|1: Arch Neurol.
Leptomeningeal carcinomatosis: cerebrospinal fluid
Habek M, Petravic D, Gjadrov-Kuvezdic K, Mahovic
Department of Neurology, Zagreb School of Medicine and University Hospital
Center, Croatia. email@example.com
PMID: 16769877 [PubMed - indexed for MEDLINE]
|2: Arch Neurol.
Atypical appearance of a primary central nervous system
Trendelenburg G, Zimmer C, Forschler A, Stadelmann C,
Department of Neurology, Charite Universitatsmedizin Berlin, Germany.
PMID: 16769876 [PubMed - indexed for MEDLINE]
Pathol Lab Med. 2006 Jul;130(7):1039-41.
Solitary fibrous tumor of the orbit with epithelioid
Warraich I, Dunn DM, Oliver JW.
Department of Pathology, Texas Tech University Health Sciences Center School
of Medicine, Lubbock 79430-8115, USA.
Extrapleural solitary fibrous tumors have often been confused with other
mesenchymal tumors, such as hemangiopericytoma, fibrous histiocytoma,
fibrous meningioma, and leiomyoma, because of morphologic similarity and
underrecognition, especially if some unusual features are present. Recently,
epithelioid solitary fibrous tumor has been reported in the mediastinum. We
report a case of solitary fibrous tumor of the orbit with biphasic
architecture, including spindle cell and epithelioid components. Both
components demonstrated immunohistochemical features of a solitary fibrous
tumor. A background of scattered vessels was present. No evidence of
significant nuclear atypia or mitotic activity was noted. In this report, we
discuss the differential diagnosis of solitary fibrous tumor with unusual
epithelioid features. Extrapleural solitary fibrous tumor should be included
in the differential diagnosis of tumors of the orbit with a spindle cell
appearance even in the presence of some epithelioid morphology.
PMID: 16831031 [PubMed - indexed for MEDLINE]2
Cancer Res. 2006 Jul 15;12(14 Pt 1):4294-305.
Systemic anti-CD25 monoclonal antibody administration
safely enhances immunity in murine glioma without eliminating regulatory T
Fecci PE, Sweeney AE, Grossi PM, Nair SK, Learn
CA, Mitchell DA, Cui X, Cummings TJ, Bigner DD,
Gilboa E, Sampson JH.
Department of Pathology, Duke University Medical Center, Durham, North
Carolina 27710, USA.
PURPOSE: Elevated proportions of regulatory T cells (T(reg)) are present in
patients with a variety of cancers, including malignant glioma, yet
recapitulative murine models are wanting. We therefore examined T(regs) in
mice bearing malignant glioma and evaluated anti-CD25 as an
immunotherapeutic adjunct. EXPERIMENTAL DESIGN: CD4+CD25+Foxp3+GITR+ T(regs)
were quantified in the peripheral blood, spleens, cervical lymph nodes, and
bone marrow of mice bearing malignant glioma. The capacities for systemic
anti-CD25 therapy to deplete T(regs), enhance lymphocyte function, and
generate antiglioma CTL responses were assessed. Lastly, survival and
experimental allergic encephalitis risks were evaluated when anti-CD25 was
combined with a dendritic cell-based immunization targeting shared tumor and
central nervous system antigens. RESULTS: Similar to patients with malignant
glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally,
CD4+CD25+Foxp3+GITR+ T(regs) represent an increased fraction of the
remaining peripheral blood CD4+ T cells, despite themselves being reduced in
number. Similar trends are observed in cervical lymph node and spleen, but
not in bone marrow. Systemic anti-CD25 administration hinders detection of
CD25+ cells but fails to completely eliminate T(regs), reducing their number
only moderately, yet eliminating their suppressive function. This
elimination of T(reg) function permits enhanced lymphocyte proliferative and
IFN-gamma responses and up to 80% specific lysis of glioma cell targets in
vitro. When combined with dendritic cell immunization, anti-CD25 elicits
tumor rejection in 100% of challenged mice without precipitating
experimental allergic encephalitis. CONCLUSIONS: Systemic anti-CD25
administration does not entirely eliminate T(regs) but does prevent T(reg)
function. This leads to safe enhancement of tumor immunity in a murine
glioma model that recapitulates the tumor-induced changes to the CD4 and
T(reg) compartments seen in patients with malignant glioma.
PMID: 16857805 [PubMed - in process]2
Cancer Res. 2006 May 15;12(10):3200-8.
Tumor-targeting properties of novel antibodies specific
to the large isoform of tenascin-C.
Brack SS, Silacci M, Birchler M, Neri D.
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied
Biosciences, Swiss Federal Institute of Technology Zurich, Switzerland.
BACKGROUND: The targeted delivery of bioactive molecules with antibodies
specific to tumor-associated antigens represents a promising strategy for
improving the efficacy of tumor therapy. The large isoform of tenascin-C, an
abundant glycoprotein of the tumor extracellular matrix, is strongly
overexpressed in adult tissue undergoing tissue remodeling, including wound
healing and neoplasia, and has been implicated in a variety of different
cancers while being virtually undetectable in most normal adult tissues.
EXPERIMENTAL DESIGN: We have used antibody phage technology to generate
good-quality human recombinant antibodies (F16 and P12) specific to the
alternatively spliced domains A1 and D of the large isoform of tenascin-C.
The tumor-targeting properties of F16 and P12 were assessed by
biodistribution studies in tumor xenografts using the antibodies in small
immunoprotein (SIP) format. RESULTS: SIP(F16) selectively accumulated at the
tumor site with 4.5%ID/g at 24 hours in the U87 glioblastoma model but was
rapidly cleared from other organs (tumor-to-organ ratios, approximately
10:1). The accumulation of SIP(P12) in the tumor was lower compared with
SIP(F16) and persistent levels of radioactivity were observed in the
intestine. CONCLUSIONS: These data suggest that the F16 antibody, specific
to domain A1 of tenascin-C, is a promising building block for the
development of antibody-based pharmaceuticals in view of its excellent
tumor-targeting performance and the strong expression of the antigen in a
variety of primary and metastatic tumors.
PMID: 16707621 [PubMed - indexed for MEDLINE]2
Cancer Res. 2006 May 15;12(10):3145-51.
Real-time, image-guided, convection-enhanced delivery of
interleukin 13 bound to pseudomonas exotoxin.
Murad GJ, Walbridge S, Morrison PF, Garmestani K,
Degen JW, Brechbiel MW, Oldfield EH, Lonser RR.
Surgical Neurology Branch, National Institute of Neurological Disorders and
Stroke, NIH, Bethesda, Maryland 20892-1414, USA.
PURPOSE: To determine if the tumor-targeted cytotoxin interleukin 13 bound
to Pseudomonas exotoxin (IL13-PE) could be delivered to the brainstem safely
at therapeutic doses while monitoring its distribution in real-time using a
surrogate magnetic resonance imaging tracer, we used convection-enhanced
delivery to perfuse rat and primate brainstems with IL13-PE and
gadolinium-bound albumin (Gd-albumin). EXPERIMENTAL DESIGN: Thirty rats
underwent convective brainstem perfusion of IL13-PE (0.25, 0.5, or 10 microg/mL)
or vehicle. Twelve primates underwent convective brainstem perfusion of
either IL13-PE (0.25, 0.5, or 10 microg/mL; n = 8), co-infusion of
125I-IL13-PE and Gd-albumin (n = 2), or co-infusion of IL13-PE (0.5 microg/mL)
and Gd-albumin (n = 2). The animals were permitted to survive for up to 28
days before sacrifice and histologic assessment. RESULTS: Rats showed no
evidence of toxicity at all doses. Primates showed no toxicity at 0.25 or
0.5 microg/mL but showed clinical and histologic toxicity at 10 microg/mL.
Quantitative autoradiography confirmed that Gd-albumin precisely tracked
IL13-PE anatomic distribution and accurately showed the volume of
distribution. CONCLUSIONS: IL13-PE can be delivered safely and effectively
to the primate brainstem at therapeutic concentrations and over clinically
relevant volumes using convection-enhanced delivery. Moreover, the
distribution of IL13-PE can be accurately tracked by co-infusion of Gd-albumin
using real-time magnetic resonance imaging.
PMID: 16707614 [PubMed - indexed for MEDLINE]3
|7: Clin Neuropathol.
Primary glioblastoma with EGFR amplification and a ring
chromosome 7 in a young patient.
Lopez-Gines C, Cerda-Nicolas M, Gil-Benso R, Pellin
A, Lopez-Guerrero JA, Benito R, del Rey J, Miro
R, Roldan R, Barbera J.
Department of Pathology, University of Valencia, Spain. firstname.lastname@example.org
Glioblastoma is the most common primary tumor of the central nervous system,
but the underlying genetic changes that give rise to these tumors are still
poorly understood. We report a primary glioblastoma with an unusual age of
presentation. The patient was a 22-year-old man with a survival of 16
months. Morphological findings showed an increase of cellularity with
positive GFAP and EGFR expression, increase of proliferate index, vascular
hyperplasia with glomeruloid structures and necrosis. Molecular analysis
showed EGFR amplification. No mutations of the TP53 or amplification of MDM2
and CDK4 were detected. Neither homozygous deletion of the 9p21 locus genes
nor aberrant methylation were found. The cytogenetic study showed a clonal
karyotype. The metaphases presented, among other anomalies, a small ring
chromosome and double-minutes chromosomes. Using FISH and CGH techniques, it
was found that the ring chromosome was a partial trisomy of chromosome 7,
and the region implicated corresponded to 7p13-q21. Partial trisomies in
glioblastoma could play an important role in defining those regions where
genes implicated in this tumor process may be found. We studied the possible
correlation of these findings with the tumoral phenotype.
PMID: 16866301 [PubMed - in process]3
|8: J Neurochem.
Genetic selection of sox1GFP-expressing neural precursors
removes residual tumorigenic pluripotent stem cells and attenuates tumor
formation after transplantation.
Chung S, Shin BS, Hedlund E, Pruszak J, Ferree
A, Kang UJ, Isacson O, Kim KS.
Udall Parkinson's Disease Research Center of Excellence, McLean Hospital,
Belmont, MA 02178, USA.
Because of their ability to proliferate and to differentiate into diverse
cell types, embryonic stem (ES) cells are a potential source of cells for
transplantation therapy of various diseases, including Parkinson's disease.
A critical issue for this potential therapy is the elimination of
undifferentiated cells that, even in low numbers, could result in teratoma
formation in the host brain. We hypothesize that an efficient solution would
consist of purifying the desired cell types, such as neural precursors,
prior to transplantation. To test this hypothesis, we differentiated
sox1-green fluorescent protein (GFP) knock-in ES cells in vitro, purified
neural precursor cells by fluorescence-activated cell sorting (FACS), and
characterized the purified cells in vitro as well as in vivo.
Immunocytofluorescence and RT-PCR analyses showed that this genetic
purification procedure efficiently removed undifferentiated pluripotent stem
cells. Furthermore, when differentiated into mature neurons in vitro, the
purified GFP+ cell population generated enriched neuronal populations,
whereas the GFP- population generated much fewer neurons. When treated with
dopaminergic inducing signals such as sonic hedgehog (SHH) and fibroblast
growth factor-8 (FGF8), FACS-purified neural precursor cells responded to
these molecules and generated dopaminergic neurons as well as other neural
subtypes. When transplanted, the GFP+ cell population generated well
contained grafts containing dopaminergic neurons, whereas the GFP-
population generated significantly larger grafts (about 20-fold) and
frequent tumor-related deaths in the transplanted animals. Taken together,
our results demonstrate that genetic purification of neural precursor cells
using FACS isolation can effectively remove unwanted proliferating cell
types and avoid tumor formation after transplantation.
PMID: 16696855 [PubMed - indexed for MEDLINE]4
|9: J Neurooncol.
2006 Jul 22; [Epub ahead of print]
Pharmacologic manipulations of mitochondrial membrane
potential (DeltaPsim) selectively in glioma cells.
Griguer CE, Oliva CR, Gillespie GY, Gobin E, Marcorelles
P, Yancey Gillespie G.
Department of Surgery, University of Alabama at Birmingham, 1918 University
Blvd., THT 1046, Birmingham, AL, 35294-0006, USA, email@example.com.
Metabolic control theory applies principles of bioenergetics for the control
or management of complex diseases. Since metabolism is a general process
underlying all biologic phenotypes, changes in metabolism can potentially
modify phenotype. Therefore, it is reasonable to assume that experimental
modulation of the availability of cellular energy can potentially alter cell
phenotypes and cell functions critical to tumor progression including cell
division. The purpose of this study was to determine if OMX-2, a
methylquinone system designed to shuttle electrons from mitochondrial
complexes, was able to target mitochondria in cancer cells and trigger cell
death. Using flow cytometry, cell viability assays, and ATP measurements, we
found that OMX-2 differentially decreased DeltaPsim without triggering cell
death. In contrast, known blockers of the Electron Transport Chain (ETC)
decreased DeltaPsim and triggered cell death. When normal cells were treated
with OMX-2, neither DeltaPsim or cell death was triggered. Furthermore,
OMX-2 modulated intracellular ATP and decreased cell numbers of glioma
cells. Cell cycle analysis indicated that OMX-2 induced a reversible cell
cycle arrest in G1/S. Finally, impairment of glycolysis by 2-Deoxyglucose
(2-DOG) acted synergistically with OMX-2 to trigger cell death. Overall,
these results indicate that it is possible to selectively target cancer
cells by decreasing DeltaPsim and induced cell cycle arrest without
triggering cell death. Moreover, pharmacological approaches designed to act
on both glycolysis and oxidative phosphorylation can be considered as a new
approach to selectively kill cancer cells.
PMID: 16862448 [PubMed - as supplied by publisher]
|10: J Neurooncol.
2006 Jul 21; [Epub ahead of print]
Delivery of chemotherapy and antibodies across the
blood-brain barrier and the role of chemoprotection, in primary and
metastatic brain tumors: report of the eleventh annual blood-brain barrier
Doolittle ND, Peereboom DM, Christoforidis GA, Hall
WA, Palmieri D, Brock PR, Campbell KC, Dickey DT,
Muldoon LL, O'neill BP, Peterson DR, Pollock B, Soussain
C, Smith Q, Tyson RM, Neuwelt EA.
Department of Neurology, Oregon Health & Science University, 3181 S.W.
Sam Jackson Park Road-L603, Portland, OR, 97239-3098, USA, firstname.lastname@example.org.
Although knowledge of molecular biology and cellular physiology has advanced
at a rapid pace, much remains to be learned about delivering chemotherapy
and antibodies across the blood-brain barrier (BBB) for the diagnosis and
treatment of central nervous system (CNS) disease. A meeting, partially
funded by an NIH R13 grant, was convened to discuss the state of the
science, current knowledge gaps, and future directions in the delivery of
drugs and proteins to the CNS, for the treatment of primary and metastatic
brain tumors. Meeting topics included CNS metastases and the BBB, and
chemoprotection and chemoenhancement in CNS disorders. The discussions
regarding CNS metastases generated possibilities of chemoprotection as a
means not only to decrease treatment-related toxicity but also to increase
chemotherapy dose intensity. The increasing incidence of sanctuary brain
metastasis from breast cancer, in part due to the difficulty of monoclonal
antibodies (mAbs) such as herceptin to cross the BBB, was one of the most
salient "take home" messages of the meeting.
PMID: 16858513 [PubMed - as supplied by publisher]4
|11: Radiology. 2006 Jul 20; [Epub
ahead of print]
Preoperative Functional MR Imaging Localization of
Language and Motor Areas: Effect on Therapeutic Decision Making in Patients
with Potentially Resectable Brain Tumors.
Petrella JR, Shah LM, Harris KM, Friedman AH, George
TM, Sampson JH, Pekala JS, Voyvodic JT.
1 Department of Radiology, Division of Neuroradiology, Brain Imaging and
Analysis Center, and Department of Surgery, Division of Neurosurgery, Duke
University Medical Center, Box 3808, Durham, NC 27710-3808.
Purpose: To prospectively evaluate the effect of preoperative functional
magnetic resonance (MR) imaging localization of language and motor areas on
therapeutic decision making in patients with potentially resectable brain
tumors. Materials and Methods: The Institutional Review Board approved this
HIPAA-compliant study, and each patient gave written informed consent.
Thirty-nine consecutive patients (19 male, 20 female; mean age, 42.2 years)
referred for functional MR imaging for possible tumor resection were
prospectively evaluated. A preoperative diagnosis of brain tumor was made in
all patients. Sentence completion and bilateral hand squeeze tasks were used
to map language and sensory motor areas. Neurosurgeons completed
questionnaires regarding the proposed treatment plan before and after
functional MR imaging and after surgery. They also gave confidence ratings
for functional MR imaging results and estimated the effect on surgical time,
extent of resection, and surgical approach. The effect of functional MR
imaging on changes in treatment plan was assessed with the Wilcoxon signed
rank test. Differences in confidence ratings between altered and unaltered
treatment plans were assessed with the Mann-Whitney U test. The estimated
influence of functional MR imaging on surgical time, extent of resection,
and surgical approach was denoted with summary statistics. Results:
Treatment plans before and after functional MR imaging differed in 19
patients (P < .05), with a more aggressive approach recommended after
imaging in 18 patients. There were no significant differences in confidence
ratings for functional MR imaging between altered and unaltered plans.
Functional MR imaging resulted in reduced surgical time (estimated
reduction, 15-60 minutes) in 22 patients who underwent surgery, a more
aggressive resection in six, and a smaller craniotomy in two. Conclusion:
Functional MR imaging enables the selection of a more aggressive therapeutic
approach than might otherwise be considered because of functional risk. In
certain patients, surgical time may be shortened, the extent of resection
increased, and craniotomy size decreased. (c) RSNA, 2006.
PMID: 16857981 [PubMed - as supplied by publisher]4