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A 3 1/2-year-old child with a posterior fossa mass.
Pigmented medullomyoblastoma.
Mehta
A, Patkar
N, Nakra
R, Nema
S.
Department of Pathology, Armed Forces Medical College, Pune, Maharashtra,
India.
PMID: 16594755 [PubMed - indexed for MEDLINE]
 http://arpa.allenpress.com/arpaonline/?request=get-abstract&issn=1543-2165&volume=130&page=565
 http://arpa.allenpress.com/arpaonline/?request=get-document&doi=10.1043%2F1543-2165(2006)130%5B565:AYCWAP%5D2.0.CO%3B2
 http://arpa.allenpress.com/pdfserv/10.1043/1543-2165(2006)130[565:AYCWAP]2.0.CO;2
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TRAIL inhibits angiogenesis stimulated by VEGF expression
in human glioblastoma cells.
Cantarella
G, Risuglia
N, Dell'eva
R, Lempereur
L, Albini
A, Pennisi
G, Scoto
GM, Noonan
DN, Bernardini
R.
1Department of Experimental and Clinical Pharmacology, University of Catania,
Viale Andrea Doria, 6, Catania 95125, Italy.
Tumour growth is tightly related to new blood vessel formation, tissue
remodelling and invasiveness capacity. A number of tissular factors fuel the
growth of glioblastoma multiforme, the most aggressive brain neoplasm. In
fact, gene array analyses demonstrated that the proapoptotic cytokine tumour
necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA
expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2),
its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as
well as the tumour invasiveness-related gene secreted protein acid rich in
cysteine (SPARC) in different human glioblastoma cell lines. Particularly,
VEGF mRNA and protein expression and release from glioblastoma cells were
also inhibited by TRAIL. The latter also exerted antimitogenic effects on
human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL
inhibited new vessel formation in the in vitro matrigel model, as well as it
exerted powerful inhibition of blood vessel formation induced by an
angiogenic cocktail administered in subcutaneous pellets in vivo in the C57
mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the
tumour invasiveness-related protein SPARC were effectively inhibited by
TRAIL in glioblastoma cell lines. In conclusion, our data indicate that
TRAIL inhibits the orchestra of factors contributing to glioblastoma
biological aggressiveness. Thus, the TRAIL system could be regarded as a
molecular target to exploit for innovative therapy of this type of
tumour.British Journal of Cancer advance online publication, 11 April 2006;
doi:10.1038/sj.bjc.6603092 www.bjcancer.com.
PMID: 16622457 [PubMed - as supplied by publisher]
 http://www.nature.com/bjc/journal/vaop/ncurrent/abs/6603092a.html;jsessionid=72306C74CD232C390EDE20E28F4954F9
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Diversity of cytogenetic and pathohistologic profiles in
glioblastoma.
Hassler
M, Seidl
S, Fazeny-Doerner
B, Preusser
M, Hainfellner
J, Rossler
K, Prayer
D, Marosi
C.
Department of Internal Medicine I, Clinical Division of Oncology.
We present a small series of patients with primary glioblastoma multiforme (GBM),
and combine individual genetic data with pathohistologic characteristics and
clinical outcome. Eighteen patients (12 men, 6 women, median age 51 years)
with histologically proven GBM underwent surgical debulking followed by
radiotherapy. Fifteen received concomitant chemotherapy. Histologic typing,
immunohistochemistry for CD34, karyotypic analysis, and classification of
the pattern of neovascularization was done in all patients. In 12/18, we
performed methylation-specific polymerase chain reaction of the MGMT gene
(O-6-methylguanine-DNA methyltransferase). The survival duration of patients
spanned 3-58 months. By classical banding methods, 15/18 patients showed at
least one aberration characteristic for primary glioblastoma (+7 in 7/18,
deletions of 9p in 10/18 and -10 or deletions from 10q in 8/18 patients). We
could not assess whether patients who survived for longer periods showed
less complex or fewer aberrations than the patients who survived less than
one year. Losses of 6p21(VEGF), 4q27(bFGF), and 12p11 approximately p13
(ING4) were associated with the "bizarre" pattern of
neoangiogenesis. Methylation of the MGMT promoter was found in 3/12
patients. Even in this small series, the main characteristic of GBM was its
diversity regarding all investigated histologic and genetic characteristics.
This extreme diversity should be considered in the design of targeted
therapies in GBM.
PMID: 16616111 [PubMed - in process]
http://www.journals.elsevierhealth.com/periodicals/cgc/article/PIIS0165460805005029/abstract
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Serum IgE, Tumor Epidermal Growth Factor Receptor
Expression, and Inherited Polymorphisms Associated with Glioma Survival.
Wrensch
M, Wiencke
JK, Wiemels
J, Miike
R, Patoka
J, Moghadassi
M, McMillan
A, Kelsey
KT, Aldape
K, Lamborn
KR, Parsa
AT, Sison
JD, Prados
MD.
Department of Neurological Surgery and Comprehensive Cancer Center
Biostatistics Core, University of California San Francisco, San Francisco,
California.
In population-based glioma patients, we examined survival in relation to
potentially pertinent constitutive polymorphisms, serologic factors, and
tumor genetic and protein alterations in epidermal growth factor receptor (EGFR),
MDM2, and TP53. Subjects were newly diagnosed adults residing in the San
Francisco Bay Surveillance Epidemiology and End Results Area during 1991 to
1994 and 1997 to 1999 with central neuropathology review (n = 873). Subjects
provided blood for serologic studies of IgE and IgG to four herpes viruses
and constitutive specimens for genotyping 22 polymorphisms in 13 genes (n =
471). We obtained 595 of 697 astrocytic tumors for marker studies. We
determined treatments, vital status, and other factors using registry,
interview, medical record, and active follow-up data. Cox regressions for
survival were adjusted for age, gender, ethnicity, study series, resection
versus biopsy only, radiation, and chemotherapy. Using a stringent P <
0.001, glioma survival was associated with ERCC1 C8092A [hazard ratio (HR),
0.72; 95% confidence limits (95% CL), 0.60-0.86; P = 0.0004] and GSTT1
deletion (HR, 1.64; 95% CL, 1.25-2.16; P = 0.0004); glioblastoma patients
with elevated IgE had 9 months longer survival than those with normal or
borderline IgE levels (HR, 0.62; 95% CL, 0.47-0.82; P = 0.0007), and EGFR
expression in anaplastic astrocytoma was associated with nearly 3-fold
poorer survival (HR, 2.97; 95% CL, 1.70-5.19; P = 0.0001). Based on our and
others' findings, we recommend further studies to (a) understand
relationships of elevated IgE levels and other immunologic factors with
improved glioblastoma survival potentially relevant to immunologic therapies
and (b) determine which inherited ERCC1 variants or other variants in the
19q13.3 region influence survival. We also suggest that tumor EGFR
expression be incorporated into clinical evaluation of anaplastic
astrocytoma patients. (Cancer Res 2006; 66(8): 4531-41).
PMID: 16618782 [PubMed - in process]
http://cancerres.aacrjournals.org/cgi/content/abstract/66/8/4531
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Radiation-Induced Caspase-8 Mediates p53-Independent
Apoptosis in Glioma Cells.
Afshar
G, Jelluma
N, Yang
X, Basila
D, Arvold
ND, Karlsson
A, Yount
GL, Dansen
TB, Koller
E, Haas-Kogan
DA.
Departments of Radiation Oncology and Comprehensive Cancer Center,
University of California at San Francisco.
Malignant gliomas are almost uniformly fatal and display exquisite radiation
resistance. Glioma cells lacking wild-type (WT) p53 function are more
susceptible to radiation-induced apoptosis than their isogenic counterparts
expressing WT p53. We explored the mechanisms of such apoptosis and found
that, in the absence of WT p53, radiation increases caspase-8 expression and
activity. Inhibition of caspase-8 expression using caspase-8 antisense or
small interfering RNA (siRNA) oligonucleotides partially blocks
radiation-induced apoptosis. In contrast, inhibition of the mitochondrial
death pathway by expression of Bcl-2 has no effect on radiation-induced
caspase-8 activity or apoptosis. Our data indicate that, in contrast to
commonly accepted models of p53-dependent radiation-induced apoptosis, in
our cell system, radiation relies on caspase-8 activity to help mediate
p53-independent cell death. In a system of inducible E2F1 activity, E2F1
activated caspase-8 and, accordingly, decreased cellular viability, effects
that were abolished by caspase-8 siRNA. In this model, in the absence of WT
p53, p21(Cip1) is not induced, and E2F1 activity is sustained and allows
transcription and activation of caspase-8. This model may explain why p53
mutations in adult gliomas paradoxically correlate with improved survival
and enhanced response to radiation. (Cancer Res 2006; 66(8): 4223-32).
PMID: 16618745 [PubMed - in process]
http://cancerres.aacrjournals.org/cgi/content/abstract/66/8/4223
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Shh pathway activity is down-regulated in cultured
medulloblastoma cells: implications for preclinical studies.
Sasai
K, Romer
JT, Lee
Y, Finkelstein
D, Fuller
C, McKinnon
PJ, Curran
T.
Departments of Developmental Neurobiology, Genetics and Tumor Cell Biology,
Hartwell Center, and Pathology, Saint Jude Children's Research Hospital,
Memphis, Tennessee.
Gene expression profiling indicates that the Sonic Hedgehog (Shh) pathway is
active in approximately 30% of human medulloblastomas, suggesting that it
could provide a useful therapeutic target. Previously, we showed that
spontaneous medulloblastomas in Ptc1(+/-)p53(-/-) mice could be eradicated
by treatment with a small-molecule inhibitor (HhAntag) of Smoothened (Smo).
Here, we compared the responses of mouse medulloblastoma cells propagated in
flank allografts, either directly or after culture in vitro, to HhAntag. We
found that Shh pathway activity was suppressed in medulloblastoma cells
cultured in vitro and it was not restored when these cells were transplanted
into the flank of nude mice. The growth of these transplanted tumor cells
was not inhibited by treatment of mice with doses of HhAntag that completely
suppressed Smo activity. Interestingly, tumor cells transplanted directly
into the flank maintained Smo activity and were sensitive to treatment with
HhAntag. These findings indicate that propagation of tumor cells in culture
inhibits Smo activity in a way that cannot be reversed by transplantation in
vivo, and they raise concerns about the use of cultured tumor cells to test
the efficacy of Shh pathway inhibitors as anticancer therapies. (Cancer Res
2006; 66(8): 4215-22).
PMID: 16618744 [PubMed - in process]
http://cancerres.aacrjournals.org/cgi/content/abstract/66/8/4215
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Related to Testes-Specific, Vespid, and Pathogenesis
Protein-1 (RTVP-1) Is Overexpressed in Gliomas and Regulates the Growth,
Survival, and Invasion of Glioma Cells.
Rosenzweig
T, Ziv-Av
A, Xiang
C, Lu
W, Cazacu
S, Taler
D, Miller
CG, Reich
R, Shoshan
Y, Anikster
Y, Kazimirsky
G, Sarid
R, Brodie
C.
Gonda (Goldschmied) Medical Diagnosis Research Center, Faculty of
Life-Sciences, Bar-Ilan University, Ramat-Gan, Israel.
In this study, we examined the expression and functions of related to
testes-specific, vespid, and pathogenesis protein 1 (RTVP-1) in glioma
cells. RTVP-1 was expressed in high levels in glioblastomas, whereas its
expression in low-grade astrocytomas and normal brains was very low.
Transfection of glioma cells with small interfering RNAs targeting RTVP-1
decreased cell proliferation in all the cell lines examined and induced cell
apoptosis in some of them. Overexpression of RTVP-1 increased astrocyte and
glioma cell proliferation and the anchorage-independent growth of the cells.
In addition, overexpression of RTVP-1 rendered glioma cells more resistant
to the apoptotic effect of tumor necrosis factor-related apoptosis-inducing
ligand and serum deprivation. To delineate the molecular mechanisms involved
in the survival effects of RTVP-1, we examined the expression and
phosphorylation of various apoptosis-related proteins. We found that
overexpression of RTVP-1 decreased the phosphorylation of c-Jun-NH(2)-kinase
and increased the expression of Bcl(2) and that the protective effect of
RTVP-1 was partially mediated by Bcl(2). Finally, we found that RTVP-1
regulated the invasion of glioma cells as was evident by their enhanced
migration through Matrigel and by their increased invasion in a spheroid
confrontation assay. The increased invasive potential of the RTVP-1
overexpressors was also shown by the increased activity of matrix
metalloproteinase 2 in these cells. Our results suggest that the expression
of RTVP-1 is correlated with the degree of malignancy of astrocytic tumors
and that RTVP-1 is involved in the regulation of the growth, survival, and
invasion of glioma cells. Collectively, these findings suggest that RTVP-1
is a potential therapeutic target in gliomas. (Cancer Res 2006; 66(8):
4139-48).
PMID: 16618735 [PubMed - in process]
http://cancerres.aacrjournals.org/cgi/content/abstract/66/8/4139
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A Hypermutation Phenotype and Somatic MSH6 Mutations in
Recurrent Human Malignant Gliomas after Alkylator Chemotherapy.
Hunter
C, Smith
R, Cahill
DP, Stephens
P, Stevens
C, Teague
J, Greenman
C, Edkins
S, Bignell
G, Davies
H, O'meara
S, Parker
A, Avis
T, Barthorpe
S, Brackenbury
L, Buck
G, Butler
A, Clements
J, Cole
J, Dicks
E, Forbes
S, Gorton
M, Gray
K, Halliday
K, Harrison
R, Hills
K, Hinton
J, Jenkinson
A, Jones
D, Kosmidou
V, Laman
R, Lugg
R, Menzies
A, Perry
J, Petty
R, Raine
K, Richardson
D, Shepherd
R, Small
A, Solomon
H, Tofts
C, Varian
J, West
S, Widaa
S, Yates
A, Easton
DF, Riggins
G, Roy
JE, Levine
KK, Mueller
W, Batchelor
TT, Louis
DN, Stratton
MR, Futreal
PA, Wooster
R.
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United
Kingdom.
Malignant gliomas have a very poor prognosis. The current standard of care
for these cancers consists of extended adjuvant treatment with the
alkylating agent temozolomide after surgical resection and radiotherapy.
Although a statistically significant increase in survival has been reported
with this regimen, nearly all gliomas recur and become insensitive to
further treatment with this class of agents. We sequenced 500 kb of genomic
DNA corresponding to the kinase domains of 518 protein kinases in each of
nine gliomas. Large numbers of somatic mutations were observed in two
gliomas recurrent after alkylating agent treatment. The pattern of mutations
in these cases showed strong similarity to that induced by alkylating agents
in experimental systems. Further investigation revealed inactivating somatic
mutations of the mismatch repair gene MSH6 in each case. We propose that
inactivating somatic mutations of MSH6 confer resistance to alkylating
agents in gliomas in vivo and concurrently unleash accelerated mutagenesis
in resistant clones as a consequence of continued exposure to alkylating
agents in the presence of defective mismatch repair. The evidence therefore
suggests that when MSH6 is inactivated in gliomas, alkylating agents convert
from induction of tumor cell death to promotion of neoplastic progression.
These observations highlight the potential of large scale sequencing for
revealing and elucidating mutagenic processes operative in individual human
cancers. (Cancer Res 2006; 66(8): 3987-91).
PMID: 16618716 [PubMed - in process]
http://cancerres.aacrjournals.org/cgi/content/abstract/66/8/3987
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Novel nanoliposomal CPT-11 infused by convection-enhanced
delivery in intracranial tumors: pharmacology and efficacy.
Noble
CO, Krauze
MT, Drummond
DC, Yamashita
Y, Saito
R, Berger
MS, Kirpotin
DB, Bankiewicz
KS, Park
JW.
Division of Hematology/Oncology, University of California at San Francisco,
California 94115, USA.
We hypothesized that combining convection-enhanced delivery (CED) with a
novel, highly stable nanoparticle/liposome containing CPT-11 (nanoliposomal
CPT-11) would provide a dual drug delivery strategy for brain tumor
treatment. Following CED in rat brains, tissue retention of nanoliposomal
CPT-11 was greatly prolonged, with >20% injected dose remaining at 12
days for all doses. Tissue residence was dose dependent, with doses of 60
microg (3 mg/mL), 0.8 mg (40 mg/mL), and 1.6 mg (80 mg/mL) resulting in
tissue half-life (t(1/2)) of 6.7, 10.7, and 19.7 days, respectively. In
contrast, CED of free CPT-11 resulted in rapid drug clearance (tissue t(1/2)
= 0.3 day). At equivalent CED doses, nanoliposomal CPT-11 increased area
under the time-concentration curve by 25-fold and tissue t(1/2) by 22-fold
over free CPT-11; CED in intracranial U87 glioma xenografts showed even
longer tumor retention (tissue t(1/2) = 43 days). Plasma levels were
undetectable following CED of nanoliposomal CPT-11. Importantly, prolonged
exposure to nanoliposomal CPT-11 resulted in no measurable central nervous
system (CNS) toxicity at any dose tested (0.06-1.6 mg/rat), whereas CED of
free CPT-11 induced severe CNS toxicity at 0.4 mg/rat. In the intracranial
U87 glioma xenograft model, a single CED infusion of nanoliposomal CPT-11 at
1.6 mg resulted in significantly improved median survival (>100 days)
compared with CED of control liposomes (19.5 days; P = 4.9 x 10(-5)) or free
drug (28.5 days; P = 0.011). We conclude that CED of nanoliposomal CPT-11
greatly prolonged tissue residence while also substantially reducing
toxicity, resulting in a highly effective treatment strategy in preclinical
brain tumor models.
PMID: 16510602 [PubMed - indexed for MEDLINE]
http://cancerres.aacrjournals.org/cgi/content/abstract/66/5/2801
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Impact of radiotherapy for pediatric CNS atypical
teratoid/rhabdoid tumor (single institute experience).
Chen
YW, Wong
TT, Ho
DM, Huang
PI, Chang
KP, Shiau
CY, Yen
SH.
Cancer Center, Neurological Institute, Taipei, Taiwan.
PURPOSE: To assess outcomes and prognostic factors in radiotherapy of
pediatric central nervous system atypical teratoid/rhabdoid tumor (AT/RT).
METHODS AND MATERIALS: Seventeen patients with central nervous system AT/RT
were retrospectively reviewed after curative radiotherapy as primary or
adjuvant therapy between January 1990 and December 2003. Overall and
failure-free survival rates were calculated using the Kaplan-Meier method.
The log-rank method was used to compare the effects of dosage (>50 Gy or
< or =50 Gy) and treatment duration (>45 days or < or =45 days).
Multivariate analysis was performed for prognostic factors. RESULTS: Median
overall survival and failure-free survival were 17 and 11 months,
respectively. The 3 longest-surviving patients were older, underwent gross
tumor removal, and completed both craniospinal and focal boost irradiation.
Multivariate analysis revealed a significant relationship between the
following: overall survival and performance status (p = 0.019), failure-free
survival and total irradiation dose (p = 0.037), time interval between
surgery and radiotherapy initiation (p = 0.031), and time interval between
surgery and radiotherapy end point (p = 0.047). CONCLUSION: Radiotherapy is
crucial in the treatment of AT/RT. We recommend initiating radiotherapy
immediately postoperatively and before systemic chemotherapy in pediatric
patients > or =3 years of age.
PMID: 16406394 [PubMed - indexed for MEDLINE]
http://www.redjournal.org/article/PIIS0360301605027355/abstract
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Supratentorial primitive neuroectodermal tumors (S-PNET)
in children: A prospective experience with adjuvant intensive chemotherapy
and hyperfractionated accelerated radiotherapy.
Massimino
M, Gandola
L, Spreafico
F, Luksch
R, Collini
P, Giangaspero
F, Simonetti
F, Casanova
M, Cefalo
G, Pignoli
E, Ferrari
A, Terenziani
M, Podda
M, Meazza
C, Polastri
D, Poggi
G, Ravagnani
F, Fossati-Bellani
F.
Neuro-Oncology Functional Unit, Department of Pediatric Oncology, Istituto
Nazionale Tumori, Milan, Italy. maura.massimino@istitutotumori.mi.it
PURPOSE: Supratentorial primitive neuroectodermal tumors (S-PNET) are rare
and have a grim prognosis, frequently taking an aggressive course with local
relapse and metastatic spread. We report the results of a mono-institutional
therapeutic trial. METHODS AND MATERIALS: We enrolled 15 consecutive
patients to preradiation chemotherapy (CT) consisting of high-dose
methotrexate, high-dose etoposide, high-dose cyclophosphamide, and high-dose
carboplatin, craniospinal irradiation (CSI) with hyperfractionated
accelerated radiotherapy (HART) plus focal boost, maintenance with
vincristine/lomustine or consolidation with high-dose thiotepa followed by
autologous stem-cell rescue. RESULTS: Median age was 9 years; 7 were male, 8
female. Site of disease was pineal in 3, elsewhere in 12. Six patients were
had no evidence of disease after surgery (NED). Of those with evidence of
disease after surgery (ED), 2 had central nervous system spread. Of the 9 ED
patients, 2 had complete response (CR) and 2 partial response (PR) after CT,
4 stable disease, and 1 progressive disease. Of the 7 ED patients before
radiotherapy, 1 had CR, 4 PR, and 2 minor response, thus obtaining a 44% CR
+ PR after CT and 71% after HART. Because of rapid progression in 2 of the
first 5 patients, high-dose thiotepa was systematically adopted after HART
in the subsequent 10 patients. Six of 15 patients relapsed (4 locally, 1
locally with dissemination, 1 with dissemination) a mean of 6 months after
starting CT, 2 developed second tumors; 5 of 6 relapsers died at a median of
13 months. Three-year progression-free survival, event-free survival, and
overall survival were 54%, 34%, and 61%, respectively. CONCLUSION:
Hyperfractionated accelerated RT was the main tool in obtaining responses in
S-PNET; introducing the myeloablative phase improved the prognosis (3/10 vs.
3/5 relapses), though the outcome remained unsatisfactory despite the
adoption of this intensive treatment.
PMID: 16343801 [PubMed - indexed for MEDLINE]
http://www.redjournal.org/article/PIIS0360301605027173/abstract
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Dose to the intracranial arteries in stereotactic and
intensity-modulated radiotherapy for skull base tumors.
Nieder
C, Grosu
AL, Stark
S, Wiedenmann
N, Busch
R, Kneschaurek
P, Molls
M.
Department of Radiation Oncology, Klinikum rechts der Isar, Technical
University of Munich, Munich, Germany. cnied@hotmail.com
PURPOSE: To examine retrospectively the maximum dose to the large skull
base/intracranial arteries in fractionated stereotactic radiotherapy (FSRT)
and intensity-modulated radiotherapy (IMRT), because of the potential risk
of perfusion disturbances. METHODS AND MATERIALS: Overall, 56 patients with
tumors adjacent to at least one major artery were analyzed. Our strategy was
to perform FSRT with these criteria: 1.8 Gy per fraction, planning target
volume (PTV) enclosed by the 95% isodose, maximum dose 107%. Dose limits
were applied to established organs at risk, but not the vessels. If FSRT
planning failed to meet any of these criteria, IMRT was planned with the
same objectives. RESULTS: In 31 patients (median PTV, 23 cm3), the FSRT plan
fulfilled all criteria. No artery received a dose > or =105%. Twenty-five
patients (median PTV, 39 cm3) needed IMRT planning. In 11 of 25 patients
(median PTV, 85 cm3), no plan satisfying all our criteria could be
calculated. Only in this group, moderately increased maximum vessel doses
were observed (106-110%, n = 7, median PTV, 121 cm3). The median PTV dose
gradient was 29% (significantly different from the 14 patients with
satisfactory IMRT plans). Three of the four patients in this group had
paranasal sinus tumors. CONCLUSION: The doses to the major arteries should
be calculated in IMRT planning for critical tumor locations if a dose
gradient >13% within the PTV can not be avoided because the PTV is large
or includes air cavities.
PMID: 16338100 [PubMed - indexed for MEDLINE]
http://www.redjournal.org/article/PIIS0360301605026064/abstract
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Possibility of using laser spectroscopy for the
intraoperative detection of nonfluorescing brain tumors and the boundaries
of brain tumor infiltrates. Technical note.
Utsuki
S, Oka
H, Sato
S, Suzuki
S, Shimizu
S, Tanaka
S, Fujii
K.
Department of Neurosurgery, Kitasato University School of Medicine,
Sagamihara, Kanagawa, Japan. utsuki@med.kitasato-u.ac.jp
The response of nonfluorescing infiltrating tumors that had been exposed to
5-aminolevulinic acid and irradiated using a laser at a wavelength of 405 nm
was analyzed intraoperatively using spectroscopy. Histological analyses
demonstrated that neoplastic cells were present in the tissue region that
displayed a peak at 636 nm, whereas no neoplastic cells were present in the
region that exhibited only the excitation light peak. The authors conclude
that the intraoperative use of laser spectroscopy can allow the diagnosis of
infiltrating tumor and the detection of boundaries of the infiltrate when
standard fluorescence techniques fail.
PMID: 16619668 [PubMed - in process]
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The human survivin promoter: a novel transcriptional
targeting strategy for treatment of glioma.
Van
Houdt WJ, Haviv
YS, Lu
B, Wang
M, Rivera
AA, Ulasov
IV, Lamfers
ML, Rein
D, Lesniak
MS, Siegal
GP, Dirven
CM, Curiel
DT, Zhu
ZB.
Department of Neurosurgery, VU Universiteit Medische Center, Amsterdam, The
Netherlands.
OBJECT: Malignant brain tumors have been proved to be resistant to standard
treatments and therefore require new therapeutic strategies. Survivin, a
recently described member of the inhibitor of apoptosis protein family, is
overexpressed in several human brain tumors, primarily gliomas, but is
downregulated in normal tissues. The authors hypothesized that the
expression of tumor-specific survivin could be exploited for treatment of
gliomas by targeting the tumors with gene therapy vectors. METHODS:
Following confirmation of survivin expression in glioma cell lines, an
adenoviral vector containing the survivin promoter and the reporter gene
luciferase was tested in established and primary glioma cells, normal
astrocytic cells, and normal human brain tissues. High levels of reporter
gene expression were observed in established tumor and primary tumor cell
lines and low levels of expression in astrocytes and normal human brain
tissue. To test oncolytic potency, the authors constructed survivin
promoter-based conditionally replicative adenoviruses (CRAds), composed of
survivin promoter-regulated E1 gene expression and an RGD-4C capsid
modification. These CRAds could efficiently replicate within and kill a
variety of established glioma tumor cells, but were inactive in a normal
human liver organ culture. Finally, survivin promoter-based CRAds
significantly inhibited the growth of glioma xenografts in vivo.
CONCLUSIONS: Together these data indicate that the survivin promoter is a
promising tumor-specific promoter for transcriptional targeting of
adenovirus-based vectors and CRAds for malignant gliomas. The strategy of
using survivin-CRAds may thus translate into an experimental therapeutic
approach that can be used in human clinical trials.
PMID: 16619663 [PubMed - in process]
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Induction of macrophagic prostaglandin E2 synthesis by
glioma cells.
Nakano
Y, Kuroda
E, Kito
T, Yokota
A, Yamashita
U.
Department of Neurosurgery, School of Medicine, University of Occupational
and Environmental Health, Kitakyushu, Japan.
OBJECT: It has been reported that glioma cells produce prostaglandin (PG)E2,
which promotes the growth of tumor cells and possesses immunosuppressive
activity, and that cyclooxygenase (COX) inhibitors impede tumor growth and
infiltration. Macrophages in tumor-bearing hosts are activated to produce
PGE2, which induces an immunosuppressive state. Note, however, that the
precise mechanism by which PGE2 induces an immunosuppressive state is still
unclear. In this study, the authors investigated the mechanism of PGE2
production in glioma-bearing hosts. METHODS: The human and murine glioma
cells that were studied did not produce a significant amount of PGE2.
However, the coculture of human peripheral blood mononuclear cells or murine
peritoneal macrophages with glioma cells or conditioned glioma medium led to
the production of a large amount of PGE2. In contrast, production of tumor
necrosis factor and interleukin (IL)-12p70 by macrophages and cytotoxic T
lymphocyte induction were suppressed by culturing with conditioned glioma
medium; this suppression was abrogated by the addition of the COX inhibitor
indomethacin. The macrophagic expression of COX-2, and particularly the
expression of microsomal PGE synthase (mPGES)-1, a terminal enzyme of the
arachidonate cascade, was enhanced by the glioma-derived soluble factors.
Furthermore, IL-12p70 production was not clearly suppressed in macrophages
from mPGES-1-deficient mice. The glioma-derived soluble factors were
sensitive to treatment with heat and papain. CONCLUSIONS: These results
indicated that PGE2 production by macrophages is enhanced by glioma-derived
soluble factors, which induce an immunosuppressive state in glioma-bearing
hosts. Therefore, the inhibition of PGE2 synthesis, targeting COX-2 and
mPGES-1, is an effective treatment for the induction of antiglioma immune
responses.
PMID: 16619662 [PubMed - in process]
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Modification of glucose metabolism in brain tumors by
using cervical spinal cord stimulation.
Clavo
B, Robaina
F, Montz
R, Domper
M, Carames
MA, Morera
J, Pinar
B, Hernandez
MA, Santullano
V, Carreras
JL.
Department of Radiation Oncology-Research, Dr. Negrin University Hospital,
Las Palmas, Spain. bernardinoclavo@terra.es
OBJECT: In previous studies the authors have shown potential increases in
locoregional blood flow and oxygenation in tumors by using electrical
cervical spinal cord stimulation (SCS). In the present report they
demonstrate the effect of cervical SCS on brain tumor metabolism, as
assessed using [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET).
METHODS: Cervical devices were inserted in 11 patients who had high-grade
gliomas, six of which had recurred. While the SCS device was deactivated,
each patient underwent an initial FDG-PET study to clarify the clinical
status. A second FDG-PET study was performed later the same day while the
stimulation device was activated to determine the effect of cervical SCS on
glucose metabolism. All 11 patients were invaluable for this PET study.
Basal glucose metabolism was higher in the tumor than in the peritumoral
areas (p = 0.048). There was a significant increase in glucose uptake during
cervical SCS in both the tumor (p = 0.035) and the peritumoral (p = 0.001)
areas, with measured increases of 43 and 38%, respectively. The estimated
potential maximal residual activity of the first FDG dose's contribution to
the activity on the second scan was 18.5 +/- 1% or less. CONCLUSIONS: This
PET study is the first in which is described the effect of cervical SCS on
glucose metabolism in brain tumors and supports previous study data
indicating a modification of locoregional blood flow and oxygenation by
cervical SCS. These results open up new approaches to modifying the effect
of radiochemotherapy in the treatment of malignant brain tumors.
PMID: 16619657 [PubMed - in process]
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Homonymous hemianopias: clinical-anatomic correlations in
904 cases.
Zhang
X, Kedar
S, Lynn
MJ, Newman
NJ, Biousse
V.
Department of Ophthalmology, Emory University School of Medicine, Atlanta,
GA, USA.
OBJECTIVE: To describe the clinical characteristics and clinical-anatomic
correlations of homonymous hemianopia (HH). BACKGROUND: Homonymous
hemianopia impairs visual function and frequently precludes driving. Most
knowledge of HH is based on relatively few cases with clinical-anatomic
correlations. METHODS: The authors reviewed medical records of all patients
with HH seen in their service between 1989 and 2004. Demographic
characteristics, characteristics of visual field defects, causes of visual
field defects, neuroradiologic definition of lesion location, and associated
neurologic deficits were recorded. RESULTS: A total of 904 HH were found in
852 patients. A total of 340 HH (37.6%) were complete and 564 HH (62.4%)
were incomplete. Homonymous quadrantanopia (264 HH, 29%) was the most common
type of incomplete HH, followed by homonymous scotomatous defects (116 HH,
13.5%), partial HH (114 HH, 13%), and HH with macular sparing (66 HH, 7%). A
total of 407 HH (45.0%) were isolated. Causes of HH included stroke (629 HH,
69.6%), trauma (123, 13.6%), tumor (102, 11.3%), brain surgery (22, 2.4%),
demyelination (13, 1.4%), other rare causes (13, 1.4%), and unknown etiology
(2, 0.2%). The lesions were most commonly located in the occipital lobes
(45%) and the optic radiations (32.2%). Every type of HH, except for
unilateral loss of temporal crescent and homonymous sectoranopia, was found
in all lesion locations along the retrochiasmal visual pathways. CONCLUSION:
Homonymous hemianopia is usually secondary to stroke, head trauma, and
tumors. Although the characteristics of visual field defects can be helpful
in lesion location, specific visual field defects do not always indicate
specific brain locations.
PMID: 16567710 [PubMed - indexed for MEDLINE]
http://www.neurology.org/cgi/content/abstract/66/6/906
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Matrilin-2 expression distinguishes clinically relevant
subsets of pilocytic astrocytoma.
Sharma
MK, Watson
MA, Lyman
M, Perry
A, Aldape
KD, Deak
F, Gutmann
DH.
Department of Neurology, Washington University School of Medicine, St.
Louis, MO 63110, USA.
Using whole genome expression microarray technology to discover clinically
relevant biomarkers for pilocytic astrocytoma (PA), the authors identified
matrilin-2 as a unique mRNA overexpressed in PA. Matrilin-2 protein
expression was similarly elevated in the majority of sporadic PA, but in
only one neurofibromatosis 1-associated PA with an unusually aggressive
clinical phenotype. These results suggest that matrilin-2 may be a specific
and clinically useful biomarker for discriminating between indolent and
clinically aggressive PA.
PMID: 16401863 [PubMed - indexed for MEDLINE]
-
-
beta1-integrin-mediated signaling essentially contributes
to cell survival after radiation-induced genotoxic injury.
Cordes
N, Seidler
J, Durzok
R, Geinitz
H, Brakebusch
C.
OncoRay -- Radiation Research in Oncology, Medical Faculty Carl Gustav Carus,
Technical University Dresden, Fetscherstrasse, Dresden, Germany. Nils.Cordes@mailbox.tu-dresden.de
Integrin-mediated adhesion to extracellular matrix proteins confers
resistance to radiation- or drug-induced genotoxic injury. To analyse the
underlying mechanisms specific for beta1-integrins, wild-type
beta1A-integrin-expressing GD25beta1A cells were compared to GD25beta1B
cells, which express signaling-incompetent beta1B variants. Cells grown on
fibronectin, collagen-III, beta1-integrin-IgG or poly-l-lysine were exposed
to 0-6 Gy X-rays in presence or depletion of growth factors and
phosphatidylinositol-3 kinase (PI3K) inhibitors (LY294002, wortmannin). In
order to test the relevance of these findings in tumor cells, human A-172
glioma cells were examined under the same conditions after siRNA-mediated
silencing of beta1-integrins. We found that beta1A-integrin-mediated
adhesion to fibronectin, collagen-III or beta1-IgG was essential for cell
survival after radiation-induced genotoxic injury. Mediated by PI3K,
pro-survival beta1A-integrin/Akt signaling was critically involved in this
process. Additionally, the beta1-integrin downstream targets p130Cas and
paxillin-impaired survival-regulating PI3K-dependent JNK. In A-172 glioma
cells, beta1-integrin knockdown and PI3K inhibition confirmed the central
role of beta1-integrins in Akt- and p130Cas/paxillin-mediated prosurvival
signaling. These findings suggest beta1-integrins as critical regulators of
cell survival after radiation-induced genotoxic injury. Elucidation of the
molecular circuitry of prosurvival beta1-integrin-mediated signaling in
tumor cells may promote the development of innovative molecular-targeted
therapeutic antitumor strategies.
PMID: 16247454 [PubMed - indexed for MEDLINE]
http://www.nature.com/onc/journal/v25/n9/abs/1209164a.html
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| 20: BMC
Cancer. 2006 Apr 19;6(1):97 [Epub ahead of print] |
|
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Nuclear FABP7 immunoreactivity is preferentially
expressed in infiltrative glioma and is associated with poor prognosis in
EGFR-overexpressing glioblastoma.
Liang
Y, Bollen
AW, Aldape
KD, Gupta
N.
ABSTRACT: BACKGROUND: We previously identified brain type fatty acid-binding
protein (FABP7) as a prognostic marker for patients with glioblastoma (GBM).
Increased expression of FABP7 is associated with reduced survival. To
investigate possible molecular mechanisms underlying this association, we
compared the expression and subcellular localization of FABP7 in non-tumor
brain tissues with different types of glioma, and examined the expression of
FABP7 and epidermal growth factor receptor (EGFR) in GBM tumors. METHODS:
Expression of FABP7 in non-tumor brain and glioma specimens was examined
using immunohistochemistry, and its correlation to the clinical behavior of
the tumors was analyzed. We also analyzed the association between FABP7 and
EGFR expression in different sets of GBM specimens using published DNA
microarray datasets and semi-quantitative immunohistochemistry. In vitro
migration was examined using SF763 glioma cell line. RESULTS: FABP7 was
present in a unique population of glia in normal human brain, and its
expression was increased in a subset of reactive astrocytes. FABP7
immunoreactivity in grade I pilocytic astrocytoma was predominantly
cytoplasmic, whereas nuclear FABP7 was detected in other types of
infiltrative glioma. Nuclear, not cytoplasmic, FABP7 immunoreactivity was
associated with EGFR overexpression in GBM (N=61, p=0.008). Expression of
the FABP7 gene in GBM also correlated with the abundance of EGFR mRNA in our
previous microarray analyses (N=34, p=0.016) and an independent public
microarray dataset (N=28, p=0.03). Compared to those negative for both
markers, nuclear FABP7-positive/EGFR-positive and nuclear FABP7-positive/EGFR-negative
GBM tumors demonstrated shortest survival, whereas those only positive for
EGFR had intermediate survival. EGFR activation increased nuclear FABP7
immunoreactivity in a glioma cell line in vitro, and inhibition of FABP7
expression suppressed EGF-induced glioma-cell migration. Our data suggested
that in EGFR-positive GBM the presence of nuclear FABP7 immunoreactivity
increases the risk of poor prognosis CONCLUSION: In this study, we
identified a possible mechanism as the basis of the association between
nuclear FABP7 and poor prognosis of GBM. FABP7 expression can be found in
all grades of astrocytoma, but neoplastic cells with nuclear FABP7 were only
seen in infiltrative types of tumors. Nuclear FABP7 may be induced by EGFR
activation to promote migration of GBM tumor cells. Positive nuclear FABP7
correlated with short survival in EGFR-positive GBM patients. Therefore,
nuclear FABP7 immunoreactivity could be used to monitor the progression of
EGFR-overexpressed GBM.
PMID: 16623952 [PubMed - as supplied by publisher]
http://www.biomedcentral.com/1471-2407/6/97
http://www.biomedcentral.com/content/pdf/1471-2407-6-97.pdf
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Volume 5, Number 17 - 24 April
2006