| 1: Cancer
Genet Cytogenet. 2005 Jul 15;160(2):126-33. |
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Characterization of ABCG2 gene amplification manifesting
as extrachromosomal DNA in mitoxantrone-selected SF295 human glioblastoma
cells.
Rao
VK, Wangsa
D, Robey
RW, Huff
L, Honjo
Y, Hung
J, Knutsen
T, Ried
T, Bates
SE.
National Institutes of Health, Center for Cancer Research, National Cancer
Institute, Building 10, Room 12C103, 9000 Rockville Pike, Bethesda, MD
20892.
The human ABCG2 gene, located on chromosome 4, encodes an ATP-binding
cassette half-transporter that has been shown to confer resistance to
chemotherapeutic agents. Relatively little is known about the mechanisms
controlling expression of ABCG2. In previous studies, we had shown that
overexpression of ABCG2 can result from rearrangement or gene amplification
involving chromosome 4. To better characterize the mechanisms of ABCG2
overexpression, SF295 glioblastoma cells were exposed to increasing amounts
of mitoxantrone to generate the SF295 MX50, MX100, MX250, and MX500
sublines, maintained in mitoxantrone concentrations ranging from 50 to 500
nmol/L. Northern blot analysis confirmed overexpression of ABCG2 mRNA, and
immunoblot analysis demonstrated increased protein expression in the
selected cell lines. Efflux of BODIPY-prazosin confirmed a functional
protein. ABCG2 gene amplification was observed in all resistant sublines, as
determined by Southern blot analysis. Fluorescence in situ hybridization
(FISH) revealed amplification of ABCG2 via double minute chromosomes (dmins)
detected in metaphase chromosome spreads in the SF295 MX50 and MX100
sublines. At higher levels of drug selection, in the MX250 and MX500
sublines, fewer dmins were observed but homogeneously staining regions (hsr)
were visible with FISH analysis, revealing reintegration of the ABCG2 gene
into multiple chromosomes. Spectral karyotyping (SKY) demonstrated multiple
clonal and nonclonal rearrangements of chromosome 4, including hsrs. These
results suggest that amplification of ABCG2 occurred initially in the form
of dmins, followed by chromosomal reintegration of the amplicon at multiple
sites. This occurred with increasing drug-selection pressure, generating a
more stable genotype.
PMID: 15993268 [PubMed - in process]
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| 2: Cancer
Genet Cytogenet. 2005 Jun;159(2):105-13. |
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Genomic deletions in cell lines derived from primitive
neuroectodermal tumors of the central nervous system.
Dallas
PB, Terry
PA, Kees
UR.
Division of Children's Leukemia and Cancer Research, Telethon Institute for
Child Health Research and Center for Child Health Research, The University
of Western Australia, P. O. Box 855, West Perth, WA 6872, Australia.
peterd@ichr.uwa.edu.au
Extensive genomic deletions affecting a variety of chromosomes are a common
finding in primitive neuroectodermal tumors of the central nervous system
(CNS-PNETs), implicating the loss of multiple tumor suppressor genes in the
pathogenesis of these tumors. We have used representational difference
analysis, microsatellite mapping, and quantitative polymerase chain reaction
to identify and verify the presence of genomic deletions on a number of
chromosomes in CNS-PNET cell lines. This systematic approach has confirmed
the importance of deletions at 10q, 16q, and 17p in PNET pathology and has
revealed other regions of deletion not commonly described (e.g., Xq, 1p, 7p,
and 13q). These data highlight the prevalence of hemizygous loss in CNS-PNET
cells, suggesting that haploinsufficiency affecting multiple tumor
suppressor genes may play a fundamental role in CNS-PNET pathogenesis. The
identification of specific genes and signaling pathways that are compromised
in CNS-PNET cells is crucial for development of more efficacious and less
invasive treatments, as are urgently needed.
PMID: 15899381 [PubMed - indexed for MEDLINE]
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| 3: Cancer Res. 2005 Jul
1;65(13):5683-9. |
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A novel role for extracellular signal-regulated kinase 5
and myocyte enhancer factor 2 in medulloblastoma cell death.
Sturla
LM, Cowan
CW, Guenther
L, Castellino
RC, Kim
JY, Pomeroy
SL.
Program in Neuroscience, Department of Neurology, Children's Hospital
Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Expression of the neurotrophin-3 receptor, tyrosine kinase C (TrkC), is
associated with favorable prognosis in medulloblastoma patients. This may be
due to increased tumor apoptosis induced by TrkC activation.
Neurotrophin-3/TrkC-induced apoptosis is inhibited by the mitogen-activated
protein (MAP) kinase (MAPK) pharmacologic antagonists SB203580 and PD98059.
In addition to extracellular signal-regulated kinase (ERK)-1/2, PD98059 also
inhibits the more recently identified neurotrophin-responsive MAPK, ERK5
(big MAPK 1). In the present study, we investigate the contribution of ERK5
and its target myocyte enhancer factor 2 (MEF2) to
neurotrophin-3/TrkC-induced medulloblastoma cell death. Neurotrophin-3 not
only enhanced ERK5 phosphorylation but also significantly enhanced the
transcriptional activity of MEF2, a specific target of ERK5. Overexpression
of both ERK5 and MEF2 induced a statistically significant increase in cell
death of neurotrophin-3-responsive and nonresponsive medulloblastoma cell
lines (Daoy-trkC and Daoy) and primary cultures of patched heterozygous
mouse medulloblastomas. Only those cells expressing MAP/ERK kinase 5 (MEK5)
plus ERK5 or MEF2 constructs underwent apoptosis, indicating that
overexpression of either is sufficient to induce medulloblastoma cell death.
Expression of a dominant-negative MEF2 or small interfering RNA for the ERK5
activator, MEK5, significantly inhibited neurotrophin-3-induced cell death.
The dominant-negative MEF2 construct also blocked MEK5/ERK5-induced cell
death, supporting a role for MEF2 downstream of ERK5. Co-immunoprecipitation
studies revealed direct interaction of phosphorylated ERK5 with MEF2 in
response to neurotrophin-3. Our investigation of the mechanism of
neurotrophin-3/TrkC-induced apoptosis has identified a novel role for both
MEK5/ERK5 and MEF2 in cell death, suggesting that these molecules can be
exploited to induce apoptosis in both TrkC-expressing and non-expressing
medulloblastoma cells.
PMID: 15994942 [PubMed - in process]
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| 4: Cancer Res. 2005 Jul
1;65(13):5607-19. |
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Identification of a novel c-Myc protein interactor, JPO2,
with transforming activity in medulloblastoma cells.
Huang
A, Ho
CS, Ponzielli
R, Barsyte-Lovejoy
D, Bouffet
E, Picard
D, Hawkins
CE, Penn
LZ.
Cancer Research Program, Canada. annie.huang@sickkids.ca
c-myc oncogene activation is critical in the pathogenesis of a spectrum of
human malignancies. The c-Myc NH2-terminal domain (MycNTD) is essential for
cellular transformation, and mediates critical protein interactions that
modulate c-Myc oncogenic properties. In medulloblastoma, the most common
malignant pediatric brain tumor, deregulated c-myc expression is linked with
poorer disease phenotypes and outcomes. The biological basis for these
associations is, however, not well understood. To better understand
mechanisms underlying Myc-mediated transformation of medulloblastoma, we
sought to identify novel MycNTD protein interactors from a medulloblastoma
cell line library using a unique two-hybrid system. We identified a novel
MycNTD binding protein, JPO2, which shows nuclear colocalization with c-Myc,
and interacts with c-Myc both in vitro and in mammalian cells. In Rat1a
transformation assays, JPO2 potentiates c-Myc transforming activity, and can
complement a transformation-defective Myc mutant. Immunohistochemical
studies indicate tumor-specific JPO2 expression in human medulloblastoma,
and an association of JPO2 expression with metastatic tumors. Significantly,
JPO2 expression induces colony formation in UW228, a medulloblastoma cell
line, whereas RNAi-mediated JPO2 knockdown impairs colony formation in
UW228, and in Myc-transformed UW228 cells. These data provide evidence for
biochemical and functional interaction between c-Myc and JPO2 in
medulloblastoma transformation. JPO2 is closely related to JPO1, a Myc
transcriptional target with transforming activity. As tumor-specific JPO1
expression in human and murine medulloblastoma has also been reported; these
collective observations suggest important functional links between the novel
JPO protein family and c-Myc in medulloblastoma transformation.
PMID: 15994933 [PubMed - in process]
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| 5: Cancer Res. 2005 Jul
1;65(13):5535-43. |
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Lyn kinase activity is the predominant cellular SRC
kinase activity in glioblastoma tumor cells.
Stettner
MR, Wang
W, Nabors
LB, Bharara
S, Flynn
DC, Grammer
JR, Gillespie
GY, Gladson
CL.
Department of Pathology-Division of Neuropathology, University of Alabama at
Birmingham, Birmingham, Alabama 35294-0007, USA.
Cellular Src activity modulates cell migration, proliferation, and
differentiation, and recent reports suggest that individual members of the
Src family may play specific roles in these processes. As we have found that
Lyn, but not Fyn, activity promotes migration of glioblastoma cells in
response to the cooperative signal generated by platelet-derived growth
factor receptor beta and integrin alpha(v)beta3, we compared the activity
and expression of Lyn and Fyn in glioblastoma (grade IV) tumor biopsy
samples with that in anaplastic astrocytoma (grade III) tumors,
nonneoplastic brain, and normal autopsy brain samples. Lyn kinase activity
was significantly elevated in glioblastoma tumor samples. Notably, the Lyn
kinase activity accounted for >90% of pan-Src kinase activity in
glioblastoma samples but only approximately 30% of pan-Src kinase activity
in the other groups. The levels of phosphorylation of the
autophosphorylation site were consistent with significantly higher Lyn
activity in glioblastoma tumor tissue than nonneoplastic brain. Although the
normalized levels of Lyn protein and the relative levels of Lyn message were
significantly higher in glioblastoma samples than nonneoplastic brain, the
normalized levels of Lyn protein did not correlate with Lyn activity in the
glioblastoma samples. There was no significant difference in the normalized
levels of c-Src and Fyn protein and message in the glioblastoma and
nonneoplastic brain. Immunostaining revealed that Lyn is located primarily
in the glioblastoma cells in the tumor biopsies. These data indicate that
Lyn kinase activity is significantly elevated in glioblastoma tumors and
suggest that it is the Lyn activity that promotes the malignant phenotype in
these tumors.
PMID: 15994925 [PubMed - in process]
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| 6: Cancer Res. 2005 Jul
1;65(13):5523-34. |
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Autocrine platelet-derived growth factor-dependent gene
expression in glioblastoma cells is mediated largely by activation of the
transcription factor sterol regulatory element binding protein and is
associated with altered genotype and patient survival in human brain tumors.
Ma
D, Nutt
CL, Shanehsaz
P, Peng
X, Louis
DN, Kaetzel
DM.
Department of Molecular and Biomedical Pharmacology, University of Kentucky
College of Medicine, Lexington, Kentucky 40536-0084, USA.
A complex profile of gene expression elicited by autocrine platelet-derived
growth factor (PDGF) signaling was identified in U87 MG glioblastoma cells
by microarray analysis. The most striking pattern observed was a
PDGF-dependent activation of at least 25 genes involved with biosynthesis
and/or uptake of cholesterol and isoprenoids, including mevalonate
pyrophosphate decarboxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
synthase, HMG-CoA reductase, and low-density lipoprotein receptor. Activity
of the HMG-CoA synthase promoter was induced by autocrine PDGF activity as
indicated by significant reductions following forced expression of
dominant-negative PDGF-A (88%) or treatment with the PDGF receptor
antagonist CT52923 (50%). Induction of the HMG-CoA synthase promoter
required a binding site for sterol regulatory element binding proteins
(SRE-BP), consistent with a key role for these transcription factors in the
induction of this gene network. Neither proteolytic activation nor nuclear
localization of SRE-BP was affected by disruption of the PDGF autocrine
loop, indicating that PDGF signaling is required for other signaling events
involved in activation of SRE-BP target genes. Analysis of an expression
databank derived from human glial tumors (n = 77) identified a subgroup
exhibiting a profile consistent with PDGF dependence, including increased
expression of SRE-BP target genes. This subgroup displayed an absence of
epidermal growth factor receptor gene amplification, decreased incidence of
allelic loss of 10q, increased frequency of TP53 mutations and allelic
losses of 1p and 19q, and longer patient survival. This study identifies
genes associated with oncogenic activity of PDGF and provides important
insights into biomarkers and therapeutic targets in malignant gliomas.
PMID: 15994924 [PubMed - in process]
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| 7: Cancer Res. 2005 May
15;65(10):4041-50. |
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bHLH-zip transcription factor Spz1 mediates
mitogen-activated protein kinase cell proliferation, transformation, and
tumorigenesis.
Hsu
SH, Hsieh-Li
HM, Huang
HY, Huang
PH, Li
H.
Institute of Molecular Biology, Academia Sinica.
BHLH-zip proteins usually play important regulatory roles in cell growth and
differentiation. In this study, we show that Spz1, a bHLH-zip transcription
factor, acts downstream of mitogen-activated protein kinase (MAPK,
extracellular signal-regulated kinase 1/2) to up-regulate cell proliferation
and tumorigenesis. In addition, through an interaction with proliferating
cell nuclear antigen (PCNA) promoter, Spz1 induced cell proliferation
concomitant with an increase in PCNA gene expression. Spz1-transfected cells
formed colony foci on soft agar and developed fibrosarcoma tumors in nude
mice. MAPK directly interacted and phosphorylated Spz1 protein, which
increased PCNA transcription and cell tumorigenic activities. Reduction of
endogenous Spz1 expression via RNA interference decreased cell proliferation
in p19 embryonic carcinoma cells. High levels of Spz1 expression were
detected in murine tumor cell lines and tumor samples of both human and Spz1
transgenic mice. Thus, Spz1 may act as a proto-oncogene, participating in
the MAPK signal pathway, and be a potential therapeutic target in the
treatment of Ras-induced tumors.
PMID: 15899793 [PubMed - indexed for MEDLINE]
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| 8: Childs
Nerv Syst. 2005 Jul 7; [Epub ahead of print] |
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Craniopharyngiomas in children: Turkey experience.
Ersahin
Y, Yurtseven
T, Ozgiray
E, Mutluer
S.
Division of Pediatric Neurosurgery, Ege University Faculty of Medicine,
35100, Bornova, Izmir, Turkey, ersahin@med.ege.edu.tr.
OBJECTIVES: Craniopharyngiomas are the most frequently encountered
suprasellar tumors in children. Although they have a benign histology, total
resection without morbidity is very difficult. METHODS: We aimed to review
the results of pediatric craniopharyngioma patients treated in eight
institutions in Turkey. There were 51 boys and 36 girls, ranging in age from
20 months to 18 years (mean 10.2 years). The most frequent symptom was
headache, followed by visual disturbances. Hydrocephalus was seen most
frequently in tumors greater than 4 cm in size (P=0.002). Hydrocephalus was
associated with the decreased gross total resection (P=0.043). The
recurrence (28%) was significantly higher in patients with subtotal and
partial tumor removal (P=0.010). Bad outcome was significantly associated
with tumor dimension (P=0.039); the greater the tumor dimension, the worse
the outcome. Outcome was significantly better in patients older than 10
years (P=0.032). Gender, tumor type and location, presence of hydrocephalus
and calcification, histological type of craniopharyngioma, and surgical
approach did not have a significant effect on the outcome. CONCLUSIONS: The
treatment should be individualized and a multidisciplinary approach should
be used. The goal of surgery should be gross total removal without mortality
and with acceptable morbidity.
PMID: 16001286 [PubMed - as supplied by publisher]
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| 9: Childs
Nerv Syst. 2005 Jul 6; [Epub ahead of print] |
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Pediatric giant cell glioblastoma: a case report and
review of the literature.
De
Prada I, Cordobes
F, Azorin
D, Contra
T, Colmenero
I, Glez-Mediero
I.
Service of Anatomic Pathology, Hospital Infantil Universitario Nino Jesus,
Avda Menedez Pelayo, 69, 28009, Madrid, Spain,
ideprada.hnjs@salud.madrid.org.
INTRODUCTION: Giant cell glioblastoma is a subtype of glioblastoma
multiforme (GM) whose most characteristic histology is the presence of
plentiful multinucleated giant cells. These tumours are very rare and
account for only 5% of GM. They do not have specific localization, although
normally they are supratentorial and affect mostly the temporal lobe. They
may occur at any age, but mostly they occur in younger people than GM. They
are infrequent in childhood, but they have longer survival in paediatric
age. CASE REPORT: We present an 11-year-old girl that was operated but whose
tumour recurred in a month after apparent total removal. DISCUSSION: We
review in the literature the clinical, histological, immuno-histochemical
and genetic characteristics, as well the prognosis of this tumour.
PMID: 15999285 [PubMed - as supplied by publisher]
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| 10: Childs
Nerv Syst. 2005 Jul 2; [Epub ahead of print] |
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Long-term results of the surgical treatment of
craniopharyngioma: the experience at the Policlinico Gemelli, Catholic
University, Rome.
Caldarelli
M, Massimi
L, Tamburrini
G, Cappa
M, Di
Rocco C.
Section of Pediatric Neurosurgery, Institute of Neurosurgery, Catholic
University Medical School, Rome, Italy.
BACKGROUND: Craniopharyngioma (CP) is the most common intracranial non-glial
tumour observed in pediatric age. Although histologically benign and
amenable to surgical treatment, its location and relation with vital nervous
and vascular structures makes the feasibility of a radical resection
difficult even in the microneurosurgery era. Beside the difficulties
experienced when performing tumour resection, post-operative complications,
such as endocrinological imbalance, represent another point that makes CP
total excision a challenge. In order to avoid such complications, some
authors have suggested to renounce to radical resection and to rely on
post-operative radiation therapy to minimise the risk of residual tumour
progression. METHODS: We report our experience with 52 children and
adolescents operated on for CP at the Department of Pediatrics, Section of
Pediatric Neurosurgery, Catholic University Medical School, Rome, between
January 1985 and December 2002. The study included 14 children <5 years
old (five less than 2 years of age), 25 between 6 and 10 years old, and 13
more than 10 years old. The most common presenting signs were related to
endocrinological imbalance (35 cases), increased intracranial pressure (32
cases), and to a lesser extent, visual compromise (17 cases). Concerning
location, CP was intrasellar in three cases; sellar/suprasellar with
prominent prechiasmatic growth in 24 cases; retrochiasmatic/3rd ventricular
in 14 cases, and giant (with an extension into the middle and/or posterior
cranial fossae) in 11 cases. The tumour was managed by means of a single
surgical approach in 47 cases and with a two-stage operation in the
remaining five cases. In 11 cases of intrasellar or intra/suprasellar
midline location, the first surgical approach was done through the
transsphenoidal route (which represented the first step of a staged
operation in five instances); in the remaining 41 patients, craniotomy was
the first surgical procedure. Radical tumour resection was achieved in 40
cases, subtotal (only small tumour remnants adherent to the carotid
arteries, 3rd ventricle floor or visual pathways) in nine, and only partial
in the remaining three cases RESULTS: Histology demonstrated the
adamantinous variant in all cases. Two surgical deaths were recorded in this
series (both following a transsphenoidal approach): one secondary to
uncontrollable intra-operative bleeding from the carotid artery, and the
other to fulminating bacterial meningoencephalitis. Morbidity included
endocrinological disturbances, namely hypopituitarism and diabetes
insipidus, in more than 80% of cases, worsening of pre-operative visual
deficit in six cases, and transitory neurological deficits in five cases.
One late death was recorded 2 years after surgery, secondary to electrolytic
imbalance although favoured by a major head trauma with subacute subdural
haematoma. Nine recurrences occurred 1-8 years after surgery (three true
recurrences, and six re-growths of incompletely resected tumours) that
required re-operation. Twelve patients underwent radiotherapy, six after an
initially incomplete tumour resection and six following relapse. One patient
presented with a malignant thalamic glioma 8 years after radiotherapy. At
long-term follow-up, all survivors showed good clinical condition, even
though approximately 60% relied on hormone replacement, and some patients
presented obesity. Diabetes insipidus has subsided in about 80% of the
cases; visual deficits improved or remained stable, whereas post-operative
neurological deficits subsided in all but one patient. CONCLUSION: In our
experience, radical resection of CP represented the first and almost unique
treatment modality. Although not insignificant, post-operative mortality and
morbidity do not seem to represent a major contraindication in attempting a
radical tumour resection whenever possible. On the other hand, extensive
hypothalamic involvement should suggest a less aggressive attitude.
PMID: 15995885 [PubMed - as supplied by publisher]
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| 11: Childs
Nerv Syst. 2005 May;21(5):399-403. Epub 2005 Feb 9. |
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Experimental models of brainstem tumors: development of a
neonatal rat model.
Jallo
GI, Penno
M, Sukay
L, Liu
JY, Tyler
B, Lee
J, Carson
BS, Guarnieri
M.
Hunterian Brain Tumor Laboratories, Johns Hopkins University, Baltimore, MD
21287, USA. gjallo1@jhmi.edu
OBJECTIVE: Brainstem tumor models are required to advance the treatment for
diffuse pontine gliomas in children. The feasibility of creating an
experimental rodent model by inoculating newborn pups with tumor cells was
examined. The study was performed to create an animal model for diffuse
brainstem tumors. METHODS: Eighty-two Fischer rat pups aged 12-24 h were
anesthetized by hypothermia. The brainstem was injected with saline to
identify anatomical coordinates for subsequent tumor cell challenges. The
newborn pups were then inoculated with F98 (n=30) or 9L (n=30) glioma cells.
Animals were returned to their mother for nursing. Tumor growth was assessed
by survival and histopathology. RESULTS: Twenty-one percent of the
saline-treated animals (17 out of 82) and 5% of the tumor cell-challenged
pups (3 out of 60) were eliminated by their mothers. Inoculations with 9L
and F98 cells produced brainstem tumors in 83% (24 out of 29) and 93% of
animals (26 out of 28) respectively that were evaluated. CONCLUSIONS: Our
results demonstrate that neonatal rat models for brainstem tumors can be
prepared using known injection coordinates and orthotopic cell lines.
Decreasing rates of maternal removal during the course of the work suggests
that the method involves a learning curve.
PMID: 15702357 [PubMed - indexed for MEDLINE]
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| 12: Childs
Nerv Syst. 2005 May;21(5):425-8. Epub 2004 Dec 4. |
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Possible spontaneous "birth" of a hydatid cyst
into the lateral ventricle.
Evliyaoglu
C, Keskil
S.
Department of Neurosurgery, Kirikkale University School of Medicine, Turkey.
cevliyaoglu@hotmail.com
INTRODUCTION: Intraventricular hydatid cyst is an extremely rare entity. We
report a solitary hydatid cyst in a lateral ventricle. CASE REPORT: A
7-year-old girl had a free floating intraventricular cyst, diagnosed by
computerized tomography examination inside the enlarged left lateral
ventricle of an associated Dandy Walker malformation. The patient underwent
surgery and the cyst was removed. CONCLUSION: To our knowledge, this is the
first case report in which the natural developmental phases of an
intraventricular hydatid cyst have been observed.
Publication Types:
PMID: 15580516 [PubMed - indexed for MEDLINE]
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| 13: Childs
Nerv Syst. 2005 May;21(5):410-5. Epub 2004 Nov 25. |
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Choroid plexus adenoma: case report and review of the
literature.
Aquilina
K, Nanra
JS, Allcutt
DA, Farrell
M.
Department of Neurosurgery, Beaumont Hospital, Dublin, Ireland.
kristianaquilina@hotmail.com
CASE REPORT: An 8-month-old infant with macrocephaly was found to have
hydrocephalus and a cystic third ventricular tumour; biopsy of the tumour
showed a choroid plexus adenoma. The tumour was attached to the ependymal
lining and was strongly adherent to the walls and floor of the anterior
third ventricle. TREATMENT: After biopsy, it was felt that a radical
resection would carry a high risk of injury to the floor of the third
ventricle and cause new neurological deficits. Therefore, an external
ventricular drain was inserted and bilateral ventriculo-peritoneal shunts
were inserted 1 week post-operatively. In view of the benign nature of the
tumour, no adjuvant radiotherapy or chemotherapy was given. OUTCOME: There
was no further tumour growth or clinical deterioration over a 6-year
follow-up period.
Publication Types:
- Case Reports
- Review
- Review of Reported Cases
PMID: 15565450 [PubMed - indexed for MEDLINE]
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| 14: Childs
Nerv Syst. 2005 May;21(5):382-4. Epub 2004 Sep 22. |
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Post-shunt ascites in infants with optic chiasmal
hypothalamic astrocytoma: role of ventricular gallbladder shunt.
Olavarria
G, Reitman
AJ, Goldman
S, Tomita
T.
Division of Pediatric Neurosurgery, Falk Brain Tumor Center, Children's
Memorial Hospital, Northwestern University Feinberg School of Medicine,
Chicago, IL 60614, USA.
INTRODUCTION: We report a series of infants with optic chiasmal hypothalamic
astrocytomas (OCHAs) who developed abdominal ascites following
ventriculo-peritoneal (VP) shunting. The mechanism of ascites development
among these patients with OCHA remains speculative and unclear. METHODS: We
treated four infants with hypothalamic tumors who were shunted for
hydrocephalus using standard VP shunts and who subsequently experienced
symptomatic ascites. RESULTS: In three patients the gallbladder proved an
effective alternative site for shunting prior to conversion to other sites,
and in one patient the gallbladder shunt remains functional and
revision-free.CONCLUSIONS: Several aspects of the gallbladder as a reservoir
for CSF make this approach appealing. Ventricular gallbladder shunting
provided an effective (at least temporarily) receptacle for CSF in these
patients.
PMID: 15449089 [PubMed - indexed for MEDLINE]
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| 15: Childs
Nerv Syst. 2005 May;21(5):404-9. Epub 2004 Sep 11. |
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Proton magnetic resonance spectroscopic imaging in
pediatric pilomyxoid astrocytoma.
Cirak
B, Horska
A, Barker
PB, Burger
PC, Carson
BS, Avellino
AM.
Division of Pediatric Neurosurgery, Department of Neurosurgery, Johns
Hopkins Medical Institutions, Baltimore, MD, USA. bayramcirak@yahoo.com
OBJECTS: A pilomyxoid astrocytoma (PmA) is considered to be either a more
aggressive variant of a pediatric pilocytic astrocytoma (PA) or a tumor of a
separate entity. METHODS: We present two cases of pediatric optic-chiasmatic
PmA. Proton magnetic resonance spectroscopic imaging (MRSI) of the PmA
revealed decreased concentrations of total choline (Cho), creatine (Cr), and
N-acetyl aspartate (NAA). In contrast, proton MR spectra of PAs showed
elevated Cho and decreased Cr and NAA signals. CONCLUSION: Low metabolite
concentrations in PmAs detected by MRSI may therefore help to distinguish
PmAs from PAs preoperatively.
Publication Types:
PMID: 15372294 [PubMed - indexed for MEDLINE]
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| 16: Clin
Cancer Res. 2005 Jul 1;11(13):4934-40. |
|
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Inhibition of glioblastoma angiogenesis and invasion by
combined treatments directed against vascular endothelial growth factor
receptor-2, epidermal growth factor receptor, and vascular
endothelial-cadherin.
Lamszus
K, Brockmann
MA, Eckerich
C, Bohlen
P, May
C, Mangold
U, Fillbrandt
R, Westphal
M.
Authors' Affiliations: Department of Neurosurgery, Institute for Anatomy II,
University Hospital Hamburg-Eppendorf, Hamburg, Germany; and ImClone
Systems, New York, New York.
PURPOSE: Inhibition of angiogenesis can influence tumor cell invasion and
metastasis. We previously showed that blockade of vascular endothelial
growth factor receptor-2 (VEGFR-2) with the monoclonal antibody DC101
inhibited intracerebral glioblastoma growth but caused increased tumor cell
invasion along the preexistent vasculature. In the present study, we
attempted to inhibit glioma cell invasion using a monoclonal antibody
against the epidermal growth factor receptor (EGFR), which in the context of
human glioblastomas, has been implicated in tumor cell invasion. In
addition, we analyzed whether blockade of vascular endothelial (VE)-cadherin
as a different antiangiogenic target could also inhibit glioblastoma
angiogenesis and growth.Experimental Designs: Nude mice who received
intracerebral glioblastoma xenografts were treated using monoclonal
antibodies against VEGFR-2 (DC101), EGFR (C225), and VE-cadherin (E4G10)
either alone or in different combinations.RESULTS: Increased tumor cell
invasion provoked by DC101 monotherapy was inhibited by 50% to 66% by
combined treatment with C225 and DC101. C225 inhibited glioblastoma cell
migration in vitro, but had no effect on the volume of the main tumor mass
or on tumor cell proliferation or apoptosis in vivo, either alone or in
combination with DC101. The anti-VE-cadherin monoclonal antibody E4G10 was a
weaker inhibitor of tumor angiogenesis and growth than DC101, and also
caused a weaker increase in tumor cell invasion.CONCLUSIONS: Inhibition of
angiogenesis achieved by blocking either VEGFR-2 or VE-cadherin can cause
increased glioma cell invasion in an orthotopic model. Increased tumor cell
invasion induced by potent inhibition of angiogenesis with DC101 could be
inhibited by simultaneous blockade of EGFR.
PMID: 16000592 [PubMed - in process]
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| 17: Clin
Cancer Res. 2005 Jul 1;11(13):4733-40. |
|
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Isochromosome 17q is a negative prognostic factor in
poor-risk childhood medulloblastoma patients.
Pan
E, Pellarin
M, Holmes
E, Smirnov
I, Misra
A, Eberhart
CG, Burger
PC, Biegel
JA, Feuerstein
BG.
Authors' Affiliations: University of California San Francisco, San
Francisco, California.
Background: Medulloblastomas are the most common primary malignant childhood
intracranial neoplasms. Patients are currently sorted into three risk groups
based on clinical criteria: standard, poor, and infant (<18 months old).
We hypothesized that genetic copy number aberrations (CNA) predict prognosis
and would provide improved criteria for predicting outcome.Methods: DNA from
35 medulloblastoma patients from four Children's Cancer Group trials was
analyzed by comparative genomic hybridization to determine CNAs. The genetic
alterations were evaluated using statistical and cluster analyses.RESULTS:
The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p,
10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected.
Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P
= 0.03) and event-free survival (P = 0.04) independent of poor risk group
classification. Age <3 tended to be associated with <3 CNAs (P =
0.06). Unsupervised cluster analysis sorted the study patients into four
subgroups based on CNAs. Supervised analysis using the program Significance
Analysis of Microarrays (SAM) quantitatively validated those CNAs identified
by unsupervised clustering that significantly distinguished among the four
subgroups.CONCLUSIONS: Medulloblastomas are genetically heterogeneous and
can be categorized into separate genetic subgroups by their CNAs using
unsupervised cluster analysis and SAM. i(17)(q10) was a significant
independent negative prognostic factor. Infant medulloblastomas may be a
distinct genetic subset from those of older patients.
PMID: 16000568 [PubMed - in process]
-
| 18: Clin
Cancer Res. 2005 Jul 1;11(13):4707-4716. |
|
-
Identification of a Novel Homozygous Deletion Region at
6q23.1 in Medulloblastomas Using High-Resolution Array Comparative Genomic
Hybridization Analysis.
Hui
AB, Takano
H, Lo
KW, Kuo
WL, Lam
CN, Tong
CY, Chang
Q, Gray
JW, Ng
HK.
Authors' Affiliations: Department of Anatomical and Cellular Pathology,
Chinese University of Hong Kong, Hong Kong SAR, PR China and Department of
Laboratory Medicine and UCSF Comprehensive Cancer Center, University of
California San Francisco, San Francisco, California.
PURPOSE: The aim of this study is to comprehensively characterize genome
copy number aberrations in medulloblastomas using high-resolution array
comparative genomic hybridization.EXPERIMENTAL DESIGN: High-density genomic
arrays containing 1,803 BAC clones were used to define recurrent chromosomal
regions of gains or losses throughout the whole genome of medulloblastoma. A
series of 3 medulloblastoma cell lines and 16 primary tumors were
investigated.RESULTS: The detected consistent chromosomal aberrations
included gains of 1q21.3-q23.1 (36.8%), 1q32.1 (47.4%), 2p23.1-p25.3
(52.6%), 7 (57.9%), 9q34.13-q34.3 (47.4%), 17p11.2-q25.3 (89.5%), and
20q13.31-q13.33 (42.1%), as well as losses of 3q26.1 (57.9%), 4q31.23-q32.3
(42.1%), 6q23.1-25.3 (57.9%), 8p22-23.3 (79%), 10q24.32-26.2 (57.9%), and
16q23.2-q24.3 (63.2%). One of the most notable aberrations was a homozygous
deletion on chromosome 6q23 in the cell line DAOY, and single copy loss on
30.3% primary tumors. Further analyses defined a 0.887 Mbp minimal region of
homozygous deletion at 6q23.1 flanked by markers SHGC-14149 (6q22.33) and
SHGC-110551 (6q23.1). Quantitative reverse transcription-PCR analysis showed
complete loss of expression of two genes located at 6q23.1, AK091351
(hypothetical protein FLJ34032) and KIAA1913, in the cell line DAOY. mRNA
levels of these genes was reduced in cell lines D283 and D384, and in 50%
and 70% of primary tumors, respectively.CONCLUSION: Current array
comparative genomic hybridization analysis generates a comprehensive pattern
of chromosomal aberrations in medulloblastomas. This information will lead
to a better understanding of medulloblastoma tumorigenesis. The delineated
regions of gains or losses will indicate locations of
medulloblastoma-associated genes. A 0.887 Mbp homozygous deletion region was
newly identified at 6q23.1. Frequent detection of reduced expression of
AK091351 and KIAA1913 genes implicates them as suppressors of
medulloblastoma tumorigenesis.
PMID: 16000565 [PubMed - as supplied by publisher]
-
| 19: Clin
Cancer Res. 2005 Jul 1;11(13):4674-4680. |
|
-
Expression and Growth Dependency of the Insulin-Like
Growth Factor I Receptor in Craniopharyngioma Cells: A Novel Therapeutic
Approach.
Ulfarsson
E, Karstrom
A, Yin
S, Girnita
A, Vasilcanu
D, Thoren
M, Kratz
G, Hillman
J, Axelson
M, Larsson
O, Girnita
L.
Authors' Affiliations: Departments of Neurosurgery, Endocrinology and
Diabetology, and Clinical Chemistry, Institution for Surgical Sciences,
Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska
University Hospital, Stockholm, Sweden; Departments of Plastic Surgery, and
Neurosurgery, University Hospital, Linkoping, Sweden.
Craniopharyngioma is a rare benign intracranial epithelial tumor that,
however, often recurs and sometimes kills the affected patients, one-third
of which are children. In many cases, the patients acquire growth hormone
deficiency and postoperatively need substitution. Generally, growth hormone
promotes local release of insulin-like growth factor I (IGF-I), which in
turn activates the IGF-I receptor (IGF-IR) if present. Together, these
circumstances raise the question whether IGF-IR may be involved in
craniopharyngioma growth. To address this issue, we analyzed phenotypically
well-characterized primary low-passage craniopharyngioma cell lines from
nine different patients for IGF-IR expression and IGF-I dependency. Two of
the cell lines showed no/very low expression of the receptor and was
independent on IGF-I, whereas five cell lines exhibited a strong expression
and was clearly contingent on IGF-I. The two remaining cell lines had low
receptor expression and IGF-I dependency. Upon treatment with an IGF-IR
inhibitor, cells with high IGF-IR expression responded promptly with
decreased Akt phosphorylation followed by growth arrest. These responses
were not seen in cells with no/very low receptor expression. Growth of cell
lines with low IGF-IR expression was only slightly affected by IGF-IR
inhibition. Taken together, our data suggest that IGF-IR may be involved in
the growth of a subset of craniopharyngiomas and points to the possibility
of the involvement of IGF-IR inhibitors as a treatment modality to obtain
complete tumor-free conditions before growth hormone substitution.
PMID: 16000560 [PubMed - as supplied by publisher]
-
| 20: Int
J Cancer. 2005 Jul 7; [Epub ahead of print] |
|
-
Matrix-degrading proteases ADAMTS4 and ADAMTS5
(disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are
expressed in human glioblastomas.
Held-Feindt
J, Paredes
EB, Blomer
U, Seidenbecher
C, Stark
AM, Mehdorn
HM, Mentlein
R.
Department of Neurosurgery, University of Kiel, Kiel, Germany.
Brain tumors, in particular glioblastomas, have a high morbidity and
mortality, mainly due to their invasive nature. A prerequisite for this
invasiveness is cell migration based on increased expression of proteases
digesting the extracellular matrix. Brevican, an important extracellular
proteoglycan that is upregulated in glioblastomas, can be degraded by
certain proteases. We demonstrate that in human glioblastomas secretory
proteases like ADAMTS4 and ADAMTS5 (aggrecanases 1 and 2; ADAMTS = a
disintegrin and metalloproteinase with thrombospondin motifs) are expressed
on the mRNA and protein levels in considerable amounts. Real-time RT-PCR
shows a higher levels of ADAMTS4 and 5 expressions in glioblastomas in situ,
compared to cultured human glioblastoma cells. The upregulation of these
proteases in vivo by cytokines may explain this difference. In vitro,
transforming growth factor-beta induces ADAMTS4, but less ADAMTS5, and
interleukin-1beta ADAMTS5, but not ADAMTS4. As demonstrated by
immunohistochemistry and confocal microscopy in situ, ADAMTS5 expression is
confined to proliferating glioblastoma cells of surgical tumor sections and
with lower intensity to astroglial cells in normal brain sections, as
opposed to brevican. In vitro, glioblastoma-derived ADAMTS5 degrades
recombinant human brevican to several smaller fragments. Our results show
that ADAMTS4 and 5 are upregulated on proliferating glioblastoma cells and
these proteases may contribute to their invasive potential. (c) 2005
Wiley-Liss, Inc.
PMID: 16003758 [PubMed - as supplied by publisher]
-
| 21: Int
J Cancer. 2005 Jul 7; [Epub ahead of print] |
|
-
Supraagonistic, bispecific single-chain antibody purified
from the serum of cloned, transgenic cows induces T-cell-mediated killing of
glioblastoma cells in vitro and in vivo.
Grosse-Hovest
L, Wick
W, Minoia
R, Weller
M, Rammensee
HG, Brem
G, Jung
G.
Institute for Cell Biology, Department of Immunology, Eberhard Karls
University Tubingen, Tubingen, Germany.
Here we characterize the antitumor activity of a recombinant bispecific
single-chain antibody isolated from the serum of cloned transgenic cows. The
antibody, termed r28M, is directed to a melanoma-associated proteoglycan,
also expressed on glioblastoma cells, and to human CD28. Bound to tumor
cells, r28M induced exceedingly efficient supraagonistic T-cell activation
via the CD28 molecule without an additional stimulus via the TCR/CD3
complex. In vitro, T cells and NK cells contributed to tumor cell killing
after r28M-mediated activation of peripheral blood mononuclear cells.
However, NK activity depended on T-cell-derived cytokines. In vivo, r28M
markedly inhibited the growth of human glioblastoma cells in nude mice. The
serum half-life of the protein after i.v. injection was approximately 6 hr.
Thus, r28M is unique not only in inducing supraagonistic CD28-mediated
T-cell activation against tumor cells in vitro and in vivo, it also meets 2
additional requirements that are critical for clinical application: a
relatively long serum half-life and the possibility of obtaining large
amounts of active material from cloned transgenic livestock. (c) 2005
Wiley-Liss, Inc.
PMID: 16003729 [PubMed - as supplied by publisher]
-
| 22: J
Clin Oncol. 2005 Jul 5; [Epub ahead of print] |
|
-
Phase II Trial of Temsirolimus (CCI-779) in Recurrent
Glioblastoma Multiforme: North Central Cancer Treatment Group.
Galanis
E, Buckner
JC, Maurer
MJ, Kreisberg
JI, Ballman
K, Boni
J, Peralba
JM, Jenkins
RB, Dakhil
SR, Morton
RF, Jaeckle
KA, Scheithauer
BW, Dancey
J, Hidalgo
M, Walsh
DJ.
North Central Cancer Treatment Group; Mayo Clinic College of Medicine,
Rochester, MN; The Johns Hopkins University, Baltimore, MD; The University
of Texas Health Science Center at San Antonio, San Antonio, TX; Wyeth,
Collegeville, PA; Cancer Therapy Evaluation Program, Investigational Drug
Branch, Cancer Therapy Evaluation Program, National Cancer Institute,
Rockville, MD; Wichita Community Clinical Oncology Program, Wichita, KS;
Iowa Oncology Research Association CCOP, Des Moines, IA; Mayo Clinic
Jacksonville, Jacksonville, FL.
Background: Temsirolimus (CCI-779) is a small-molecule inhibitor of the
mammalian target of rapamycin (mTOR) and represents a rational therapeutic
target against glioblastoma multiforme (GBM). METHODS: Recurrent GBM
patients with </= 1 chemotherapy regimen for progressive disease were
eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly.
RESULTS: Sixty-five patients were treated. The incidence of grade 3 or
higher nonhematologic toxicity was 51%, and consisted mostly of
hypercholesterolemia (11%), hypertriglyceridemia (8%), and hyperglycemia
(8%). Grade 3 hematologic toxicity was observed in 11% of patients.
Temsirolimus peak concentration (Cmax), and sirolimus Cmax and area under
the concentration-time curve were decreased in patients receiving p450
enzyme-inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively,
but were still within the therapeutic range of preclinical models. Twenty
patients (36%) had evidence of improvement in neuroimaging, consisting of
decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement,
on stable or reduced steroid doses. Progression-free survival at 6 months
was 7.8% and median overall survival was 4.4 months. Median time to
progression (TTP) for all patients was 2.3 months and was significantly
longer for responders (5.4 months) versus nonresponders (1.9 months).
Development of grade 2 or higher hyperlipidemia in the first two treatment
cycles was associated with a higher percentage of radiographic response (71%
v 31%; P = .04). Significant correlation was observed between radiographic
improvement and high levels of phosphorylated p70s6 kinase in baseline tumor
samples (P = .04). CONCLUSION: Temsirolimus is well tolerated in recurrent
GBM patients. Despite the effect of EIACs on temsirolimus metabolism,
therapeutic levels were achieved. Radiographic improvement was observed in
36% of temsirolimus-treated patients, and was associated with significantly
longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor
samples appear to predict a patient population more likely to derive benefit
from treatment. These findings should be validated in other studies of mTOR
inhibitors.
PMID: 15998902 [PubMed - as supplied by publisher]
-
| 23: J Neurochem.
2005 Jun 30; [Epub ahead of print] |
|
Probing the infiltrating character of brain tumors:
inhibition of RhoA/ROK-mediated CD44 cell surface shedding from glioma cells
by the green tea catechin EGCg.
Annabi
B, Bouzeghrane
M, Moumdjian
R, Moghrabi
A, Beliveau
R.
Laboratoire d'Oncologie Moleculaire, Departement de Chimie-Biochimie,
Universite du Quebec a Montreal, Quebec, Canada.
Glioma cell-surface binding to hyaluronan (HA), a major constituent of the
brain extracellular matrix (ECM) environment, is regulated through a complex
membrane type-1 matrix metalloproteinase (MT1-MMP)/CD44/caveolin interaction
that takes place at the leading edges of invading cells. In the present
study, intracellular transduction pathways required for the HA-mediated
recognition by infiltrating glioma cells in brain was investigated. We show
that the overexpression of the GTPase RhoA up-regulated MT1-MMP expression
and triggered CD44 shedding from the U-87 glioma cell surface. This
potential implication in cerebral metastatic processes was also observed in
cells overexpressing the full-length recombinant MT1-MMP, while the
overexpression of a cytoplasmic domain truncated from of MT1-MMP failed to
do so. This suggests that the cytoplasmic domain of MT1-MMP transduces
intracellular signaling leading to RhoA-mediated CD44 shedding. Treatment of
glioma cells with the Rho-kinase (ROK) inhibitor Y27632, or with EGCg, a
green tea catechin with anti-MMP and anti-angiogenesis activities,
antagonized both RhoA- and MT1-MMP-induced CD44 shedding. Conversely,
overexpression of recombinant ROK stimulated CD44 release. Taken together,
our results suggest that RhoA/ROK intracellular signaling regulates
MT1-MMP-mediated CD44 recognition of HA. These molecular processes may
partly explain the diffuse brain-infiltrating character of glioma cells
within the surrounding parenchyma and thus be a target for new approaches to
anti-tumor therapy.
PMID: 15992376 [PubMed - as supplied by publisher]
-
| 24: J Neurooncol.
2005 Mar;72(1):89-90. |
|
-
Glioneuronal tumor with unique imaging and histologic
features.
Bisson
EF, Pendlebury
WW, Horgan
MA.
Publication Types:
PMID: 15803381 [PubMed - indexed for MEDLINE]
-
| 25: J Neurooncol.
2005 Mar;72(1):85-8. |
|
-
Atypical teratoid/rhabdoid tumor case report: treatment
with surgical excision, radiation therapy, and alternative medicines.
Howes
TL, Buatti
JM, O'Dorisio
MS, Kirby
PA, Ryken
TC.
Department of Radiation Oncology, University of Iowa Hospitals and Clinics,
W 189 Z GH, Iowa City, IA 52242, USA.
Intracranial atypical teratoid/rhabdoid tumors (AT/RT) are rare with a poor
prognosis. We report one case of a 7-year old girl living over 17 months
after the diagnosis of AT/RT in the left frontal lobe. Treatment was partial
surgical resection and post-operative radiation therapy. Radiation therapy
resulted in complete response with no evidence of residual or recurrent
disease more than 17 months after diagnosis. The patient has been maintained
on an extensive regimen of alternative therapies since completion of
radiation therapy.
Publication Types:
PMID: 15803380 [PubMed - indexed for MEDLINE]
-
| 26: J Neurooncol.
2005 Mar;72(1):77-84. |
|
-
Continuous remission of newly diagnosed and relapsed
central nervous system atypical teratoid/rhabdoid tumor.
Zimmerman
MA, Goumnerova
LC, Proctor
M, Scott
RM, Marcus
K, Pomeroy
SL, Turner
CD, Chi
SN, Chordas
C, Kieran
MW.
Department of Pediatric Oncology, Pediatric Neuro-Oncology, Dana-Farber
Cancer Institute, Rm # SW331, 44 Binny Street, Boston, MA 02115, USA.
Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant lesions of
childhood that carry a very poor prognosis. AT/RT can occur in the central
nervous system (CNS AT/RT) and disease in this location carries an even
worse prognosis with a median survival of 7 months. In spite of multiple
treatment regimens consisting of maximal surgical resection (including
second look surgery), radiation therapy (focal and craniospinal), and
multi-agent intravenous, oral and intrathecal chemotherapy, with or without
high-dose therapy and stem cell rescue, only seven long-term survivors of
CNS AT/RT have been reported, all in patients with newly diagnosed disease.
For this reason, many centers now direct such patients, particularly those
under 5 years of age, or those with recurrent disease, towards comfort care
rather than attempt curative therapy. We now report on four children, two
with newly diagnosed CNS AT/RT and two with progressive disease after
multi-agent chemotherapy who are long term survivors (median follow-up of 37
months) using a combination of surgery, radiation therapy, and intensive
chemotherapy. The chemotherapy component was modified from the Intergroup
Rhabdomyosarcoma Study Group (IRS III) parameningeal protocol as three of
the seven reported survivors in the literature were treated using this type
of therapy. Our four patients, when added to the three reported survivors in
the literature using this approach, suggest that patients provided this
aggressive therapy can significantly alter the course of their disease. More
importantly, we report on the first two survivors after relapse with
multi-agent intravenous and intrathecal chemotherapy treated with this
modified regimen.
Publication Types:
- Case Reports
- Review
- Review of Reported Cases
PMID: 15803379 [PubMed - indexed for MEDLINE]
-
| 27: J Neurooncol.
2005 Mar;72(1):57-62. |
|
-
Human interferon beta, nimustine hydrochloride, and
radiation therapy in the treatment of newly diagnosed malignant
astrocytomas.
Watanabe
T, Katayama
Y, Yoshino
A, Fukaya
C, Yamamoto
T.
Department of Neurological Surgery, Nihon University School of Medicine,
30-1 Oyaguchi-kamimachi, Tokyo, Itabashi-ku, Japan. takao@med.nihon-u.ac.jp
Previous investigators have reported encouraging results for malignant
gliomas treated using a combination of human interferon beta (IFN-beta) with
nimustine hydrochloride (ACNU) and radiation therapy (termed IAR therapy).
This study was undertaken to examine further the efficacy of the IAR regimen
followed by maintenance therapy with IFN-beta and ACNU in patients with
newly diagnosed malignant astrocytomas. Fifty-eight patients were enrolled
onto the trial. IFN-beta (2 x 10(6) IU/m(2)/day x 5 days/week for 8
consecutive weeks) and ACNU (80 mg/m(2) on days 1 and 36) were administered
intravenously concomitant with radiation therapy followed by IFN-beta (every
2 weeks) and ACNU (every 6 weeks). Of 33 patients assessable for a response,
11 responded (33%), with 4 complete responses. The estimated median overall
survival (OS) was 16 months, with values of 58 and 13 months for anaplastic
astrocytoma (AA) and glioblastoma (GB) patients, respectively. The overall
progression free survival (PFS) was 11 months, with values of 31 and 7
months for AA and GB patients, respectively. The IAR therapy was safe and
well tolerated. Based on a statistical analysis of the factors that affected
the PFS and OS, histologic grade, postoperative Karnofsky performance scale
(KPS), and extent of surgery were identified as independent predictors. The
postoperative KPS stood out as the most powerful prognostic factor, which
was also the best predictor for the response to IAR therapy. Our findings
suggest a possible benefit for IAR therapy followed by maintenance therapy
mainly in AA. In addition, they emphasize the importance of a preserved KPS
after cytoreductive surgery, which could produce a potential benefit for
adjuvant therapy and could ultimately lead to a prolonged survival.
Publication Types:
PMID: 15803376 [PubMed - indexed for MEDLINE]
-
| 28: J Neurooncol.
2005 Mar;72(1):29-34. |
|
-
DeltaNp73 antisense activates PUMA and induces apoptosis
in neuroblastoma cells.
Simoes-Wust
AP, Sigrist
B, Belyanskaya
L, Hopkins
Donaldson S, Stahel
RA, Zangemeister-Wittke
U.
Molecular Oncology Laboratory, University Hospital Zurich, Haeldeliweg 4,
CH-8044, Zurich, Switzerland.
The p73 gene codes for various different protein isoforms. They include
proteins expressed under the control of the P1 promoter that contain a
transactivation domain and are similar in function to p53 (TAp73 isoforms),
as well as proteins regulated by the P2 promoter that lack this domain and
function as dominant negative inhibitors of TAp73 and p53 (DeltaNp73
isoforms). Whereas TAp73 functions as a tumor suppressor with pro-apoptotic
function, DeltaNp73 is likely to prevent the induction of apoptosis in tumor
cells and to participate in oncogenesis. Here we used a loss-of-function
strategy to assess the role of DeltaNp73 in SH-SY5Y neuroblastoma cells. An
antisense oligonucleotide designed to target DeltaNp73 mRNA, but not TAp73,
was used to effectively downregulate this transcript. DeltaNp73
downregulation was accompanied by increased levels of the pro-apoptotic BH3
family member PUMA at the mRNA and protein level, and by conformational
activation of BAX which translocated to mitochondria. These DeltaNp73
antisense-mediated alterations led to the induction of apoptosis as detected
by decreased cell viability, augmented DNA fragmentation and increased
caspase-3 activity in cell lysates. Our results demonstrate the
cytoprotective role of DeltaNp73 in neuroblastoma and suggest its use as a
target for molecular intervention therapy.
PMID: 15803372 [PubMed - indexed for MEDLINE]
-
| 29: J Neurooncol.
2005 Mar;72(1):25-8. |
|
-
Analysis of chromosome 7 in adult and pediatric
ependymomas using chromogenic in situ hybridization.
Santi
M, Quezado
M, Ronchetti
R, Rushing
EJ.
Department of Pathology, Children's Hospital National Medical Center,
Washington, DC, USA.
Few studies have yielded reliable data that distinguish between ependymal
neoplasms based on molecular genetic attributes. The present study utilizes
chromogenic in situ hybridization (CISH), a relatively recent hybridization
technique, to retrospectively examine chromosome 7-copy number in pediatric
and adult ependymomas. Of the 27 hybridizations, polysomy of chromosome 7
was detected in 10 out of 15 (66%) adult ependymomas, and in only three out
of 12 (25%) pediatric lesions. All myxopapillary ependymomas showed
polysomy. The remaining tumors were diploid. The authors conclude that (1)
there are distinct genetic subsets of ependymoma, in particular, increases
in copy number of chromosome 7 are almost exclusively found in myxopapillary
ependymoma, and that (2) CISH is a rapid and sensitive method of stratifying
morphological variants of ependymoma and potentially other central nervous
system (CNS) tumors. These results encourage further investigations with
CISH on a larger scale to determine its merit as an ancillary diagnostic and
prognostic tool.
PMID: 15803371 [PubMed - indexed for MEDLINE]
-
| 30: J Neurooncol.
2005 Mar;72(1):17-23. |
|
-
Antisense bcl-2 transfection up-regulates anti-apoptotic
and anti-oxidant thioredoxin in neuroblastoma cells.
Li
Y, Lu
Z, Chen
F, Guan
J, Hu
L, Xu
Y, Chen
J.
Department of Pathology, Peking Union Medical College Hospital, Beijing,
P.R. China. yitingl@bcm.tmc.edu
Antisense bcl-2 therapy combined with chemotherapy has been proved to be
effective in various tumors. However, the role played by antisense bcl-2
therapy alone is not clear. In this study, we compared the apoptosis and the
protein profiles of antisense bcl-2 transfected human neuroblastoma SK-N-MC
cells to the control cells. Flow cytometric data indicated that antisense
bcl-2 transfection did not lead to more extensive apoptosis in SK-N-MC cells
(14.9 +/- 3.8%) than the control cells (10.3 +/- 2.3%). The above
observation was confirmed by fluorescence microscopy using Hoechst 33258
staining. However, antisense bcl-2 induced changes in the expression of
various proteins as shown by proteomic comparison, which included the
up-regulation of the anti-apoptotic and anti-oxidant protein thioredoxin. By
western blot validation, thioredoxin was found to be up-regulated by
2.9-folds with the corresponding down-regulation of Bcl-2 by 2.1-folds. The
up-regulation of thioredoxin may be a compensating mechanism for cell
survival in neuroblastoma when Bcl-2 expression is suppressed, and it may to
some extent attenuate the effectiveness of antisense bcl-2 therapy.
PMID: 15803370 [PubMed - indexed for MEDLINE]
-
| 31: J Neurooncol.
2005 Feb;71(3):333-4. |
|
-
Successful treatment of a chemoresistant tumor with
temozolomide in an adult patient: report of a recurrent intracranial
mesenchymal chondrosarcoma.
Aksoy
S, Abali
H, Kilickap
S, Guler
N.
Publication Types:
PMID: 15735926 [PubMed - indexed for MEDLINE]
-
| 32: J Neurooncol.
2005 Feb;71(3):307-13. |
|
-
Gamma Knife radiosurgery for intracranial metastatic
melanoma: an analysis of survival and prognostic factors.
Koc
M, McGregor
J, Grecula
J, Bauer
CJ, Gupta
N, Gahbauer
RA.
Division of Radiation Oncology, Arthur G. James Cancer Hospital and Research
Institute, The Ohio State University, Columbus, OH, USA. mkoc@atauni.edu.tr
Objective of this study was to evaluate retrospectively the effectiveness of
Gamma Knife radiosurgery for intracranial metastatic melanoma and to
identify prognostic factors related to survival. Twenty-six patients with
intracranial metastases (72 lesions) from melanoma underwent Gamma Knife
radiosurgery. In 14 patients (54%) whole-brain radiotherapy (WBRT) was
performed as part of the initial treatment, and in 12 patients (38%)
immunotherapy and/or chemotherapy was given after Gamma Knife radiosurgery.
The median tumor volume for Gamma Knife radiosurgery treated lesions was
1.72 cm3. The median prescribed radiation dose was 18 Gy (range 8-22 Gy)
typically prescribed to the isodose at the tumor margin. Univariate and
multivariate analyses were used to determine significant prognostic factors
affecting survival. Overall median survival was 6 months after Gamma Knife
radiosurgery, and 1-year survival was 25%. The median survival from the
onset of brain metastases was 9 months and from the original diagnosis of
melanoma was 50 months (range 4-160 months). There were no major acute or
late GKS complications. In univariate testing, the Karnofsky score equal to
or higher than 90% (P < 0.01, log-rank test), supratentorial localization
(P < 0.001, log-rank test), intracranial tumor volume less than 1 cm3 (P
< 0.02, log-rank test), and absence of neurological signs or symptoms
before Gamma Knife radiosurgery (P < 0.003, log-rank test) were
significant favorable factors for survival. In multivariate regression
analyses, the most important predictors associated with increased survival
were a KPS > or = 90 (P < 0.023), female sex (P < 0.004),
supratentorial localization (P < 0.01), and absence of neurological
symptoms (P < 0.008). Radiosurgery is a noninvasive, safe, and effective
treatment option for patients with single or multiple intracranial
metastases from melanoma. Female sex, Karnofsky score > or = 90,
supratentorial localization and lack of symptoms before the Gamma Knife
radiosurgery were good independent predictors of survival.
Publication Types:
PMID: 15735922 [PubMed - indexed for MEDLINE]
-
| 33: J Neurooncol.
2005 Feb;71(3):281-6. |
|
-
Assessing perfusion changes during whole brain
irradiation for patients with cerebral metastases.
Millar
BA, Purdie
TG, Yeung
I, Pond
GR, Billingsley
S, Wong
R, Haddad
P, Wong
CS, Laperriere
N.
Department of Radiation Oncology, Princess Margaret Hospital, Toronto,
Ontario, Canada. barbara-ann.millar@rmp.uhn.on.ca
PURPOSE: To assess perfusion changes within brain and correlate these with
clinical symptoms during whole brain radiotherapy (WBRT) for cerebral
metastases. MATERIALS AND METHODS: Fourteen patients with cerebral
metastases underwent dynamic CT perfusion scans during palliative whole
brain irradiation. Perfusion scans were performed on Day 1 prior to initial
radiotherapy treatment, then on Day 2, and on Day 5 immediately after
completion of radiotherapy. Measurements of cerebral blood flow (CBF),
cerebral blood volume (CBV), mean transit time (MTT) and capillary surface
area permeability product (PS) were performed for each perfusion scan, and
daily symptom assessment was taken prior to initial perfusion scan and
thereafter prior to each daily radiation treatment. RESULTS: Utilizing Day 1
as baseline, a 19% increase (P = 0.033) was noted in PS at Day 2, (median
1.47 ml/100 g/min), which returned to Day 1 range at Day 5 (median 1.31
ml/100 g/min). When symptoms were correlated with perfusion parameters, a
statistically significant association between change in MTT with change in
headache scores was observed, baseline to Day 2 (P = 0.019), and a trend
between change in nausea scores with change in CBV (P = 0.059) as well as
change in MTT (P = 0.098), baseline to Day 5. CONCLUSION: This study has
demonstrated the feasibility of a non-invasive technique to assess changes
occurring within the human brain during a course of radiation treatment.
Dynamic perfusion tomography provides insight into the pathophysiological
processes taking place and allows correlation with patient symptomatology.
Publication Types:
- Clinical Trial
- Controlled Clinical Trial
PMID: 15735918 [PubMed - indexed for MEDLINE]
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| 34: J Neurooncol.
2005 Feb;71(3):271-6. |
|
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Combined chemotherapy and radiotherapy for intracranial
germinomas in adult patients: a single-institution study.
Silvani
A, Eoli
M, Salmaggi
A, Lamperti
E, Fariselli
L, Milanesi
I, Broggi
G, Solero
CL, Giombini
S, Boiardi
A.
Department of Neuro-Oncology, Istituto Nazionale Neurologico Carlo Besta,
Milan, Italy. silvani@istituto-besta.it
We report on our experience in the treatment of intracranial germinomas (18
pure germinomas and two germinomas with syncytiotrophoblastic giant cells)
according to a strategy of radiotherapy doses and fields reduction after a
neoadjuvant chemotherapy (Cisplatin-vinblastine and bleomycin combination).
Radiation therapy was delivered after the completion of the third and last
course of chemotherapy. For the solitary germinoma the target volume was the
gross tumour volume. In the five multifocal germinoma patients the whole
ventricle volume was irradiated. For the single disseminated germinoma
patient we treated the whole central nervous system. The cumulative doses
were 30 Gy for the pure germinomas. For the STGCs, a cumulative dose of 35
Gy was used. The median follow-up was 55 months (range 12-120). 18 patients
were alive without recurrence of disease. In the two patients with STGCs the
death took place 16 and 35 months after diagnosis.
Publication Types:
PMID: 15735916 [PubMed - indexed for MEDLINE]
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| 35: J Neurooncol.
2005 Feb;71(3):257. |
|
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Cavernous hemangioma of the thalamus.
Mhoyan
A, Fulbright
R, Bannykh
SI.
Department of Pathology, University of California, San Diego, USA.
Publication Types:
PMID: 15735913 [PubMed - indexed for MEDLINE]
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| 36: J Neurooncol.
2005 Jan;71(1):67-72. |
|
-
Intramedullary spinal cord metastases in breast cancer:
report of four cases and review of the literature.
Kosmas
C, Koumpou
M, Nikolaou
M, Katselis
J, Soukouli
G, Markoutsaki
N, Kostopoulou
V, Gaglia
A, Mylonakis
N, Karabelis
A, Pectasides
D.
Second Department of Medical Oncology, Metaxa Cancer Hospital, Piraeus,
Greece. ckosm@ath.forthnet.gr
Intramedullary spinal cord metastases (ISCM) are usually the result of
rapidly progressing systemic cancer. Breast cancer represents one of the
most common solid tumors associated with the development of ISCM at rather
advanced stages of disease. In the present report we describe four new cases
with advanced breast cancer developing ISCM. All cases presented herein
indicated that ISCM is a late manifestation of disseminated breast cancer.
Three of these patients had been treated for approximately 1-3 years for
metastatic disease. Once ISCM developed, concurrent asymptomatic brain
metastases were detected in one case, concurrent symptomatic brain disease
(cerebellar) was present at the time of cervical ISCM diagnosis in another
patient, and in another case, ISCM developed metachronously at 18 months
after the diagnosis of symptomatic brain metastases treated by whole brain
radiotherapy. One of these cases had brain metastases at presentation, while
at relapse developed leptomeningeal carcinomatosis treated successfully, but
followed shortly, as a terminal event, by ISCM and parenchymal brain
recurrence.All but one patient experienced a rather rapidly evolving disease
course leading to death after 2-5 months from widespread neuraxis
dissemination of their cancer, while one patient is still alive 6 months
after the diagnosis of ISCM. All four cases, added to the list of the
anecdotally reported cases of ISCM after breast cancer, undermine the
ominous prognosis and limited treatment options available for this disease
manifestation, and an extensive literature review and discussion of similar
cases is provided.
Publication Types:
- Case Reports
- Review
- Review of Reported Cases
PMID: 15719278 [PubMed - indexed for MEDLINE]
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| 37: J Neurooncol.
2005 Jan;71(1):49-52. |
|
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Isolated primary intracerebral mycetoma: presenting as a
mass lesion in a patient with prostate cancer and multiple myeloma.
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Volume 4, Number 29 - 12 July 2005