| 1: Cancer
Genet Cytogenet. 2006 Apr 1;166(1):74-81. |
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Methylation of RASSF1A and TRAIL pathway-related genes is
frequent in childhood intracranial ependymomas and benign choroid plexus
papilloma.
Michalowski MB, de Fraipont F, Michelland S, Entz-Werle
N, Grill J, Pasquier B, Favrot MC, Plantaz D.
Centre d'Innovation en Biologie, Departement de Biologie Integree-Pavillon
B, Centre Hospitalier Universitaire de la Tronche, Grenoble-38043, France.
Ependymomas (EP) represent the third most frequent type of central nervous
system (CNS) tumor of childhood, after astrocytomas and medulloblastomas. No
prognostic biological markers are available, and differentiation from
choroid plexus papilloma (CPP) is difficult. The present objective was, for
a sample of 27 children with intracranial EP and 7 with CPP, to describe and
compare the methylation status of 19 genes (with current HUGO symbol, if
any): p15INK4a (CDKN2B), p16INK4a and p14ARF (both CDKN2A), APC, RB1,
RASSF1A (RASSF1), BLU (ZMYND10) FHIT, RARB, MGMT, DAPK (DAPK1), ECAD (CDH1),
CASP8, TNFRSF10C, TNFRSF10D, FLIP (CFLAR), INI1 (SMARCB1), TIMP3, and NF2.
Three adult corteses were used as a control. We detected a similar
percentage of methylated tumors in both groups (71% in CPP and 77% in EP).
No gene was methylated in that control group. RASSF1A was the most
frequently methylated gene in both benign tumors (66%) and EP (56%). The
genes associated with apoptosis were methylated in both groups of tumors.
The percentages of TRAIL pathway genes (CASP8, TFRSF10C, and TFRSF10D)
methylated were 30, 9.5, and 36.4%, respectively, in ependymomas and 50, 50,
and 16.7%, respectively, in choroid plexus papillomas. No other gene was
methylated in the benign tumors, whereas FHIT was methylated in 22%, RARB in
14.8%, BLU in 13.6%, p16INK4a in 11.1%, TNFRSF10C in 9.5%, and DAPK in 7.4%
of ependymomas. Although we did not observe a statistical relationship
between methylation and clinical outcome, the methylation pattern does not
appear to be randomly distributed in ependymoma and may represent a
mechanism of tumor development and evolution.
PMID: 16616114 [PubMed - indexed for MEDLINE]
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| 2: Cancer Res. 2006 May
15;66(10):5295-303. |
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Protein 4.1B/Differentially Expressed in Adenocarcinoma
of the Lung-1 Functions as a Growth Suppressor in Meningioma Cells by
Activating Rac1-Dependent c-Jun-NH2-kinase Signaling.
Gerber MA, Bahr SM, Gutmann DH.
Department of Neurology, Washington University School of Medicine, St.
Louis, Missouri.
Meningiomas are the second most common brain tumor in adults, yet
comparatively little is presently known about the dysregulated growth
control pathways involved in their formation and progression. One of the
most frequently observed genetic changes in benign meningioma involves loss
of protein 4.1B expression. Previous studies from our laboratory have shown
that protein 4.1B growth suppression in meningioma is associated with the
activation of the c-Jun-NH(2)-kinase (JNK) pathway and requires localization
of a small unique region (U2 domain) of protein 4.1B to the plasma membrane.
To define the relationship between protein 4.1B expression and JNK
activation, as well as to determine the mechanism of JNK activation by
protein 4.1B, we used a combination of genetic and pharmacologic approaches.
In this report, we show that protein 4.1B/differentially expressed in
adenocarcinoma of the lung-1 (DAL-1) expression in meningioma cells in vitro
results in JNK activation, which requires the sequential activation of Src,
Rac1, and JNK. In addition, inhibition of Rac1 or JNK activation abrogates
protein 4.1B/DAL-1 growth suppression and cyclin A regulation. Last, protein
4.1B/DAL-1 regulation of this critical growth control pathway in meningioma
cells requires the presence of the U2 domain. Collectively, these
observations provide the first mechanistic insights into the function of
protein 4.1B as a growth regulator in meningioma cells. (Cancer Res 2006;
66(10): 5295-303).
PMID: 16707455 [PubMed - in process]
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| 3: Cancer Res. 2006 May
15;66(10):5190-200. |
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Lack of Rb and p53 Delays Cerebellar Development and
Predisposes to Large Cell Anaplastic Medulloblastoma through Amplification
of N-Myc and Ptch2.
Shakhova O, Leung C, van Montfort E, Berns A, Marino
S.
Institute of Clinical Pathology, University Hospital, Zurich, Switzerland
and Division of Molecular Genetics and Centre of Biomedical Genetics,
Netherlands Cancer Institute, Amsterdam, the Netherlands.
Medulloblastomas are among the most common malignant brain tumors in
childhood. They typically arise from neoplastic transformation of granule
cell precursors in the cerebellum via deregulation of molecular pathways
involved in normal cerebellar development. In a mouse model, we show here
that impairment of the balance between proliferation and differentiation of
granule cell precursors in the external granular layer of the developing
cerebellum predisposes but is not sufficient to induce neoplastic
transformation of these progenitor cells. Using array-based chromosomal
comparative genomic hybridization, we show that genetic instability
resulting from inactivation of the p53 pathway together with deregulation of
proliferation induced by Rb loss eventually leads to neoplastic
transformation of these cells by acquiring additional genetic mutations,
mainly affecting N-Myc and Ptch2 genes. Moreover, we show that p53 loss
influences molecular mechanisms that cannot be mimicked by the loss of
either p19(ARF), p21, or ATM. (Cancer Res 2006; 66(10): 5190-200).
PMID: 16707443 [PubMed - in process]
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| 4: Clin
Cancer Res. 2006 May 15;12(10):3019-27. |
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Phosphatidylinositol 3'-Kinase/AKT Signaling Is Activated
in Medulloblastoma Cell Proliferation and Is Associated with Reduced
Expression of PTEN.
Hartmann W, Digon-Sontgerath B, Koch A, Waha A, Endl
E, Dani I, Denkhaus D, Goodyer CG, Sorensen N,
Wiestler OD, Pietsch T.
Authors' Affiliations: Department of Neuropathology and Institute of
Molecular Medicine and Experimental Immunology, University of Bonn Medical
Center, Bonn, Germany.
PURPOSE: Medulloblastomas represent the most frequent malignant brain tumors
of childhood. They are supposed to originate from cerebellar neural
precursor cells. Recently, it has been shown that Sonic Hedgehog-induced
formation of medulloblastoma in an animal model is significantly enhanced by
activation of the phosphatidylinositol 3'-kinase (PI3K) signaling pathway.
EXPERIMENTAL DESIGN: To examine a role for PI3K/AKT signaling in the
molecular pathogenesis of human medulloblastoma, we did an
immunohistochemical study of the expression of Ser(473)-phosphorylated (p)-AKT
protein in 22 medulloblastoma samples: All samples displayed p-AKT
expression. To investigate if an activated PI3K/AKT pathway is required for
medulloblastoma cell growth, we treated five human medulloblastoma cell
lines with increasing concentrations of the PI3K inhibitor LY294002 and
analyzed cellular proliferation and apoptosis. The antiproliferative effect
could be antagonized by overexpressing constitutively active AKT. As the
activation of PI3K/AKT signaling may be associated with alterations of the
PTEN gene located at 10q23.3, a chromosomal region subject to frequent
allelic losses in medulloblastoma, we screened PTEN for mutations and mRNA
expression. RESULTS: Proliferation of all of the medulloblastoma cell lines
was dependent on PI3K/AKT signaling, whereas apoptosis was not prominently
affected. Allelic loss was detected in 16% of the cases. One medulloblastoma
cell line was found to carry a truncating mutation in the PTEN coding
sequence. Even more important, PTEN mRNA and protein levels were found to be
significantly lower in medulloblastomas compared with normal cerebellar
tissue of different developmental stages. Reduction of PTEN expression was
found to be associated with PTEN promoter hypermethylation in 50% of the
tumor samples. CONCLUSIONS: We conclude that activation of the PI3K/AKT
pathway constitutes an important step in the molecular pathogenesis of
medulloblastoma and that dysregulation of PTEN may play a significant role
in this context.
PMID: 16707597 [PubMed - in process]
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| 5: J
Clin Oncol. 2006 May 10;24(14):e23-5. |
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Comment on:
- J Clin Oncol. 2003 Aug 15;21(16):3060-5.
Long-term follow-up after reduced-intensity conditioning
allogeneic transplantation for acute myeloid leukemia/myelodysplastic
syndrome: late CNS relapses despite graft-versus-host disease.
Davies JK, Taussig DC, Oakervee H, Davies AJ, Agrawal
SG, Gribben JG, Lister TA, Cavenagh JD.
Publication Types:
PMID: 16682729 [PubMed - indexed for MEDLINE]
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| 6: J
Neurol Neurosurg Psychiatry. 2006 Apr;77(4):562-3. |
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Comment in:
- J Neurol Neurosurg Psychiatry. 2006 Apr;77(4):427.
Unusual magnetic resonance imaging and cerebrospinal
fluid findings in paraneoplastic cerebellar degeneration: a sequential
study.
de Andres C, Esquivel A, de Villoria JG, Graus F,
Sanchez-Ramon S.
Publication Types:
PMID: 16543544 [PubMed - indexed for MEDLINE]
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| 7: J
Neurol Neurosurg Psychiatry. 2006 Apr;77(4):529-30. |
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Comment in:
- J Neurol Neurosurg Psychiatry. 2006 Apr;77(4):427.
Clinical insights into paraneoplastic cerebellar
degeneration.
Scheid R, Voltz R, Briest S, Kluge R, von
Cramon DY.
Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig,
Germany. scheid@cbs.mpg.de
Neuroimaging is usually unremarkable in paraneoplastic cerebellar
degeneration (PCD), at least in the early stages of the disease. A patient
with proven PCD is reported in whom it could be shown that cerebellar
atrophy evolved very rapidly and was present in early imaging studies. Even
with the use of the whole spectrum of modern diagnostic tools, the
underlying malignancy can be difficult to diagnose. In addition to
mammography, MRI is recommended in these cases and repeat FDG-PET may be
necessary.
Publication Types:
PMID: 16543537 [PubMed - indexed for MEDLINE]
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| 8: J
Neurol Neurosurg Psychiatry. 2006 Apr;77(4):525-8. |
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Comment in:
- J Neurol Neurosurg Psychiatry. 2006 Apr;77(4):427.
Cerebellar hypermetabolism in paraneoplastic cerebellar
degeneration.
Choi KD, Kim JS, Park SH, Kim YK, Kim SE,
Smitt PS.
Department of Neurology, College of Medicine, Seoul National University,
Republic of Korea.
A 51 year old man with paraneoplastic cerebellar degeneration from gastric
adenocarcinoma showed cerebellar hypermetabolism and increased perfusion on
brain FDG-PET scan and SPECT during the acute stage of his illness. The
patient underwent subtotal gastrectomy. The intensity of the hypermetabolism
had decreased markedly on follow-up FDG-PET 3 months later following two
cycles of chemotherapy. We suggest that the cerebellar hypermetabolism may
have been due to an acute inflammatory process associated with an
immunological reaction.
Publication Types:
PMID: 16543536 [PubMed - indexed for MEDLINE]
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| 9: J Neurooncol.
2006 May 19; [Epub ahead of print] |
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A phase II study of carboplatin and chronic high-dose
tamoxifen in patients with recurrent malignant glioma.
Tang P, Roldan G, Brasher PM, Fulton D, Roa W,
Murtha A, Cairncross JG, Forsyth PA.
Department of Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
PURPOSE: To determine the response rate, time to disease progression,
survival, and toxicity of intravenous carboplatin and chronic oral high-dose
tamoxifen in patients with recurrent malignant gliomas. PATIENTS AND
METHODS: Patients with histological confirmation of recurrent malignant
gliomas were eligible for this multicenter phase II trial. Treatment
consisted of 400 mg/m(2) carboplatin intravenously every 4 weeks and oral
high dose chronic tamoxifen (80 mg bid in women and 100 mg bid in men).
RESULTS: Twenty seven patients met the eligibility criteria and were
evaluable for response. The histological subtypes were: 16 (59%)
glioblastoma multiforme (GBM), malignant astrocytoma (5 patients), malignant
mixed glioma (5 patients), and glioblastoma/gliosarcoma (1 patient).
Twenty-two patients (82%) had an ECOG performance status of 0 or 1. No
complete responses were observed, 4 patients (15%) achieved a partial
response, and 14 patients (52%) had stable disease. Median time to
progression was 3.65 months (95%CI 2.56, 4.83). Median overall survival was
14.09 months (95%CI 7.06, 19.91). One patient with a recurrent GBM had a
sustained partial response and is progression free 81 months since starting
treatment. Another patient with mixed malignant oligoastrocytoma also had a
prolonged partial response (lasting 63 months) and is alive 84 months after
treatment for recurrence. The most frequently reported grade 3 or 4
toxicities were fatigue (19%), nausea (11%) and anorexia (11%). CONCLUSIONS:
Carboplatin and high dose tamoxifen has similar response rates to other
regimens for recurrent malignant gliomas and are probably equivalent to
those found using tamoxifen as monotherapy. Long-lasting periods of disease
free survival in some patients (particularly those with malignant mixed
oligo astrocytomas) were found.
PMID: 16710748 [PubMed - as supplied by publisher]
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| 10: J Neurooncol.
2006 May 19; [Epub ahead of print] |
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Radiation induced adult medulloblastoma: a case report.
Howes TL, Buatti JM, Kirby PA, Carlisle TL, Ryken
TC.
Department of Radiation Oncology, University of Iowa Health Care, W189Z
General Hospital, 200 Hawkins Drive, Iowa City, IA, 52242, USA, john-buatti@uiowa.edu.
Adult medulloblastoma is a rare intracranial tumor. Our patient is a 61 year
old woman treated with cranial irradiation 15 years previously for a low
grade astrocytoma in the left posterior temporal lobe that was recently
diagnosed with medulloblastoma in the right cerebellum. This is the first
reported case of radiation induced adult medulloblastoma.
PMID: 16710747 [PubMed - as supplied by publisher]
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| 11: J Neurooncol.
2006 May 19; [Epub ahead of print] |
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Activity of lysosomal exoglycosidases in human gliomas.
Wielgat P, Walczuk U, Szajda S, Bien M, Zimnoch
L, Mariak Z, Zwierz K.
Department of Pharmaceutical Biochemistry, Medical University of Bialystok,
ul. Mickiewicza 2A , 15-089, Bialystok, Poland, pwielg@amb.edu.pl.
There is a lot of data suggesting that modifications of cell glycoconjugates
may be important in progression of cancer. In the present work we studied
activities of lysosomal exoglycosidases: beta-hexosaminidase and its
isoenzymes A and B, beta-galactosidase and alpha-mannosidase, in human
gliomas. Enzyme activity was determined spectrophotometrically based on the
release of p-nitrophenol from p-nitrophenyl-derivative of appropriate
sugars. The activities of the exoglycosidases tested were significantly
higher in malignant glial tumors than in control tissue (normal brain
tissue) and non-glial tumors. The highest activities of exoglycosidases were
observed in high-grade gliomas, and a positive correlation of enzyme
activities and degree of malignancy was noted. Our results suggest that
lysosomal exoglycosidases may participate in the progression and dynamical
development of glial tumors.
PMID: 16710745 [PubMed - as supplied by publisher]
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| 12: J Neurooncol.
2006 May 13; [Epub ahead of print] |
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Female predominance in meningiomas can not be explained
by differences in progesterone, estrogen, or androgen receptor expression.
Korhonen K, Salminen T, Raitanen J, Auvinen A, Isola
J, Haapasalo H.
Department of Neurosurgery, University Hospital of Turku, PO Box 52, 20520 ,
Turku, Finland, katariina.korhonen@tyks.fi.
The female predominance in meningioma incidence and association between
meningioma and breast cancer suggest that growth of meningiomas is
hormone-dependent. There are several discrepancies in literature about the
proliferative effect of sex hormones on meningiomas. This study aims to
evaluate the hormone receptor status of meningiomas and assess its relation
to age, sex, histological grade, recurrence, and proliferation activity. The
material was based on consecutive patients operated for meningioma at
Tampere University Hospital in 1989-1999. The occurrence of progesterone,
estrogen and androgen receptor in patients with primary and recurrent
meningiomas was studied immunohistochemically by using specific monoclonal
antibodies. Hormonal status was determined in 510 tumor samples. 443 samples
were from primary meningiomas and 67 from recurrent tumors. Of the samples,
455 were benign (WHO grade I), 49 atypical (grade II), and 6 malignant
(grade III). Of the primary tumor samples, 88% were progesterone receptor
positive, 40% were positive for estrogen and 39% for androgen receptors.
Grade I meningiomas had significantly higher incidence for estrogen and
androgen receptors than higher grade meningiomas. Estrogen positive tumor
samples had significantly higher proliferation index than estrogen negative
samples. No difference in expression of sex hormone receptors was observed
by sexes or age group. Estrogen and androgen receptors may have more
influence on the pathogenesis of meningiomas than earlier thought. The
higher incidence of meningiomas in women can not be explained by differences
of sex hormone receptor expression.
PMID: 16703453 [PubMed - as supplied by publisher]
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| 13: Neuroradiology. 2006
Apr;48 Suppl 1:34-40. |
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Diffusion-perfusion in intra-axial brain tumors with high
relaxivity contrast agents.
Cotton F.
MRI Center, Centre Hospitalier Lyon Sud, 69495, Pierre Benite, France.
A high relaxivity contrast agent is indicated for use in MRI of the central
nervous system to visualize lesions with an abnormal blood-brain barrier
(BBB) or abnormal vascularity of the brain. We evaluated MultiHance (gadobenate
dimeglumine, Gd-BOPTA) on T2*-weighted perfusion imaging in 33
histologically proven intra-axial brain tumors. The higher T1 relaxivity,
and therefore better contrast-enhanced T1 imaging led to significantly
better tumor delineation. The higher T2 relaxivity allowed high quality T2*
perfusion MRI and post processed rCBV maps, with a dose of 0.1 mmol/kg
MultiHance.
PMID: 16699850 [PubMed - in process]
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| 14: Neurosurgery. 2006
Apr;58(4 Suppl 2):ONS-E373; discussion ONS-E373. |
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two-stage operation for resection of spinal cord
astrocytomas: technical case report of three cases.
Hida K, Iwasaki Y, Seki T, Yano S.
Department of Neurosurgery, Hokkaido University Graduate School of Medicine,
Sapporo, Japan. kazuhida@med.hokudai.ac.jp
OBJECTIVE AND IMPORTANCE: Surgery for excision of intramedullary spinal cord
tumors without increasing neurological deficit is one of the more difficult
operations in spinal surgery. In particular, infiltrating astrocytomas
without a clear cleavage between the tumor and normal spinal cord parenchyma
are difficult to remove totally without producing additional neurological
impairment. In this study, we describe a two-stage resection facilitating
total resection of intramedullary tumors. CLINICAL PRESENTATION: Three cases
of spinal cord astrocytomas were treated using a two-staged method.
TECHNIQUE: The first surgery included myelotomy, biopsy and duroplasty. A
thin expanded polytetrafluoroethylene sheet was placed between the dorsal
surface of the spinal cord and dura mater to prevent adhesions. Two or 3
weeks after surgery, a second surgery was performed to remove the now
exophytic tumor. RESULTS: Magnetic resonance imaging scans showed exophytic
extrusion of the tumor in all three cases before the second operation. In
each patient, we were able to carry out gross total removal of the tumors
without additional neurological deficit except for transient joint position
sense loss in one case. All three patients remain neurologically stable
without evidence of tumor recurrence more than 3 years after surgery.
CONCLUSION: A two-stage operation may enhance the surgeon's ability to
completely resect extensive low-grade spinal cord astrocytomas and, at the
same time preserve neurological function.
Publication Types:
PMID: 16575295 [PubMed - indexed for MEDLINE]
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| 15: BMC
Cancer. 2006 May 18;6(1):133 [Epub ahead of print] |
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Treatment of Primary Glioblastoma Multiforme with
Cetuximab, Radiotherapy and Temozolomide (GERT) - Phase I/II Trial: Study
Protocol.
Combs SE, Heeger S, Haselmann R, Edler L, Debus
J, Schulz-Ertner D.
ABSTRACT: BACKGROUND: The implementation of combined radiochemotherapy (RCHT)
with temozolomide (TMZ) has lead to a significant increase in overall
survival times in patients with Glioblastoma multiforme (GBM), however,
outcome still remains unsatisfactory. The majority of GBMs show an
overexpression and/or amplification of the epidermal growth factor receptor
(EGFR). Therefore, addition of EGFR-inhibition with cetuximab to the current
standard treatment approach with radiotherapy and TMZ seems promising.
Methods/design: GERT is a one-armed single-center phase I/II trial. In a
first step, dose-escalation of TMZ from 50 mg/m2 to 75mg/m2 together with
radiotherapy and cetuximab will be performed. Should safety be proven, the
phase II trial will be initiated with the standard dose of 75mg/m2 of TMZ.
Cetuximab will be applied in the standard application dose of 400mg/m2 in
week 1, thereafter at a dose of 250mg/m2 weekly. A total of 46 patients will
be included into this phase I/II trial. Primary endpoints are feasibility
and toxicity, secondary endpoints are overall and progression-free survival.
An interim analysis will be performed after inclusion of 15 patients into
the main study. Patients' enrolment will be performed over a period of 2
years. The observation time will end 2 years after inclusion of the last
patient. DISCUSSION: The goal of this study is to evaluate the safety and
efficacy of combined RCHT-immunotherapy with TMZ and cetuximab as first-line
treatment for patients with primary GBM.
PMID: 16709245 [PubMed - as supplied by publisher]
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Volume 5, Number 21 - 22 May 2006