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Old 11-25-2009, 10:57 PM   #1
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Brain mets

Extensive 9/27/2010 overview of brain/CNS mets treatments from Breast Cancer Watch:

J Neurooncol. 2007 Mar;82(1):91-3. Epub 2006 Sep 26.

A lipoxygenase inhibitor in breast cancer brain metastases.(Boswellia serrata)

PDF(3pgs): http://www.springerlink.com/content/...2/fulltext.pdf

Flavin DF.
Foundation for Collaborative Medicine and Research, Greenwich, CT 06831, USA. Dana_FK@hotmail.com
The complication of multiple brain metastases in breast cancer patients is a life threatening condition with limited success following standard therapies. The arachidonate lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase growth stimulating products therefore appeared to be a worthwhile consideration for testing in brain metastases not responding to standard therapy.
Boswellia serrata, a lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were successfully reversed using this method in a breast cancer patient who had not shown improvement after standard therapy. The results suggest a potential new area of therapy for breast cancer patients with brain metastases that may be useful as an adjuvant to our standard therapy.

PMID: 17001517 [PubMed - indexed for MEDLINE]

The patient was started on capecitabine and given radiation therapy of 44 Gy with no improvement seen for the first 2 weeks. The severity and inoperability of
her condition made using an additional therapy a consideration. An oxidoreductase [plant lipoxygenases (LOX)] inhibitor was applied (Boswellia serrata) which has no known major side effects. The enzyme, LOX, arachidonate: oxygen oxidoreductase (form mammalian LOX) is thought to be responsible for edema in primary brain tumors and present ongoing studies on LOX inhibitors in Germany indicate an overall improvement in response to radiation therapy as well as a decrease in some primary brain tumors seen even without radiation. Although it was not known if LOX inhibitors would be helpful in breast cancer brain metastases it was worth considering in this case since she had not only several large tumors but also additional extremely small tumors scattered throughout the brain. She was immediately placed on a LOX inhibitor. Following 10 weeks of therapy, the patient was scheduled for a new CT since her CEA and Ca 15–3 tumor markers had increased. The CT results showed a complete disappearance of all signs of metastases in her brain (Fig. 2a, b).
The patient has been maintained on the LOX inhibitor,
Boswellia serrata, 3 · 800 mg/day
with no new signs of cerebral involvement of her breast cancer for over 4 years, however, there have recently been skeletal metastases which most likely indicates LOX has a limited skeletal tissue involvement in cancer.

Boswellia serrata


Prof. Thomas Simmet has researched Boswellia serrata on astrocytomes, a tumor noted for its propensity to metastasize. Prof. Simmet's background is in pharmacology, and he suggests that the boswellic acids reduce inflammation. I was familiar with this research because boswellia is used extensively in Ayurveda to reduce the symptoms of arthritis. Prof. Simmet proposes that boswellia inhibits the production of an enzyme that causes the leukotriene production associated with inflammation. In laboratory tests, Prof. Simmet observed that the more malignant the tumor, the more leukotrienes it produces. This seems to perpetuate a cycle of almost unstoppable growth.
Working with a neurosurgeon, Michael Winking, 25 patients were administered a dry extract of boswellia for one week. The tumors were then surgically removed. About half the patients had such significant regressions that the tumors had all but disappeared. They used a dosage of 800 mg. three times a day.
CT before Boswellia
CT after Boswellia [10 weeks]
CT images compliments of Dr. Dana Flavin-Koenig
Foundation for Collaborative Medicine and Research

At the university hospitals of Bochum and Giessen, patients with gliome tumors were administered somewhat higher dosages of Boswellia serrata, 3600 mg. per day. Within only a few days, many symptoms associated with brain tumors, such as headaches and lameness, were greatly lessened. While much of this effect might be more related to the reduction in edema than to the regression of the tumor, swelling and the resultant pressures are serious side effects of malignancy that impact the quality of life. The reports of these trials are preliminary and researchers are unwilling to speculate as to the long-term results and whether or not tumor growth is arrested.

Planta Med. 2000 Mar;66(2):110-3.
Concentration-dependent potentiating and inhibitory effects of Boswellia extracts on 5-lipoxygenase product formation in stimulated PMNL.

Safayhi H, Boden SE, Schweizer S, Ammon HP.
Department of Pharmacology, University of Tuebingen, Germany. hasan.safayhi@uni-tuebingen.de
Preparations from the gum of Boswellia spec. have been used in the traditional medicine for the treatment of inflammatory diseases. Extracts from B. serrata gum were shown to inhibit leukotriene biosynthesis by impairing the 5-lipoxygenase (5-LO) activity. In order to identify the minimal effective concentrations of extracts in vitro we studied the effects of ethanolic extracts from commercially available resins from two regions (B. serrata gum from India and Olibanum in granis from Arabia) on the 5-LO product formation from endogenous substrate in calcium and ionophore stimulated neutrophils in a defined concentration range. Both extracts inhibited 5-LO product formation in vitro in concentrations greater than 10 to 15 micrograms/ml as reported previously for an ethanolic B. serrata extract. In contrast, lower concentrations of extracts (1 to 10 micrograms/ml) even potentiated 5-LO product formation, especially the biosynthesis of 5(S)-HETE. The in vitro data underline the major importance of drug standardization when Boswellia resin containing preparations are used for the treatment of diseases.

From a wide variety of studies, boswellic acids have been shown to:
  • Inhibit leukotriene biosynthesis
  • Inhibit 5-lipoxygenase
  • Inhibit topoisomerase I
  • Inhibit topoisomerase IIalpha
  • Induce apoptosis in glioma cells
  • Inhibit NF-kappaB
  • Reduce diarrhea
Further research into the constituent components of boswellia indicate that it is also directly cytotoxic to brain tumor cancer cells. Boswellia extracts have been shown to be both cytotoxic to glioma cells and anti-proliferative in a dose-dependent manner during studies with rats10.

J Neurooncol. 2009 Jan;91(1):47-50. Epub 2008 Aug 19.
Long-lasting successful cerebral response with sorafenib in advanced renal cell carcinoma.

Valcamonico F, Ferrari V, Amoroso V, Rangoni G, Simoncini E, Marpicati P, Vassalli L, Grisanti S, Marini G.
Department of Medical Oncology, Spedali Civili di Brescia, Brescia, Italy. franzval@yahoo.it
We report the case of a 75-year old woman who received sorafenib (Nexavar), Bayer Pharmaceuticals Corporation, West Haven, CT) for a CNS relapse of clear cell renal cell carcinoma. After four months of sorafenib treatment, a brain magnetic resonance imaging showed 95%-volumetric regression of cerebral metastasis. To the best of our knowledge, this is the first almost complete resolution of brain metastases in renal cell carcinoma treated with sorafenib that has been described.

PMID: 18712279 [PubMed - indexed for MEDLINE]

PMID: 10763581 [PubMed - indexed for MEDLINE]
Noscapine Crosses the Blood-Brain Barrier and Inhibits Glioblastoma Growth

Full Text: http://clincancerres.aacrjournals.or...0/15/5187.full


The opium alkaloid noscapine is a commonly used antitussive agent available in Europe, Asia, and South America. Although the mechanism by which it suppresses coughing is currently unknown, it is presumed to involve the central nervous system. In addition to its antitussive action, noscapine also binds to tubulin and alters microtubule dynamics in vitro and in vivo. In this study, we show that noscapine inhibits the proliferation of rat C6 glioma cells in vitro (IC50 = 100 μm) and effectively crosses the blood-brain barrier at rates similar to the ones found for agents such as morphine and [Met]enkephalin that have potent central nervous system activity (P ≤ 0.05). Daily oral noscapine treatment (300 mg/kg) administered to immunodeficient mice having stereotactically implanted rat C6 glioblasoma into the striatum revealed a significant reduction of tumor volume (P ≤ 0.05). This was achieved with no identifiable toxicity to the duodenum, spleen, liver, or hematopoietic cells as determined by pathological microscopic examination of these tissues and flow cytometry. Furthermore, noscapine treatment resulted in little evidence of toxicity to dorsal root ganglia cultures as measured by inhibition of neurite outgrowth and yielded no evidence of peripheral neuropathy in animals. However, evidence of vasodilation was observed in noscapine-treated brain tissue. These unique properties of noscapine, including its ability to cross the blood-brain barrier, interfere with microtubule dynamics, arrest tumor cell division, reduce tumor growth, and minimally affect other dividing tissues and peripheral nerves, warrant additional investigation of its therapeutic potential.
Artemisinin is thought to penetrate the CNS and may work: LINK to thread

Brain Cancer Treatment Kills Tumors by 'Cooking' with Laser– Cleveland Clinic

Posted Feb 24 2009 10:44pm

This a brand new technique and is not FDA approved yet, but they are hoping by the end of the year to have approval on this process.
There is a video at the link that explains more. From the pictures below it certainly looks at though it has done something for the patient who had a brain tumor that grew back. The patient had to be kept unconscious for 12 hours for the procedure to take place. I am guessing this could also work on other areas of the body too with tumors.
Body temperature is maintained as the patient is inside an MRI for the entire procedure. This procedure is offering hope to those who have had what has been considered inoperable surgery for their brain tumors. BD
Ruth Perko is one of at least 97,000 Americans diagnosed with a malignant brain tumor each year, according to the National Cancer Institute, and nothing can prepare her for the experimental treatment she's about to receive.
With the probe now inside Perko's brain tumor, doctors fire the laser. Each burst lasts anywhere from 30 seconds to a few minutes and generates up to 160 degrees (Fahrenheit) of heat, enough to restrict blood flow to the area and kill the cancer cells. Doctors carefully monitor the temperature by keeping Perko in an MRI machine throughout the procedure.
"We can monitor the temperature rise in the tumor, second by second, while we're scanning the patient," said Dr. Stephen Jones, a neuro radiologist at the Cleveland Clinic. "Better than that," he said, "we can see the predictive margins of response where we are killing the tumor... where the cancer cells are dying."
This is the before picture.

This is the after picture.

Cancer. 2009 Nov 20. [Epub ahead of print]
Disruption of the blood brain barrier by brain metastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breast cancer.
Yonemori K, Tsuta K, Ono M, Shimizu C, Hirakawa A, Hasegawa T, Hatanaka Y, Narita Y, Shibui S, Fujiwara Y.

Breast and Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
BACKGROUND:: Generally, the blood-brain barrier (BBB) of brain metastasis was thought to be disrupted. METHODS:: We retrospectively performed immunohistochemical staining for glucose transporter 1 (GLUT1) and breast cancer resistance protein (BCRP) to evaluate the status of the BBB in resected brain metastases. Associations between expression of GLUT1 and/or BCRP and the immunohistochemical profiles of breast cancers, such as the statuses of hormone receptors, human epidermal growth factor receptor 2 (HER2/neu), and a basal-type marker (cytokeratin 5/6, HER1), were also analyzed. RESULTS:: The study included 29 breast cancer patients with brain metastasis who had undergone brain tumor resections. Among the 29 patients, there was no expression of GLUT1 and BCRP in the intratumor microvessels of 9 (32%) and 11 (38%) patients, respectively. There was no expression of both GLUT1 and BCRP in 8 patients (28%). The expression of GLUT1 was significantly associated with that of BCRP (P < .001). A positive correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of HER2/neu-positive breast cancer (P = .012), while a negative correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of triple negative or basal-type breast cancer (P = .014 and P = .003 for triple negative and basal-type, respectively). CONCLUSIONS:: Brain metastases of triple negative or basal-type breast cancers may often disrupt the BBB, whereas brain metastases of HER2/neu-positive breast cancer tend to preserve the BBB. Cancer 2010. (c) 2009 American Cancer Society.

PMID: 19937674

Xeloda/5fu for brain mets?

Behav Brain Res.. [Epub ahead of print]

Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil.

Elbeltagy M, Mustafa S, Umka J, Lyons L, Salman A, Chur-Yoe GT, Bhalla N, Bennett G, Wigmore PM.
Department of Anatomy, Menoufiya University, Egypt; School of Biomedical Sciences, Institute of Neuroscience, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Cancer patients who have been treated with systemic adjuvant chemotherapy have described experiencing deteriorations in cognition. A widely used chemotherapeutic agent, 5-fluorouracil (5-FU), readily crosses the blood-brain barrier and so could have a direct effect on brain function. In particular this anti mitotic drug could reduce cell proliferation in the neurogenic regions of the adult brain. In contrast reports indicate that hippocampal dependent neurogenesis and cognition are enhanced by the SSRI antidepressant Fluoxetine. In this investigation the behavioural effects of chronic (two week) treatment with 5-FU and (three weeks) with Fluoxetine either separately or in combination with 5-FU were tested on adult Lister hooded rats. Behavioural effects were tested using a context dependent conditioned emotional response test (CER) which showed that animals treated with 5-FU had a significant reduction in freezing time compared to controls. A separate group of animals was tested using a hippocampal dependent spatial working memory test, the object location recognition test (OLR). Animals treated only with 5-FU showed significant deficits in their ability to carry out the OLR task but co administration of Fluoxetine improved their performance. 5-FU chemotherapy caused a significant reduction in the number of proliferating cells in the sub granular zone of the dentate gyrus compared to controls. This reduction was eliminated when Fluoxetine was co administered with 5-FU. Fluoxetine on its own had no effect on proliferating cell number or behaviour. These findings suggest that 5-FU can negatively affect both cell proliferation and hippocampal dependent working memory and that these deficits can be reversed by the simultaneous administration of the antidepressant Fluoxetine.

PMID: 19914299 [PubMed - as supplied by publisher]

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

JournalJournal of Neuro-Oncology
PublisherSpringer Netherlands
ISSN0167-594X (Print) 1573-7373 (Online)
IssueVolume 93, Number 3 / July, 2009
CategoryClinical study - patient study
Subject CollectionMedicine
SpringerLink DateSunday, January 25, 2009
Cyrus Chargari2, Youlia M. Kirova2 , Véronique Diéras2, Pablo Castro Pena2, Francois Campana2, Paul H. Cottu2, JeanYves Pierga2, Alain Fourquet2 and Institut Curie Breast Cancer Study Group1
(1) Institut Curie, Paris, France
(2) Department of Radiation Oncology, Department of Medical Oncology, Institut Curie, 26, Rue d’Ulm, 75005 Paris, France
Received: 23 September 2008 Accepted: 30 December 2008 Published online: 25 January 2009
Abstract 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/m2 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.

http://www.ohsu.edu/xd/education/sch...le-display.cfm Edward Neuwelt, M.D.

Title: Professor
Email: neuwelte@ohsu.edu

Primary Affiliation

Blood Brain Barrier and Neuro-Oncology Program Program Affiliations
  • Neuroscience Graduate Program
  • Neurology
Background Edward A. Neuwelt, M.D. is a Professor in the Departments of Neurology and Neurosurgery at Oregon Health & Science University and the Portland Veterans Affairs Medical Center in Portland, Oregon. He divides his time between clinical work, primarily in the area of neuro-oncology including both operative neurosurgery and chemotherapy, and directing his research laboratory.

Program History

In the early 1980s, Edward A. Neuwelt, M.D., an OHSU neurosurgeon, pioneered a unique method of outwitting the brain's protective blood-brain barrier. By temporarily opening this barrier, chemotherapy, antibodies and other potential new therapeutics can pass into the brain and reach the tumor.

Since then, Dr. Neuwelt has devoted his neuro-oncology practice to researching and refining this treatment for patients with brain tumors. A recent development is the use of chemoprotective agents which may provide bone marrow and hearing protection for patients undergoing platinum-based chemotherapy with BBBD.

Faculty Appointments:
In Texas, Dr. Neuwelt was Assistant Professor in both Surgery and Biochemistry at the University of Texas Southwestern Medical School. He was also Chief of the Neurosurgery Service at the Dallas Veterans Administration Hospital in Dallas, Texas from 1978 – 1981. Dr. Neuwelt moved his laboratory to Portland Oregon in 1981 where he joined the faculty at the Oregon Health & Science University, both in the Department of Neurology and Biochemistry and Molecular Biology. He was Chief of the Neurosurgery Service at the Veterans Affairs Medical Center in Portland, Oregon 1981 – 1989, and he maintains an affiliation with the Portland VA Neurosurgery Service. Currently Dr. Neuwelt is a Professor in the departments of Neurology and Neurological Surgery. He is a member of the Neuroscience Graduate Program and the Biochemistry and Molecular Biology Graduate Program at OHSU, and also regularly teaches the neurology and neurosurgery house staff on topics related to brain tumors.
Activities and Organizations:
Dr. Neuwelt is the principal investigator of three NIH R01 grants, one VA Merit Review grant, and a DOD Center of Excellence award. (see Preclinical Research) He has been a regular member of the VA Merit Review Study Section on Neurobiology, and an NIH Study Section (NSP-A) that reviews program project and center grants. Dr. Neuwelt is a regular reviewer of neuroscience-related journals, including Neurosurgery, for which he was a member of the editorial board. He initiated and is director of Think First Oregon, a brain and spinal cord injury prevention program. He has eight approved patents, five of which have been licensed to Adherex, Inc. to investigate thiol agent chemoprotection. In collaboration with Dr. James Rosenbaum and Dr. Richard Rosenbaum, Dr. Neuwelt set up and directs a science class for high school students that introduces young people to laboratory research. With regard to the BBB Program, Dr. Neuwelt has overseen the expansion of the program to eight institutions across the US and internationally including Canada and Israel, as well as the annual Blood-Brain Barrier (BBB) Consortium meeting funded by an R13 grant.

Research Interests

The OHSU Blood-Brain Barrier and Neuro-Oncology Program conducts innovative patient-oriented research in all aspects of imaging and therapy of brain tumors. Dr. Neuwelt’s research interests have centered around the blood-brain barrier (BBB) and brain tumor therapy. In his initial VA Merit Review grant in 1978, Dr. Neuwelt predicted that manipulation of the BBB with transient osmotic shrinkage had the potential for a therapeutic role in brain tumor therapy. This hypothesis has been verified (Kraemer 2001), and the BBB disruption technique is now central to the preclinical and clinical research studies in the Neuwelt laboratory. Overall, Dr. Neuwelt’s research interests have centered around improving brain tumor therapy, reducing chemotherapy side effects, and improving brain tumor imaging. Dr. Neuwelt currently has a VA Merit review grant, three NIH research grants, an R13 NIH meeting grant, and is a member of a DOD breast cancer Center of Excellence.
Cancers in the brain are difficult to treat because of neurotoxicity, tumor resistance, and minimal delivery of potential therapies across the blood-brain barrier. We do basic science and preclinical studies of new approaches to delivery, treatment, and imaging in primary and metastatic brain tumor models.

Selected Publications

Dr. Neuwelt has written or edited several books and book chapters, and has over 200 peer reviewed scientific publications. Please refer to his listing here

Dr. Neuwelt attended Northwestern University in Chicago, Illinois from 1965 – 1968 and then received his M.D., magna cum laude, from the University of Colorado School of Medicine in Denver, Colorado in 1972. For his postgraduate Training, Dr. Neuwelt did a surgical internship at the University of Texas Southwestern Medical School in Dallas, Texas, 1972 – 1973, followed by a Neurosurgical Residency at the same institution from 1973 – 1978. During this time, Dr. Neuwelt also completed two neuro-oncology and neurosurgery research fellowships, first at the National Cancer Institute, National Institutes of Health (NIH) (1974 – 1976) and then Queen Square Hospital in London, England (1976). While at the NIH, Dr. Neuwelt also completed his military duty as a Clinical Associate (Lt. Commander) in the United States Public Health Service, Neurosurgery and Enzymology Sections in Baltimore, Maryland (July, 1974 - July, 1976). Dr. Neuwelt is certified by the American Board of Neurological Surgery and is a fully trained neuro-oncologist.

Neuro-Oncology Blood-Brain Barrier Program

German researchers detail how metastatic cancer takes root in the brain

By Greg Freiherr | January 11, 2010


As many as one in four cancer patients develop metastatic cancers of the brain. Existing therapies seldom do more than slow the disease. Adding to the urgency to find a way to prevent brain metastasis is the increasing number of such cases.

"Improvements in the treatment of malignancy have enhanced survival time," said Dr. Frank Winkler, who leads the Neurooncology Research Group at the Ludwig-Maximilians-Universität (LMU) Neurological Clinic in Munich. "But this also means that more patients are at risk of developing brain metastases."

In the hope of finding ways to stop this process, Winkler and colleagues at LMU and neighboring Max Planck Institute for Neurobiology have defined, in animals, the steps that lead some tumor cells to metastasize. Reporting days before Christmas in the online version of Nature Medicine, Winkler and colleagues detailed the process of brain metastasis. To do so they used two-photon microscopy to look deeply into animal tissues and visualize at high resolution structures that lay hundreds of micrometers below the surface of the living brain.

The metastatic process begins, they found, when circulating tumor cells are trapped in a network of blood vessels. The cells then pass through tiny gaps between cells in the vessel wall, escaping into the surrounding brain tissue, yet sticking to the outer surface of the vessel. Here is where the process begins in earnest, as between four and fifty cells form micrometastases that ultimately fuse, triggering the growth of new blood vessels to feed the mass.

Interrupting any one of the steps will stop metastatic cancer in its tracks, according to Winkler. His team is now looking for ways to do exactly that. One may already be at hand. In their animal research, the team detailed how the anticancer drug Avastin can suppress the emergence of metastases by blocking the formation of new blood vessels. In the absence of such angiogenesis, even cells that had attached to the outer vessel wall and proliferated strongly at first eventually died, he says.

"We now want to test other types of cancer drugs for their effects on the single steps of metastasis formation," Winkler said. "It may be possible to discover new substances that allow us to treat existing metastases effectively, or even prevent them from developing at all."

Nat Med. 2010 Jan;16(1):116-22. Epub 2009 Dec 20.
Real-time imaging reveals the single steps of brain metastasis formation.

Kienast Y, von Baumgarten L, Fuhrmann M, Klinkert WE, Goldbrunner R, Herms J, Winkler F.
Department of Neurology, Ludwig-Maximilians University, Munich, Germany.
Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.

PMID: 20023634 [PubMed - indexed for MEDLINE]

Strahlenther Onkol. 2010 Feb;186(2):63-69. Epub 2010 Jan 26.
DEGRO Practical Guidelines for Palliative Radiotherapy of Breast Cancer Patients: Brain Metastases and Leptomeningeal Carcinomatosis.

Feyer P, Sautter-Bihl ML, Budach W, Dunst J, Haase W, Harms W, Sedlmayer F, Souchon R, Wenz F, Sauer R.
Klinikum Neukölln, Berlin, Germany, petra.feyer@vivantes.de.
PURPOSE: : To provide recommendations for palliative treatment of brain metastases (BM) and leptomeningeal carcinomatosis (LC) in breast cancer patients with specific emphasis on radiooncologic aspects. METHODS: : The breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) performed a comprehensive survey of the literature comprising national and international guidelines, lately published randomized trials, and relevant retrospective analyses. The search included publications between 1995-2008 (PubMed and Guidelines International Network [G-I-N]). Recommendations were devised according to the panel's interpretation of the evidence referring to the criteria of EBM. RESULTS: : Aim of any treatment of BM and LC is to alleviate symptoms and improve neurologic deficits. Close interdisciplinary cooperation facilitates rapid diagnosis and onset of therapy, tailored to the individual and clinical situation. Treatment decisions for BM should be based on the allocation to three prognostic groups defined by recursive partitioning analysis (RPA). Karnofsky Performance Score (KPS) is the strongest prognostic parameter. Together with the extent of the disease, KPS determines whether excision or radiosurgery/stereotactic radiotherapy is feasible and if exclusive or additional whole-brain radiotherapy (WBRT) is indicated. With adequate therapy, survival may be up to 3 years. For LC, treatment is mostly indicated for patients with positive cytology or in case of strongly indicative signs and symptoms. Radiotherapy (WBRT and involved-field irradiation of bulky spinal lesions) and chemotherapy (systemically or intrathecally applied methotrexate, thiotepa and cytarabine) are both effective and may prolong survival from several weeks to 4-6 months. CONCLUSION: : Radiotherapy is an effective tool for palliative treatment of BM and LC.

PMID: 20127222 [PubMed - as supplied by publisher]


Mom's treatment history (link)
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Old 11-29-2009, 05:04 PM   #2
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Re: Brain mets

Cancer Res. 2007 Apr 15;67(8):3560-4.
Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors.

Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS.
Department of Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario, Canada.
Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an antiangiogenic therapy could result in loss of stemness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities, we investigated the impact of antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted antiangiogenic agent, antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide. Targeted antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (SFU) in the tumor, whereas all treatment groups that combined both antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of antiangiogenic therapy to enhance the efficacy of chemotherapy.

PMID: 17440065 [PubMed - indexed for MEDLINE]

Public release date: 22-Jul-2010
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Contact: Kim Irwin
University of California - Los Angeles
Irradiating stem cell niche doubles survival in brain cancer patients

Patients with deadly glioblastomas who received high doses of radiation that hit a portion of the brain that harbors neural stem cells had double the progression-free survival time as patients who had lower doses or no radiation targeting the area, a study from the Radiation Oncology Department at UCLA's Jonsson Comprehensive Cancer Center has found.
Patients who underwent high doses of radiation that hit the specific neural stem cell site, known as the stem cell niche, experienced 15 months of progression-free survival, while patients receiving lower or no doses to this region experienced 7.2 months of progression-free survival, said Dr. Frank Pajonk, an associate professor of radiation oncology, a cancer center researcher and senior author of the study.
Pajonk said the study, published today in the early online edition of the journal BMC Cancer, could result in changes in the way radiation therapy is given to patients with these deadly brain cancers.
"Our study found that if you irradiated a part of the brain that was not necessarily part of the tumor the patients did better," Pajonk said. "We have been struggling for years to come up with new combinations of drugs and targeted therapies that would improve survival for patients with glioblastoma. It may be that by re-shaping our radiation techniques we can extend survival for these patients."
The retrospective study focused on the cases of 55 adult patients with grade 3 or grade 4 glioblastomas who received radiation at UCLA between February 2003 and May 2009. Pajonk said a prospective study is needed to confirm the results.
There is some evidence that many if not all cancers may spring from stem cells or progenitor cells that normally repair damage to the body, but that somehow become mutated and transform into cancer. In this case, Pajonk said the neural stem cell niche, called the periventricular region of the brain, may also be harboring stem cells that have transformed into brain cancer stem cells. However, the niche serves as a sort of safe harbor for the cancer stem cells, keeping them away from the site of the tumor but able to re-grow it once it's removed and the malignant areas of the brain have been treated.
Pajonk theorizes that the brain cancer stem cells in the patients whose niches were irradiated with higher doses may have been damaged or eliminated, giving these patients more time before their cancer recurred.
"This suggests that the neural stem cell niche in the brain may be harboring cancer stem cells, thus providing novel therapy targets," the study states. "We hypothesize that higher radiation doses to these niches improve patient survival by eradicating the cancer stem cells."
Glioblastomas are the deadliest form of brain cancer. Surgery, chemotherapy and radiation are not usually effective and life expectancy is about 12 to 18 months. New and more effective treatments are needed to help this patient population, Pajonk said.
The radiation therapy could damage neural stem cells as well as the cancer stem cells, Pajonk said, but those may be replaceable at some future date using induced pluripotent stem cells made from the patient's own cells. The induced pluripotent stem cells, which like embryonic stem cells can make every cell in the body, could be induced into becoming neural stem cells to replace those damaged or eradicated by the radiation to the niche.

Cancer Chemother Pharmacol. 2010 Jan 28. [Epub ahead of print]
Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase I trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors.

Morgan RJ, Synold T, Mamelak A, Lim D, Al-Kadhimi Z, Twardowski P, Leong L, Chow W, Margolin K, Shibata S, Somlo G, Yen Y, Frankel P, Doroshow JH.
Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA, rmorgan@coh.org.
PURPOSE: This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid. METHODS: Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m(2)/d IV, administered as a 72 h continuous infusion on days 1-3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks. RESULTS: Seventeen patients received 39 cycles of treatment: median 2, (range 1-5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60-90%) and age: 52 (range 24-75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m(2)/d, the median CSF/plasma ratio was 19.4% (range 15.1-59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02-3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2-5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs. CONCLUSIONS: The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m(2)/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.

PMID: 20107803 [PubMed - as supplied by publisher]


Breast Cancer Metastasis Gene Linked to Poor Survival
High expression of HK2 found in brain metastases compared with primary tumors
Sep 3, 2009

THURSDAY, Sept. 3 (HealthDay News) -- Expression of a gene involved in glucose metabolism and cell death is higher in breast cancer brain metastases compared with primary tumors, and high expression is associated with poor survival, according to a study published online Sept. 1 in Molecular Cancer Research.
Diane Palmieri, Ph.D., from the National Cancer Institute in Bethesda, Md., and colleagues compared global gene expression by microarray in eight brain metastases of breast tumors and nine unlinked primary breast tumors matched for histology, tumor-node-metastasis stage, and hormone receptor status.
The researchers found that the expression of four genes was significantly reduced in brain metastases, while the expression of another was increased. In particular, the expression of hexokinase 2 (HK2), which is important in glucose metabolism and apoptosis, was higher in the brain metastases, and blocking expression reduced cell growth when glucose was limiting. Increased HK2 expression in a separate group of 123 breast cancer brain metastases was significantly associated with poor survival after craniotomy.
"The data suggest that HK2 overexpression is associated with metastasis to the brain in breast cancer and it may be a therapeutic target," Palmieri and colleagues conclude.
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Can we protect the brain against tumor metastasis?

Posted on June 15, 2009 by speakingofresearch


The tumor cells bind to a blood vessel structure called the vascular basement membrane (VBM), but what the Oxford scientists really wanted to know was what caused the tumor cells to bind to the VBM. Once again using mice with cranial windows fitted they found that an enzyme named focal adhesion kinase was highly active where the tumor cells were interacting with the VBM. Focal adhesion kinase is part of a pathway through which a class of proteins known as the integrins control the interaction between many cells and either other cells or extracellular proteins such as the components of the vascular basement membrane, an observation which suggested that an integrin plays a key role in the binding of tumor cells to the VBM. They next found that a particular integrin named Beta 1 integrin is present on all the tumor cell lines they were studying, and that antibodies blocking it could prevent the tumor cells from binding components of the VBM in vitro and to blood vessels in human brain tissue slices.
But would the anti-Beta 1 integrin blocking antibody prevent tumor metastasis in living animals? The answer was yes, the antibodies greatly reduced the growth tumors from human breast tumor cells that were injected directly into the brains of mice. To further emphasize the importance of Beta 1 integrin in brain metastasis they found that when mouse lymphoma cells that had been genetically engineered to lack Beta 1 integrin were injected into mouse brains they formed far smaller tumors than non-GM lymphoma cells.
1) Carbonell W.S. et al. “The vascular basement membrane as “soil” in brain metastasis.” PLoS ONE Volume 4(6):e5857 (2009) DOI:10.1371/journal.pone.0005857
2) Park C.C. et al. “Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo.”Cancer Res. Volume 66(3), Pages 1526-1535 (2006) DOI:10.1158/0008-5472.CAN-05-3071

New Scientific Publication Highlights Long-Term Survival of Brain Cancer Patients Treated With Peregrine Pharmaceuticals' Cotara(R)

-Article in Current Cancer Therapy Reviews Reports on GBM Patients Who Have Survived More than Nine Years after Treatment with Cotara-

TUSTIN, Calif., Feb. 11 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals, Inc. (PPHM) today reported publication of data in the online edition of the journal Current Cancer Therapy Reviews that supports the clinical potential of the company's novel brain cancer agent Cotara® for the treatment of patients with glioblastoma multiforme (GBM), the deadliest form of brain cancer.(1) Cotara specifically targets cells at the center of brain tumors, so its radioactive payload is able to kill cancer cells while leaving healthy tissue largely unaffected. Cotara is currently being tested in a Phase II clinical trial in recurrent GBM patients.
The new data from investigators at the Huntsman Cancer Institute at the University of Utah Medical Center and researchers at Peregrine Pharmaceuticals reports on long-term patient follow-up from an earlier Phase I trial in 28 GBM patients with recurrent disease. Data presented from the study showed that seven of 28, or 25% of the patients survived more than one year after treatment and three of the 28, or 10.7% of the GBM patients treated in this study have survived more than five years after treatment, including two patients who have survived more than nine years, a positive finding compared to the 3.4% five-year survival rate from initial diagnosis reported by the U.S. Brain Tumor Registry. Additionally, the median survival time of the 28 patients was 38 weeks, a 58% increase over the historical median survival time of 24 weeks for GBM patients treated with standard-of-care therapy.
"The positive results seen in this trial suggest that Cotara has the potential to be a valuable new therapy for patients with glioblastoma, a devastating disease with few treatment options," said lead author Randy L. Jensen, M.D., Ph.D., a researcher at the Huntsman Cancer Institute and associate professor, Department of Neurosurgery at the University of Utah Medical Center. "Our experience with GBM patients treated with Cotara in this trial showed that it demonstrated superior median overall survival compared to historical data, and resulted in long-term survival for a number of patients, a rare occurrence in this deadly disease. These promising data highlight the importance of completing the current clinical trials to confirm these results and of advancing this promising agent towards possible regulatory approval."
Cotara is currently being studied in a Phase II clinical trial for the treatment of GBM in patients who have experienced a first relapse. Interim data from this study was presented at the XIV World Congress of Neurological Surgery in September 2009. It highlighted 10 GBM patients treated at one of the clinical sites and included follow-up durations ranging from seven weeks to over 73 weeks, showing an interim median recurrence-free survival of 33 weeks and an interim median overall survival of 41 weeks. Patient enrollment in this trial has now passed the half way mark. Patient enrollment was recently completed in a Cotara dosimetry and dose confirmation trial in recurrent GBM patients. Data from this study presented at the Society of Nuclear Medicine 2009 Annual Meeting showed that Cotara appeared to be safe and well tolerated, strongly concentrating in the brain tumor while leaving other organs largely unaffected. A number of patients in this trial have surpassed the median expected survival time for relapsed GBM patients. Patient follow-up is continuing.
"The new data published today reinforces and updates the encouraging results we have reported from all three trials of Cotara in GBM patients," noted Joseph Shan, vice president of clinical and regulatory affairs at Peregrine. "Data from the two current Cotara trials presented at medical conferences last year has shown encouraging signs of efficacy and confirmed the ability of Cotara to specifically deliver high doses of radiation to GBM tumors, resulting in significant anti-tumor effects. We look forward to completing the ongoing trials while we assess a variety of clinical and regulatory options to make Cotara more widely available to patients with this devastating disease."
Senior author Missag H. Parseghian, Ph.D., senior director of research and development at Peregrine added, "In total, more than 65 patients with recurrent GBM have received Cotara in the current and previous clinical studies. Localization and accumulation of the drug to the tumor have been excellent and longer-term survivors (greater than one year from the time of Cotara treatment) have been observed in all of the trials."
Overall, Cotara has been administered to a total of 125 patients with brain, colon or liver cancer. Promising data from these studies support Cotara's ability to specifically target solid tumors and its anti-tumor activity, as well as its acceptable safety profile.
(1) Current Cancer Therapy Reviews, (February) 2010, Clinical Update: Treatment of Glioblastoma Multiforme with Radiolabeled Antibodies that Target Tumor Necrosis, pp.13-18 (6) Authors: Randy L. Jensen, Joseph S. Shan, Bruce D. Freimark, Debra A. Harris, Steven W. King, Jennifer Lai, Missag H. Parseghian
About Cotara®
Cotara is an experimental treatment for brain cancer that links a radioactive isotope to a targeted monoclonal antibody designed to bind to the DNA histone complex that is exposed by dead and dying cells found at the center of solid tumors. Cotara's targeting mechanism enables it to bind to the dying tumor cells, delivering its radioactive payload to the adjacent living tumor cells and essentially destroying the tumor from the inside out, with minimal radiation exposure to healthy tissue. Cotara is delivered using convection-enhanced delivery (CED), an NIH-developed method that targets the specific tumor site in the brain. Cotara has been granted orphan drug status and fast track designation for the treatment of glioblastoma multiforme and anaplastic astrocytoma by the U.S. Food and Drug Administration.

Br J Cancer. 2010 Feb 16;102(4):685-92. Epub 2010 Jan 12.
In vivo effects of rosiglitazone in a human neuroblastoma xenograft.

Cellai I, Petrangolini G, Tortoreto M, Pratesi G, Luciani P, Deledda C, Benvenuti S, Ricordati C, Gelmini S, Ceni E, Galli A, Balzi M, Faraoni P, Serio M, Peri A.
Correspondence: Professor A Peri, E-mail: a.peri@dfc.unifi.it
Endocrine Unit, Department of Clinical Physiopathology, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), University of Florence, 50139 Florence, Italy.
Background:Neuroblastoma (NB) is the most common extra-cranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. There is in vitro evidence that the peroxisome proliferator-activated receptor gamma (PPARgamma) might be a target for pharmacological intervention in NB. We have previously demonstrated that the PPARgamma agonist rosiglitazone (RGZ) exerts strong anti-tumoural effects in the human NB cell line, SK-N-AS. The aim of this study was to evaluate whether RGZ maintains its anti-tumoural effects against SK-N-AS NB cells in vivo.Methods and results:For this purpose, tumour cells were subcutaneously implanted in nude mice, and RGZ (150 mg kg(-1)) was administered by gavage daily for 4 weeks. At the end of treatment, a significant tumour weight inhibition (70%) was observed in RGZ-treated mice compared with control mice. The inhibition of tumour growth was supported by a strong anti-angiogenic activity, as assessed by CD-31 immunostaining in tumour samples. The number of apoptotic cells, as determined by cleaved caspase-3 immunostaining, seemed lower in RGZ-treated animals at the end of the treatment period than in control mice, likely because of the large tumour size observed in the latter group.Conclusions:To our knowledge, this is the first demonstration that RGZ effectively inhibits tumour growth in a human NB xenograft and our results suggest that PPARgamma agonists may have a role in anti-tumoural strategies against NB.

PMID: 20068562 [PubMed - in process]

Br J Cancer. 2009 Mar 24;100(6):894-900. Epub 2009 Feb 24.
Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients.

Park YH, Park MJ, Ji SH, Yi SY, Lim DH, Nam DH, Lee JI, Park W, Choi DH, Huh SJ, Ahn JS, Kang WK, Park K, Im YH.
Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
In patients with human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer, treatment with trastuzumab has been shown to markedly improve the outcome. We investigated the role of trastuzumab on brain metastasis (BM) in HER2-positive breast cancer patients. From 1999 to 2006, 251 patients were treated with palliative chemotherapy for HER2-positive metastatic breast cancer at Samsung Medical Center. The medical records of these patients were analysed to study the effects of trastuzumab on BM prevalence and outcomes. Patients were grouped according to trastuzumab therapy: pre-T (no trastuzumab therapy) vs post-T (trastuzumab therapy). The development of BM between the two treatment groups was significantly different (37.8% for post-T vs 25.0% for pre-T, P=0.028). Patients who had received trastuzumab had longer times to BM compared with patients who were not treated with trastuzumab (median 15 months for post-T group vs 10 months for pre-T group, P=0.035). Time to death (TTD) from BM was significantly longer in the post-T group than in the pre-T group (median 14.9 vs 4.0 months, P=0.0005). Extracranial disease control at the time of BM, 12 months or more of progression-free survival of extracranial disease and treatment with lapatinib were independent prognostic factors for TTD from BM.

PMID: 19240719 [PubMed - indexed for MEDLINE]

Cancer Biol Ther. 2009 Oct;8(20):1924-33. Epub 2009 Oct 12.
Modulation of KCa channels increases anticancer drug delivery to brain tumors and prolongs survival in xenograft model.

Ningaraj NS, Sankpal UT, Khaitan D, Meister EA, Vats TS.
Memorial Health University Medical Center, Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Hoskins Center for Biomedical Research, Savannah, GA, USA. ningana1@memorialhealth.com
Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some antitumor activity against brain tumors, so does Trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing gliomas. Nevertheless, intact BTB and active efflux system may prevent their entry to brain tumors. Previously we have shown that potassium channel agonists increased carboplatin and Her-2 neu antibody delivery in animal glioma models. Here, we studied whether potassium channel agonist increase TMZ and Herceptin delivery across the BTB to elicit antitumor activity and increase survival in nude mice with human glial tumor. The K(Ca) channel activity and expression was also evaluated in human glioma tissues. We administered NS-1619, calcium-dependent potassium (K(Ca)) channel agonist, with [(14)C]-TMZ, and quantified TMZ delivery. The results clearly demonstrate that when given systemically both TMZ and Herceptin do not cross the BTB in significant amounts, however, NS-1619 co-infusion with [(14)C]-TMZ and Herceptin resulted in enhanced drug delivery to brain-tumor cells. The combination treatment of TMZ and Herceptin also showed improved antitumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with brain tumor, when co-infused with K(Ca) channel agonists. In conclusion, K(Ca) channel agonists may benefit brain tumor patients by increasing anti-neoplastic agent's delivery to brain tumors. A clinical outcome of this research is the discovery of a novel drug delivery system that circumvents the BBB/BTB to benefit brain tumor patients.

PMID: 19738431 [PubMed - in process]

PLoS One. 2009 Dec 15;4(12):e8314.
Neural stem cells as a novel platform for tumor-specific delivery of therapeutic antibodies.

Frank RT, Edmiston M, Kendall SE, Najbauer J, Cheung CW, Kassa T, Metz MZ, Kim SU, Glackin CA, Wu AM, Yazaki PJ, Aboody KS.
Division of Hematology, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA. rikfrank@gmail.com
BACKGROUND: Recombinant monoclonal antibodies have emerged as important tools for cancer therapy. Despite the promise shown by antibody-based therapies, the large molecular size of antibodies limits their ability to efficiently penetrate solid tumors and precludes efficient crossing of the blood-brain-barrier into the central nervous system (CNS). Consequently, poorly vascularized solid tumors and CNS metastases cannot be effectively treated by intravenously-injected antibodies. The inherent tumor-tropic properties of human neural stem cells (NSCs) can potentially be harnessed to overcome these obstacles and significantly improve cancer immunotherapy. Intravenously-delivered NSCs preferentially migrate to primary and metastatic tumor sites within and outside the CNS. Therefore, we hypothesized that NSCs could serve as an ideal cellular delivery platform for targeting antibodies to malignant tumors. METHODS AND FINDINGS: As proof-of-concept, we selected Herceptin (trastuzumab), a monoclonal antibody widely used to treat HER2-overexpressing breast cancer. HER2 overexpression in breast cancer is highly correlated with CNS metastases, which are inaccessible to trastuzumab therapy. Therefore, NSC-mediated delivery of trastuzumab may improve its therapeutic efficacy. Here we report, for the first time, that human NSCs can be genetically modified to secrete anti-HER2 immunoglobulin molecules. These NSC-secreted antibodies assemble properly, possess tumor cell-binding affinity and specificity, and can effectively inhibit the proliferation of HER2-overexpressing breast cancer cells in vitro. We also demonstrate that immunoglobulin-secreting NSCs exhibit preferential tropism to tumor cells in vivo, and can deliver antibodies to human breast cancer xenografts in mice. CONCLUSIONS: Taken together, these results suggest that NSCs modified to secrete HER2-targeting antibodies constitute a promising novel platform for targeted cancer immunotherapy. Specifically, this NSC-mediated antibody delivery system has the potential to significantly improve clinical outcome for patients with HER2-overexpressing breast cancer.

PMID: 20016813 [PubMed - in process]

Drug now used to treat erectile dysfuncton may enhance delivery of herceptin to certain brain tumors

LOS ANGELES (May 7, 2010) -- New research by scientists at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute suggests that a drug currently approved to treat erectile dysfunction may significantly enhance the delivery of the anti-cancer drug Herceptin to certain hard-to-treat brain tumors. The research, published in the journal PLoS ONE, could help doctors improve treatments for lung and breast cancers that have metastasized to the brain.
While cancers that originate in the brain are relatively rare -- approximately 22,000 patients are diagnosed with a primary brain tumor every year -- nearly 10 times that many people develop brain tumors from cancers that began elsewhere in the body. Lung cancer remains the leading cause of cancer death in the U.S., and about 20 percent of lung cancers metastasize to the brain. Breast cancer and melanoma may also spread to the brain, and once this happens, the cancer becomes extremely difficult to treat and the prognosis turns poor.
Even if a cancer is susceptible to drugs, these drugs must penetrate the "blood-brain barrier" if they're to treat cancer that's metastasized to the brain. "Mother Nature created this barrier to protect our brains from dangerous substances, but here we need to get through the barrier to deliver the drugs, and that's a problem," says study author Julia Y. Ljubimova, M.D., Ph.D., a research scientist at the Cedars-Sinai Maxine Dunitz Neurosurgical Institute in Los Angeles.
Keith Black, M.D., chairman of Cedars-Sinai's Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute, is the lead research scientist on this project and senior author of the paper. He has studied the blood-brain barrier for about two decades, and his work in this field received the Jacob Javits award from the National Advisory Neurological Disorders and Stroke Council of the National Institutes of Health in June 2000. Since then, research conducted by his team found that the erectile dysfunction drugs sildenafil (Viagra) and vardenafil (Levitra), which inhibit the enzyme phosphodiesterase 5 (PDE5), could increase the permeability of the blood-brain tumor barrier and boost the effectiveness of the chemotherapy drug doxorubicin.
"No matter how effective against cancer a chemotherapeutic agent may be, it can have little impact on brain tumors if it cannot cross the blood-brain tumor barrier," he said. "As we find new drugs that are able to target these tumor cells, it is imperative that we develop better ways to enable the medications to reach their targets."
In the current study, the researchers examined whether PDE5 inhibitors might also increase the blood-brain tumor barrier's permeability to Herceptin, a monoclonal antibody used to treat lung and breast tumors that are positive for HER2/neu. Herceptin is a large molecule that does not easily cross the blood-brain tumor barrier, a limitation that severely reduces its effectiveness at treating brain metastases.
The researchers first measured vardenafil's effects on the permeability of the blood-brain tumor barrier. Using a mouse model, the scientists showed that vardenafil led to a two-fold increase in the amount of Herceptin that reached brain metastases of lung and breast cancers. Next, they examined whether this increase in blood-brain barrier permeability improved Herceptin's effectiveness at treating these brain metastases by giving mice vardenafil in tandem with Herceptin. The results showed that the combination of vardenafil plus Herceptin boosted mean survival by 20 percent, compared to Herceptin alone (72+/-18 days versus 59+/-9 days).
Mice whose tumors were not HER2-positive did not experience the same increase in survival that those with HER2-positive tumors did when given vardenafil, indicating that the survival benefit was indeed due to an increase in the amount of Herceptin reaching the tumors, says Ljubimova.
"Now that we've demonstrated that big molecules can cross the blood-brain tumor barrier, we're going to continue this strategy with other big molecule drugs, such as nanomedicine drugs" says Ljubimova. "This opens a new world for brain tumor treatments."

Citation: Hu J, Ljubimova JY, Inoue S, Konda B, Patil R, et al. (2010) Phosphodiesterase Type 5 Inhibitors Increase Herceptin Transport and Treatment Efficacy in Mouse Metastatic Brain Tumor Models. PLoS ONE 5(4): e10108. doi:10.1371/journal.pone.0010108

PLoS One. 2010 Apr 19;5(4):e10108.
Phosphodiesterase type 5 inhibitors increase Herceptin transport and treatment efficacy in mouse metastatic brain tumor models.

Hu J, Ljubimova JY, Inoue S, Konda B, Patil R, Ding H, Espinoza A, Wawrowsky KA, Patil C, Ljubimov AV, Black KL.
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

BACKGROUND: Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB), significantly limiting drug use in brain cancer treatment. METHODOLOGY/PRINCIPAL FINDINGS: We examined the effect of phosphodiesterase 5 (PDE5) inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14)C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu) by cultured mouse brain endothelial cells (MBEC). The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14)C]dextran (2.6-fold increase) and to Herceptin (2-fold increase). Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p<0.01). Log-rank survival analysis of mice bearing HER2-positive intracranial breast tumor also showed a significant survival increase (p<0.02) in the group treated with Herceptin plus vardenafil as compared to other groups. However, vardenafil did not exert any beneficial effect on survival of mice bearing intracranial breast tumor with low HER2 expression and co-treated with Herceptin (p>0.05). CONCLUSIONS/SIGNIFICANCE: These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.

PMID: 20419092 [PubMed - in process]PMCID: PMC2856671Free PMC Article

J Cereb Blood Flow Metab. 2010 Mar 10. [Epub ahead of print]
17-beta-Estradiol: a powerful modulator of blood-brain barrier BCRP activity.

Hartz AM, Mahringer A, Miller DS, Bauer B.
Department of Biochemistry and Molecular Biology, Medical School, University of Minnesota, Duluth, Minnesota, USA.
The ATP-driven efflux transporter, breast cancer resistance protein (BCRP), handles many therapeutic drugs, including chemotherapeutics, limiting their ability to cross the blood-brain barrier. This study provides new insight into rapid, nongenomic regulation of BCRP transport activity at the blood-brain barrier. Using isolated brain capillaries from rats and mice as an ex vivo blood-brain barrier model, we show that BCRP protein is highly expressed in brain capillary membranes and functionally active in intact capillaries. We show that nanomolar concentrations of 17-beta-estradiol (E2) rapidly reduced BCRP transport activity in the brain capillaries. This E2-mediated effect occurred within minutes and did not involve transcription, translation, or proteasomal degradation, indicating a nongenomic mechanism. Removing E2 after 1 h fully reversed the loss of BCRP activity. Experiments using agonists and antagonists for estrogen receptor (ER)alpha and ERbeta and brain capillaries from ERalpha and ERbeta knockout mice demonstrated that E2 could signal through either receptor to reduce BCRP transport function. We speculate that this nongenomic E2-signaling pathway could potentially be used for targeting BCRP at the blood-brain barrier, in brain tumors, and in brain tumor stem cells to improve chemotherapy of the central nervous system.

Journal of Cerebral Blood Flow & Metabolism advance online publication, 10 March 2010; doi:10.1038/jcbfm.2010.36.

PMID: 20216549 [PubMed - as supplied by publisher]

Curr Opin Mol Ther. 2010 Apr;12(2):168-75.
Telomerase inhibitors for the treatment of brain tumors and the potential of intranasal delivery.

Hashizume R, Gupta N.
University of California San Francisco, Hellen Diller Family Cancer Research Center, Mission Bay, 1450 3rd Street, HD 200, San Francisco, CA 94158-0520, USA. rintaro.hashizume@ucsf.edu

A fundamental limitation in the treatment of brain tumors is that < 1% of most therapeutic agents administered systemically are able to cross the blood-brain barrier (BBB). The development of new strategies that circumvent the BBB should increase the likelihood of tumor response to selected therapeutic agents. Intranasal delivery (IND) is a practical, noninvasive method of bypassing the BBB to deliver therapeutic agents to the brain. This technique has demonstrated promising results in the treatment of neurological disorders. Telomerase is a reverse transcriptase that is expressed in the vast majority of malignant gliomas, although not in the healthy brain. Telomerase inhibition can therefore be used as a therapeutic strategy for selectively targeting malignant gliomas. The first successful IND of a telomerase inhibitor as a therapy for brain tumors was GRN-163, an oligonucleotide N3'-->5' thiophosphoramidate telomerase inhibitor, which was successfully administered into intracerebral tumors in rats with no apparent toxicity. GRN-163 exhibited favorable tumor uptake and inhibited tumor growth, leading to prolonged lifespan in treated animals. The IND of telomerase inhibitors represents a new therapeutic approach that appears to selectively kill tumor cells, without inducing toxic effects in the surrounding healthy brain tissue.

PMID: 20373260 [PubMed - indexed for MEDLINE]

PLoS One. 2010 Aug 12;5(8):e12124.
Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells.

Gurung RL, Lim SN, Khaw AK, Soon JF, Shenoy K, Mohamed Ali S, Jayapal M, Sethu S, Baskar R, Hande MP.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.



BACKGROUND: A major concern of cancer chemotherapy is the side effects caused by the non-specific targeting of both normal and cancerous cells by therapeutic drugs. Much emphasis has been placed on discovering new compounds that target tumour cells more efficiently and selectively with minimal toxic effects on normal cells.
METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxic effect of thymoquinone, a component derived from the plant Nigella sativa, was tested on human glioblastoma and normal cells. Our findings demonstrated that glioblastoma cells were more sensitive to thymoquinone-induced antiproliferative effects. Thymoquinone induced DNA damage, cell cycle arrest and apoptosis in the glioblastoma cells. It was also observed that thymoquinone facilitated telomere attrition by inhibiting the activity of telomerase. In addition to these, we investigated the role of DNA-PKcs on thymoquinone mediated changes in telomere length. Telomeres in glioblastoma cells with DNA-PKcs were more sensitive to thymoquinone mediated effects as compared to those cells deficient in DNA-PKcs.
CONCLUSIONS/SIGNIFICANCE: Our results indicate that thymoquinone induces DNA damage, telomere attrition by inhibiting telomerase and cell death in glioblastoma cells. Telomere shortening was found to be dependent on the status of DNA-PKcs. Collectively, these data suggest that thymoquinone could be useful as a potential chemotherapeutic agent in the management for brain tumours.

PMID: 20711342 [PubMed - in process]PMCID: PMC2920825Free PMC Article

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Re: Brain mets

Intracranial Lesions Mimicking Neoplasms

Accepted July 25, 2008


In this review, we have compiled a unique series of cases that presented both clinically and radiologically as intracranial mass lesions. Tumor was initially considered in each of the cases. However, pathology revealed a variety of nonneoplastic etiologies, including demyelinating disease, vascular disease, inflammation, and infection, as well as posttreatment effects. Although tumor is often the most likely diagnostic consideration in a patient presenting with a contrast-enhancing mass lesion within the brain parenchyma with surrounding edema and mass effect, that is not always the case. Not uncommonly, there can be significant overlap in the radiologic presentation between neoplastic and nonneoplastic diseases. Both neoplastic and nonneoplastic diseases can produce abnormal contrast enhancement, mass effect, and perilesional edema on both computed tomography (CT) and magnetic resonance imaging (MRI). Occasionally, some of these nonneoplastic etiologies may produce signs and symptoms mimicking tumoral disease clinically.1 As such, these situations may offer a diagnostic challenge to both the clinician and radiologist, and often these patients undergo biopsy. In most cases, the pathologist can readily differentiate between neoplasia and nonneoplastic imitators. However, because the benign nature of some pseudoneoplastic lesions may not be immediately apparent on pathologic examination, it behooves the pathologist to be aware of their existence. The purpose of this case series is to alert pathologists, radiologists, and other clinicians involved in the care of neurooncologic patients to consider nonneoplastic etiologies in the differential diagnosis of both intra-axial and extra-axial mass lesions.
Tumor-mimicking conditions from several etiologic categories are presented in tabular form, including infection and inflammation, demyelinating disease, vascular disease, and post treatment conditions, with accompanying illustrations and discussion of the current and pertinent literature. Case examples of each condition discussed are described in the Table .

Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):504-512.
Intracranial Metastatic Disease Spares the Limbic Circuit: A Review of 697 Metastatic Lesions in 107 Patients.
Marsh JC, Herskovic AM, Gielda BT, Hughes FF, Hoeppner T, Turian J, Abrams RA.

Department of Radiation Oncology, Rush University Medical Center, Chicago, Illinois.
PURPOSE: We report the incidence of metastatic involvement of the limbic circuit in a retrospective review of patients treated at our institution. This review was performed to assess the feasibility of selectively sparing the limbic system during whole-brain radiotherapy and prophylactic cranial irradiation. METHODS AND MATERIALS: We identified 697 intracranial metastases in 107 patients after reviewing contrast-enhanced CT and/or MR image sets for each patient. Lesions were localized to the limbic circuit or to the rest of the brain/brain stem. Patients were categorized by tumor histology (e.g., non-small-cell lung cancer, small-cell lung cancer, breast cancer, and other) and by total number of intracranial metastases (1-3, oligometastatic; 4 or more, nonoligometastatic). RESULTS: Thirty-six limbic metastases (5.2% of all metastases) were identified in 22 patients who had a median of 16.5 metastases/patient (limbic metastases accounted for 9.9% of their lesions). Sixteen metastases (2.29%) involved the hippocampus, and 20 (2.86%) involved the rest of the limbic circuit; 86.2% of limbic metastases occurred in nonoligometastatic patients, and 13.8% occurred in oligometastatic patients. The incidence of limbic metastases by histologic subtype was similar. The incidence of limbic metastases in oligometastatic patients was 4.9% (5/103): 0.97%, hippocampus; 3.9%, remainder of the limbic circuit. One of 53 oligometastatic patients (1.9%) had hippocampal metastases, while 4/53 (7.5%) had other limbic metastases. CONCLUSIONS: Metastatic involvement of the limbic circuit is uncommon and limited primarily to patients with nonoligometastatic disease, supporting our hypothesis that it is reasonable to selectively exclude or reduce the dose to the limbic circuit when treating patients with prophylactic cranial irradiation or whole-brain radiotherapy for oligometastatic disease not involving these structures. Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 20117288 [PubMed - as supplied by publisher]

The limbic system performs a number of vital functions including acquisition and consolidation of memory, regulation of emotional and autonomic responses to external stimuli, psychomotor activation, concentration/ attention span, executive planning, and visual-spatial orientation. Based on many years of clinical experience in treating intracranial metastases, we have noted a very low incidence of involvement of the limbic circuit in metastatic disease. We postulate that it may be reasonable and safe to exclude and/or reduce the dose to these structures when treating patients with either whole-brain radiation therapy (WBRT) or prophylactic cranial irradiation (PCI). In order to confirm this hypothesis, we performed this study.

The NovoTTF-100A delivers low intensity alternating electric fields to the patient’s tumor site (SCIENCE).
The Device
The NovoTTF-100A is a non-invasive device, consisting of four sets of insulated electrodes attached to an electronic box. The electrodes are placed on the outside of the shaved scalp. The electrodes generally resemble bandages with wires attached. The electrodes connect to a portable TTField-generating box running off a battery or plugged into a wall supply. The device is lightweight (approximately 6 lbs) and fits neatly into a dedicated carrying case that will be provided to the patient.
The Device and Treatment
The NovoTTF-100A is a portable, investigational device for cancer treatment using TTFields – Tumor Treating Fields (SCIENCE). The device is intended for continuous home use by patients (TREATMENT) with a newly diagnosed GBM tumor (ELIGIBILITY). Results from a pilot study of the device suggest that the investigational treatment may increase the length of time before disease progression and increase median overall survival newly diagnosed GBM patients. These results were from a small study and have not yet been validated. The device has not yet been proven to be safe and effective for any indication. (CLINICAL EXPERIENCE).
Electrical Device for Cancer Treatment Polarizes Audiences

Toxicity advantage over chemotherapy


December 2, 2010 (Montreal, Quebec) — An investigational glioblastoma treatment that delivers alternating electric fields through scalp electrodes might also have application in other cancers, particularly nonsmall-cell lung cancer (NSCLC), according to an Israeli presenter here at the Society for Neuro-Oncology 15th Annual Scientific Meeting.
"We do this to all our patients; we intoxicate them," said Dr. Ram about the adverse effects of chemotherapy. "Even if NovoTTF did not extend survival, if it was equivalent to chemotherapy [for survival], then it may still improve quality of life."
Dr. Ram did not know the median length of time that the NovoTTF cohort wore the device, but an earlier phase 2 study followed some of them for 59 months. "Seventy percent are still alive — that's unheard of," he remarked.
"There were concerns that patients might have more headaches or seizures, but there were none," he said.
Dr. Ram reported that the rate of adverse events related to the central nervous system (CNS) was similar for NovoTTF and chemotherapy (66% vs 67%), as were serious CNS adverse events (21% vs 22%), seizures (15% vs 12%), and headaches (18% vs 13%).
"There are no real concerns that this does anything hazardous to the brain," he said.
Trial: http://clinicaltrials.gov/ct2/show/NCT00916409

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Anticancer Res. 2005 May-Jun;25(3A):1531-7.
Brain metastases in breast cancer--an in vitro study to evaluate new systemic chemotherapeutic options.

Honig A, Rieger L, Sutterlin A, Kapp M, Dietl J, Sutterlin MW, Kämmerer U.
Department of Obstetrics and Gynecology, University of Wuerzburg, Germany. arnd_hoenig@hotmail.com
BACKGROUND: Fifteen-30% of breast cancer patients develop central nervous system (CNS) metastases. The most potent drugs for the treatment of breast cancer like taxanes, anthracyclines and trastuzumab have limited efficacy for brain metastases. No standardized therapy has yet been established for this condition. Drugs with proven efficacy in the CNS and which are commonly used for primary brain tumors were applied. We evaluated the capacity of these drugs to inhibit breast tumor cell growth in vitro. MATERIALS AND METHODS: Twelve primary cell cultures of pulmonary/pleural metastases of breast cancer and 3 commercially available cell lines were used for non-radioactive cytotoxicity assays to evaluate the efficacy of 3 different concentrations of Topotecan, Cisplatin, Nimustine, Vincristine, Irinothecan, Caelyx (pegylated liposomal Doxorubicin) and Etoposide. RESULTS: Topotecan, Cisplatin, Caelyx and Vincristine showed significantly higher cytostatic activity in vitro than Irinotecan, Etoposide and Nimustine. With regard to the median cytotoxicity, the order of drugs in our assays was Topotecan, Cisplatin, Vincristine, Caelyx, Irinotecan, Etoposide and Nimustine. Nimustine showed almost no efficacy against breast cancer cells. CONCLUSION: Topotecan, Cisplatin, Vincristine and Caelyx seem to be suitable candidates for further clinical evaluation. The data and the "liposomal packaging" suggest that Caelyx might be effective in the CNS. Since pulmonary metastases are often associated with brain metastases, evaluating primary cell cultures from malignant pleural effusions could be a valuable approach for the testing of new cytostatic drugs for brain metastases.

PMID: 16033055 [PubMed - indexed for MEDLINE]

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Brain Tumor Cells Made More Responsive to Radiation

ScienceDaily (Dec. 2, 2009) — Duke University Medical Center researchers have figured out how stem cells in the malignant brain cancer glioma may be better able to resist radiation therapy. And using a drug to block a particular signaling pathway in these cancer stem cells, they were able to kill many more glioma cells with radiation in a laboratory experiment.

The work builds off earlier research which showed that cancer stem cells resist the effects of radiation much better than other cancer cells.
The Duke team identified a known signaling pathway called Notch as the probable reason for the improved resistance. Notch also operates in normal stem cells, where it is important for cell-cell communication that controls cell growth and differentiation processes. The study was published in late November by Stem Cells journal.
"This is the first report that Notch signaling in tumor tissue is related to the failure of radiation treatments," said lead author Jialiang Wang, Ph.D., a research associate in the Duke Division of Surgery Sciences and the Duke Translational Research Institute. "This makes the Notch pathway an attractive drug target. The right drug may be able to stop the real bad guys, the glioma stem cells."
Stem cells in a cancer are the source of cancer cell proliferation, Wang said. Hundreds of cancer stem cells can quickly become a million tumor cells.
The Duke researchers, in collaboration with a team led by Dr. Jeremy Rich at Cleveland Clinic, used drugs called gamma-secretase inhibitors that target a key enzyme involved in Notch signaling pathway on gliomas in a lab dish. These inhibitors are being studied by other researchers for their ability to fight tumors in which Notch is abnormally activated, such as leukemia, breast and brain tumors.
"In our study, gamma-secretase inhibitors alone only moderately slowed down tumor cell growth," said senior author Dr. Bruce Sullenger, Duke Vice Chair for Research and Joseph W. and Dorothy W. Beard Professor of Surgery. "But when we looked at these molecules combined with radiation at clinically relevant doses, the combination caused massive cell death in the tumors and significantly reduced survival of glioma stem cells. These findings often correlate with better tumor control."
Wang said ongoing clinical trials are testing gamma-secretase inhibitors as stand-alone therapy for breast and brain tumors. "Our study suggests that Notch inhibition using these drugs would provide significant therapeutic benefits if combined with radiotherapy, and I hope that future research will study this combination therapy in this vulnerable patient population," Wang said. "More effective radiation may be attainable if we can stop Notch signaling in the tumor stem cells."
Other authors include Timothy P. Wakeman and Xiao-Fan Wang of the Duke Department of Pharmacology and Cancer Biology; Rebekah R. White of the Duke Department of Surgery and the Duke Translational Research Institute; and Justin D. Lathia and Anita B. Hjelmeland of the Department of Stem Cell Biology and Regenerative Medicine at Cleveland Clinic, and Jeremy Rich, Dr. Wang's mentor who was at Duke and now heads that department at the Cleveland Clinic.
The research was supported by a Basic Research Fellowship from the American Brain Tumor Association, a Howard Hughes Medical Institute Early Career Award, NIH grants, the Childhood Brain Tumor Foundation, the Pediatric Brain Tumor Foundation of the United States, Accelerate Brain Cancer Cure, the Alexander and Margaret Stewart Trust, Brain Tumor Society, the Goldhirsh Foundation, the Sidney Kimmel Foundation, and the Damon Runyon Cancer Research Foundation.
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For the First Time, a Glioma - Brain Cancer - may be Eliminated by a Chinese Research/Medical Team, Using a Novel Stem Cell Based Therapy of Cellonis Biotech, Beijing


BEIJING, Dec. 17 /PRNewswire-Asia/ -- Using a novel stem cell based technology of Cellonis Biotechnologies, Beijing, a Chinese research/medical team may eliminate a glioma -- brain cancer -- of a 36 year old Norwegian patient in a hospital in Beijing. The treatment shows that the activated immune system can directly kill tumor stem cells as well as cancer daughter cells. The amazing outcome of this novel treatment within a Comprehensive Cancer Therapy tells Cellonis that the future vaccination therapies may be targeted towards cancer stem cell lysates to improve the antigen-presenting Dendritic Cell response.
(Photo: http://www.newscom.com/cgi-bin/prnh/20091217/CNTH007)

Arve Johnsen , 36, from Norway, a patient diagnosed with glioma in 2006 and relapsed in 2009 after surgical resection. He arrived in Beijing in August 2009 with his wife Vanja and a one-year-old daughter, with the hope that the doctors in Norway were wrong. They told the family there is no other option anymore in the Scandinavian countries or in Europe for Arve to control the progress of disease and prolong his life. Driven by the hope that their daughter could grow up with a father, the Johnsen family started a research campaign to find other treatments worldwide, to give Arve a new hope.

Comprehensive Cancer Therapy in China
The Johnsen's, having heard about the sustainable success of a Comprehensive Cancer Therapy (CCT) in China, decided to try for this last chance in a country 10,000 km away from Norway. This kind of CCT had been developed in the past few years by a Chinese team of scientific researchers and clinical doctors in Beijing, combining conventional cancer treatments with Traditional Chinese Medicine (TCM) and cell therapies.
The role of cancer stem cells in the tumors
Scientists previously believed that tumors are lumps of cancer tissue that must be completely removed or destroyed to cure a patient. But over the past few years, researchers have learned that cancer stem cells (CSCs), comprising a small population of cells, appear to be responsible for the initiation, upkeep and relapse of malignant tumors. Even if a tumor is almost completely obliterated, it will regenerate from the surviving CSCs and become even more resistant to treatment than before.
Current therapies, including cell therapy, generally do not target CSCs. This allows CSCs to survive until after chemotherapy or radiation treatments. Killing those cells is a promising strategy to eliminate tumors and prevent them from re-growing.

Lily Shum : Perfect integration of stem cells and immunotherapies

"The CSCs may explain why common treatments, particularly chemotherapy, are not sufficient to kill tumors. In fact, despite the continuous development of new chemotherapeutic agents, brain tumors can develop and remain resistant to those therapies. The integration of stem cells and immune technologies seems to give us a chance to find out a new way to target at CSCs," says Prof.
Lily Shum , PhD, the chief scientist of Cellonis.

"The difficult issue in our project is how to capture and classify CSCs. With our patented technologies, we are able to isolate the CSCs from patient's brain tumor tissues, culture them and induce the multi-drug and radiation resistance. These cells possess very strong carcinogenicity, self-renewal, and also a very strong drug and radiation resistance."

Lily Shum adds, "The Dendritic Cell (DC) is a very useful tool to conduct a specific immune response against brain CSCs." As we know, DC is an antigen-presenting cell that stimulates the innate immune system, as a messenger, it transfers "the information of cancer cell - antigen" to "the killers of the immune system - the T cells," and then T cells can recognize and lyse cells bearing those antigens. "We educate the DC with the brain CSCs, and then conduct the specific immune response which targets the CSCs."

Dinggang Li : Comprehensive Cancer Therapies

"The outcome of the first pilot study with Johnsen is amazing. The PET-CT scan for Johnsen shows that all the tumor disappeared after the treatment," says Dr.
Dinggang Li, M.D. PhD. He has developed and conducted CCT for more than 100 international cancer patients in the past few years. DCs loaded with different kinds of brain cancer related antigens that target cancer cells and the CIK cell treatment are the main elements of his comprehensive treatment for cancer. "In the first cycle of treatment, we treated him with comprehensive approaches including SHG-44 loading DC, CIK cell therapy and TCM, but we had not been able to control the progression of the disease, the tumors continued to grow. We gave him the DC therapy which targets brain CSCs in the 2nd cycle of treatment, and it showed a very promising response."

Dr. Cindy HAO: More clinical trials to confirm the outcome
Cindy HAO, M.D., CEO of Cellonis Biotechnologies is optimistic for the future of this new brain cancer approach. "It gives us a strong confidence to make more efforts toward this direction. This pilot treatment study shows us that the activated immune system can directly kill tumor stem cells as well as tumor daughter cells. But first of all we need to extend our further clinical trials to confirm the outcome. And it also tells us that the future vaccination therapies may be targeted toward Cancer Stem Cell Lysates to improve the antigen-presenting DC response."

For more information, please contact:

Urs. J. Lienert, M.B.A.
Director International
Cellonis Biotechnologies Co., Ltd.
Floor 7, Huizhong Science & Technology Center
No 1, Shangdi Seventh Road
Haidian District Beijing, 100085
P.R. China
Email: urs.lienert@cellonis.com; Lienert.Cellonis@yahoo.com
Phone: +86-10-6296-2795; Cell: +86-150-1054-7487
Cell: +41-76-584-87-60 (Switzerland)
(from 20 December 2009 to 15 January 2010)
SOURCE Cellonis Biotechnologies


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An oral, brain barrier crossing, Anthracycline amenable to metronomic delivery:

Penetration of Idarubicin into Malignant Brain Tumor Tissue

Authors: Boogerd W.1; Tjahja I.S.2; van de Sandt M.M.3; Beijnen J.H.4
Source: Journal of Neuro-Oncology, Volume 44, Number 1, August 1999 , pp. 65-69(5)
Publisher: Springer
Anthracyclines are effective in breast cancer and have in vitro cytotoxicity in glioma. In patients with glioma anthracyclines are not effective possibly because the hydrophilic drugs do not reach cytotoxic levels in tumor tissue. Idarubicin is more lipophilic than the other anthracyclines and is more cytotoxic in glioma cell lines. The uptake of idarubicin and its major metabolite idarubicinol in brain tumor tissue were measured in a patient with a brain metastasis from breast cancer and in 4 patients with malignant glioma after an oral dose of idarubicin (45 mg/m^2 in 1 patient; 25 mg/m^2 in 4 patients), given 15–24 h before brain tumor resection. The concentrations of idarubicin and of idarubicinol in tumor tissue exceeded the concurrent plasma concentrations as well as the peak plasma concentrations in all cases. The median tumor: concurrent plasma ratio of idarubicinol was 5.7 (range 1.7–18). The concentration of idarubicinol in the marginal zone between brain and tumor tissue was lower than in central tumor tissue, but was still higher than the plasma concentration in 2 of the 3 examined cases. Bone marrow suppression (platelets CTC grade 2, granulocytes CTC grade 4) occurred after a single dose of 45 ml/m^2. No toxicity was seen at a dose of 25 mg/m^2. These results, the in vitro activity of idarubicin in glioma, the convenience of oral administration, and its toxicity profile make clinical studies with idarubicin in malignant glioma, and perhaps also in brain metastases from breast cancer worthwhile.
1: Department of Neurology, Slotervaart Hospital, Amsterdam; Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands
Department of Neurosurgery, Slotervaart Hospital, Amsterdam 3: Department of Pathology, Slotervaart Hospital, Amsterdam
Department of Pharmacy, Slotervaart Hospital, Amsterdam; Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands

J Neurooncol. 2010 Jan 12. [Epub ahead of print]
Metronomic treatment of malignant glioma xenografts with irinotecan (CPT-11) inhibits angiogenesis and tumor growth.

Takano S, Kamiyama H, Mashiko R, Osuka S, Ishikawa E, Matsumura A.
Department of Neurosurgery, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba city, Ibaraki, 305-8575, Japan, shingo4@md.tsukuba.ac.jp.
Irinotecan (CPT-11) has shown emerging promise in the treatment of malignant gliomas. It is believed the mechanism of action of irinotecan is to sensitize glioma cells to the cytotoxic action of radiation therapy and alkylating agents. However, clinical trials using weekly or three-weekly doses of CPT-11 have demonstrated imaging responses in only 10-15% of patients. In this study, we evaluated another mechanism of action, angiosuppression by CPT-11 of ACNU-resistant gliomas, using a metronomic administration schedule. Two different types of treatment, (1) conventional and (2) metronomic, were applied to the subcutaneous U87 model. We found that metronomic administration of CPT-11 significantly inhibited malignant glioma growth by inhibiting angiogenesis; this treatment procedure reduced the number of tumor vessels and the area of hypoxic lesions and reduced expression of VEGF and HIF-1alpha, the most important angiogenic factors in gliomas. Metronomic treatment was superior to conventional treatment with regard to the severe systemic side effect of body weight loss. The growth inhibitory effect was very similar for both low and high doses of CPT-11. These angiosuppressive effects of CPT-11 show promise for another use of CPT-11 in metronomic and scheduled angiosuppressive chemotherapy with low dose and long-term administration for malignant gliomas without systemic side effects.

PMID: 20066473 [PubMed - as supplied by publisher]

Ai Zheng. 2007 Dec;26(12):1392-6.
[A new treatment protocol targeting tumor vasculature--- metronomic chemotherapy combined radiotherapy]

[Article in Chinese]
Qiu H, Wang GM.
Department of Radiotherapy, Huadong Hospital, Shanghai, 200040, PR China. qiuhao_limoges@188.com
Tumor growth and metastasis depend on its angiogenesis ability. The anti-angiogenic treatment is considered as a hopeful treatment for tumors. The anti-angiogenic efficacy of classic cytotoxic agents, such as cyclophosphomide, methotraxate, taxol, and so on, could be enhanced by changing the dose delivering schedule, naming "metronomic chemotherapy". Additionally, tumor vasculature and hypoxic status are important predictive factors for the efficacy of radiotherapy. Furthermore, the anti-angiogenic treatment can enhance the irradiation sensitivity of tumors. This review have summarized the anti-angiogenic mechanism of metronomic chemotherapy combined radiotherapy and the preliminary applications in clinic and proposed that the combination of radiotherapy and metronomic chemotherapy can overcome the hypoxia-related radioresistance and increase the efficacy of radiotherapy.

PMID: 18076810 [PubMed - indexed for MEDLINE]

Mo Med. 2009 Nov-Dec;106(6):428-31.
Brain metastases secondary to breast cancer: treatment with surgical resection and stereotactic radiosurgery.

Tolentino PJ.
Brain and NeuroSpine Clinic of Missouri, LLC, Cape Girardeau, MO, USA. ptolentino@brainandneurospine.com
Intracerebral metastases are a serious complication for a significant proportion of cancer patients. Successful management may involve multiple treatments including surgical resection, whole-brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS). We report the successful treatment of a solitary brain metastasis using a combination of surgical resection and SRS at Southeast Missouri Hospital, a community hospital that serves a primarily rural population.

PMID: 20063515 [PubMed - in process]

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Drug Combination Shrinks Breast Cancer Metastases In Brain

ScienceDaily (Dec. 17, 2007) — A combination of a "targeted" therapy and chemotherapy shrank metastatic brain tumors by at least 50 percent in one-fifth of patients with aggressive HER2-positive breast cancer, according to data presented by Dana-Farber Cancer Institute investigators at the San Antonio Breast Cancer Symposium.
Lapatinib (Tykerb) and capecitabine (Xeloda) were paired in an extension of a Phase 2 clinical trial in which lapatinib given alone shrank brain metastases significantly in six percent of 241 patients.
In the extension trial, capecitabine was added to lapatinib in 49 patients whose metastases -- cancerous colonies in the brain spread from their primary cancer -- had progressed while on treatment. With the combination therapy, brain metastases shrank by 20 percent or more in 18 patients (37 percent) and shrank by at least 50 percent in 10 patients (20 percent), reported Nancy Lin, MD, of Dana-Farber's Breast Oncology Center.
"Very few medications have shown activity in the treatment of brain metastases, particularly in HER-2-positive metastatic breast cancer patients," said Lin, who led the study with Eric Winer, MD, director of the Dana-Farber Breast Oncology Center. "Therefore, these data are quite encouraging, and further studies are warranted."
Lapatinib is an oral small-molecule drug from GlaxoSmithKline that is approved along with capecitabine for treating patients with advanced or metastatic breast cancer whose tumors are driven by the abnormal growth signal, HER-2, and who have already undergone therapy including trastuzumab (Herceptin), a taxane drug, and an anthracycline compound. Lapatinib, like trastuzumab, blocks the HER-2 signal.
Up to one-third of women with advanced, HER-2-positive breast cancer may develop metastases to the brain.
"Although radiation treatment is often effective, as women live longer with metastatic cancer, some develop worsening of brain metastases despite radiation," said Lin. "Because cancer in the brain can have a major impact on quality of life, it is important to have treatment options to address this problem."
The data was presented on Dec. 16, 2007.


Brain tumor radiation resistance defeated

DURHAM, N.C., Dec. 10 (UPI) -- U.S. scientists say they discovered how stem cells in a type of malignant brain resist radiation, and then used a drug to reduce that resistance.
Researchers from Duke University and the Cleveland Clinic said their work was based on research showing cancer stem cells can better resist the effects of radiation than other cancer cells. The earlier research identified a signaling pathway in normal cells called "Notch" that controls cell growth and differentiation.
The researchers then identified the Notch signaling pathway as the most likely reason for the radiation resistance of the cancer stem cells.
The lead author of the study, Jialiang Wang of Duke University, said the finding marked the first report that Notch signaling in tumor tissue is related to the failure of
"This makes the Notch pathway an attractive drug target," Wang said. "The right drug may be able to stop the real bad guys, the glioma stem cells."
The Duke and Cleveland Clinic researchers say they targeted a key enzyme of the Notch pathway by using drugs called gamma-secretase inhibitors. Senior author Dr. Bruce Sullenger of Duke said use of such drugs, in combination with radiation, "caused massive cell death in the and significantly reduced survival of glioma stem cells."
The research is detailed in the journal Stem Cells.

Efficacy of intracerebral delivery of cisplatin in combination with photon irradiation for treatment of brain tumors

JournalJournal of Neuro-Oncology
PublisherSpringer Netherlands
ISSN0167-594X (Print) 1573-7373 (Online)
CategoryLaboratory Investigation - Human/Animal Tissue
Subject CollectionMedicine
SpringerLink DateFriday, December 11, 2009

Julia Rousseau1, 2, 3, Rolf F. Barth4, Manuel Fernandez1, 2, 3, Jean-François Adam1, 2, 3, Jacques Balosso1, 2, 3, 5, François Estève1, 2, 3, 5 and Hélène Elleaume1, 2, 3, 5
(1) INSERM U836, Equipe 6, ESRF, Medical Beamline, BP 220, 38043 Grenoble Cedex 9, France
(2) Université Joseph Fourier, Grenoble, France
(3) European Synchrotron Radiation Facility, Grenoble, France
(4) Department of Pathology, The Ohio State University, Columbus, OH 43210, USA
(5) Centre Hospitalier Universitaire, Grenoble, France
Received: 17 August 2009 Accepted: 13 November 2009 Published online: 11 December 2009
Abstract We have evaluated the efficacy of intracerebral (i.c.) convection-enhanced delivery (CED) of cisplatin in combination with photon irradiation for the treatment of F98 glioma-bearing rats. One thousand glioma cells were stereotactically implanted into the brains of Fischer rats and 13 days later cisplatin (6 μg/20 μl) was administered i.c. by CED at a flow rate of 0.5 μl/min. On the following day the animals were irradiated with a single 15 Gy dose of X-rays, administered by a linear accelerator (LINAC) or 78.8 keV synchrotron X-rays at the European Synchrotron Radiation Facility (ESRF). Untreated controls had a mean survival time (MST) ± standard error of 24 ± 1 days compared to >59 ± 13 days for rats that received cisplatin alone with 13% of the latter surviving >200 days. Rats that received cisplatin in combination with either 6 MV (LINAC) or 78.8 keV (synchrotron) X-rays had almost identical MSTs of >75 ± 18 and >74 ± 19 days, respectively with 17 and 18% long-term survivors. Microscopic examination of the brains of long-term surviving rats revealed an absence of viable tumor cells and cystic areas at the presumptive site of the tumor. Our data demonstrate that i.c. CED of cisplatin in combination with external X-irradiation significantly enhanced the survival of F98 glioma-bearing rats. This was independent of the X-ray beam energy and probably was not due to the production of Auger electrons as we previously had postulated. Our data provide strong support for the approach of concomitantly administering platinum-based chemotherapy in combination with radiotherapy for the treatment of brain tumors. Since a conventional LINAC can be used as the radiation source, this should significantly broaden the clinical applicability of this approach compared to synchrotron radiotherapy, which could only be carried out at a very small number of specialized facilities.
Keywords F98 rat glioma - Cisplatin - Convection-enhanced delivery - Chemotherapy - Radiotherapy
Presented in part at the 100th Annual Meeting of the American Association for Cancer Research, Denver, CO, April 18–22, 2009.

Hélène Elleaume
Email: h.elleaume@esrf.fr

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Old 02-23-2010, 02:44 AM   #7
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well its very useful article as we have to get some knowledge abt our own brain,,,its good,,
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I recently done my MBA and now days I want to do some online Microsoft certifications and I Found this online notes is a best helping source to get online accurate information which is more helpful for my preparation.
mcse and ccie information and icnd
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Thank you Rich for all that information. I was too overwhelming and I need plain english in WBR which is what I am going through right now. I need sucess stories. Thanks again. Sally
Dx March 2004 HER2+ er/pr+ 8/16 + lymphnodes mets to the liver Stage IV / 6 cycles of TCH and 33 rads . NED Continued Herceptin 3 years w/ Femara. Tumor markers start to rise in Jan of 2007 and swiched to Tamoxifen. August of 2007 found more mets to liver and lymphnodes outside of liver. Went on Tykerb/Xeleoda--spots on liver gone found large mass between intestines. March 2008 started TCH. Stopped Carboplatin due to allergy. Still on Taxotere and Herceptin. Nov 2008 mass is gone. 3 new spot on liver and one on spine. Radiation on spine. tykerb/gemzar for liver mets. PET in April 09 showed shrinkage still a little activity, continue tykerb/gemzar until Aug 09. PET showed new spot on my spine more on my liver and a bunch of enlarged lymphnodes in upper chest. Start Adriamycin Sep 09. more radiation on spine . April 2010- Still on Adriamycin 3wks on 1 wk off and zometa every 28 days. PET -May 2010 showed progression. Starting Herceptin/Navelbine on June '10
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Old 08-27-2010, 07:07 AM   #10
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Re: Brain mets

I really need to hear what you ladies have gone through with WBR. How successful or anything you have to share. Everything I read seems like a death scentence. I have a 12 year old daughter with Asperburger's (Autistic) and she needs me more now than ever. I am very scared and worried. Any encouraging stories would be helpful right now. Thanks Sally
Dx March 2004 HER2+ er/pr+ 8/16 + lymphnodes mets to the liver Stage IV / 6 cycles of TCH and 33 rads . NED Continued Herceptin 3 years w/ Femara. Tumor markers start to rise in Jan of 2007 and swiched to Tamoxifen. August of 2007 found more mets to liver and lymphnodes outside of liver. Went on Tykerb/Xeleoda--spots on liver gone found large mass between intestines. March 2008 started TCH. Stopped Carboplatin due to allergy. Still on Taxotere and Herceptin. Nov 2008 mass is gone. 3 new spot on liver and one on spine. Radiation on spine. tykerb/gemzar for liver mets. PET in April 09 showed shrinkage still a little activity, continue tykerb/gemzar until Aug 09. PET showed new spot on my spine more on my liver and a bunch of enlarged lymphnodes in upper chest. Start Adriamycin Sep 09. more radiation on spine . April 2010- Still on Adriamycin 3wks on 1 wk off and zometa every 28 days. PET -May 2010 showed progression. Starting Herceptin/Navelbine on June '10
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Re: Brain mets


I have had three rounds of Gamma-knife radiosurgery to treat the recurrence of my Central Neurocytoma which is unrelated to breast cancer.

I've been visiting the http://www.braintumor.org/ site for more information since two of the three residue tumors are growing again. The members of that support group are mostly dealing with primary brain tumors. But I thought the fast-growing type of brain tumor such as GBM might be behaving similarly to (much worse than) Breast cancer. GBM used to be considered 'lethal', but as you can see on that site, there are many long-term survivors out there.

You have been through so much. But several of the Her2support members have been NED after getting their brain mets treated - including our founder, Christine. (See 'long-term survivor' thread - use the 'Search' button)

There is a life-long limit on radiation dosage. I'm thinking that since your brain mets were quite small, the WBR should take care of it. (Radiation damages the DNA of fast-growing cancer cells and prevents them from reproducing. The cancer cells eventually die.)

Sending you good vibes. Hang in there.

Erythema Nodosum 85
Life-long Central Neurocytoma 4x5x6.5 cm 23 hrs 62090 semi-coma 10 d PT OT ST 30 d
3 Infertility tmts 99 > 3 u. fibroids > Pills
CN 3 GKRS 52301
IDC 1.2 cm Her2 +++ ER 5% R. Lmptmy SLNB+1 71703 6 FEC 33 R Tamoxifen
Recc IIB 2.5 cm Bi-L Mast 61407 2/9 nds PET
6 TCH Cellulitis - Lymphedema - compression sleeve & glove
H w x 4 MUGA 51 D, J 49 M
Diastasis recti
Tamoxifen B. scan
Irrtbl bowel 1'09
Colonoscopy 313
BRCA1 V1247I
hptc hemangioma
GI - > yogurt
hysterectomy/oophorectomy 011410
Exemestane 25 mg tab 102912 ~ 101016 stopped due to r. hip/l.thigh pain after long walk
DEXA 1/13
1-2016 lesions in liver largest 9mm & 1.3 cm onco. says not cancer.
3-11 Appendectomy - visually O.K., a lot of puss. Final path result - not cancer.
Start Vitamin D3 and Calcium supplement (600mg x2)
10-10 Stopped Exemestane due to r. hip/l.thigh pain OKed by Onco 11-08-2016
7-23-2018 9 mm groundless(granules?) nodule within the right lower lobe with indolent behavior. Due to possible adenocarcinoma, Recommend annual surveilence.
7-10-2019 CT to check lung nodule.


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Old 08-30-2010, 10:47 AM   #12
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Re: Brain mets

Here's an article by Mayo Clinic:


Erythema Nodosum 85
Life-long Central Neurocytoma 4x5x6.5 cm 23 hrs 62090 semi-coma 10 d PT OT ST 30 d
3 Infertility tmts 99 > 3 u. fibroids > Pills
CN 3 GKRS 52301
IDC 1.2 cm Her2 +++ ER 5% R. Lmptmy SLNB+1 71703 6 FEC 33 R Tamoxifen
Recc IIB 2.5 cm Bi-L Mast 61407 2/9 nds PET
6 TCH Cellulitis - Lymphedema - compression sleeve & glove
H w x 4 MUGA 51 D, J 49 M
Diastasis recti
Tamoxifen B. scan
Irrtbl bowel 1'09
Colonoscopy 313
BRCA1 V1247I
hptc hemangioma
GI - > yogurt
hysterectomy/oophorectomy 011410
Exemestane 25 mg tab 102912 ~ 101016 stopped due to r. hip/l.thigh pain after long walk
DEXA 1/13
1-2016 lesions in liver largest 9mm & 1.3 cm onco. says not cancer.
3-11 Appendectomy - visually O.K., a lot of puss. Final path result - not cancer.
Start Vitamin D3 and Calcium supplement (600mg x2)
10-10 Stopped Exemestane due to r. hip/l.thigh pain OKed by Onco 11-08-2016
7-23-2018 9 mm groundless(granules?) nodule within the right lower lobe with indolent behavior. Due to possible adenocarcinoma, Recommend annual surveilence.
7-10-2019 CT to check lung nodule.


Advocacy is a passion .. not a pastime - Joe
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Old 08-30-2010, 07:38 PM   #13
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Join Date: May 2008
Location: Hershey, PA. Live The Sweet Life!
Posts: 1,971
Re: Brain mets


Please read Rich's initial post (Nov. 26, 2009) on this thread regarding Boswellia serrata, 3 · 800 mg/day.

Smile On!

Dx'd w/multifocal DCIS/IDS 3/08
7mm invasive component
Partial mast. 5/08
Stage 1b, ER 80%, PR 90%, HER-2 6.9 on FISH
0/5 nodes
4 AC, 4 TH finished 9/08
Herceptin every 3 weeks. Finished 7/09
Tamoxifen 10/08. Switched to Femara 8/09
Bilat SPM w/reconstruction 10/08
Clinical Trial w/Clondronate 12/08
Stopped Clondronate--too hard on my gizzard!
Switched back to Tamoxifen due to tendon pain from Femara

11 Years NED
I think I just might hang around awhile....

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Old 09-03-2010, 08:56 PM   #14
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Posts: 1
Re: Brain mets

Thank you Rich for all that information.
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