such a regional variation alerts population-based researchers to consider varying survival trends within the state's population. PMID:18979721

  10. 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

  11. 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

  12. Researchers Find 8 Immune Genes in Aggressive Brain Cancer

    MedlinePlus

    ... news/fullstory_159031.html Researchers Find 8 Immune Genes in Aggressive Brain Cancer Discovery might eventually lead ... 25, 2016 (HealthDay News) -- Researchers have identified immune genes that may affect how long people live after ...

  13. Involvement of tumor acidification in brain cancer pathophysiology

    PubMed Central

    Honasoge, Avinash; Sontheimer, Harald

    2013-01-01

    Gliomas, primary brain cancers, are characterized by remarkable invasiveness and fast growth. While they share many qualities with other solid tumors, gliomas have developed special mechanisms to convert the cramped brain space and other limitations afforded by the privileged central nervous system into pathophysiological advantages. In this review we discuss gliomas and other primary brain cancers in the context of acid-base regulation and interstitial acidification; namely, how the altered proton (H+) content surrounding these brain tumors influences tumor development in both autocrine and paracrine manners. As proton movement is directly coupled to movement of other ions, pH serves as both a regulator of cell activity as well as an indirect readout of other cellular functions. In the case of brain tumors, these processes result in pathophysiology unique to the central nervous system. We will highlight what is known about pH-sensitive processes in brain tumors in addition to gleaning insight from other solid tumors. PMID:24198789

  14. "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…

  15. Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient.

    PubMed

    Boly, M; Tshibanda, L; Vanhaudenhuyse, A; Noirhomme, Q; Schnakers, C; Ledoux, D; Boveroux, P; Garweg, C; Lambermont, B; Phillips, C; Luxen, A; Moonen, G; Bassetti, C; Maquet, P; Laureys, S

    2009-08-01

    Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level-dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally defined neuroanatomical networks. However, the functional significance of these spontaneous BOLD fluctuations remains poorly understood. By means of 3 T functional MRI, we demonstrate absent cortico-thalamic BOLD functional connectivity (i.e. between posterior cingulate/precuneal cortex and medial thalamus), but preserved cortico-cortical connectivity within the default network in a case of vegetative state (VS) studied 2.5 years following cardio-respiratory arrest, as documented by extensive behavioral and paraclinical assessments. In the VS patient, as in age-matched controls, anticorrelations could also be observed between posterior cingulate/precuneus and a previously identified task-positive cortical network. Both correlations and anticorrelations were significantly reduced in VS as compared to controls. A similar approach in a brain dead patient did not show any such long-distance functional connectivity. We conclude that some slow coherent BOLD fluctuations previously identified in healthy awake human brain can be found in alive but unaware patients, and are thus unlikely to be uniquely due to ongoing modifications of conscious thoughts. Future studies are needed to give a full characterization of default network connectivity in the VS patients population. PMID:19350563

  16. Role of the neural niche in brain metastatic cancer

    PubMed Central

    Termini, John; Neman, Josh; Jandial, Rahul

    2014-01-01

    Metastasis is the relenteless 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 since 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 biological 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 towards 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 the bidirectional interactions between the brain milieu and metastatic cancer. PMID:25035392

  17. [First brain dead donor heart transplantation under new legislation in Japan and future aspects of heart transplantation in Japan].

    PubMed

    Matsuda, H; Fukushima, N

    1999-12-01

    After the brain death and organ transplantation law was settled in 1997, the first case of heart transplantation (HTx) was carried out successfully. The patient was 47 year-old male with hypertrophic cardiomyopathy of dilated phase and on Novacor Implantable LVAS for 4 months. The distance from the donor hospital was about 200 km taking 2 hours for transport, and total ischemic time was 3 hours and 24 minutes. The post-transplant course was smooth. The patient was discharged on 75 postoperative day. We described current status of HTx in Japan and worldwide and discussed current problems and future aspects of HTx in Japan. PMID:10638227

  18. Common astrocytic programs during brain development, injury and cancer

    PubMed Central

    Silver, Daniel J.; Steindler, Dennis A.

    2011-01-01

    In addition to radial glial cells of neurohistogenesis, immature astrocytes with stem-cell-like properties cordon off emerging functional patterns in the developing brain. Astrocytes also can be stem cells during adult neurogenesis, and a proposed potency of injury-associated reactive astrocytes has recently been substantiated. Astrocytic cells might additionally be involved in cancer stem cell-associated gliomagenesis. Thus, there are distinguishing roles for stem-cell-like astrocytes during brain development, in neurogenic niches in the adult, during attempted reactive neurogenesis after brain injury or disease and during brain tumorigenesis. PMID:19398132

  19. Changing Patterns of Organ Donation: Brain Dead Donors Are Not Being Lost by Donation After Circulatory Death.

    PubMed

    Nelson, Helen M; Glazier, Alexandra K; Delmonico, Francis L

    2016-02-01

    The clinical characteristics of all New England Organ Bank (NEOB) donors after circulatory death (DCD) donors were analyzed between July 1, 2009, and June 30, 2014. During that 5-year period, there were 494 authorized medically suitable potential DCDs that the NEOB evaluated, constituting more than 30% of deceased donors coordinated annually by the NEOB. From the cohort of 494 authorized potential DCDs, 331 (67%) became actual DCD, 82 (17%) were attempted as a DCD but did not progress to donation, and 81 (16%) transitioned to an actual donor after brain death (DBD). Two hundred seventy-six organs were transplanted from the 81 donors that transitioned from DCD to actual DBD, including 24 heart, 70 liver, 12 single and 14 bilateral lung, and 12 pancreas transplants. When patients with devastating brain injury admitted to the intensive care units are registered donors, the Organ Procurement Organization staff should share the patient's donation decision with the health care team and the patient's family, as early as possible after the comfort measures only discussion has been initiated. The experience of the NEOB becomes an important reference of the successful implementation of DCD that enables an expansion of deceased donation (inclusive of DBD). PMID:26516669

  20. 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

  1. Mortality from brain cancer and leukaemia among electrical workers.

    PubMed Central

    Loomis, D P; Savitz, D A

    1990-01-01

    The relation of brain cancer and mortality from leukaemia to electrical occupations was investigated in a case-control study based on all deaths in 1985 and 1986 in the 16 states in the United States that report occupational data from death certificates to the national vital statistics registry. The case series comprised all 2173 men who died of primary brain cancer (International Classification of Diseases-9 ((ICD-9) code 191) and all 3400 who died of leukaemia (ICD-9 codes 204-208). Each was matched with 10 controls who died of other causes in the same year. Men employed in any electrical occupation had age race adjusted odds ratios (ORs) of 1.4 (95% confidence interval (CI) 1.1-1.7) for brain cancer and 1.0 (95% CI 0.8-1.2) for leukaemia, compared with men in all other occupations. Brain cancer odds ratios were larger for electrical engineers and technicians (OR 2.7, 95% CI 2.1-3.4), telephone workers (OR 1.6, 95% CI 1.1-2.4), electric power workers (OR 1.7, 95% CI 1.1-2.7), and electrical workers in manufacturing industries (OR 2.1, 95% CI 1.3-3.4). There was some evidence of excess leukaemia among the same groups (ORs of 1.1-1.5) despite absence of an association for all electrical workers. The excess of deaths from brain cancer was concentrated among men aged 65 or older, whereas leukaemia was associated with electrical work only among younger decedents and those with acute lymphocytic leukaemia. These results from a large and geographically diverse population corroborate reports of increased mortality from brain cancer among electrical workers, but gives only limited support to suggestions of excess deaths from leukaemia. PMID:2207035

  2. 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

  3. New insights and emerging therapies for breast cancer brain metastases.

    PubMed

    Lim, Elgene; Lin, Nancy U

    2012-07-01

    Breast cancer brain metastases (BCBMs) are the second most frequent secondary central nervous system metastases following those associated with non-small-cell lung cancer. It is increasingly evident that BCBM arises as a function of the biology of the primary tumor and the metastatic niche, which combine to create a unique microenvironment in the brain impacting both metastatic colonization and therapeutic response. Clinical outcomes are improving for BCBM patients as a result of modern combinatorial therapies, challenging the traditionally nihilistic approach to this patient subgroup. This review will focus on the breast cancer subtypes with the highest incidence of BCBM-human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and triple-negative (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) breast cancer (TNBC)-and will characterize differences in the clinical behavior of brain metastases that arise from these different subtypes. We will also highlight some of the recent preclinical studies that may shed light on the biological mechanisms and mediators underlying brain metastases. Finally, we will review published and current prospective trials of systemic therapies specifically for BCBM, including novel pathway-specific therapies. PMID:22888567

  4. EGFR and HER2 signaling in breast cancer brain metastasis

    PubMed Central

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

    2016-01-01

    Breast cancer occurs in approximately 1 in 8 women and 1 in 37 women with breast cancer succumbed to the disease. Over the past decades, new diagnostic tools and treatments have substantially improved the prognosis of women with local diseases. However, women with metastatic disease still have a dismal prognosis without effective treatments. Among different molecular subtypes of breast cancer, the HER2-enriched and basal-like subtypes typically have higher rates of metastasis to the brain. Basal-like metastatic breast tumors frequently express EGFR. Consequently, HER2- and EGFR-targeted therapies are being used in the clinic and/or evaluated in clinical trials for treating breast cancer patients with brain metastases. In this review, we will first provide an overview of the HER2 and EGFR signaling pathways. The roles that EGFR and HER2 play in breast cancer metastasis to the brain will then be discussed. Finally, we will summarize the preclinical and clinical effects of EGFR- and HER2-targeted therapies on breast cancer metastasis. PMID:26709660

  5. The DEAD-box RNA helicase 51 controls non-small cell lung cancer proliferation by regulating cell cycle progression via multiple pathways.

    PubMed

    Wang, Xiaojing; Liu, Hongli; Zhao, Chengling; Li, Wei; Xu, Huanbai; Chen, Yuqing

    2016-01-01

    The genetic regulation of cell cycle progression and cell proliferation plays a role in the growth of non-small cell lung cancer (NSCLC), one of the most common causes of cancer-related mortality. Although DEAD-box RNA helicases are known to play a role in cancer development, including lung cancer, the potential involvement of the novel family member DDX51 has not yet been investigated. In the current study we assessed the role of DDX51 in NSCLC using a siRNA-based approach. DDX51 siRNA-expressing cells exhibited a slower cell proliferation rate and underwent arrest in S-phase of the cell cycle compared with control cells. Microarray analyses revealed that DDX51siRNA expression resulted in the dysregulation of a number of cell signalling pathways. Moreover, injection of DDX51 siRNA into an animal model resulted in the formation of smaller tumours compared with the control group. We also assessed the expression of DDX51 in patients with NSCLC, and the data revealed that the expression was correlated with patient age but no other risk factors. Overall, our data suggest for the first time that DDX51 aids cell cancer proliferation by regulating multiple signalling pathways, and that this protein might be a therapeutic target for NSCLC. PMID:27198888

  6. The DEAD-box RNA helicase 51 controls non-small cell lung cancer proliferation by regulating cell cycle progression via multiple pathways

    PubMed Central

    Wang, Xiaojing; Liu, Hongli; Zhao, Chengling; Li, Wei; Xu, Huanbai; Chen, Yuqing

    2016-01-01

    The genetic regulation of cell cycle progression and cell proliferation plays a role in the growth of non-small cell lung cancer (NSCLC), one of the most common causes of cancer-related mortality. Although DEAD-box RNA helicases are known to play a role in cancer development, including lung cancer, the potential involvement of the novel family member DDX51 has not yet been investigated. In the current study we assessed the role of DDX51 in NSCLC using a siRNA-based approach. DDX51 siRNA-expressing cells exhibited a slower cell proliferation rate and underwent arrest in S-phase of the cell cycle compared with control cells. Microarray analyses revealed that DDX51siRNA expression resulted in the dysregulation of a number of cell signalling pathways. Moreover, injection of DDX51 siRNA into an animal model resulted in the formation of smaller tumours compared with the control group. We also assessed the expression of DDX51 in patients with NSCLC, and the data revealed that the expression was correlated with patient age but no other risk factors. Overall, our data suggest for the first time that DDX51 aids cell cancer proliferation by regulating multiple signalling pathways, and that this protein might be a therapeutic target for NSCLC. PMID:27198888

  7. [Systemic treatment of brain metastases from breast cancer].

    PubMed

    Taillibert, S; Conforti, R; Bonneterre, J; Bachelot, T; Le Rhun, E; Bernard-Marty, C

    2015-02-01

    An increase in the incidence of breast cancer patients with brain metastases has been observed over the last years, mainly because the recent development of new drugs including therapies targeting HER2 (human epidermal growth factor receptor 2) resulted in an increased survival of these patients. With HER2+ patients living longer and the well-known neurotropism of HER2+ tumour cells, the resulting high incidence of brain metastases is not really surprising. Moreover, brain metastases more often occur within a context of existing extracranial metastases. These need to be treated at the same time in order to favourably impact patients' survival. Consequently, the management of breast cancer patients with brain metastases clearly relies on a multidisciplinary approach, including systemic treatment. A working group including neuro-oncologists, neurosurgeons, radiation oncologists and oncologists was created in order to provide French national guidelines for the management of brain metastases within the "Association des neuro-oncologues d'expression française" (ANOCEF). The recommendations regarding the systemic treatment in breast cancer patients are reported here including key features of their management. PMID:25662600

  8. 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

  9. Targeting energy metabolism in brain cancer: review and hypothesis

    PubMed Central

    Seyfried, Thomas N; Mukherjee, Purna

    2005-01-01

    Malignant brain tumors are a significant health problem in children and adults and are often unmanageable. As a metabolic disorder involving the dysregulation of glycolysis and respiration, malignant brain cancer is potentially manageable through changes in metabolic environment. A radically different approach to brain cancer management is proposed that combines metabolic control analysis with the evolutionarily conserved capacity of normal cells to survive extreme shifts in physiological environment. In contrast to malignant brain tumors that are largely dependent on glycolysis for energy, normal neurons and glia readily transition to ketone bodies (β-hydroxybutyrate) for energy in vivo when glucose levels are reduced. The bioenergetic transition from glucose to ketone bodies metabolically targets brain tumors through integrated anti-inflammatory, anti-angiogenic, and pro-apoptotic mechanisms. The approach focuses more on the genomic flexibility of normal cells than on the genomic defects of tumor cells and is supported from recent studies in orthotopic mouse brain tumor models and in human pediatric astrocytoma treated with dietary energy restriction and the ketogenic diet. PMID:16242042

  10. Brain abscess

    MedlinePlus

    Brain abscesses commonly occur when bacteria or fungi infect part of the brain. As a result, swelling and irritation (inflammation) develop. Infected brain cells, white blood cells, live and dead bacteria, ...

  11. Brain metastasis in breast cancer: a comprehensive literature review.

    PubMed

    Rostami, Rezvan; Mittal, Shivam; Rostami, Pooya; Tavassoli, Fattaneh; Jabbari, Bahman

    2016-05-01

    This comprehensive review provides information on epidemiology, size, grade, cerebral localization, clinical symptoms, treatments, and factors associated with longer survival in 14,599 patients with brain metastasis from breast cancer; the molecular features of breast cancers most likely to develop brain metastases and the potential use of these predictive molecular alterations for patient management and future therapeutic targets are also addressed. The review covers the data from 106 articles representing this subject in the era of modern neuroimaging (past 35 years). The incidence of brain metastasis from breast cancer (24 % in this review) is increasing due to advances in both imaging technologies leading to earlier detection of the brain metastases and introduction of novel therapies resulting in longer survival from the primary breast cancer. The mean age at the time of breast cancer and brain metastasis diagnoses was 50.3 and 48.8 years respectively. Axillary node metastasis was noted in 32.8 % of the patients who developed brain metastasis. The median time intervals between the diagnosis of breast cancer to identification of brain metastasis and from identification of brain metastasis to death were 34 and 15 months, respectively. The most common symptoms experienced in patients with brain metastasis consisted of headache (35 %), vomiting (26 %), nausea (23 %), hemiparesis (22 %), visual changes (13 %) and seizures (12 %). A majority of the patients had multiple metastases (54.2 %). Cerebellum and frontal lobes were the most common sites of metastasis (33 and 16 %, respectively). Of the primary tumors for which biomarkers were recorded, 37 % were estrogen receptor (ER)+, 41 % ER-, 36 % progesterone receptor (PR)+, 34 % PR-, 35 % human epithelial growth factor receptor 2 (HER2)+, 41 % HER2-, 27 % triple negative and 18 % triple positive (TP). Treatment in most patients consisted of a multimodality approach often with two or more of the

  12. The Blood-Brain Barrier Challenge for the Treatment of Brain Cancer, Secondary Brain Metastases, and Neurological Diseases.

    PubMed

    Weidle, Ulrich H; Niewöhner, Jens; Tiefenthaler, Georg

    2015-01-01

    Formation of metastases from various tumor entities in the brain is a major problem for the treatment of advanced cancer. We describe target molecules and tools for the delivery of small molecules or proteins across the blood-brain barrier (BBB), and the treatment of brain tumors and metastases with antibody-related moieties. In addition, drugs preventing formation of metastases or interfering with the growth of established metastases are described, as well as pre-clinical metastasis models and corresponding clinical data. Furthermore, we discuss the delivery of effector proteins and antibody-based moieties fused with an antibody-based scaffold across the BBB in several model systems which might be applicable for the treatment of brain metastases. PMID:26136217

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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. PMID:25134466

  18. Rationale for the Use of Upfront Whole Brain Irradiation in Patients with Brain Metastases from Breast Cancer

    PubMed Central

    Tallet, Agnes V.; Azria, David; Le Rhun, Emilie; Barlesi, Fabrice; Carpentier, Antoine F.; Gonçalves, Antony; Taillibert, Sophie; Dhermain, Frédéric; Spano, Jean-Philippe; Metellus, Philippe

    2014-01-01

    Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy. PMID:24815073

  19. Concurrent capecitabine and whole-brain radiotherapy for treatment of brain metastases in breast cancer patients.

    PubMed

    Chargari, Cyrus; Kirova, Youlia M; Diéras, Véronique; Castro Pena, Pablo; Pena, Pablo Castro; Campana, Francois; Cottu, Paul H; Pierga, JeanYves; Fourquet, Alain

    2009-07-01

    Preclinical data have demonstrated that ionizing radiation acts synergistically with capecitabine. This report retrospectively assessed the use of capecitabine concurrently with whole-brain radiotherapy (WBRT) in patients with brain metastases from breast cancer. From January 2003 to March 2005, five breast cancer patients with brain metastases were referred for WBRT with concurrent capecitabine. Median age was 44 years (range: 38-53). The median dose of capecitabine was 1,000 mg/m(2) twice daily for 14 days (day1-14). Treatment cycles were repeated every 21 days, concurrently with WBRT (30 Gy, 3 Gy per fraction, 5 days per week). Median survival after starting WBRT plus capecitabine was 6.5 months (range 1-34 months). One patient achieved a complete response. Two patients achieved partial response, including one with local control lasting until most recent follow-up. One patient had stable disease. The remaining patient was not assessable for response because of early death. Most commonly reported adverse events were nausea (n = 2) and headache (n = 2), always grade 1. Other toxicities were grade 3 hand/foot syndrome (n = 1), moderate anemia requiring transfusion and dose reduction of capecitabine (n = 1), and grade 1 mucositis (n = 1). Although promising, these preliminary data warrant further assessment of capecitabine-based chemoradiation in brain metastases from breast cancer and need to be further validated in the setting of a clinical trial. PMID:19169856

  20. Appropriate Contrast Enhancement Measures for Brain and Breast Cancer Images

    PubMed Central

    Gupta, Suneet; Porwal, Rabins

    2016-01-01

    Medical imaging systems often produce images that require enhancement, such as improving the image contrast as they are poor in contrast. Therefore, they must be enhanced before they are examined by medical professionals. This is necessary for proper diagnosis and subsequent treatment. We do have various enhancement algorithms which enhance the medical images to different extents. We also have various quantitative metrics or measures which evaluate the quality of an image. This paper suggests the most appropriate measures for two of the medical images, namely, brain cancer images and breast cancer images. PMID:27127497

  1. [Complex treatment of breast cancer patients with brain metastases].

    PubMed

    Medvedev, S V; Tkachev, S I; Moskvina, E A; Mikhina, Z P; Naskhletashvili, D R; Bulychkin, P V; Romanov, D S; Trofimova, O P; Berdnik, A V; Bykova, Yu B; Gutnik, R A; Yazhgunovich, I P; Fedoseenko, D I

    2015-01-01

    Brain metastases in breast cancer develop for 24-32 months after the detection of the primary tumor. The study included patients with brain metastases who were divided into three groups: the first group--with early chemoradiotherapy (CRT) without induction chemotherapy (IC) by capecitabine; the second group--with delayed CRT with 4 or 8 courses of IC by capecitabine; the third group (a historical control) who received only whole brain radiation therapy. The median time to progression of intracranial metastases was 15.3, 12 and 5 months, respectively. The median time to the intracranial progression significantly less in the third group (5 months) compared with the first (15.3 months) (p = 0.0007) and the second (12 months) (p = 0.027) groups. The overall survival rate was 22.1, 15.1 and 6.8 months in three groups, respectively. PMID:26995988

  2. [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

  3. Gene Expression Profiling of Breast Cancer Brain Metastasis.

    PubMed

    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

  4. 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

  5. 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

  6. 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

  7. GE-20GENOMIC CHARACTERIZATION OF BREAST CANCER BRAIN METASTASES

    PubMed Central

    Michelhaugh, Sharon; Bollig-Fischer, Aliccia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

    2014-01-01

    BACKGROUND: The incidence of central nervous system metastasis from primary breast cancer has steadily increased with introduction of more effective molecular-targeted therapies resulting in improved long-term survival. Current standard-of-care treatment modalities for CNS metastases include microsurgical resection, whole-brain radiation therapy, and stereotactic radiosurgery, either alone or in combination. There are currently no FDA-approved drugs with an indication for breast cancer brain metastases. Clearly, there is a dire need to identify biomarkers permitting earlier and accurate diagnosis of CNS metastases, development of prevention strategies in high-risk individuals, and establishing more effective treatment options such as targeted systemic and intrathecal therapies. METHODS: Extracted DNA from metastatic brain tumors (MBTs) and matched tissues from primary breast tumors was quantified and array comparative genomic hybridizations (aCGH) were performed with Agilent SurePrint arrays (G3 ISCA CGH + SNP 180K) using a commercially-available, genetically-normal female DNA standard. Bioinformatics analysis was performed using Agilent CytoGenomics Edition 2.5.8.1. Data were filtered against the Cancer Gene Census (Wellcome Trust Sanger Institute) to identify genes with well-characterized roles in cancer. RESULTS: From genomic copy number data analysis tailored to uncover the most frequent gene aberrations in breast cancer MBTs, we identified that MYC oncogene amplification was among the most common. Pathway analysis of the analyzed gene set of recurring gene aberrations identified the Human Embryonic Stem Cell Pluripotency pathway as being over-represented. The genes in this pathway showing copy number gain include NTRK1, PIK3CA and SOX2. Direct comparisons of MBTs with their matched primary tumor (n = 4) revealed a range of examples for highly similar and divergent patterns of gene aberrations. In one case ERBB2 was confirmed to be in the MBT, and not in the

  8. Detection of Human Brain Cancer Infiltration ex vivo and in vivo Using Quantitative Optical Coherence Tomography*

    PubMed Central

    Kut, Carmen; Chaichana, Kaisorn L.; Xi, Jiefeng; Raza, Shaan M.; Ye, Xiaobu; McVeigh, Elliot R.; Rodriguez, Fausto J.; Quinones-Hinojosa, Alfredo; Li, Xingde

    2015-01-01

    More complete brain cancer resection can prolong survival and delay recurrence. However, it is challenging to distinguish cancer from non-cancer tissues intraoperatively, especially at the transitional, infiltrative zones. This is especially critical in eloquent regions (e.g. speech and motor areas). This study tested the feasibility of label-free, quantitative optical coherence tomography (OCT) for differentiating cancer from non-cancer in human brain tissues. Fresh ex vivo human brain tissues were obtained from 32 patients with grades II-IV brain cancer and 5 patients with non-cancer brain pathologies. Based on volumetric OCT imaging data, pathologically confirmed brain cancer tissues (both high-grade and low-grade) had significantly lower optical attenuation values at both cancer core and infiltrated zones when compared with non-cancer white matter, and OCT achieved high sensitivity and specificity at an attenuation threshold of 5.5 mm-1 for brain cancer patients. We also used this attenuation threshold to confirm the intraoperative feasibility of performing in vivo OCT-guided surgery using a murine model harboring human brain cancer. Our OCT system was capable of processing and displaying a color-coded optical property map in real time at a rate of 110-215 frames per second, or 1.2-2.4 seconds for an 8-16 mm3 tissue volume, thus providing direct visual cues for cancer versus non-cancer areas. Our study demonstrates the translational and practical potential of OCT in differentiating cancer from non-cancer tissue. Its intraoperative use may facilitate safe and extensive resection of infiltrative brain cancers and consequently lead to improved outcomes when compared with current clinical standards. PMID:26084803

  9. Design and evaluation of new chemotherapeutics of aloe-emodin (AE) against the deadly cancer disease: an in silico study.

    PubMed

    Mulakayala, Chaitanya; Banaganapalli, Babajan; Mulakayala, Naveen; Pulaganti, Madhusudana; C M, Anuradha; Chitta, Suresh Kumar

    2013-05-23

    The Bcl-2 family proteins include pro- and antiapoptotic factors acting as critical arbiters of apoptotic cell death decisions in most circumstances. Evasion of apoptosis is one of the hallmarks of cancer, relevant to tumorigenesis as well as resistance to cytotoxic drugs, and deregulation of Bcl-2 proteins was observed in many cancers. Since Bax-mediated induction of apoptosis is a crucial mechanism in cancerous cells, we aimed at conducting in silico analysis on Bax in order to predict the possible interactions for anticancer agents. The present report depicts the binding mode of aloe-emodin and its structurally modified derivatives onto Bax. The structural information about the binding site of Bax for docked compounds obtained from this study could aid in screening and designing new anticancer agents or selective inhibitors for chemotherapy against Bax. PMID:24432130

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

    PubMed

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

    2015-09-01

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

  11. Monocarboxylate transporters in the brain and in cancer.

    PubMed

    Pérez-Escuredo, Jhudit; Van Hée, Vincent F; Sboarina, Martina; Falces, Jorge; Payen, Valéry L; Pellerin, Luc; Sonveaux, Pierre

    2016-10-01

    Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1-4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. PMID:26993058

  12. 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

  13. 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. PMID:25310691

  14. 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

  15. What Are the Key Statistics about Brain and Spinal Cord Cancers?

    MedlinePlus

    ... and spinal cord tumors? What are the key statistics about brain and spinal cord tumors? The American ... cord tumors .” Visit the American Cancer Society’s Cancer Statistics Center for more key statistics. Last Medical Review: ...

  16. Common Class of Breast Cancer Drugs May Not Trigger 'Chemo Brain'

    MedlinePlus

    ... medlineplus/news/fullstory_158436.html Common Class of Breast Cancer Drugs May Not Trigger 'Chemo Brain': Study Anthracyclines ... 2016 THURSDAY, April 21, 2016 (HealthDay News) -- Some breast cancer patients complain of a fogged mental condition often ...

  17. 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

  18. 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. PMID:25724666

  19. CXCR4/CXCL12 in Non-Small-Cell Lung Cancer Metastasis to the Brain

    PubMed Central

    Cavallaro, Sebastiano

    2013-01-01

    Lung cancer represents the leading cause of cancer-related mortality throughout the world. Patients die of local progression, disseminated disease, or both. At least one third of the people with lung cancer develop brain metastases at some point during their disease, even often before the diagnosis of lung cancer is made. The high rate of brain metastasis makes lung cancer the most common type of tumor to spread to the brain. It is critical to understand the biologic basis of brain metastases to develop novel diagnostic and therapeutic approaches. This review will focus on the emerging data supporting the involvement of the chemokine CXCL12 and its receptor CXCR4 in the brain metastatic evolution of non-small-cell lung cancer (NSCLC) and the pharmacological tools that may be used to interfere with this signaling axis. PMID:23322021

  20. 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.

  1. 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

  2. Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development

    PubMed Central

    Blakeley, Jaishri; Portnow, Jana

    2014-01-01

    Importance of the field: Many promising targeted agents and combination therapies are being investigated for brain cancer. However, the results from recent clinical trials have been disappointing. A better understanding of the disposition of drug in the brain early in drug development would facilitate appropriate channeling of new drugs into brain cancer clinical trials. Areas covered in this review: Barriers to successful drug activity against brain cancer and issues affecting intratumoral drug concentrations are reviewed. The use of the microdialysis technique for extracellular fluid (ECF) sampling and its application to drug distribution studies in brain are reviewed using published literature from 1995 to the present. The benefits and limitations of microdialysis for performing neuorpharmacokinetic (nPK) and neuropharmacodynamic (nPD) studies are discussed. What the reader will gain: The reader will gain an appreciation of the challenges involved in identifying agents likely to have efficacy in brain cancer, an understanding of the general principles of microdialysis, and the power and limitations of using this technique in early drug development for brain cancer therapies. Take home message: A major factor preventing efficacy of anti-brain cancer drugs is limited access to tumor. Intracerebral microdialysis allows sampling of drug in the brain ECF. The resulting nPK/nPD data can aid in the rational selection of drugs for investigation in brain tumor clinical trials. PMID:20969450

  3. 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.

  4. Targeting Tregs in Malignant Brain Cancer: Overcoming IDO.

    PubMed

    Wainwright, Derek A; Dey, Mahua; Chang, Alan; Lesniak, Maciej S

    2013-01-01

    One of the hallmark features of glioblastoma multiforme (GBM), the most common adult primary brain tumor with a very dismal prognosis, is the accumulation of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Regulatory T cells (Tregs) segregate into two primary categories: thymus-derived natural Tregs (nTregs) that develop from the interaction between immature T cells and thymic epithelial stromal cells, and inducible Tregs (iTregs) that arise from the conversion of CD4(+)FoxP3(-) T cells into FoxP3 expressing cells. Normally, these Treg subsets complement one another's actions by maintaining tolerance of self-antigens, thereby suppressing autoimmunity, while also enabling effective immune responses toward non-self-antigens, thus promoting infectious protection. However, Tregs have also been shown to be associated with the promotion of pathological outcomes, including cancer. In the setting of GBM, nTregs appear to be primary players that contribute to immunotherapeutic failure, ultimately leading to tumor progression. Several attempts have been made to therapeutically target these cells with variable levels of success. The blood brain barrier-crossing chemotherapeutics, temozolomide, and cyclophosphamide (CTX), vaccination against the Treg transcriptional regulator, FoxP3, as well as mAbs against Treg-associated cell surface molecules CD25, CTLA-4, and GITR are all different therapeutic approaches under investigation. Contributing to the poor success of past approaches is the expression of indoleamine 2,3-dioxygenase 1 (IDO), a tryptophan catabolizing enzyme overexpressed in GBM, and critically involved in regulating tumor-infiltrating Treg levels. Herein, we review the current literature on Tregs in brain cancer, providing a detailed phenotype, causative mechanisms involved in their pathogenesis, and strategies that have been used to target this population, therapeutically. PMID:23720663

  5. Targeting Tregs in Malignant Brain Cancer: Overcoming IDO

    PubMed Central

    Wainwright, Derek A.; Dey, Mahua; Chang, Alan; Lesniak, Maciej S.

    2013-01-01

    One of the hallmark features of glioblastoma multiforme (GBM), the most common adult primary brain tumor with a very dismal prognosis, is the accumulation of CD4+CD25+Foxp3+ regulatory T cells (Tregs). Regulatory T cells (Tregs) segregate into two primary categories: thymus-derived natural Tregs (nTregs) that develop from the interaction between immature T cells and thymic epithelial stromal cells, and inducible Tregs (iTregs) that arise from the conversion of CD4+FoxP3− T cells into FoxP3 expressing cells. Normally, these Treg subsets complement one another’s actions by maintaining tolerance of self-antigens, thereby suppressing autoimmunity, while also enabling effective immune responses toward non-self-antigens, thus promoting infectious protection. However, Tregs have also been shown to be associated with the promotion of pathological outcomes, including cancer. In the setting of GBM, nTregs appear to be primary players that contribute to immunotherapeutic failure, ultimately leading to tumor progression. Several attempts have been made to therapeutically target these cells with variable levels of success. The blood brain barrier-crossing chemotherapeutics, temozolomide, and cyclophosphamide (CTX), vaccination against the Treg transcriptional regulator, FoxP3, as well as mAbs against Treg-associated cell surface molecules CD25, CTLA-4, and GITR are all different therapeutic approaches under investigation. Contributing to the poor success of past approaches is the expression of indoleamine 2,3-dioxygenase 1 (IDO), a tryptophan catabolizing enzyme overexpressed in GBM, and critically involved in regulating tumor-infiltrating Treg levels. Herein, we review the current literature on Tregs in brain cancer, providing a detailed phenotype, causative mechanisms involved in their pathogenesis, and strategies that have been used to target this population, therapeutically. PMID:23720663

  6. 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…

  7. 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…

  8. Comparison of Two Therapeutic Strategies in Patients With Non-squamous Non-small Cell Lung Cancer (NSCLC) With Asymptomatic Brain Metastases

    ClinicalTrials.gov

    2015-11-29

    Non-small Cell Lung Cancer Metastatic; Non Epidermoid; Non-small Cell Lung Cancer; Adenocarcinoma of Lung Metastatic to Brain; Cerebral Metastases; Cerebral Radiotherapy; Brain Radiotherapy; Bevacizumab

  9. Uptake of ANG1005, a Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer

    PubMed Central

    Thomas, Fancy C.; Taskar, Kunal; Rudraraju, Vinay; Goda, Satyanarayana; Thorsheim, Helen R.; Gaasch, Julie A.; Palmieri, Diane; Steeg, Patricia S.; Lockman, Paul R.; Smith, Quentin R.

    2010-01-01

    Purpose We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport. Methods The transfer coefficient (Kin) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer. Results The BBB Kin for 125I-ANG1005 uptake (7.3 ± 0.2 × 10−3 mL/s/g) exceeded that for 3H-paclitaxel (8.5 ± 0.5 × 10−5) by 86 fold. Over 70% of 125I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain 125I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of 125I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of 14C-paclitaxel by 4–54 fold. Conclusions The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel. PMID:19774344

  10. 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. PMID:26015269

  11. 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. PMID:12963976

  12. 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.

  13. Detection of human brain cancer infiltration ex vivo and in vivo using quantitative optical coherence tomography.

    PubMed

    Kut, Carmen; Chaichana, Kaisorn L; Xi, Jiefeng; Raza, Shaan M; Ye, Xiaobu; McVeigh, Elliot R; Rodriguez, Fausto J; Quiñones-Hinojosa, Alfredo; Li, Xingde

    2015-06-17

    More complete brain cancer resection can prolong survival and delay recurrence. However, it is challenging to distinguish cancer from noncancer tissues intraoperatively, especially at the transitional, infiltrative zones. This is especially critical in eloquent regions (for example, speech and motor areas). This study tested the feasibility of label-free, quantitative optical coherence tomography (OCT) for differentiating cancer from noncancer in human brain tissues. Fresh ex vivo human brain tissues were obtained from 32 patients with grade II to IV brain cancer and 5 patients with noncancer brain pathologies. On the basis of volumetric OCT imaging data, pathologically confirmed brain cancer tissues (both high- and low-grade) had significantly lower optical attenuation values at both cancer core and infiltrated zones when compared with noncancer white matter, and OCT achieved high sensitivity and specificity at an attenuation threshold of 5.5 mm(-1) for brain cancer patients. We also used this attenuation threshold to confirm the intraoperative feasibility of performing in vivo OCT-guided surgery using a murine model harboring human brain cancer. Our OCT system was capable of processing and displaying a color-coded optical property map in real time at a rate of 110 to 215 frames per second, or 1.2 to 2.4 s for an 8- to 16-mm(3) tissue volume, thus providing direct visual cues for cancer versus noncancer areas. Our study demonstrates the translational and practical potential of OCT in differentiating cancer from noncancer tissue. Its intraoperative use may facilitate safe and extensive resection of infiltrative brain cancers and consequently lead to improved outcomes when compared with current clinical standards. PMID:26084803

  14. miR-20b is up-regulated in brain metastases from primary breast cancers

    PubMed Central

    Ahmad, Aamir; Ginnebaugh, Kevin R.; Sethi, Seema; Chen, Wei; Ali, Rouba; Mittal, Sandeep; Sarkar, Fazlul H.

    2015-01-01

    Brain metastases are frequent in patients with advanced breast cancer and are associated with poor prognosis. However, unique molecular biomarkers have not yet been established. We hypothesized that microRNA-20b (miR-20b) plays a role in breast cancer brain metastasis. Our study cohort comprised of eleven breast cancer patients with brain metastasis and nine control patients (age, stage, and follow-up matched) with breast cancer without brain metastasis. Cases were reviewed microscopically to select tumor blocks with >50% tumor cells, RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks and expression of miR-20b analyzed using qRT-PCR. We further tested the effect of miR-20b overexpression on colony formation and invasion in vitro using MCF-7 and MDA-MB-231 cells. In the patient-derived samples, miR-20b expression was significantly higher in brain metastases of breast cancer patients, compared to primary breast tumors as well as the patients without brain metastasis. miR-20b also significantly induced the colony formation and invasiveness of breast cancer cells. Further, miR-20b levels were observed to be high in brain-metastasizing cells, compared to bone-metastasizing cells. Together, our findings suggest a novel role of miR-20b in breast cancer brain metastasis that warrants further investigation for its potential to be developed as prognostic and/or therapeutic target. PMID:25893380

  15. Brain Tumors

    MedlinePlus

    ... brain. Brain tumors can be benign, with no cancer cells, or malignant, with cancer cells that grow quickly. Some are primary brain ... targeted therapy. Targeted therapy uses substances that attack cancer cells without harming normal cells. Many people get ...

  16. 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

  17. FDG and (82)Rb PET/MRI features of brain metastasis of breast cancer.

    PubMed

    Lu, Yang

    2015-06-01

    A 64-year-old woman with stage IV breast cancer underwent an FDG and Rb PET brain studies. The PET brain images were fused with MRI brain T1 post-contrast images. The known enhancing left superoposterior frontal brain metastasis is positive on both FDG Rb PET/MRI images. The Rb PET/MRI showed better target-to-noise ratio, but showed nonspecific uptake in the superior sagittal sinus. PMID:25674864

  18. 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. PMID:26159887

  19. [Advances in diagnosis and treatment of brain metastases from the primary lung cancer].

    PubMed

    Liu, Yi; Chen, Jun

    2013-07-01

    Lung cancer with brain metastasis was 23% to 65%, and is the most common type in brain metastasis tumors with the poor prognosis. At present, diagnosis and treatment of brain metastases from lung carcinoma and its molecular mechanism have become one hot spot of amount researches. Here, we made a systematic review of the progress of the clinical features, diagnosis and treatment of brain metastases from lung and its molecular mechanism. PMID:23866671

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

    PubMed

    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

  1. [The dead mother].

    PubMed

    Green, A

    1993-03-01

    This study is not concerned, as the title might suggest, with the actual death of the mother but with the child's experience of a mother who is physically present but internally absent due to depression. The child simultaneously introjects and splits off the mother imago, making mourning and "burial" equally impossible. The consequence of this cathectic deprivation is what the author calls "psychic holes" or "white depression". Green attributes to the dead mother a similar structuring function for the psychic apparatus to that attributed to the dead father in Freud's Totem and Taboo, and places the dead mother complex side by side with the Oedipus complex. PMID:8465007

  2. 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.

  3. 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.

  4. [Systemic treatment of brain metastases from breast cancer: cytotoxic chemotherapy and targeted therapies].

    PubMed

    Bachelot, Thomas; Le Rhun, Emilie; Labidi-Gally, Intidar; Heudel, Pierre; Gilabert, Marine; Bonneterre, Jacques; Pierga, Jean-Yves; Gonçalves, Anthony

    2013-01-01

    Prevalence of brain metastases is increasing in breast cancer. Brain metastases represent a poor-prognosis disease for which local treatments continue to play a major role. In spite of the presence of a physiological blood-brain barrier limiting their activity, some systemic treatments may display a significant antitumor activity at the central nervous system level. In HER2-positive metastatic breast cancer with brain metastases not previously treated with whole brain radiotherapy, capecitabine and lapatinib combination obtains a volumetric reponse in two thirds of patients (LANDSCAPE study). If confirmed, these results could modify in selected patients the layout of therapeutic strategies. Promoting novel targeted approaches and innovative therapeutic combinations is a critical need to improve survival of breast cancer patients with brain metastases. PMID:23305997

  5. 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. PMID:26116144

  6. Whole brain radiotherapy for brain metastases from breast cancer: estimation of survival using two stratification systems

    PubMed Central

    Viani, Gustavo A; Castilho, Marcus S; Salvajoli, João V; Pellizzon, Antonio Cassio A; Novaes, Paulo E; Guimarães, Flavio S; Conte, Maria A; Fogaroli, Ricardo C

    2007-01-01

    Background Brain metastases (BM) are the most common form of intracranial cancer. The incidence of BM seems to have increased over the past decade. Recursive partitioning analysis (RPA) of data from three Radiation Therapy Oncology Group (RTOG) trials (1200 patients) has allowed three prognostic groups to be identified. More recently a simplified stratification system that uses the evaluation of three main prognostics factors for radiosurgery in BM was developed. Methods To analyze the overall survival rate (OS), prognostic factors affecting outcomes and to estimate the potential improvement in OS for patients with BM from breast cancer, stratified by RPA class and brain metastases score (BS-BM). From January 1996 to December 2004, 174 medical records of patients with diagnosis of BM from breast cancer, who received WBRT were analyzed. The surgery followed by WBRT was used in 15.5% of patients and 84.5% of others patients were submitted at WBRT alone; 108 patients (62.1%) received the fractionation schedule of 30 Gy in 10 fractions. Solitary BM was present in 37.9 % of patients. The prognostic factors evaluated for OS were: age, Karnofsky Performance Status (KPS), number of lesions, localization of lesions, neurosurgery, chemotherapy, absence extracranial disease, RPA class, BS-BM and radiation doses and fractionation. Results The OS in 1, 2 and 3 years was 33.4 %, 16.7%, and 8.8 %, respectively. The RPA class analysis showed strong relation with OS (p < 0.0001). The median survival time by RPA class in months was: class I 11.7, class II 6.2 and class III 3.0. The significant prognostic factors associated with better OS were: higher KPS (p < 0.0001), neurosurgery (P < 0.0001), single metastases (p = 0.003), BS-BM (p < 0.0001), control primary tumor (p = 0.002) and absence of extracranial metastases (p = 0.001). In multivariate analysis, the factors associated positively with OS were: neurosurgery (p < 0.0001), absence of extracranial metastases (p <0.0001) and RPA

  7. 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.

  8. Cabazitaxel in castration resistant prostate cancer with brain metastases: 3 case reports.

    PubMed

    De Placido, Sabino; Rescigno, Pasquale; Federico, Piera; Buonerba, Carlo; Bosso, Davide; Puglia, Livio; Izzo, Michela; Policastro, Tania; Di Lorenzo, Giuseppe

    2014-06-16

    Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequently in clinical practice, especially brain metastases. Despite the new drugs now available for metastatic castration resistant prostate cancer, no clinical evidence exists about their effectiveness on brain metastases. We describe the clinical history of 3 patients treated with cabazitaxel plus whole brain radiotherapy. These case reports demonstrate that cabazitaxel is highly active and well tolerated in brain metastases. PMID:24945013

  9. Cabazitaxel in castration resistant prostate cancer with brain metastases: 3 case reports

    PubMed Central

    Placido, Sabino De; Rescigno, Pasquale; Federico, Piera; Buonerba, Carlo; Bosso, Davide; Puglia, Livio; Izzo, Michela; Policastro, Tania; Lorenzo, Giuseppe Di

    2014-01-01

    Prostate cancer is the most common non-cutaneous malignancy for men. The skeleton is the most common metastatic site but, following an improvement in survival, metastases in uncommon sites are being found more frequently in clinical practice, especially brain metastases. Despite the new drugs now available for metastatic castration resistant prostate cancer, no clinical evidence exists about their effectiveness on brain metastases. We describe the clinical history of 3 patients treated with cabazitaxel plus whole brain radiotherapy. These case reports demonstrate that cabazitaxel is highly active and well tolerated in brain metastases. PMID:24945013

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

    PubMed

    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. 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

  12. 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.

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

    PubMed Central

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

    2015-01-01

    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. PMID:25970776

  14. Transferrin receptor-targeted vitamin E TPGS micelles for brain cancer therapy: preparation, characterization and brain distribution in rats.

    PubMed

    Sonali; Agrawal, Poornima; Singh, Rahul Pratap; Rajesh, Chellappa V; Singh, Sanjay; Vijayakumar, Mahalingam R; Pandey, Bajrangprasad L; Muthu, Madaswamy Sona

    2016-06-01

    The effective treatment of brain cancer is hindered by the poor transport across the blood-brain barrier (BBB) and the low penetration across the blood-tumor barrier (BTB). The objective of this work was to formulate transferrin-conjugated docetaxel (DTX)-loaded d-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS) micelles for targeted brain cancer therapy. The micelles with and without transferrin conjugation were prepared by the solvent casting method and characterized for their particle size, polydispersity, drug encapsulation efficiency, drug loading, in vitro release study and brain distribution study. Particle sizes of prepared micelles were determined at 25 °C by dynamic light scattering technique. The external surface morphology was determined by transmission electron microscopy analysis and atomic force microscopy. The encapsulation efficiency was determined by spectrophotometery. In vitro release studies of micelles and control formulations were carried out by dialysis bag diffusion method. The particle sizes of the non-targeted and targeted micelles were <20 nm. About 85% of drug encapsulation efficiency was achieved with micelles. The drug release from transferrin-conjugated micelles was sustained for >24 h with 50% of drug release. The in vivo results indicated that transferrin-targeted TPGS micelles could be a promising carrier for brain targeting due to nano-sized drug delivery, solubility enhancement and permeability which provided an improved and prolonged brain targeting of DTX in comparison to the non-targeted micelles and marketed formulation. PMID:26431064

  15. 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

  16. 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 Central

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

    2013-01-01

    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 16th 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

  17. 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

  18. 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. PMID:24564367

  19. "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

  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. 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

  2. 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

  3. Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases

    PubMed Central

    2011-01-01

    Introduction Activation status of the phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer brain metastases (BCBMs) is largely unknown. We examined expression of phospho(p)-AKT, p-S6, and phosphatase and tensin homologue (PTEN) in BCBMs and their implications for overall survival (OS) and survival after BCBMs. Secondary analyses included PI3K pathway activation status and associations with time to distant recurrence (TTDR) and time to BCBMs. Similar analyses were also conducted among the subset of patients with triple-negative BCBMs. Methods p-AKT, p-S6, and PTEN expression was assessed with immunohistochemistry in 52 BCBMs and 12 matched primary BCs. Subtypes were defined as hormone receptor (HR)+/HER2-, HER2+, and triple-negative (TNBC). Survival analyses were performed by using a Cox model, and survival curves were estimated with the Kaplan-Meier method. Results Expression of p-AKT and p-S6 and lack of PTEN (PTEN-) was observed in 75%, 69%, and 25% of BCBMs. Concordance between primary BCs and matched BCBMs was 67% for p-AKT, 58% for p-S6, and 83% for PTEN. PTEN- was more common in TNBC compared with HR+/HER2- and HER2+. Expression of p-AKT, p-S6, and PTEN- was not associated with OS or survival after BCBMs (all, P > 0.06). Interestingly, among all patients, PTEN- correlated with shorter time to distant and brain recurrence. Among patients with TNBC, PTEN- in BCBMs was associated with poorer overall survival. Conclusions The PI3K pathway is active in most BCBMs regardless of subtype. Inhibition of this pathway represents a promising therapeutic strategy for patients with BCBMs, a group of patients with poor prognosis and limited systemic therapeutic options. Although expression of the PI3K pathway did not correlate with OS and survival after BCBM, PTEN- association with time to recurrence and OS (among patients with TNBC) is worthy of further study. PMID:22132754

  4. 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.

  5. 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.

  6. αB-crystallin: a Novel Regulator of Breast Cancer Metastasis to the Brain

    PubMed Central

    Malin, Dmitry; Strekalova, Elena; Petrovic, Vladimir; Deal, Allison M.; Ahmad, Abraham Al; Adamo, Barbara; Miller, C. Ryan; Ugolkov, Andrey; Livasy, Chad; Fritchie, Karen; Hamilton, Erika; Blackwell, Kimberly; Geradts, Joseph; Ewend, Matt; Carey, Lisa; Shusta, Eric V.; Anders, Carey K.; Cryns, Vincent L.

    2013-01-01

    Purpose Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBC. Experimental Design αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among breast cancer patients with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMECs) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte co-culture blood-brain barrier (BBB) model were examined. Additionally, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. Results In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among TNBC patients. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, while silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs at least in part through an α3β1 integrin-dependent mechanism. αB-crystallin overexpression promoted brain metastasis, while silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models. Conclusion αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. PMID:24132917

  7. 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

  8. [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

  9. Complete response of brain metastases from breast cancer overexpressing Her-2/neu to radiation and concurrent Lapatinib and Capecitabine.

    PubMed

    Abboud, Mirna; Saghir, Nagi S El; Salame, Joseph; Geara, Fady B

    2010-01-01

    Breast cancers that overexpress the human epidermal growth factor receptor 2 (HER-2) have a predilection to metastasize to the brain. Therapeutic options for brain metastases with systemic therapy remain a challenge in those patients since targeted and chemotherapeutic agents have limited penetration through the blood-brain barrier. Here we report the case of a patient with brain metastases from breast cancer overexpressing HER-2 who achieved a complete radiologic response after treatment by radiation and concurrent Lapatinib and Capecitabine. PMID:21070441

  10. Assessment of prognostic scores in brain metastases from breast cancer

    PubMed Central

    Tabouret, Emeline; Metellus, Philippe; Gonçalves, Anthony; Esterni, Benjamin; Charaffe-Jauffret, Emmanuelle; Viens, Patrice; Tallet, Agnés

    2014-01-01

    Background Breast cancer (BC) is the second most common cause of brain metastases (BM). Optimal management of BM from BC is still debated. In an attempt to provide appropriate treatment and to assist with optimal patient selection, several specific prognostic classifications for BM from BC have been established. We evaluated the prognostic value and validity of the 6 proposed scoring systems in an independent population of BC patients with BM. Methods We retrospectively reviewed all consecutive BC patients referred to our institution for newly diagnosed BM between October 1995 and July 2011 (n = 149). Each of the 6 scores proposed for BM from BC (Sperduto, Niwinska, Park, Nieder, Le Scodan, and Claude) was applied to this population. The discriminative ability of each score was assessed using the Brier score and the C-index. Individual prognostic values of clinical and histological factors were analyzed using uni- and multivariate analyses. Results Median overall survival was 15.1 months (95% CI,11.5–18.7). Sperduto-GPA (P < .001), Nieder (P < .001), Park (P < .001), Claude (P < .001), Niwinska (P < .001), and Le Scodan (P = .034) scores all showed significant prognostic value. The Nieder score showed the best discriminative ability (C-index, 0.672; Brier score error reduction, 16.1%). Conclusion The majority of prognostic scores were relevant for patients with BM from BC in our independent population, and the Nieder score seems to present the best predictive value but showed a relatively low positive predictive value. Thus, these results remain insufficient and challenge the routine use of these scoring systems. PMID:24311640

  11. Multi-scale, multi-resolution brain cancer modeling.

    PubMed

    Zhang, Le; Chen, L Leon; Deisboeck, Thomas S

    2009-03-01

    In advancing discrete-based computational cancer models towards clinical applications, one faces the dilemma of how to deal with an ever growing amount of biomedical data that ought to be incorporated eventually in one form or another. Model scalability becomes of paramount interest. In an effort to start addressing this critical issue, here, we present a novel multi-scale and multi-resolution agent-based in silico glioma model. While 'multi-scale' refers to employing an epidermal growth factor receptor (EGFR)-driven molecular network to process cellular phenotypic decisions within the micro-macroscopic environment, 'multi-resolution' is achieved through algorithms that classify cells to either active or inactive spatial clusters, which determine the resolution they are simulated at. The aim is to assign computational resources where and when they matter most for maintaining or improving the predictive power of the algorithm, onto specific tumor areas and at particular times. Using a previously described 2D brain tumor model, we have developed four different computational methods for achieving the multi-resolution scheme, three of which are designed to dynamically train on the high-resolution simulation that serves as control. To quantify the algorithms' performance, we rank them by weighing the distinct computational time savings of the simulation runs versus the methods' ability to accurately reproduce the high-resolution results of the control. Finally, to demonstrate the flexibility of the underlying concept, we show the added value of combining the two highest-ranked methods. The main finding of this work is that by pursuing a multi-resolution approach, one can reduce the computation time of a discrete-based model substantially while still maintaining a comparably high predictive power. This hints at even more computational savings in the more realistic 3D setting over time, and thus appears to outline a possible path to achieve scalability for the all

  12. Regional brain activation during verbal declarative memory in metastatic breast cancer

    PubMed Central

    Kesler, Shelli R.; Bennett, F. Chris; Mahaffey, Misty L.; Spiegel, David

    2010-01-01

    Purpose To determine the neurofunctional basis of verbal memory dysfunction in women with metastatic breast cancer. This objective was based on previous research suggesting memory and other cognitive deficits in this population. We attempted to determine if verbal memory impairments were related to the most commonly studied disease parameters including adjuvant chemotherapy and chronic stress-related disruption of limbic system structures. Experimental Design We utilized functional magnetic resonance imaging (fMRI) to test our hypothesis that women with breast cancer would demonstrate significantly lower brain activation during a verbal declarative memory tasks compared to age and education-matched healthy female controls. We also assessed several stress-related variables including diurnal cortisol levels to test our hypothesis that women with breast cancer would demonstrate higher stress and this would contribute to brain activation deficits during memory tasks. Results Women with breast cancer had significantly lower prefrontal cortex activation during the memory encoding condition compared to controls. However, the breast cancer group demonstrated significantly greater activation than controls during the recall condition in multiple, diffuse brain regions. There were no significant differences between the groups in stress-related variables. Women who were treated with CMF chemotherapy demonstrated lower prefrontal cortex activation during memory encoding. Conclusions These results suggest that women with metastatic breast cancer may be at risk for verbal memory impairments as a result of altered functional brain activation profiles. These findings may be associated with chemotherapy type and/or other aspects of the breast cancer disease process. PMID:19843664

  13. 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 ...

  14. 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

  15. Probing the mechanical properties of brain cancer cells using a microfluidic cell squeezer device

    PubMed Central

    Khan, Z. S.; Vanapalli, S. A.

    2013-01-01

    Despite being invasive within surrounding brain tissues and the central nervous system, little is known about the mechanical properties of brain tumor cells in comparison with benign cells. Here, we present the first measurements of the peak pressure drop due to the passage of benign and cancerous brain cells through confined microchannels in a “microfluidic cell squeezer” device, as well as the elongation, speed, and entry time of the cells in confined channels. We find that cancerous and benign brain cells cannot be differentiated based on speeds or elongation. We have found that the entry time into a narrow constriction is a more sensitive indicator of the differences between malignant and healthy glial cells than pressure drops. Importantly, we also find that brain tumor cells take a longer time to squeeze through a constriction and migrate more slowly than benign cells in two dimensional wound healing assays. Based on these observations, we arrive at the surprising conclusion that the prevailing notion of extraneural cancer cells being more mechanically compliant than benign cells may not apply to brain cancer cells. PMID:24403988

  16. Relaxins enhance growth of spontaneous murine breast cancers as well as metastatic colonization of the brain.

    PubMed

    Binder, Claudia; Chuang, Eugenia; Habla, Christina; Bleckmann, Annalen; Schulz, Matthias; Bathgate, Ross; Einspanier, Almuth

    2014-01-01

    Relaxins are known for their tissue remodeling capacity which is also a hallmark of cancer progression. However, their role in the latter context is still unclear, particularly in breast cancer. In a mouse model with spontaneously arising breast cancer due to erbB2-overexpression we show that exposure to porcine relaxin results in significantly enhanced tumour growth as compared to control animals. This is accompanied by increased serum concentrations of progesterone and estradiol as well as elevated expression of the respective receptors and the relaxin receptor RXFP1 in the tumour tissue. It is also associated with enhanced infiltration by tumour-associated macrophages which are known to promote tumour progression. Additionally, we show in an ex vivo model of metastatic brain colonization that porcine relaxin as well as human brain-specific relaxin-3 promotes invasion into the brain tissue and enhance interaction of breast cancer cells with the resident brain macrophages, the microglia. Relaxin signaling is mediated via RXFP1, since R 3/I5, a specific agonist of the relaxin-3 receptor RXFP3 in the brain, does not significantly enhance invasion. Taken together, these findings strongly support a role of relaxins in the progression of breast cancer where they foster primary tumour growth as well as metastatic colonization by direct and indirect means. PMID:23963762

  17. Dead Sea rhodopsins revisited.

    PubMed

    Bodaker, Idan; Suzuki, Marcelino T; Oren, Aharon; Béjà, Oded

    2012-12-01

    The Dead Sea is a unique hypersaline ecosystem with near toxic magnesium levels (∼2 M), dominance of divalent cations and a slightly acidic pH. Previously, we reported a haloarchaeon related to Halobacterium salinarum to dominate in a microbial bloom that developed in 1992 in the upper water layers of the lake following massive freshwater runoff. Whether this clade also dominated an earlier bloom in 1980-1982 cannot be ascertained as no samples for cultivation-independent analysis were preserved. The presence of the light-driven proton pump bacteriorhodopsin was reported in the 1980-1982 bloom of prokaryotes that had developed in the Dead Sea. To test the hypothesis that bacteriorhodopsin proton pumping may play a major role in determining what type of haloarchaea may dominate in specific bloom conditions, we compared rhodopsin genes recovered from Dead Sea biomass collected in different periods with genes coding for retinal proteins in isolated haloarchaea. Novel bacteriorhodopsin and sensory rhodopsin genes were found in samples collected in 2007 and 2010. The fact that no rhodopsin genes were recovered from samples collected during the 1992 bloom, which was dominated by a single species, suggests that different clades were present in the 1980-1982 and 1992 blooms, and that bacteriorhodopsin proton pumping did not necessarily play a determinative role in the dominance of specific halophiles in the blooms. PMID:23760932

  18. 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.

  19. 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

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

    SciTech Connect

    Yang, Heekyoung; Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710; Cancer Stem Cell Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710 ; Yoon, Su Jin; Jin, Juyoun; Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710; Cancer Stem Cell Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710 ; 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.

  1. [Radiotherapy plus concomitant systemic therapies for patients with brain metastases from breast cancer].

    PubMed

    Cao, K I; Kirova, Y M

    2014-06-01

    The incidence of brain metastases from breast cancer is increasing with diagnosis and therapeutics progress, especially with systemic therapies. The occurrence of multiple brain metastases remains a delicate situation when surgery and stereotactic radiosurgery are not indicated, nor available. Treatment strategy is based on the patient's general condition and extracranial disease status. Whole brain radiation therapy remains the gold standard local treatment but its efficacy is limited with a median overall survival of 6 months. New strategies are needed for increasing survival and patients' quality of life. Combining radiation therapy and chemotherapy has been a subject of interest. This article sums up the different radiotherapy plus concomitant systemic therapies combinations for the treatment of brain metastases from breast cancer. PMID:24731405

  2. 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. PMID:26653284

  3. Towards hyperpolarized 13C-succinate imaging of brain cancer

    NASA Astrophysics Data System (ADS)

    Bhattacharya, Pratip; Chekmenev, Eduard Y.; Perman, William H.; Harris, Kent C.; Lin, Alexander P.; Norton, Valerie A.; Tan, Chou T.; Ross, Brian D.; Weitekamp, Daniel P.

    2007-05-01

    We describe a novel 13C enriched precursor molecule, sodium 1- 13C acetylenedicarboxylate, which after hydrogenation by PASADENA (Parahydrogen and Synthesis Allows Dramatically Enhanced Nuclear Alignment) under controlled experimental conditions, becomes hyperpolarized 13C sodium succinate. Fast in vivo 3D FIESTA MR imaging demonstrated that, following carotid arterial injection, the hyperpolarized 13C-succinate appeared in the head and cerebral circulation of normal and tumor-bearing rats. At this time, no in vivo hyperpolarized signal has been localized to normal brain or brain tumor. On the other hand, ex vivo samples of brain harvested from rats bearing a 9L brain tumor, 1 h or more following in vivo carotid injection of hyperpolarized 13C sodium succinate, contained significant concentrations of the injected substrate, 13C sodium succinate, together with 13C maleate and succinate metabolites 1- 13C-glutamate, 5- 13C-glutamate, 1- 13C-glutamine and 5- 13C-glutamine. The 13C substrates and products were below the limits of NMR detection in ex vivo samples of normal brain consistent with an intact blood-brain barrier. These ex vivo results indicate that hyperpolarized 13C sodium succinate may become a useful tool for rapid in vivo identification of brain tumors, providing novel biomarkers in 13C MR spectral-spatial images.

  4. 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. |

  5. 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.

  6. 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 ...

  7. 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

  8. 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.

  9. 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.

  10. Pediatric Brain Tumor Foundation

    MedlinePlus

    ... you insights into your child's treatment. LEARN MORE Brain tumors and their treatment can be deadly so ... to make progress in “immunogenomics” Read more >> Pediatric Brain Tumor Foundation 302 Ridgefield Court, Asheville, NC 28806 ...

  11. Brain Cancer Treatment Shows Promise in Early Trial

    MedlinePlus

    ... sparing healthy cells," said study co-leader Dr. Timothy Cloughesy. He is director of the neuro-oncology ... in months," said study co-lead author Dr. Michael Vogelbaum, associate director of the brain tumor neuro- ...

  12. Brain Cancer Treatment Shows Promise in Early Trial

    MedlinePlus

    ... Dr. Timothy Cloughesy. He is director of the neuro-oncology program at the University of California, Los ... Michael Vogelbaum, associate director of the brain tumor neuro-oncology center at the Cleveland Clinic. Here's how ...

  13. Significance of Trask protein interactions in brain metastatic cohorts of lung cancers.

    PubMed

    Wu, Hua; Shang, Li-Qun; Chen, Rui-Lin; Yang, Shu-Mei; Wang, Shui-Li; Wang, Jun; Sun, Gang

    2015-06-01

    A class of adhesion protein that occurs in the membrane with both extracellular and intracellular domain and play vital role in maintaining multicellularity is TRASK, also called CUB-domain containing protein1, CD318 (CDCP1). Specifically, in the current study, documented aggressive grades of lung cancers and distant metastatic tissues were examined for protein interactions of Trask and compared with lung cancer variants in situ. The intracellular domain of Trask has the ability to undergo tyrosine phosphorylation and thereafter undergo increased genomic expression, as well as interact with cytoskeletal proteins in the cell periphery and other local signal transduction machinery to induce invadopodia formation and distant metastasis. We incorporated proximity ligation assay to examine protein interactions of Trask in metastatic lung cancer tissues and compare with advanced and low-grade lung cancers restricted to the primary site of origins. Here, we provide direct evidence that activated Trask, which is a phosphorylated form, binds with cytoskeletal proteins actin and spectrin. These interactions were not seen in locally growing lung cancer and cancer in situ. These interactions may be responsible for invadopodia formation and breaking free from a multicellular environment. Functional studies demonstrated interaction between Trask and the STOCs Orai1 and Stim1. Calcium release from internal stores was highest in metastatic lung cancers, suggesting this mechanism as an initial stimulus for the cells to respond chaotically to external growth factor stimulation, especially in aggressive metastatic variants of lung cancers. Recently, inhibitors of STOCs have been identified, and preclinical evidence may be obtained whether these drugs may be of benefit in preventing the deadly consequences of lung cancer. PMID:25775948

  14. Magnetic field exposure in relation to leukemia and brain cancer mortality among electric utility workers.

    PubMed

    Savitz, D A; Loomis, D P

    1995-01-15

    Reports of leukemia and brain cancer among men in electrical occupations suggest a small increase in risk, but most previous studies have failed to classify magnetic field exposure accurately or to consider potential confounders. The authors conducted an historical cohort mortality study of 138,905 men employed at five large electric power companies in the United States between 1950 and 1986 with at least 6 months of work experience. Exposure was estimated by linking individual work histories to data from 2,842 workshift magnetic field measurements. Mortality follow-up identified 20,733 deaths based on 2,656,436 person-years of experience. Death rates were analyzed in relation to magnetic field exposure history with Poisson regression. Total mortality and cancer mortality rose slightly with increasing magnetic field exposure. Leukemia mortality, however, was not associated with indices of magnetic field exposure except for work as an electrician. Brain cancer mortality was modestly elevated in relation to duration of work in exposed jobs and much more strongly associated with magnetic field exposure indices. Brain cancer risk increased by an estimated factor of 1.94 per microtesla-year of magnetic field exposure in the previous 2-10 years, with a mortality rate ratio of 2.6 in the highest exposure category. In contrast to other studies, these data do not support an association between occupational magnetic field exposure and leukemia but do suggest a link to brain cancer. PMID:7817968

  15. CyberKnife therapy of 24 multiple brain metastases from lung cancer: A case report

    PubMed Central

    YANG, GUIQING; WANG, YISHAN; WANG, YUANYUAN; LIN, SIXIANG; SUN, DONGNING

    2013-01-01

    Brain metastasis is a significant cause of morbidity and mortality and a critical complication of non-central nervous system primary carcinoma. The present study describes the clinical case of a 46-year-old male with lung cancer and life-threatening brain metastases. The patient was diagnosed with lung cancer with a clinical stage of T2N0M1 (stage IV). Six months after the initial diagnosis and administration of conformal radiotherapy combined with three cycles of chemotherapy, an enhanced computed tomography (CT) scan of the brain revealed abnormalities with double-dosing of intravenous contrast. The CT scan identified >24 lesions scattered in the whole brain. The patient was treated with three-fraction Cyberknife radiotherapy at 22 Gy, delivered to the brain metastases at the Center for Tumor Treatment of People’s Liberation Army 107th Hospital. Following CyberKnife therapy, a CT scan of the brain revealed that most of the tumors had disappeared with almost no residual traces. The stereotactic radiosurgery (SRS) conducted using CyberKnife, an image-guided frameless robotic technology for whole-body radiosurgery, had produced a marked response. The present case report demonstrates that CyberKnife therapy plays a significant role in the management of multiple meta-static brain tumors. PMID:24137362

  16. 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

  17. Breast Cancer With Brain Metastases: Clinicopathologic Features, Survival, and Paired Biomarker Analysis

    PubMed Central

    Shen, Qi; Hess, Kenneth R.; Suki, Dima; Aldape, Kenneth D.; Sawaya, Raymond; Ibrahim, Nuhad K.

    2015-01-01

    Background. The aim of this study was to describe clinicopathologic features of patients with breast cancer brain metastasis (BCBM); to evaluate survival after diagnosis of BCBM; and to compare estrogen receptor (ER), progesterone receptor (PR), and HER2 expression in the paired primary and brain tumors. Materials and Methods. We identified 140 consecutive patients who underwent craniotomy for BCBM (either for diagnostic purpose or with therapeutic intent) at the University of Texas MD Anderson Cancer Center between 2002 and 2009. Results. Most patients had invasive ductal histology (91%), grade 3 tumors (67%), and positive axillary lymph node (64%). Of the tumors, 56% were ER-negative, 62% were PR-negative, 44% were HER2-positive, and 28% were triple negative (TN). Brain metastasis (BM) was solitary in 51% of patients. Median interval from breast cancer diagnosis to BM was 46 months; median survival after BM was 14.1 months. In the univariate analysis, younger age, solitary brain metastasis, and ER or PR positivity in the breast tumors were associated with longer survival. There was a statistical trend toward increased survival in HER2-positive patients compared with HER2-negative patients (18 vs. 11 months). In the multivariate analysis, predictors for longer survival included younger age, solitary brain lesion, and HER2 positivity in the breast cancer. Biomarkers were evaluated in paired primary and brain tumors in 35 patients for ER status, 34 for PR status, and 36 for HER2 status. Discordant rates were 28% for ER, 20% for PR, and 3% for HER2. Conclusion. Compared with unselected breast cancer patients at the same institution, patients with breast cancer who had brain metastases had a higher proportion of hormone receptor-negative, HER2-positive, and TN tumors. Younger age, solitary brain lesion, and HER2 expression were independent predictors of better survival in patients with BCBM. HER2 status was highly concordant between the paired primary and brain tumors

  18. 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. PMID:17556764

  19. Treatment of brain metastases of renal cell cancer with combined hypofractionated stereotactic radiotherapy and whole brain radiotherapy with hippocampal sparing

    PubMed Central

    VRÁNA, DAVID; ŠTUDENTOVÁ, HANA; MATZENAUER, MARCEL; VLACHOVÁ, ZUZANA; CWIERTKA, KAREL; GREMLICA, DAVID; KALITA, ONDŘEJ

    2016-01-01

    Renal cell cancer patients with brain metastatic disease generally have poor prognosis. Treatment options include surgery, radiotherapy, targeted therapy or best supportive care with respect to disease burden, patient preference and performance status. In the present case report the radiotherapy technique combining whole brain radiotherapy with hippocampal sparing (hippocampal avoidance whole brain radiotherapy HA-WBRT) and hypofractionated stereotactic radiotherapy (SRT) of the brain metastases is performed in a patient with metastatic renal cell carcinoma. HA-WBRT was administered to 30 Gy in 10 fractions with sparing of the hippocampal structures and SRT of 21 Gy in 3 fractions to brain metastases which has preceded the HA-WBRT. Two single arc volumetric modulated arc radiotherapy (VMAT) plans were prepared using Monaco planning software. The HA-WBRT treatment plan achieved the following results: D2=33.91 Gy, D98=25.20 Gy, D100=14.18 Gy, D50=31.26 Gy. The homogeneity index was calculated as a deduction of the minimum dose in 2% and 98% of the planning target volume (PTV), divided by the minimum dose in 50% of the PTV. The maximum dose to the hippocampus was 17.50 Gy and mean dose was 11.59 Gy. The following doses to organs at risk (OAR) were achieved: Right opticus Dmax, 31.96 Gy; left opticus Dmax, 30.96 Gy; chiasma D max, 32,76 Gy. The volume of PTV for stereotactic radiotherapy was 3,736 cm3, with coverage D100=20.95 Gy and with only 0.11% of the PTV being irradiated to dose below the prescribed dose. HA-WBRT with SRT represents a feasible technique for radiotherapy of brain metastatic disease, however this technique is considerably demanding on departmental equipment and staff time/experience. PMID:27313693

  20. Brain cancer mortality in the United States, 1986 to 1995: A geographic analysis1

    PubMed Central

    Fang, Zixing; Kulldorff, Martin; Gregorio, David I.

    2004-01-01

    The Atlas of Cancer Mortality in the United States, 1950–94 (Devesa et al.) published in 1999 by the National Institutes of Health suggests that there are elevated rates of brain and other nervous system cancer in the northwestern, north central, and southeastern parts of the country. Being descriptive in nature, the atlas does not evaluate whether observed patterns are simply due to random variation or if they are reflective of true geographical differences in disease risk or treatment practices. To formally test for geographical clustering of disease, we analyzed U.S. brain cancer mortality data from 1986 to 1995 with Tango’s Excess Events test, the Cuzick-Edwards k-Nearest-Neighbors test, and the spatial scan statistic. All tests revealed statistically significant geographical clustering for both adult men and women. The spatial scan statistic indicated that the most likely cluster of high mortality was in parts of Arkansas, Mississippi, and Oklahoma (relative risk [RR] = 1.22, P < 0.0001) for women and in parts of Tennessee and Kentucky (RR = 1.15, P < 0.0001) for men. Several secondary clusters were detected, but there were no statistically significant clusters of a very localized nature and a high RR. For childhood brain cancer, there were no statistically significant geographical clusters. It is reassuring that no local brain cancer mortality “hot spots” with very high RRs were found. While the causes of the large geographical clusters with modest RRs are unclear, the geographical pattern of brain cancer mortality provides valuable information that can help in formulating etiological hypotheses and in targeting high-risk populations for further epidemiological and health services research. PMID:15279710

  1. 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

  2. Correlates of Physiological and Psychological Stress Among Parents of Childhood Cancer and Brain Tumor Survivors

    PubMed Central

    Pollock, Elizabeth A.; Litzelman, Kristin; Wisk, Lauren E.; Witt, Whitney P.

    2013-01-01

    Objectives First, we sought to determine if parents of children with cancer or a brain tumor had greater stress compared to parents of healthy children, and to evaluate the correlates of stress among parents of children with cancer or brain tumors. Second, we sought to examine the relationship between perceived stress and symptoms of stress, and how that relationship may differ for parents of children with cancer. Methods In-person interviewer-assisted surveys were administered to 73 case dyads (children with cancer or a brain tumor and their parents) and 133 comparison dyads (children without health problems and their parents from a community sample). Descriptive analyses and multivariable logistic regressions were performed for case-comparison and case-only analyses to distinguish correlates of parental stress. Results Parents of children with cancer exhibited higher levels of physiological symptoms of stress than parents of healthy children. Poor sleep quality and greater social stress (negative social interactions) were significant correlates of increased levels of stress in parents of children with cancer (odds ratio 4.23, 95% confidence interval 1.15–15.60; and odds ratio 1.07, 95% confidence interval 1.00–1.14, respectively). A subset of parents reported symptoms of stress but not perceived stress, and this discordance was more pronounced among cancer caregivers. Conclusions Implementation of screening tools that include symptoms of stress may help clinicians to comprehensively identify parents of children with cancer who are in need of additional services. Targeted stress-reduction interventions that address sleep quality and negative social interactions may mitigate the deleterious effects of caregiving, improving the psychosocial well-being of both parents and children with cancer. PMID:23384776

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

    PubMed Central

    Koo, Taeryool

    2016-01-01

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

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

    PubMed

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

    2016-06-01

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

  5. 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. PMID:26276806

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-07-01

    Brain metastasis from uterine cervical cancer is rare, with an incidence of 0.5%, and usually occurs late in the course of the disease. We report a case of uterine cervical cancer with brain metastasis as the initial site of presentation. A 50-year-old woman with headache, vertigo, amnesia and loss of appetite was admitted for persistent vomiting. Contrast enhanced computed tomography showed a solitary right frontal cerebral lesion with ring enhancement and uterine cervical tumor. She was diagnosed with uterine cervical squamous cell carcinoma with parametrium invasion and no other distant affected organs were detected. The cerebral lesion was surgically removed and pathologically proved to be metastasis of uterine cervical squamous cell carcinoma. The patient underwent concurrent chemoradiotherapy, followed by cerebral radiation therapy, but multiple metastases to the liver and lung developed and the patient died 7 months after diagnosis of brain metastasis. PMID:25656985

  8. Regulation of local steroidogenesis in the brain and in prostate cancer: lessons learned from interdisciplinary collaboration.

    PubMed

    Fokidis, H Bobby; Adomat, Hans H; Kharmate, Geetanjali; Hosseini-Beheshti, Elham; Guns, Emma S; Soma, Kiran K

    2015-01-01

    Sex steroids play critical roles in the regulation of the brain and many other organs. Traditionally, researchers have focused on sex steroid signaling that involves travel from the gonads via the circulation to intracellular receptors in target tissues. This classic concept has been challenged, however, by the growing number of cases in which steroids are synthesized locally and act locally within diverse tissues. For example, the brain and prostate carcinoma were previously considered targets of gonadal sex steroids, but under certain circumstances, these tissues can upregulate their steroidogenic potential, particularly when circulating sex steroid concentrations are low. We review some of the similarities and differences between local sex steroid synthesis in the brain and prostate cancer. We also share five lessons that we have learned during the course of our interdisciplinary collaboration, which brought together neuroendocrinologists and cancer biologists. These lessons have important implications for future research in both fields. PMID:25223867

  9. Notching on Cancer's Door: Notch Signaling in Brain Tumors.

    PubMed

    Teodorczyk, Marcin; Schmidt, Mirko H H

    2014-01-01

    Notch receptors play an essential role in the regulation of central cellular processes during embryonic and postnatal development. The mammalian genome encodes for four Notch paralogs (Notch 1-4), which are activated by three Delta-like (Dll1/3/4) and two Serrate-like (Jagged1/2) ligands. Further, non-canonical Notch ligands such as epidermal growth factor like protein 7 (EGFL7) have been identified and serve mostly as antagonists of Notch signaling. The Notch pathway prevents neuronal differentiation in the central nervous system by driving neural stem cell maintenance and commitment of neural progenitor cells into the glial lineage. Notch is therefore often implicated in the development of brain tumors, as tumor cells share various characteristics with neural stem and progenitor cells. Notch receptors are overexpressed in gliomas and their oncogenicity has been confirmed by gain- and loss-of-function studies in vitro and in vivo. To this end, special attention is paid to the impact of Notch signaling on stem-like brain tumor-propagating cells as these cells contribute to growth, survival, invasion, and recurrence of brain tumors. Based on the outcome of ongoing studies in vivo, Notch-directed therapies such as γ-secretase inhibitors and blocking antibodies have entered and completed various clinical trials. This review summarizes the current knowledge on Notch signaling in brain tumor formation and therapy. PMID:25601901

  10. 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

  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. Treatment of brain metastases from HER-2-positive breast cancer: current status and new concepts.

    PubMed

    Bartolotti, Marco; Franceschi, Enrico; Brandes, Alba A

    2013-11-01

    Breast cancer is the second most common source of brain metastases (BM). The incidence of BM in breast cancer patients has increased over the past decade, especially among patients with HER-2-positive breast cancer. This is probably due to how aggressive the HER-2-positive disease is but also to the prolongation of survival obtained with current treatments, which allow good control of extracranial disease but are unable to cross the blood-brain barrier. At present, whole-brain radiotherapy, surgery and radiosurgery/stereotactic radiotherapy represent the cornerstone of treatment for BM, while the role of pharmacological therapy remains uncertain. Lapatinib demonstrated activity against BM from HER-2-positive breast cancer in small Phase II and retrospective studies, mainly in combination with capecitabine, and cases of dramatic responses to such treatment are present in literature. In this review we focus on the available clinical data regarding the treatment of BM from HER-2-positive breast cancer and on new concepts about the treatment and evaluation of the CNS response. PMID:24156325

  13. 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

  14. 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. PMID:26645485

  15. [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

  16. Isolated brain metastasis as a late recurrence of completely resected non-small cell lung cancer

    PubMed Central

    JU, LIXIA; HAN, MINGQUAN

    2016-01-01

    The brain is one of the most common sites for non-small cell lung cancer (NSCLC) metastasis; however, late isolated brain metastasis as a recurrence of NSCLC is rare. The present study describes a case of isolated solitary brain metastasis as a late recurrence of NSCLC, which occurred >2 years following the successful resection of the primary tumor, and was identified by magnetic resonance imaging. To the best of our knowledge, this is the first report of isolated brain metastasis as a postoperative recurrence of NSCLC. The aim of the present study was to highlight that, despite its rarity, such recurrence should be considered possible, and particular attention to the treatment of such patients should be paid. PMID:27347208

  17. 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)

  18. Inhibition of Type I Insulin-Like Growth Factor Receptor Signaling Attenuates the Development of Breast Cancer Brain Metastasis

    PubMed Central

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

    2013-01-01

    Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system. PMID:24039934

  19. Intercellular cooperation and competition in brain cancers: lessons from Drosophila and human studies.

    PubMed

    Waghmare, Indrayani; Roebke, Austin; Minata, Mutsuko; Kango-Singh, Madhuri; Nakano, Ichiro

    2014-11-01

    Glioblastoma (GBM) is a primary brain cancer with an extremely poor prognosis. GBM tumors contain heterogeneous cellular components, including a small subpopulation of tumor cells termed glioma stem cells (GSCs). GSCs are characterized as chemotherapy- and radiotherapy-resistant cells with prominent tumorigenic ability. Studies in Drosophila cancer models demonstrated that interclonal cooperation and signaling from apoptotic clones provokes aggressive growth of neighboring tumorigenic clones, via compensatory proliferation or apoptosis induced proliferation. Mechanistically, these aggressive tumors depend on activation of Jun-N-terminal kinase (upstream of c-JUN), and Drosophila Wnt (Wg) in the apoptotic clones. Consistent with these nonmammalian studies, data from several mammalian studies have shown that c-JUN and Wnt are hyperactivated in aggressive tumors (including GBM). However, it remains elusive whether compensatory proliferation is an evolutionarily conserved mechanism in cancers. In the present report, we summarize recent studies in Drosophila models and mammalian models (e.g., xenografts of human cancer cells into small animals) to elucidate the intercellular interactions between the apoptosis-prone cancer cells (e.g., non-GSCs) and the hyperproliferative cancer cells (e.g., GSCs). These evolving investigations will yield insights about molecular signaling interactions in the context of post-therapeutic phenotypic changes in human cancers. Furthermore, these studies are likely to revise our understanding of the genetic changes and post-therapeutic cell-cell interactions, which is a vital area of cancer biology with wide applications to many cancer types in humans. PMID:25232184

  20. Brain tumor - children

    MedlinePlus

    ... children; Neuroglioma - children; Oligodendroglioma - children; Meningioma - children; Cancer - brain tumor (children) ... The cause of primary brain tumors is unknown. Primary brain tumors may ... (spread to nearby areas) Cancerous (malignant) Brain tumors ...

  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. 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

  3. 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…

  4. Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies

    PubMed Central

    Passaro, Antonio; Gori, Bruno; Del Signore, Ester; Migliorino, Maria Rita; Ricciardi, Serena; Fulvi, Alberto; de Marinis, Filippo

    2014-01-01

    Bone and brain metastases are a very common secondary localization of disease in patients with lung cancer. The prognosis of these patients is still poor with a median survival of less than 1 year. Current therapeutic approaches include palliative radiotherapy and systemic therapy with chemotherapy and targeted agents. For bone metastasis, zoledronic acid is the most commonly used bisphosphonate to prevent, reduce the incidence and delay the onset of skeletal-related events (SREs). Recently, denosumab, a fully human monoclonal antibody directed against the receptor activator of nuclear factor κB (RANK) ligand inhibiting the maturation of pre-osteoclasts into osteoclasts, showed increased time to SREs and overall survival compared with zoledronic acid. The treatment of brain metastasis is still controversial. Available standard therapeutic options, such as whole brain radiation therapy and systemic chemotherapy, provide a slight improvement in local control, overall survival and symptom relief. More recently, novel target agents such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and afatinib have shown activity in patients with brain metastasis. Inter alia, in patients harboring EGFR mutations, the administration of EGFR TKIs is followed by a response rate of 70–80%, and a longer progression-free and overall survival than those obtained with standard chemotherapeutic regimens. This review is focused on the evidence for therapeutic strategies in bone and brain metastases due to lung cancer. PMID:24790650

  5. 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.

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

    ScienceCinema

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

    2009-09-01

    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.

  7. 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

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

    PubMed

    Yang, Heekyoung; Yoon, Su Jin; Jin, Juyoun; Choi, Seung Ho; Seol, Ho Jun; Lee, Jung-Il; Nam, Do-Hyun; Yoo, Hae Yong

    2011-03-01

    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. PMID:21291864

  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. PMID:26164063

  10. 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

  11. Probabilistic modeling of short survivability in patients with brain metastasis from lung cancer.

    PubMed

    Makond, Bunjira; Wang, Kung-Jeng; Wang, Kung-Min

    2015-05-01

    The prediction of substantially short survivability in patients is extremely risky. In this study, we proposed a probabilistic model using Bayesian network (BN) to predict the short survivability of patients with brain metastasis from lung cancer. A nationwide cancer patient database from 1996 to 2010 in Taiwan was used. The cohort consisted of 438 patients with brain metastasis from lung cancer. We utilized synthetic minority over-sampling technique (SMOTE) to solve the imbalanced property embedded in the problem. The proposed BN was compared with three competitive models, namely, naive Bayes (NB), logistic regression (LR), and support vector machine (SVM). Statistical analysis showed that performances of BN, LR, NB, and SVM were statistically the same in terms of all indices with low sensitivity when these models were applied on an imbalanced data set. Results also showed that SMOTE can improve the performance of the four models in terms of sensitivity, while keeping high accuracy and specificity. Further, the proposed BN is more effective as compared with NB, LR, and SVM from two perspectives: the transparency and ability to show the relation of factors affecting brain metastasis from lung cancer; it allows decision makers to find the probability despite incomplete evidence and information; and the sensitivity of the proposed BN is the highest among all standard machine learning methods. PMID:25804445

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

    PubMed

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

    2015-10-01

    Cerebral metastases are the most common brain neoplasms seen clinically in the adults and comprise more than half of all brain tumours. Actual treatment options for brain metastases that include surgical resection, radiotherapy and chemotherapy are rarely curative, although palliative treatment improves survival and life quality of patients carrying brain-metastatic tumours. Chemotherapy in particular has also shown limited or no activity in brain metastasis of most tumour types. Many chemotherapeutic agents used systemically do not cross the blood-brain barrier (BBB), whereas others may transiently weaken the BBB and allow extravasation of tumour cells from the circulation into the brain parenchyma. Increasing evidence points out that the interaction between the BBB and tumour cells plays a key role for implantation and growth of brain metastases in the central nervous system. The BBB, as the tightest endothelial barrier, prevents both early detection and treatment by creating a privileged microenvironment. Therefore, as observed in several in vivo studies, precise targetting the BBB by a specific transient opening of the structure making it permeable for therapeutic compounds, might potentially help to overcome this difficult clinical problem. Moreover, a better understanding of the molecular features of the BBB, its interrelation with metastatic tumour cells and the elucidation of cellular mechanisms responsible for establishing cerebral metastasis must be clearly outlined in order to promote treatment modalities that particularly involve chemotherapy. This in turn would substantially expand the survival and quality of life of patients with brain metastasis, and potentially increase the remission rate. Therefore, the focus of this review is to summarise the current knowledge on the role and function of the BBB in cancer metastasis. PMID:26032862

  13. Brain metabolomic profiles of lung cancer patients prior to treatment characterized by proton magnetic resonance spectroscopy

    PubMed Central

    Benveniste, Helene; Zhang, Shaonan; Reinsel, Ruth A; Li, Haifang; Lee, Hedok; Rebecchi, Mario; Moore, William; Johansen, Christoffer; Rothman, Douglas L; Bilfinger, Thomas V

    2012-01-01

    Cancer patients without evidence of brain metastases often exhibit constitutional symptoms, cognitive dysfunction and mood changes at the time of clinical diagnosis, i.e. prior to surgical and/or chemotherapy treatment. At present however, there is limited information on brain metabolic and functional status in patients with systemic cancers such as lung cancer prior to initiation of treatment. Therefore, a prospective, observational study was conducted on patients with a clinical diagnosis of lung cancer to assess the cerebral metabolic status before treatment using proton magnetic resonance spectroscopy (1HMRS). Together with neurocognitive testing, 1HMRS was performed in the parietal and occipital cortices of patients diagnosed with a lung mass (N=17) and an age-matched control group (N=15). Glutamate concentrations in the occipital cortex were found to be lower in the patients compared to controls and the concentrations of creatine and phosphocreatine were significantly lower in the parietal cortex of the patients. The lung cancer patients were also characterized by greater fatigue scores (but not depression) prior to treatment when compared to controls. In addition, the serum concentration of interleukin-6 (proinflammatory cytokine) was higher in patients compared to controls; and the concentration of tumor-necrosis factor alpha ([TNF-α]) was positively correlated to the metabolic activity of the lung tumor as defined by the 2-deoxy-2-(18F)fluoro-D-glucose (18FDG) positron emission tomography (PET) derived maximal standardized uptake values (SUVmax). Finally, multivariate statistical modeling revealed that the concentration of N-acetyl-aspartate [NAA] in the occipital cortex was negatively associated with [TNF-α]. In conclusion, our data demonstrate that the cerebral metabolic status of patients with lung cancer is changed even prior to treatment. In addition, the association between inflammatory cytokines, SUVmax and [NAA] points towards interactions

  14. Prediction of Clinical Outcomes by Chemokine and Cytokine Profiling In CSF from Radiation Treated Breast Cancer Primary with Brain Metastases

    NASA Astrophysics Data System (ADS)

    Lok, Edwin

    Whole brain radiation is the standard treatment for patients with brain metastasis but unfortunately tumors can recover from radiation-induced damage with the help of the immune system. The hypothesis that differences in immunokines in the cerebrospinal fluid (CSF) pre- and post-irradiation could reveal tumor biology and correlate with outcome of patients with metastatic breast cancer to the brain is tested. Collected CSF samples were analyzed using Luminex's multiplexing assays to survey global immunokine levels while Enzyme-Linked Immunosorbent Assays were used to quantify each individual immunokines. Cluster analysis was performed to segregate patients based on their common immunokine profile and each cluster was correlated with survival and other clinical parameters. Breast cancer brain metastasis was found to have altered immunokine profiles in the CSF, and that Interleukin-1α expression was elevated after irradiation. Therefore, immunokine profiling in the CSF could enable cancer physicians to monitor the status of brain metastases.

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

    ClinicalTrials.gov

    2016-05-13

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

  16. Migration Phenotype of Brain-Cancer Cells Predicts Patient Outcomes.

    PubMed

    Smith, Chris L; Kilic, Onur; Schiapparelli, Paula; Guerrero-Cazares, Hugo; Kim, Deok-Ho; Sedora-Roman, Neda I; Gupta, Saksham; O'Donnell, Thomas; Chaichana, Kaisorn L; Rodriguez, Fausto J; Abbadi, Sara; Park, JinSeok; Quiñones-Hinojosa, Alfredo; Levchenko, Andre

    2016-06-21

    Glioblastoma multiforme is a heterogeneous and infiltrative cancer with dismal prognosis. Studying the migratory behavior of tumor-derived cell populations can be informative, but it places a high premium on the precision of in vitro methods and the relevance of in vivo conditions. In particular, the analysis of 2D cell migration may not reflect invasion into 3D extracellular matrices in vivo. Here, we describe a method that allows time-resolved studies of primary cell migration with single-cell resolution on a fibrillar surface that closely mimics in vivo 3D migration. We used this platform to screen 14 patient-derived glioblastoma samples. We observed that the migratory phenotype of a subset of cells in response to platelet-derived growth factor was highly predictive of tumor location and recurrence in the clinic. Therefore, migratory phenotypic classifiers analyzed at the single-cell level in a patient-specific way can provide high diagnostic and prognostic value for invasive cancers. PMID:27292647

  17. Brain tumor - primary - adults

    MedlinePlus

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  18. 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 ...

  19. 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)

  20. Multiple calcified brain metastases in a man with invasive ductal breast cancer.

    PubMed

    Ressl, Nadine; Oberndorfer, Stefan

    2015-01-01

    We report a case of a 52-year-old Caucasian man with invasive ductal carcinoma of the breast. One year after initial diagnosis, he developed a generalised epileptic seizure and neuroimaging showed multiple, calcified intracerebral lesions. Owing to these atypical cerebral imaging findings, comprehensive serological and cerebrospinal fluid analysis was conducted and a latent toxoplasmosis was suspected. In order to distinguish between metastases and an infectious disease, a cerebral biopsy was performed, which verified brain metastases. The patient received whole-brain radiotherapy. The last cerebral CT scan, 18 months later showed stable disease. Calcification of brain metastases in patients with breast cancer is very rare. Owing to their non-characteristic radiological appearance with a lack of contrast enhancement, diagnosis of metastases can be difficult. Infectious diseases should be considered within the diagnostic work up. Owing to possible pitfalls, we recommend a widespread differential diagnostic work up in similar cases, and even in cases with a confirmed primary tumour. PMID:26472289

  1. 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. PMID:24643985

  2. 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.

  3. 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.

  4. 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

  5. DESERVE - Dead Sea Research Venue

    NASA Astrophysics Data System (ADS)

    Mohsen, A.; Weber, M. H.; Kottmeier, C.

    2013-12-01

    DESERVE 'Dead Sea Research Venue' focuses on the Dead Sea region as it is a unique environment and may be considered as one of the most inspiring natural laboratories on Earth. The Dead Sea Region is an exceptional ecosystem whose seismic activity has influenced all facets of the development, from ground water availability to human evolution. DESERVE addresses three grand challenges: Environmental Risks, Water Availability, Climate Change and comprises long term monitoring of geophysical parameters, studies of coupled processes in the atmosphere, hydrosphere and lithosphere as well as modeling of prediction and remediation strategies of geogenic risks. The Dead Sea has been selected for this integrated approach because it constitutes an outstanding 'natural laboratory' to study these phenomena, as - all 3 challenges are critical in this region. - the region is especially sensitive to climate change and human influences such as ground and surface water over-exploitation for agriculture and industrial purposes. - environmental processes are subject to boundary conditions that cannot be found elsewhere on Earth - understanding their interactions and the future evolution of the whole Dead Sea region are of key importance for economic development in peaceful cooperation. Results obtained in the Dead Sea region are also of prototype relevance for other (semi)-arid terminal basins of the world.

  6. 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

  7. 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

  8. 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

  9. 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.

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

    PubMed Central

    Xing, Fei; Sharma, Sambad; Liu, Yin; Mo, Yin-Yuan; Wu, Kerui; Zhang, Ying-Yu; Pochampally, Radhika; Martinez, Luis A; Lo, Hui-wen; Watabe, Kounosuke

    2014-01-01

    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 due 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, while 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 two genes essential for brain invasion, RhoC and TNFα that affect the invasion of cancer cells and permeability of BBB, respectively. Importantly, high levels of TNFα 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 plays a critical role in brain metastasis of breast cancer by modulating the RhoC-TNFα network and that this miR-509 axis may represent a potential therapeutic target or serve as a prognostic tool for brain metastasis. PMID:25659578

  11. 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

  12. 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

  13. Brain-Expressed X-linked (BEX) proteins in human cancers.

    PubMed

    Kazi, Julhash U; Kabir, Nuzhat N; Rönnstrand, Lars

    2015-12-01

    The Brain-Expressed X-linked (BEX) family proteins are comprised of five human proteins including BEX1, BEX2, BEX3, BEX4 and BEX5. BEX family proteins are expressed in a wide range of tissues and are known to play a role in neuronal development. Recent studies suggest a role of BEX family proteins in cancers. BEX1 expression is lost in a subgroup of patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Expression of BEX1 controls cell surface receptor signaling and restores imatinib response in resistant cells. BEX2 is overexpressed in a group of breast cancer patients and also in gliomas. Increased BEX2 expression led to enhanced NF-κB signaling as well as cell proliferation. Although BEX2 acts as tumor promoter in a subset of breast cancer, BEX3 expression displayed an opposite role. Overexpression of BEX3 resulted in inhibition of tumor formation in breast cancer mouse xenograft models. The role of BEX4 and BEX5 in cancer has not yet been defined. Collectively this suggests that BEX family members have distinct roles in cancers. While BEX1 and BEX3 act as tumor suppressors, BEX2 seems to act as an oncogene. PMID:26408910

  14. Brain and Central Nervous System Cancer Incidence in Navarre (Spain), 1973-2008 and Projections for 2014

    PubMed Central

    Etxeberria, J.; San Román, E.; 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. PMID:25561983

  15. Profound prevention of experimental brain metastases of breast cancer by temozolomide in an MGMT-dependent manner

    PubMed Central

    Palmieri, Diane; Duchnowska, Renata; Woditschka, Stephan; Hua, Emily; Qian, Yongzhen; Biernat, Wojciech; Sosińska-Mielcarek, Katarzyna; Gril, Brunilde; Stark, Andreas; Hewitt, Stephen; Liewehr, David J; Steinberg, Seth M; Jassem, Jacek; Steeg, Patricia S

    2014-01-01

    Purpose Brain metastases of breast cancer cause neurocognitive damage and are incurable. We evaluated a role for temozolomide in the prevention of brain metastases of breast cancer in experimental brain metastasis models. Experimental Design Temozolomide was administered in mice following earlier injection of brain-tropic human epidermal growth factor receptor 2 (HER2)-positive Jimt1-BR3 and triple negative 231-BR-EGFP sublines, the latter with and without expression of 06-methylguanine-DNA methyltransferase (MGMT). Additionally, the percentage of MGMT-positive tumor cells in 62 patient-matched sets of breast cancer primary tumors and resected brain metastases was determined immunohistochemically. Results Temozolomide, when dosed at 50, 25, 10 or 5 mg/kg, 5 days/week, beginning 3 days after inoculation, completely prevented the formation of experimental brain metastases from MGMT-negative 231-BR-EGFP cells. At a 1 mg/kg dose, temozolomide prevented 68% of large brain metastases, and was ineffective at a dose of 0.5 mg/kg. When the 50 mg/kg dose was administered beginning on days 18 or 24, temozolomide efficacy was reduced or absent. Temozolomide was ineffective at preventing brain metastases in MGMT-transduced 231-BR-EGFP and MGMT-expressing Jimt-1-BR3 sublines. In 62 patient-matched sets of primary breast tumors and resected brain metastases, 43.5% of the specimens had concordant low MGMT expression, while in another 14.5% of sets high MGMT staining in the primary tumor corresponded with low staining in the brain metastasis. Conclusions Temozolomide profoundly prevented the outgrowth of experimental brain metastases of breast cancer in an MGMT-dependent manner. These data provide compelling rationale for investigating the preventive efficacy of temozolomide in a clinical setting. PMID:24634373

  16. 46 CFR 171.117 - Dead covers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Dead covers. 171.117 Section 171.117 Shipping COAST... Dead covers. (a) Except as provided in paragraph (b) of this section, each port light with the sill located below the margin line must have a hinged, inside dead cover. (b) The dead cover on a port...

  17. 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

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

    PubMed Central

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

    2015-01-01

    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. PMID:26315660

  19. 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.

  20. 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. PMID:25876647

  1. 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

  2. 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.

  3. 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

  4. 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. PMID:25714248

  5. 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

  6. [A Case of Effective Whole-Brain Irradiation and Lapatinib/Capecitabine Combination Therapy for HER2-Positive Breast Cancer with Multiple Brain Metastases].

    PubMed

    Shibasaki, Masayuki; Tanabe, Asami; Toda, Tateo; Sakata, Hiroki; Ijichi, Masayoshi; Kusaka, Kouji; Bandai, Yasutsugu

    2015-06-01

    We report the case of a 48-year-old female patient with HER2-positive and hormone receptor-negative breast cancer with multiple liver metastases. She underwent 6 cycles of FEC followed by docetaxel plus trastuzumab (TZB), resulting in a clinical complete response. After 15 cycles of a TZB-containing regimen, she complained of dizziness and nausea, and imaging examinations revealed multiple brain metastases. Whole-brain irradiation(33.6 Gy) was performed, and the chemotherapy regimen was changed to lapatinib (LAP: orally at 1,250 mg/day, every day) and capecitabine (CAP: orally at 2,000 mg/m2, every day for 2 weeks, followed by a 1-week rest interval, as 1 cycle). After 6 weeks of the new treatment, magnetic resonance imaging revealed marked shrinkage of brain metastases. A clinical complete response was maintained for 19 months. While brain metastasis is an important problem with treatment with TZB, LAP is drawing attention because of its ability to pass the blood-brain barrier because of its small molecular weight. LAP/CAP combination therapy may be an effective treatment option for brain metastases of HER2-positive breast cancer in which TZB essentially has no effect. PMID:26199252

  7. Efficacy and Safety of Bevacizumab in Active Brain Metastases from Non-Small Cell Lung Cancer

    PubMed Central

    De Braganca, Kevin C.; Janjigian, Yelena Y.; Azzoli, Christopher G.; Kris, Mark G.; Pietanza, Maria C.; Nolan, Craig P.; Omuro, Antonio M.; Holodny, Andrei I.; Lassman, Andrew B.

    2011-01-01

    Background Bevacizumab is effective for the treatment of non-small cell lung cancer (NSCLC). Ongoing trials are exploring the safety of bevacizumab in patients with inactive, previously treated brain metastases. However, bevacizumab safety and efficacy in the treatment of active brain metastases is unknown. Bevacizumab received accelerated FDA approval for progressive glioblastoma, a primary brain tumor, because of high response rates and low incidence of intracranial hemorrhage. Methods We retrospectively identified patients treated with bevacizumab for active (treatment naïve or progressive) central nervous system (CNS) metastases from NSCLC. MRI scans performed at least 6 weeks after initiating bevacizumab were assessed for response. Results There were six patients, four women and two men with a median age of 60 years (range 59–77) at initiation of bevacizumab. Five patients had progressive CNS metastases despite prior treatment including surgery, radiotherapy, and/or chemotherapy; one patient had treatment-naïve brain metastases. Two patients had leptomeningeal metastases, isolated or coexistent with parenchymal brain metastases in one patient each. Bevacizumab was administered alone to one patient and in combination with various cytotoxic chemotherapies in the others. Toxicity included an asymptomatic (Grade 1) intra-tumoral hemorrhage which occurred in one of three patients receiving concurrent anticoagulation with bevacizumab. There was no recurrent CNS bleeding in two patients with a prior history of such hemorrhage. Best response (RECIST) was partial in two, stable disease in three, and progression in one. Median progression-free survival (PFS) was 4.7 months and median overall survival (OS) was 14.1 months following initiation of bevacizumab. Clinical benefit was also observed in the form of improved symptoms and reduced corticosteroid requirements. Conclusions Bevacizumab should be used with caution in patients with active CNS metastases pending

  8. 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

  9. 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

  10. [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