| 1: Brain.
2006 Aug 3; [Epub ahead of print] |
|
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TGF-{beta} and metalloproteinases differentially suppress
NKG2D ligand surface expression on malignant glioma cells.
Eisele G, Wischhusen J, Mittelbronn M, Meyermann R,
Waldhauer I, Steinle A, Weller M, Friese MA.
Department of General Neurology, Hertie Institute for Clinical Brain
Research, University of Tubingen, Tubingen, Germany.
NKG2D ligands (NKG2DL) are expressed by infected and transformed cells. They
transmit danger signals to NKG2D-expressing immune cells, leading to lysis
of NKG2DL-expressing cells. We here report that the NKG2DL MHC class
I-chain-related molecules A and B (MICA/B) and UL16-binding proteins (ULBP)
1-3 are expressed in human brain tumours in vivo, while expression levels
are low or undetectable in normal brain. MICA and ULBP2 expression decrease
with increasing WHO grade of malignancy, while MICB and ULBP1 are expressed
independently of tumour grade. We further delineate two independent
mechanisms that can explain these expression patterns: (i) transforming
growth factor-beta (TGF-beta) is upregulated during malignant progression
and selectively downregulates MICA, ULBP2 and ULBP4 expression, while MICB,
ULBP1 and ULBP3 are unaffected. (ii) Cleavage of MICA and ULBP2 is reduced
by inhibition of metalloproteinases (MP), whereas no changes in the
expression levels of other NKG2DL were detected. Consequently,
NKG2DL-dependent NK cell-mediated lysis is enhanced by depletion of TGF-beta
or inhibition of MP. Thus, escape from NKG2D-mediated immune surveillance of
malignant gliomas in vivo may be promoted by the inhibition of MICA and
ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding
from the cell surface. Loss of MICA and ULBP2, in contrast to other NKG2DL,
may be particularly important in glioma immune escape, and differential
regulation of human NKG2DL expression is part of the immunosuppressive
properties of human malignant glioma cells.
PMID: 16891318 [PubMed - as supplied by publisher]
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| 2: Cancer. 2006 Aug 7; [Epub
ahead of print] |
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Increased expression of avian erythroblastosis virus E26
oncogene homolog 1 in World Health Organization grade 1 meningiomas is
associated with an elevated risk of recurrence and is correlated with the
expression of its target genes matrix metalloproteinase-2 and MMP-9.
Okuducu AF, Zils U, Michaelis SA, Mawrin C, von
Deimling A.
Institute of Neuropathology, Charite-Universitaetsmedizin Berlin, Campus
Virchow-Klinikum, Berlin, Germany.
BACKGROUND: The transcription factor avian erythroblastosis virus E26 (V-Ets)
oncogene homolog 1 (Ets-1) is involved in tumor development and progression
through the transcriptional regulation of several matrix-degrading enzyme
systems, including matrix metalloproteinases (MMPs). It has been
demonstrated that the MMPs are expressed strongly in high-grade meningiomas.
To determine the biologic significance of Ets-1 in the progression of benign
meningiomas, the authors investigated the expressions of Ets-1 and its
target genes MMP-2 and MMP-9 in primary and recurrent, Grade 1 meningiomas.
METHODS: The expression levels of Ets-1, MMP-2, and MMP-9 were examined by
immunohistochemistry in 70 Grade 1 meningiomas, including 36 primary tumors
without recurrence after 5 years of follow-up and 17 pairs of primary tumors
and subsequent recurrences. RESULTS: The results demonstrated higher
expression of Ets-1, MMP-2, and MMP-9 proteins in meningiomas with
subsequent recurrences compared with meningiomas from patients who had no
recurrences (P < .001). In addition, Ets-1 expression was correlated with
the expression of both MMP-2 and MMP-9. CONCLUSIONS: Ets-1 may be involved
in meningioma recurrence by up-regulating MMP-2 and MMP-9. Increased
expression of these genes in World Health Organization grade 1 meningiomas
may serve as an indicator for a high risk of recurrence. Cancer 2006. (c)
2006 American Cancer Society.
PMID: 16894529 [PubMed - as supplied by publisher]
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| 3: Cancer. 2006 Aug 7; [Epub
ahead of print] |
|
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Role of spinal MRI in the follow-up of children treated
for medulloblastoma.
Bartels U, Shroff M, Sung L, Dag-Ellams U, Laperriere
N, Rutka J, Bouffet E.
Division of Haematology/Oncology, Hospital for Sick Children, Toronto,
Ontario, Canada.
BACKGROUND.: The purpose of the current study was to describe the usefulness
of spinal magnetic resonance imaging (MRI) in children with medulloblastoma
or primitive neuroectodermal tumor (PNET) of the posterior fossa. METHODS.:
Children consecutively diagnosed with medulloblastoma/PNET and followed in
the Hospital for Sick Children/Toronto were identified. A homogenous cohort
of children treated with craniospinal irradiation as part of their initial
treatment was considered. Contrast-enhanced spinal MRIs done concomitantly
with cranial MRIs (doublets) were reviewed. Recurrence was defined as any
new abnormal lesion (in the brain or in the spine) in symptomatic or
asymptomatic patients. Doublets after the first recurrence were excluded in
the final analysis. The utility of a spinal MRI in the presence of a
negative cranial MRI was assessed. RESULTS.: In all, 73 patients (21 females
and 52 males; median age, 6.6 years, median follow-up time, 4.3 years) had
at least 1 evaluable doublet during the follow-up period. Since concomitant
cranial and spinal MRI was introduced as the standard evaluation for
medulloblastoma/PNET in 1991, 286 doublets were evaluable. Fourteen spinal
MRIs and 25 cranial MRIs showed new nodular or leptomeningeal lesions. In 2
patients, repeat MRIs ruled out recurrence (false-positive). All confirmed
spinal recurrences were associated with intracranial recurrence. Of 261
doublets with negative cranial MRI, no new lesion was identified on spinal
MRI. CONCLUSIONS.: An absence of progression on cranial MRI is highly
predictive of absence of progression on spinal MRI. There is little evidence
that surveillance spinal MRI (in children who underwent craniospinal
radiation as part of their initial treatment) improves the detection of
recurrences in children with medulloblastoma. Cancer 2006. (c) 2006 American
Cancer Society.
PMID: 16894528 [PubMed - as supplied by publisher]3
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| 4: Cancer Res. 2006 Jun
15;66(12):6002-7. |
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The small alpha5beta1 integrin antagonist, SJ749, reduces
proliferation and clonogenicity of human astrocytoma cells.
Maglott A, Bartik P, Cosgun S, Klotz P, Ronde
P, Fuhrmann G, Takeda K, Martin S, Dontenwill M.
Departement de Pharmacologie et Physicochimie, Universite Louis Pasteur
Strasbourg, Illkirch, France.
The potential role of alpha5beta1 integrins in cancer has recently attracted
much interest. However, few alpha5beta1-selective antagonists have been
developed compared with other integrins. The most specific nonpeptidic
alpha5beta1 antagonist described thus far, SJ749, inhibits angiogenesis by
affecting adhesion and migration of endothelial cells. We investigated the
effects of SJ749 in two human astrocytoma cell lines, A172 and U87, which
express different levels of alpha5beta1. SJ749 dose-dependently inhibited
adhesion of both cell types on fibronectin. Application of SJ749 to spread
cells led to formation of nonadherent spheroids for A172 cells but had no
effect on U87 cell morphology. SJ749 also reduced proliferation of A172
cells due to a long lasting G0-G1 arrest, whereas U87 cells were only
slightly affected. However, under nonadherent culture conditions (soft
agar), SJ749 significantly reduced the number of colonies formed only by U87
cells. As U87 cells express more alpha5beta1 than A172 cells, we
specifically examined the effect of SJ749 on A172 cells overexpressing
alpha5. Treatment of alpha5-A172 cells with SJ749 decreased colony formation
similarly to that observed in U87 cells. Therefore, in nonadherent
conditions, the effect of SJ749 on tumor cell growth characteristics depends
on the level of alpha5beta1 expression. Our study highlights the importance
of alpha5beta1 as an anticancer target and shows for the first time that a
small nonpeptidic alpha5beta1-specific antagonist affects proliferation of
tumor cells.
PMID: 16778170 [PubMed - indexed for MEDLINE]
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| 5: Childs
Nerv Syst. 2006 Jun;22(6):547-55. Epub 2006 Apr 11. |
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Vascular complications of cranial radiation.
Keene DL, Johnston DL, Grimard L, Michaud J, Vassilyadi
M, Ventureyra E.
Department of Pediatrics, Children's Hospital of Eastern Ontario, 401 Smyth
Road, Ottawa, ON K1H 8L1, Canada. dkeene@cheo.on.ca
OBJECTIVES: Cerebral vascular disease has been reported as a long-term
complication of cranial radiotherapy. The purpose of this study was to
examine the frequency and risk factors associated with development of
cerebral vascular disease in children after cranial radiation. MATERIALS AND
METHODS: A retrospective chart review of all cancer patients treated between
1985 and 2003 who were under the age of 18 years at the time of initial
radiotherapy was performed. Variables examined include diagnosis and site of
malignancy, age at the time of radiotherapy, sex, total radiation dosage,
number of fractions, duration, and whether the patient had proven cerebral
vascular event. RESULTS: Two hundred and forty-four patients met the study
criteria. One hundred and 13 cases involved tumors of the central nervous
system. The remaining patients had systemic neoplastic disease. Post
radiation cerebral vascular disease occurred in 11 (5%) patients, and all
but one patient had a tumor involving the central nervous system (mainly in
the posterior fossa and supratentorial midline). CONCLUSION: There is an
increased risk of cerebral vascular disease after radiation therapy in
childhood, especially in children who received high dose radiation at the
posterior fossa and supratentorial axial region.
PMID: 16607532 [PubMed - indexed for MEDLINE]3
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| 6: Childs
Nerv Syst. 2006 Jun;22(6):609-13. Epub 2006 Mar 29. |
|
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Pediatric cerebellar pleomorphic xanthoastrocytoma with
anaplastic features: a case of long-term survival after multimodality
therapy.
Chang HT, Latorre JG, Hahn S, Dubowy R, Schelper
RL.
Department of Pathology, SUNY Upstate Medical University, 750 E. Adams St.,
Syracuse, NY 13210, USA. changh@upstate.edu
CASE REPORT: A 4-year-old girl had a large midline cerebellar solid and
cystic mass partially attached to the meninges. The original diagnosis was
glioblastoma multiforme and she was treated by a gross-total surgical
resection followed by chemotherapy and radiation therapy to the posterior
fossa during the ensuing 14 months. She has received no further therapy and
appears to be doing well 12 years later. This unusual favorable clinical
outcome prompted our review of this case. METHODS: Additional special stains
and immunocytochemistry were performed on the paraffin embedded tumor
sections. RESULTS: We have confirmed the original histopathological
observations of hypercellularity and focal nuclear pleomorphism, atypical
mitoses, vascular hyperplasia, as well as focal necrosis. However, the
additional stains revealed that the tumor is a relatively well-circumscribed
meningeal-based astrocytic tumor (positive for GFAP) with extensive
reticulin deposit and focal neuronal differentiation (positive for
synaptophysin). A Ki67 labeling index is generally very low, but is positive
in up to 5-10% of tumor cells focally. In the light of the favorable
clinical outcome and the overall histological features, this tumor may be
best reclassified as a rare example of cerebellar pleomorphic
xanthoastrocytoma with foci of anaplasia.
Publication Types:
PMID: 16570197 [PubMed - indexed for MEDLINE]4
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| 7: Childs
Nerv Syst. 2006 Jun;22(6):628-31. Epub 2006 Mar 23. |
|
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Lipomyelomeningocele and arteriovenous malformation: case
reports and a review of the literature.
Tubbs RS, Oakes WJ.
Department of Cell Biology, University of Alabama at Birmingham, Birmingham,
AL 35233, USA. rstubbs@uab.edu
INTRODUCTION: The caudal end of the human embryo is a major site of
multipotential cells. We now present two cases of simultaneous arteriovenous
malformation and lipomyelomeningocele and review the literature regarding
this potential association. DISCUSSION: In the context of rarity and
following a review of the literature, both an arteriovenous malformation and
lipomyelomeningocele in the same patient appears to be more than
serendipitous. The natural history of these vascular malformations in
patients with concomitant lipoma or lipomyelomeningocele cannot be
determined from such a small group. However, only one patient in our review
was found to have consequences thought to be related to their arteriovenous
malformation, which was in the upper thoracic region and not related to a
lipomyelomeningocele.
Publication Types:
PMID: 16555082 [PubMed - indexed for MEDLINE]3
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| 8: Childs
Nerv Syst. 2006 Jun;22(6):577-85. Epub 2006 Mar 23. |
|
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Pinealoblastomas in children.
Cuccia V, Rodriguez F, Palma F, Zuccaro G.
Unit of Pediatric Neurosurgery, Hospital Nacional de Pediatria, "Prof.
Juan P. Garrahan", Combate de los Pozos 1881, 1245, Capital Federal,
Buenos Aires, Argentina. vcuccia@fibertel.com.ar
INTRODUCTION: Series of pinealoblastomas (PB) usually comprise small number
of cases as this tumor type is extremely rare and occurs mainly in childhood
(especially under 9 years of age). Frequently, PB are reported together with
others pineal parenchymal tumors (PPT) or pineal tumors, making
characterization far from adequate. MATERIALS AND METHODS: Our series of CNS
pediatric tumors comprises 1,350 cases of whom 16 are PPT, 12 PB, two
pineocytomas (PC), and two mixed or transitional tumors (PC/PB). We have
only analyzed the PB considering clinical features, treatment strategy,
prognosis, recurrences, and mortality. RESULTS: PB represented 0.89%. Mean
age was 7 years. Male-female ratio was 8/4. All patients complained of
increased intracranial pressure, eight presented ocular symptoms, two
cerebellar, and one endocrine disturbances. Patients underwent CT scans
and/or MRI. All children had negative serum and CSF markers and only one
case had positive tumor cells in the CSF on admission. Hydrocephalus (12/12)
was treated with ventriculoperitoneal shunt in 11/12 and endoscopic third
ventriculostomy (ETV) in 1/12. We performed 11 surgical procedures (seven by
occipital transtentorial approach) and one endoscopic biopsy. Total removal
was achieved in two, partial removal (50-90%) in seven, and biopsy in three
patients or <50%. Adjuvant therapy included radiotherapy and
chemotherapy. Recurrences appeared in 8/12 cases (mean time of
recurrence=27.28 months). Six patients died (mean survival=29.55 months).
Mean follow up for the six patients alive was 54 months and mean follow up
for all 12 children was 38.7 months. CONCLUSION: In our opinion, PB have a
poor prognosis and are very aggressive, especially in small children.
Survival rate at 1 and 5 years in the present series is 66.6% (8/12) and 50%
(6/12), respectively. We propose an algorithm for the treatment of pediatric
patients with PB.
Publication Types:
PMID: 16555075 [PubMed - indexed for MEDLINE]3
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| 9: Childs
Nerv Syst. 2006 Jun;22(6):572-6. Epub 2006 Mar 16. |
|
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Spontaneous regression of cerebellar astrocytoma after
subtotal resection.
Steinbok P, Poskitt K, Hendson G.
Division of Neurosurgery, Department of Surgery, University of British
Columbia, Vancouver, British Columbia, Canada.
CASE REPORT: The authors report a child in whom residual cerebellar
astrocytoma after surgical resection was documented on serial computed
tomography scans to undergo gradual complete regression spontaneously over a
period of 11 years. In this case, the time course of regression has been
well documented. CONCLUSION: The time course of regression may provide clues
as to the underlying cause of this phenomenon.
Publication Types:
PMID: 16552566 [PubMed - indexed for MEDLINE]4
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| 10: Childs
Nerv Syst. 2006 Jun;22(6):599-604. Epub 2006 Mar 21. |
|
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Neuroendoscopic techniques in the treatment of arachnoid
cysts in children and comparison with other operative methods.
Nowoslawska E, Polis L, Kaniewska D, Mikolajczyk
W, Krawczyk
J, Szymanski
W, Zakrzewski
K, Podciechowska
J, Polis
B.
The Department of Neurosurgery, Research Institute of Polish Mother's
Memorial Hospital (RIPMMH), Rzgowska 281/289, Lodz 93-338, Poland. enowos@poczta.onet.pl
OBJECTIVE: The authors intended to evaluate the application of
neuroendoscopic techniques for the treatment of arachnoid cysts in children
and compare it with other operative methods. METHODS: The analysis covered
the results of treatment of 44 children with arachnoid cysts who were
subjected to neuroendoscopic procedures and 62 patients who underwent other
operations. RESULTS: The neuroendoscopic treatment of arachnoid cysts was
very effective because of low rate of reoperative treatment (six out of 44
patients), no need to change the operative method (40 effective out of total
44 operative procedures), and low rate of persistent worsening (none of 44
patients worsened). CONCLUSIONS: Summing up all the mentioned aspects of
neuroendoscopic techniques, the neuroendoscopic techniques were the most
suitable operative procedures in the treatment of arachnoid cysts in the
presented group of patients, providing that the connection between the lumen
of the arachnoid cyst and the cerebrospinal fluid cisterns was of good
quality.
Publication Types:
PMID: 16550440 [PubMed - indexed for MEDLINE]
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| 11: Childs
Nerv Syst. 2006 Jun;22(6):556-61. Epub 2006 Feb 21. |
|
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Meningeal melanocytoma.
O'Brien
DF, Crooks
D, Mallucci
C, Javadpour
M, Williams
D, du
Plessis D, Broome
J, Foy
P, Pizer
B.
Department of Neurosurgery, Royal Liverpool Children's Hospital NHS Trust
Alder Hey and the Walton Centre for Neurology and Neurosurgery NHS Trust,
Liverpool, UK. dfobstl@hotmail.com
BACKGROUND: Meningeal melanocytoma was first described over 30 years ago as
a benign tumour derived from melanocytes. Since then, data suggest that its
mode of presentation is variable without a clear predilection for any
particular site in the neuroaxis. Although classified as a benign tumour,
this tumour shows a marked tendency towards reduced survival following
subtotal resection and transformation over time in a limited number to
malignant melanoma. Incomplete resection of these tumours without
postoperative radiotherapy has only a 42% 5-year survival rate. Its
classification as a benign tumour should be revised, given the published
5-year survival data. ILLUSTRATIVE CASE: We report a fatal case of meningeal
melanocytoma in the cerebello-pontine angle in a 10-year-old child. This
case exemplifies the vascular nature of these lesions even with minimal
vascular blush on angiography. An updated literature search is presented,
the results of which highlight the need for close follow-up and adjuvant
treatment following subtotal resection.
Publication Types:
PMID: 16491422 [PubMed - indexed for MEDLINE]3
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| 12: Childs
Nerv Syst. 2006 Jun;22(6):619-22. Epub 2006 Jan 14. |
|
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Meningeal solitary fibrous tumour in a child.
de
Ribaupierre S, Meagher-Villemure
K, Agazzi
S, Rilliet
B.
Neurosurgery Department, Centre Hospitalier Universitaire Vaudois (CHUV),
Rue du Bugnon, 1011 Lausanne, Switzerland. s_derib@hotmail.com
INTRODUCTION: Meningeal solitary fibrous tumour is a relatively recent
pathological entity that has rarely been described in children. With
radiological techniques, it cannot be distinguished from meningiomas, and
the diagnosis has to be confirmed histologically. CASE REPORT: We discuss
the possible histogenesis of this tumour and the need for recognizing this
lesion as a separate entity. We report the case of a 12-year-old boy who
developed a meningeal solitary fibrous tumour; the main clinical symptoms
were progressive headaches for a long period and recent transient
hemiparesis. CONCLUSION: This child presents an uneventful evolution without
additional therapy 3.5 years after surgery.
Publication Types:
PMID: 16416152 [PubMed - indexed for MEDLINE]3
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| 13: Childs
Nerv Syst. 2006 Jun;22(6):614-8. Epub 2005 Dec 21. |
|
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Non-anaplastic pleomorphic xanthoastrocytoma with
neuroradiological evidences of leptomeningeal dissemination.
Passone
E, Pizzolitto
S, D'Agostini
S, Skrap
M, Gardiman
MP, Nocerino
A, Scarzello
G, Perilongo
G.
Paediatric Clinic, School of Medicine, University of Udine, Udine, Italy.
CASE REPORT: A case of a non-anaplastic pleomorphic xanthoastrocytoma (PXA)
presenting with leptomeningeal dissemination (LMD) affecting a 9-year-old
girl is presented. DISCUSSION: The neoplasia in this young girl had the
otherwise classical clinical features of PXA: the relatively advanced
paediatric age of the patient, the seizures as presenting sign; the primary
site in the temporal lobe; and the MRI findings of the partially solid and
cystic superficial lesion. Only the tumour involvement of the chiasma and
the infundibulus was a relatively unusual finding. In a 5-year period, the
tumour underwent malignant transformation, bringing the child to death
because of the primary tumour progression. However, the leptomeningeal
deposits remained unchanged throughout the clinical course. CONCLUSION: To
our knowledge, this is the first case of a non-anaplastic PXA presenting
with disseminated disease. Thus, it was thought important to describe this
case in order to add further information regarding the spectrum of the
presenting clinical features of this rare neoplasm and the phenomenon of LMD
of non-malignant glioma.
Publication Types:
PMID: 16369851 [PubMed - indexed for MEDLINE]3
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| 14: Clin
Cancer Res. 2006 Aug 1;12(15):4738-46. |
|
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Temozolomide-mediated radiation enhancement in
glioblastoma: a report on underlying mechanisms.
Chakravarti
A, Erkkinen
MG, Nestler
U, Stupp
R, Mehta
M, Aldape
K, Gilbert
MR, Black
PM, Loeffler
JS.
Authors' Affiliations: Department of Radiation Oncology, Massachusetts
General Hospital/Harvard Medical School.
PURPOSE: In this study, we investigated the mechanisms by which temozolomide
enhances radiation response in glioblastoma cells. EXPERIMENTAL DESIGN:
Using a panel of four primary human glioblastoma cell lines with
heterogeneous O(6)-methylguanine-DNA methyltransferase (MGMT) protein
expression, normal human astrocytes, and U87 xenografts, we investigated (a)
the relationship of MGMT status with efficacy of temozolomide-based
chemoradiation using a panel of in vitro and in vivo assays; (b) underlying
mechanisms by which temozolomide enhances radiation effect in glioblastoma
cells; and (c) strategies to overcome resistance to radiation + temozolomide.
RESULTS: Temozolomide enhances radiation response most effectively in
glioblastomas without detectable MGMT expression. On concurrent radiation +
temozolomide administration in MGMT-negative glioblastomas, there seems to
be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA
damage compared either with radiation alone or with sequentially
administered temozolomide. Our data suggest that O(6)-benzylguanine can
enhance the antitumor effects of concurrent radiation + temozolomide in
MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage.
O(6)-Benzylguanine was most effective when administered concurrently with
radiation + temozolomide and had less of an effect when administered with
temozolomide in the absence of radiation or when administered sequentially
with radiation. Our in vivo data using U87 xenografts confirmed our in vitro
findings. CONCLUSIONS: The present study shows that temozolomide enhances
radiation response most effectively in MGMT-negative glioblastomas by
increasing the degree of radiation-induced double-strand DNA damage. In
MGMT-positive glioblastomas, depletion of MGMT by the addition of
O(6)-benzylguanine significantly enhances the antitumor effect of concurrent
radiation + temozolomide. These are among the first data showing mechanisms
of synergy between radiation and temozolomide and the effect of MGMT.
PMID: 16899625 [PubMed - in process]4
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| 15: Clin
Cancer Res. 2006 Aug 1;12(15):4730-4737. |
|
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The Combination of Ionizing Radiation and Peripheral
Vaccination Produces Long-term Survival of Mice Bearing Established Invasive
GL261 Gliomas.
Newcomb
EW, Demaria
S, Lukyanov
Y, Shao
Y, Schnee
T, Kawashima
N, Lan
L, Dewyngaert
JK, Zagzag
D, McBride
WH, Formenti
SC.
Authors' Affiliations: Departments of Pathology, Environmental Medicine, and
Radiation Oncology, Division of Neuropathology and Neurosurgery, New York
University Cancer Institute, New York University School of Medicine, New
York, New York; and Department of Radiation Oncology, Experimental Division,
University of California at Los Angeles School of Medicine, Los Angeles,
California.
PURPOSE: High-grade glioma treatment includes ionizing radiation therapy.
The high invasiveness of glioma cells precludes their eradication and is
responsible for the dismal prognosis. Recently, we reported the
down-regulation of MHC class I (MHC-I) products in invading tumor cells in
human and mouse GL261 gliomas. Here, we tested the hypothesis that
whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261
tumors and enhances the effectiveness of immunotherapy. EXPERIMENTAL DESIGN:
MHC-I molecule expression on GL261 cells was analyzed in vitro and in vivo
by flow cytometry and immunohistochemistry, respectively. To test the
response of established GL261 gliomas to treatment, mice with measurable (at
CT imaging) brain tumors were randomly assigned to four groups receiving (a)
no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccination with
irradiated GL261 cells secreting granulocyte-macrophage colony-stimulating
factor, or (d) WBRT and vaccination. Endpoints were tumor response and
survival. RESULTS: An ionizing radiation dose of 4 Gy maximally up-regulated
MHC-I molecules on GL261 cells in vitro. In vivo, WBRT induced the
expression of the beta2-microglobulin light chain subunit of the MHC class I
complex on glioma cells invading normal brain and increased CD4+ and CD8+ T
cell infiltration. However, the survival advantage obtained with WBRT or
vaccination alone was minimal. In contrast, WBRT in combination with
vaccination increased long-term survival to 40% to 80%, compared with 0% to
10% in the other groups (P < 0.002). Surviving animals showed antitumor
immunity by rejecting challenge tumors. CONCLUSION: Ionizing radiation can
be successfully combined with peripheral vaccination for the treatment of
established high-grade gliomas.
PMID: 16899624 [PubMed - as supplied by publisher]3
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| 16: Clin
Cancer Res. 2006 Aug 1;12(15):4687-4694. |
|
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Valproic Acid Prolongs Survival Time of Severe Combined
Immunodeficient Mice Bearing Intracerebellar Orthotopic Medulloblastoma
Xenografts.
Shu
Q, Antalffy
B, Su
JM, Adesina
A, Ou
CN, Pietsch
T, Blaney
SM, Lau
CC, Li
XN.
Authors' Affiliations: Laboratory of Molecular Neuro-Oncology, Department of
Pathology, and Texas Children's Cancer Center, Texas Children's Hospital,
Baylor College of Medicine, Houston, Texas and Department of Neuropathology,
University of Bonn Medical Center, Bonn, Germany.
PURPOSE: To develop novel orthotopic xenograft models of medulloblastoma in
severe combined immunodeficient mice and to evaluate the in vivo antitumor
efficacy of valproic acid. EXPERIMENTAL DESIGN: Orthotopic xenografts were
developed by injecting 10(3) to 10(5) tumor cells from four medulloblastoma
cell lines (D283-MED, DAOY, MHH-MED-1, and MEB-MED-8A) into the right
cerebellum of severe combined immunodeficient mice. Animals were then
examined for reproducibility of tumorigenicity, cell number-survival time
relationship, and histopathologic features. Tumor growth was monitored in
vivo by serially sectioning the xenograft brains at 2, 4, 6, and 8 weeks
postinjection. Valproic acid treatment, administered at 600 mug/h for 2
weeks via s.c. osmotic minipumps, was initiated 2 weeks after injection of
10(5) medulloblastoma cells, and treated and untreated animals were
monitored for differences in survival. Changes in histone acetylation,
proliferation, apoptosis, differentiation, and angiogenesis in xenografts
were also evaluated. RESULTS: Tumorigenicity was maintained at 100% in
D283-MED, DAOY, and MHH-MED-1 cell lines. These cerebellar xenografts
displayed histologic features and immunohistochemical profiles
(microtubule-associated protein 2, glial fibrillary acidic protein, and
vimentin) similar to human medulloblastomas. Animal survival time was
inversely correlated with injected tumor cell number. Treatment with
valproic acid prolonged survival time in two (D283-MED and MHH-MED-1) of the
three models and was associated with induction of histone hyperacetylation,
inhibition of proliferation and angiogenesis, and enhancement of apoptosis
and differentiation. CONCLUSION: We have developed intracerebellar
orthotopic models that closely recapitulated the biological features of
human medulloblastomas and characterized their in vivo growth
characteristics. Valproic acid treatment of these xenografts showed potent
in vivo anti-medulloblastoma activity. These xenograft models should
facilitate the understanding of medulloblastoma pathogenesis and future
preclinical evaluation of new therapies against medulloblastoma.
PMID: 16899619 [PubMed - as supplied by publisher]4
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| 17: Clin
Cancer Res. 2006 Aug 1;12(15):4523-32. |
|
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In vitro Drug Response and Molecular Markers Associated
with Drug Resistance in Malignant Gliomas.
Fruehauf
JP, Brem
H, Brem
S, Sloan
A, Barger
G, Huang
W, Parker
R.
Authors' Affiliations: University of California-Irvine Chao Family Clinical
Cancer Research Center, Orange, California.
PURPOSE: Drug resistance in malignant gliomas contributes to poor clinical
outcomes. We determined the in vitro drug response profiles for 478 biopsy
specimens from patients with the following malignant glial histologies:
astrocytoma (n = 71), anaplastic astrocytoma (n = 39), glioblastoma
multiforme (n = 259), oligodendroglioma (n = 40), and glioma (n = 69).
EXPERIMENTAL DESIGN: Samples were tested for drug resistance to
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, dacarbazine,
paclitaxel, vincristine, and irinotecan. Biomarkers associated with drug
resistance were detected by immunohistochemistry, including multidrug
resistance gene-1, glutathione S-transferase pi (GSTP1),
O(6)-methylguanine-DNA methyltransferase (MGMT), and mutant p53. RESULTS: In
vitro drug resistance in malignant gliomas was independent of prior therapy.
High-grade glioblastomas showed a lower level of extreme drug resistance
than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14%
versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A
substantial percentage of brain tumors overexpressed biomarkers associated
with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53
(41%). MGMT and GSTP1 overexpression was independently associated with in
vitro resistance to BCNU, whereas coexpression of these two markers was
associated with the greatest degree of BCNU resistance. CONCLUSIONS:
Assessment of in vitro drug response and profiles of relevant
tumor-associated biomarkers may assist the clinician in stratifying patient
treatment regimens.
PMID: 16899598 [PubMed - in process]3
-
| 18: Eur
J Cancer. 2006 Aug 7; [Epub ahead of print] |
|
-
Safety and pharmacokinetics of temozolomide using a
dose-escalation, metronomic schedule in recurrent paediatric brain tumours.
Baruchel
S, Diezi
M, Hargrave
D, Stempak
D, Gammon
J, Moghrabi
A, Coppes
MJ, Fernandez
CV, Bouffet
E.
New Agent and Innovative Therapy Program, Department of Paediatrics,
Division of Haematology/Oncology, The Hospital for Sick Children, 555
University Avenue, Toronto, Ont., Canada M5G 1X8.
The aims of this study were to determine the maximum tolerated dose (MTD),
toxicity and pharmacokinetics of oral temozolomide administered over 42 d in
children with recurrent/refractory brain tumours. Cohorts of 3-6 patients
were treated for 42 d, followed by a 7-d rest period for a maximum of 6
cycles. Patients were stratified as heavily pre-treated (HPT) and
non-heavily pre-treated (NHPT). Starting doses were 50 mg/m(2) (HPT) or 75
mg/m(2) (NHPT). Out of 28 patients enrolled, 20 were evaluable for toxicity
and 19 for pharmacokinetics. Three patients in the NHPT group developed
grade 3/4 haematological toxicity, 2 experienced dose-limiting toxicity (thrombocytopenia)
at 100 mg/m(2), and 9/20 developed grade 3 lymphopenia. MTD in both strata
was 85 mg/m(2). Responses were observed in 4 patients: 2 complete responses
(CR) in medulloblastoma and supratentorial primitive neuroectodermal tumours
(PNET), and 2 partial responses (PR) in high-grade glioma, respectively.
Overall cumulative exposure was at least 1.5 times higher than in the 5-d
administration schedule. In conclusion, the recommended dose of temozolomide
is 85 mg/m(2)x42 d. Dose-limiting toxicities are thrombocytopenia and
lymphopenia. The observed response rate warrants phase II studies.
PMID: 16899365 [PubMed - as supplied by publisher]3
-
| 19: Int
J Radiat Oncol Biol Phys. 2006 Aug 1; [Epub ahead of print] |
|
-
Phase II radiation therapy oncology group trial of
conventional radiation therapy followed by treatment with recombinant
interferon-Beta for supratentorial glioblastoma: results of RTOG 9710.
Colman
H, Berkey
BA, Maor
MH, Groves
MD, Schultz
CJ, Vermeulen
S, Nelson
DF, Mehta
MP, Yung
WK.
Neuro-Oncology, University of Texas-M. D. Anderson Cancer Center, Houston,
TX USA; Brain Tumor Center, University of Texas-M. D. Anderson Cancer
Center, Houston, TX USA, University of Texas-M. D. Anderson Cancer Center,
Houston, TX.
PURPOSE: The aim of this study was to determine whether recombinant human
interferon beta-1a (rhIFN-beta), when given after radiation therapy,
improves survival in glioblastoma. METHODS AND MATERIALS: After surgery, 109
patients with newly diagnosed supratentorial glioblastoma were enrolled and
treated with radiation therapy (60 Gy). A total of 55 patients remained
stable after radiation and were treated with rhIFN-beta (6 MU/day i.m., 3
times/week). Outcomes were compared with the Radiation Therapy Oncology
Group glioma historical database. RESULTS: RhIFN-beta was well tolerated,
with 1 Grade 4 toxicity and 8 other patients experiencing Grade 3 toxicity.
Median survival time (MST) of the 55 rhIFN-beta-treated patients was 13.4
months. MST for the 34 rhIFN-beta-treated in RPA Classes III and IV was 16.9
vs. 12.4 months for historical controls (hazard ratio [HR] = 1.27, 95%
confidence interval [CI] = 0.89-1.81). There was also a trend toward
improved survival across all RPA Classes comparing the 55 rhIFN-beta treated
patients and 1,658 historical controls (HR = 1.24, 95% CI = 0.94-1.63). The
high rate of early failures (54/109) after radiation and before initiation
of rhIFN-beta was likely caused by stricter interpretation of early
radiographic changes in the current study. Matched-pair and intent-to-treat
analyses performed to try to address this bias showed no difference in
survival between study patients and controls. CONCLUSION: RhIFN-beta given
after conventional radiation therapy was well tolerated, with a trend toward
survival benefit in patients who remained stable after radiation therapy.
These data suggest that rhIFN-beta warrants further evaluation in additional
studies, possibly in combination with current temozolomide-based regimens.
PMID: 16887285 [PubMed - as supplied by publisher]3
-
| 20: Int
J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1274; author
reply 1274-5. |
|
-
Comment on:
- Int
J Radiat Oncol Biol Phys. 2006 Mar 1;64(3):962-7.
Integral radiation dose to normal structures with
conformal external beam radiation: in regards to Aoyama et al. (Int J Radiat
Oncol Biol Phys 2006;64:962-967).
Penagaricano
JA.
Publication Types:
PMID: 16798421 [PubMed - indexed for MEDLINE]
-
| 21: Int
J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1273; author
reply 1273-4. |
|
-
Comment on:
- Int
J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1038-43.
The importance of radiotherapy in AT/RT patients less
than 3 years of age: in regards to Chen et al. (Int J Radiat Oncol Biol Phys
2006;64:1038-1043).
Stadler
P, Peters
O.
Publication Types:
PMID: 16798419 [PubMed - indexed for MEDLINE]
-
| 22: J Neurochem. 2006 Aug 8; [Epub ahead of print] |
|
-
Acyl-based anandamide uptake inhibitors cause rapid
toxicity to C6 glioma cells at pharmacologically relevant concentrations.
De
Lago E, Gustafsson
SB, Fernandez-Ruiz
J, Nilsson
J, Jacobsson
SO, Fowler
CJ.
Department of Pharmacology and Clinical Neuroscience, Umea University, Umea,
Sweden.
Compounds blocking the uptake of the endogenous cannabinoid anandamide (AEA)
have been used to explore the functions of the endogenous cannabinoid system
in the CNS both in vivo and in vitro. In this study, the effects of four
commonly used acyl-based uptake inhibitors
[N-(4-hydroxyphenyl)arachidonylamide (AM404), N-(4-hydroxy-2-methylphenyl)
arachidonoyl amide (VDM11),
(5Z,8Z,11Z,14Z)-N-(3-furanylmethyl)-5,8,11,14-eicosatetraenamide (UCM707)
and (9Z)-N-[1-((R)-4-hydroxybenzyl)-2-hydroxyethyl]-9-octadecen-amide
(OMDM2)] and the related compound arvanil on C6 glioma cell viability were
investigated. All five compounds reduced the ability of the cells to
accumulate calcein, reduced the total nucleic acid content and increased the
activity of lactate dehydrogenase recovered in the cell medium. AM404 (10
microm) and VDM11 (10 microm) acted rapidly, reducing cell viability after 3
h of exposure when cell densities of 5000 per well were used. In contrast,
UCM707 (30 microm), OMDM2 (10 microm) and the related compound arvanil (10
microm) produced a more slowly developing effect on cell viability, although
robust effects were seen after 6-9 h of exposure. At higher cell densities,
the toxicities of AM404 and UCM707 were reduced. Comparison of the compounds
with arachidonic acid, arachidonic acid methyl ester, AEA, arachidonoyl
glycine and oleic acid suggested that the toxicity of the arachidonoyl-based
compounds was related primarily to the acyl side-chain rather than the head
group. A variety of pre-treatments blocking possible metabolic pathways and
receptor targets were tested, but the only consistent protective treatment
against the effects of these compounds was the antioxidant N-acetyl-l-cysteine.
It is concluded that AM404, VDM11, UCM707 and OMDM2 produce a rapid loss of
C6 glioma cell viability over the same concentration range as is required
for the inhibition of AEA uptake in vitro, albeit with a longer latency.
Such effects should be kept in mind when acyl-derived compounds are used to
probe the function of the endocannabinoid system in the CNS, particularly in
chronic administration protocols.
PMID: 16899063 [PubMed - as supplied by publisher]
-
| 23: Neurology.
2006 Aug 8;67(3):543-4; author reply 543-4. |
|
-
Is protracted low-dose temozolomide feasible in glioma
patients?
Wong
ET.
Publication Types:
PMID: 16894133 [PubMed - in process]
-
| 24: Neurology.
2006 Jul 11;67(1):178-9. |
|
-
Hemangioblastoma of the obex mimicking anorexia nervosa.
Pavesi
G, Berlucchi
S, Feletti
A, Opocher
G, Scienza
R.
Department of Neurosurgery, Padua City Hospital, Italy. giacomo.pavesi@sanita.padova.it
Publication Types:
PMID: 16832109 [PubMed - indexed for MEDLINE]
-
| 25: Neurology.
2006 Jul 11;67(1):114-9. |
|
-
CSF levels of growth factors and plasminogen activators
in leptomeningeal metastases.
van
de Langerijt B, Gijtenbeek
JM, de
Reus HP, Sweep
FC, Geurts-Moespot
A, Hendriks
JC, Kappelle
AC, Verbeek
MM.
Department of Neurology, Laboratory of Pediatrics and Neurology, Radboud
University Nijmegen Medical Centre, 830 LKN, P.O. Box 9101, 6500 HB Nijmegen,
the Netherlands.
OBJECTIVE: To investigate the diagnostic value of transforming growth factor
beta(1) (TGFbeta(1)), vascular endothelial growth factor (VEGF), urokinase-type
plasminogen activator (uPA), and tissue-type plasminogen activator (tPA) in
CSF for leptomeningeal metastasis (LM). METHODS: The authors measured
concentrations of biomarkers by ELISA in matched samples of CSF and serum,
collected from 132 patients with a solid malignancy with LM (n = 19) and
without LM (n = 54) and patients with viral (n = 16) and bacterial (n = 16)
meningitis and a variety of nonmalignant, noninfectious neurologic disorders
(n = 27). Indexes of the biomarkers (CSF/serum value relative to CSF/serum
albumin ratios) were calculated to correct for the serum contribution to the
CSF marker concentration. RESULTS: CSF VEGF concentration was significantly
higher in LM than in all other groups. VEGF indexes were also higher,
although not significant. In contrast, the tPA index was significantly
decreased in LM compared with all other groups. The combination of the VEGF
and tPA indexes resulted in a sensitivity of 100% for LM and a specificity
of 73% for the patient group with a primary tumor but without LM.
CONCLUSION: Patients with leptomeningeal metastasis have high vascular
endothelial growth factor (VEGF) indexes and low tissue-type plasminogen
activator (tPA) indexes. As cytologic examination of CSF lacks 100%
sensitivity for the diagnosis of leptomeningeal metastasis (LM), the
combination VEGF and tPA index analysis may be of additional value in the
diagnostic workup of patients suspected of having LM.
PMID: 16832089 [PubMed - indexed for MEDLINE]
-
| 26: Neuroradiology.
2006 Aug 1; [Epub ahead of print] |
|
-
Meningiomas with conventional MRI findings resembling
intraaxial tumors: can perfusion-weighted MRI be helpful in differentiation?
Hakyemez
B, Yildirim
N, Erdoethan
C, Kocaeli
H, Korfali
E, Parlak
M.
Department of Radiology, Uludag University Medical School, Bursa, Turkey.
INTRODUCTION: To investigate the contribution of perfusion-weighted MRI to
the differentiation of meningiomas with atypical conventional MRI findings
from intraaxial tumors. METHODS: We retrospectively analyzed 54 meningiomas,
12 glioblastomas and 13 solitary metastases. We detected 6 meningiomas with
atypical features on conventional MRI resembling intraaxial tumors. The
regional cerebral blood flow (rCBV) ratios of all tumors were calculated via
perfusion-weighted MRI. The signal intensity-time curves were plotted and
three different curve patterns were observed. The type 1 curve resembled
normal brain parenchyma or the postenhancement part was minimally below the
baseline, the type 2 curve was similar to the type 1 curve but with the
postenhancement part above the baseline, and the type 3 curve had the
postenhancement part below the baseline accompanied by widening of the
curve. Student's t-test was used for statistical analysis. RESULTS: On CBV
images meningiomas were hypervascular and the mean rCBV ratio was
10.58+/-2.00. For glioblastomas and metastatic lesions, the rCBV ratios were
5.02+/-1.40 and 4.68+/-1.54, respectively. There was a statistically
significant difference in rCBV ratios between meningiomas and glioblastomas
and metastases (P<0.001). Only one of the meningiomas displayed a type 2
curve while five showed a type 3 curve. Glioblastomas and metastases
displayed either a type 1 or a type 2 curve. None of the meningiomas showed
a type 1 curve and none of the glioblastomas or metastases showed a type 3
curve. CONCLUSION: Differentiating meningiomas with atypical conventional
MRI findings from malignant intraaxial tumors can be difficult. Calculation
of rCBV ratios and construction of signal intensity-time curves may
contribute to the differentiation of meningiomas from intraaxial tumors.
PMID: 16896907 [PubMed - as supplied by publisher]
-
| 27: Neurosurgery.
2006 Jul;59(1 Suppl 1):ONS75-83; discussion ONS75-83. |
|
-
The endoscopic extended transsphenoidal approach for
craniopharyngiomas.
Frank
G, Pasquini
E, Doglietto
F, Mazzatenta
D, Sciarretta
V, Farneti
G, Calbucci
F.
Center of Surgery for Pituitary Tumours, Department of Neuroscience,
Bellaria Hospital, Bologna, Italy. Giorgio.Frank@ausl.bologna.it
OBJECTIVE: The endoscope has recently been applied to the supradiaphragmatic
transsphenoidal approach, but only case reports dealing with different
pathological features have been described. The authors present their
experience with this technique in 10 patients with craniopharyngiomas.
METHODS: A pure endoscopic endonasal technique was used. From November 1998
through May 2005, four males and six females with a craniopharyngioma,
either purely supradiaphragmatic (six patients) or with a significant
suprasellar component (four patients), were treated. The tumors had a mean
diameter of 2.9 cm (range, 1-4 cm); four patients had a major prechiasmatic
component and six had a retrochiasmatic one. RESULTS: Seven total, one
subtotal, and two partial resections were obtained. Vision symptoms improved
significantly in six out of eight patients. Endocrine function did not
improve after surgery, and diabetes insipidus was the most frequent deficit,
although it was transient in five out of eight patients. Cerebrospinal fluid
leak was the most frequent complication and required reoperation in two
patients. Postoperative obesity occurred in two patients. No recurrence has
yet been documented in the total resection group. The mean follow-up period
is 37 months (range, 3-75 mo). CONCLUSION: The endoscopic technique allows
results comparable with the best microscopic series. We think that this
technique increases the safety of the procedure because of improved vision.
Further studies are required to better define the exact location of the
tumor with respect to the arachnoidal plane, the extra-arachnoidal
craniopharyngioma being the most suitable for a radical removal using a
transsphenoidal supradiaphragmatic approach.
PMID: 16888556 [PubMed - in process]
-
| 28: Neurosurgery.
2006 Jul;59(1 Suppl 1):ONS68-74; discussion ONS68-74. |
|
-
The impact of petrosal vein preservation on postoperative
auditory function in surgery of petrous apex meningiomas.
Gharabaghi
A, Koerbel
A, Lowenheim
H, Kaminsky
J, Samii
M, Tatagiba
M.
Department of Neurosurgery, University Hospital Tuebingen, Tuebingen,
Germany. alireza.gharabaghi@uni-tuebingen.de
OBJECTIVE: The importance of preserving the superior petrosal vein has
received increasing attention in the surgical treatment of pathologies
involving the petrous apex. Recent reports have associated postoperative
auditory nerve dysfunction with petrosal vein sacrifice. However, there is
no systematic clinical study available thus far focusing on the
postoperative auditory function after petrosal vein obliteration. METHODS:
In 55 patients with meningiomas involving the petrous apex, pre- and
intraoperative findings including petrosal vein sectioning were analyzed
retrospectively concerning their impact on postoperative auditory function.
RESULTS: The petrosal vein was preserved in 26 (47%) cases. In 27 (49%)
cases, this vein was not preserved. Hearing loss occurred in 11% of all
cases. In the preserved-vein group, postoperative hearing loss occurred in 3
of 26 (11%) cases and in the sacrificed-vein group in 3 of 27 (11%) cases.
CONCLUSION: Sacrifice of the petrosal vein during surgery of petrous apex
meningiomas seems not to have an impact on postoperative auditory function.
PMID: 16888554 [PubMed - in process]
-
| 29: Neurosurgery.
2006 Jul;59(1 Suppl 1):ONS108-14; discussion ONS108-14. |
|
-
A surgical technique for the removal of clinoidal
meningiomas.
Lee
JH, Sade
B, Park
BJ.
Brain Tumor Institute and Department of Neurosurgery, Cleveland Clinic
Foundation, Cleveland, Ohio 44195, USA. leej@ccf.org
Clinoidal meningiomas, also referred to as medial or inner sphenoid wing
meningiomas, are often difficult and challenging to remove completely and
safely, especially when they become large enough to encircle, compress, or
displace the adjacent critical neurovascular structures such as the optic
nerve, the internal carotid artery and its branches, and the oculomotor
nerve. In this article, the authors describe the detailed surgical technique
used in their practice in addition to subtle nuances learned from their
experience of operating on more than 40 patients with clinoidal meningiomas
over the past several years. The primary goals of surgery are to achieve
aggressive tumor removal with avoidance of intraoperative morbidity and, in
addition, for those with preoperative compromised vision, to provide
improvement in their visual function after surgery.
PMID: 16888540 [PubMed - in process]
-
|
Volume 5, Number 33 - 14 August 2006