| 1: Clin Cancer Res. 2004 Dec 1;10(23):7875-83. |
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Apurinic endonuclease activity in adult gliomas and time
to tumor progression after alkylating agent-based chemotherapy and after
radiotherapy.
Bobola MS, Emond MJ, Blank A, Meade EH, Kolstoe DD, Berger MS, Rostomily
RC, Silbergeld DL, Spence AM, Silber JR.
Department of Neurological Surgery, University of Washington, 1959 N.E
Pacific Street, Seattle, WA 98195-6470, USA.
PURPOSE: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair
enzyme that cleaves DNA at cytotoxic abasic sites caused by alkylating
agents and radiation. We have observed that human glioma cells deficient in
Ap endo activity are hypersensitive to clinically used alkylators (Silber et
al., Clin Cancer Res 2002;8:3008.). Here we examine the association of
glioma Ap endo activity with clinical response after alkylating agent-based
chemotherapy or after radiotherapy. EXPERIMENTAL DESIGN: Cox proportional
hazards regression models were used to analyze the relationship of Ap endo
activity with time to tumor progression (TTP). RESULTS: In a univariate
model with Ap endo activity entered as a continuous variable, the hazard
ratio (HR) for progression after alkylator therapy in 30 grade III gliomas
increased by a factor of 1.061 for every 0.01 increase in activity (P =
0.013). Adjusting for age, gender, extent of resection, and prior treatment
strengthened slightly the association (HR = 1.094; P = 0.003). Similarly,
the HR for progression after radiotherapy in 44 grade II and III tumors
increased by a factor of 1.069 (P = 0.008). Adjusting for the aforementioned
variables had little effect on the association. In contrast, we observed no
association between activity and TTP in grade IV gliomas after either
alkylator therapy in 34 tumors or radiotherapy in 26 tumors. CONCLUSIONS:
Our data suggest that Ap endo activity mediates resistance to alkylating
agents and radiation and may be a useful predictor of progression after
adjuvant therapy in a subset of gliomas.
PMID: 15585620 [PubMed - in process]
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| 2: Clin Cancer Res. 2004 Dec 1;10(23):7820-6. |
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Molecular stratification of diagnostically challenging
high-grade gliomas composed of small cells: the utility of fluorescence in
situ hybridization.
Korshunov A, Sycheva R, Golanov A.
Department of Neuropathology, NN Burdenko Neurosurgical Institute, Fadeeva
str. 5, Moscow, 125047, Russia. akorshunov@nsi.ru
PURPOSE: There is considerable morphologic overlap between various entities
of high-grade gliomas, and, therefore, a further planning of their optimal
treatment is a controversial issue. The aim of this study was molecular
stratification of morphologically ambiguous high-grade gliomas composed from
small cells. Fluorescence in situ hybridization (FISH) with commercially
available probes was used for this purpose. EXPERIMENTAL DESIGN: We analyzed
a set of 114 high-grade small-cell gliomas that were difficult to interpret
diagnostically because of their distinct cytological origin. FISH assay with
locus probes for EGFR, p16, PTEN, and 1p and 19q was done. RESULTS:
Morphologically uniform high-grade gliomas composed of small cells varied
greatly in terms of molecular features and clinical outcome. Four clinically
relevant subsets of patients whose tumors showed distinctly different
molecular profiles were identified as follows: (a) 13 patients whose tumors
exhibited no discernable molecular alterations (5-year survival rate, 83%);
(b) 20 patients whose tumors harbored either 1p/19q codeletion or isolated
deletion of 19q unaccompanied by other molecular abnormalities (5-year
survival rate, 59%); (c) 35 patients whose tumors showed p16 and/or PTEN
deletions unaccompanied by EGFR amplification (5-year survival rate, 8%);
and (d) 46 patients whose tumors harbored EGFR amplification (5-year
survival rate, 0). CONCLUSIONS: The FISH method provides clinically useful
information in the molecular analysis of morphologically ambiguous malignant
small-cell gliomas that could potentially enhance the quality of patient
care.
PMID: 15585613 [PubMed - in process]
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| 3: Clin Neuropathol. 2004 Nov-Dec;23(6):292-7. |
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Meningioma with eosinophilic granular inclusions.
Alexander RT, McLendon RE, Cummings TJ.
Duke University Medical Center, Durham, NC, USA. rusty4i@yahoo.com
Rare meningiomas have been described that contain eosinophilic inclusions
that have a granular or granulofilamentous ultrastructure. We describe a
66-year-old woman who developed a planum sphenoidale meningioma.
Histologically, the tumor was composed of meningothelial cells arranged in
fascicles and whorls, typical of a well-differentiated meningioma. Many
tumor cells contained round intracytoplasmic eosinophilic inclusions that
were periodic acid Schiff-negative and red on Masson trichrome. The
inclusions were immunopositive for vimentin, and were immunonegative for
epithelial membrane antigen, smooth muscle actin, desmin and type IV
collagen. Ultrastructural examination showed the inclusions were composed of
round to oval, well-demarcated, non-membrane-bound, osmiophilic granular
material. The inclusions within this tumor had histochemical,
immunohistochemical and ultrastructural properties not described in other
reported meningiomas with eosinophilic granular or granulofilamentous
inclusions.
PMID: 15584214 [PubMed - in process]
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| 4: Clin Neuropathol. 2004 Nov-Dec;23(6):286-91. |
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Heavily lipidized, calcified giant cell glioblastoma in
an 8-year-old patient, associated with neurofibromatosis type 1 (NF1):
report of a case with long-term survival.
Kroh H, Matyja E, Marchel A, Bojarski P.
Department of Neurosurgery, Medical Academy, Polish Academy of Sciences,
Warsaw, Poland.
Giant cell glioblastoma (GCG-BM) with predominance of bizarre,
multinucleated giant cells is a rare subtype of glioblastoma, however, its
clinical behavior and histological features are still not fully understood.
We report an unusual case of a heavily lipidized form of giant cell glioma
corresponding mostly to GCGBM in a young patient with neurofibromatosis 1
(NF1). Histologically, the tumor revealed numerous characteristic
histopathological features of giant cell glioblastoma including cellular
pleomorphism with numerous giant tumor cells, pseudopalisades around
necrotic foci and mitotic activity, accompanied by additional unique
morphological elements such as massive lipidization of the neoplastic cells,
abundant microcalcifications and angiomatous pattern of vascularization.
Such aberrant morphology might be associated with the unusually long
survival period of 12 years without clinical evidence of tumor recurrence.
The coexistence of intracerebral heavily lipidized, calcified giant cell
glioblastoma with NF1 has not been previously reported in literature.
PMID: 15584213 [PubMed - in process]
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| 5: Clin Neuropathol. 2004 Nov-Dec;23(6):257-61. |
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Argon plasma coagulation (APC) in brain tumor surgery:
experimental study and clinical experiences.
Tirakotai W, Mennel HD, Celik I, Kolodziej M, Bertalanffy H, Riegel T.
Department of Neurosurgery, Philipps University, Marburg, Germany.
riegel@med.uni-marburg.de
OBJECTIVE: The present study aims to provide preliminary results of the
thermal effects on rat brain tissue after argon plasma coagulation (APC). It
also presents and discusses the clinical experiences in the treatment of
brain tumor using APC. MATERIALS AND METHODS: A controlled study of APC in
the rat brain was conducted. Twelve rats were randomly divided into 2
experimental groups. In the first group (n = 6), histopathological
evaluation was performed 2 days following the coagulation. In the second
group (n = 6), the evaluation was performed 12 days post operation. In a
prospective study of APC-treated tumor tissue in 3 patients, the depth of
plasma penetration and histological alteration were evaluated. RESULTS: In
the animal experiment, extent of tissue defect became significantly smaller
after 12 days (p = 0.010). The maximum depth of tissue alteration after APC
application was limited to 2.15 mm (range: 1.5-2.15 mm) at day 2. The
histological alteration of tissue after the thermal injury can be divided
into 3 zones. In addition, the depth of tissue alteration in the APC-treated
human brain tumor was measured in vertical and horizontal planes under light
microscope. Similar to the animal experiment result, penetration of the
plasma energy in human brain tumors was limited to a maximum of 2.13 mm
(range: 1.6-2.13 mm). CONCLUSION: The limited depth of energy penetration
may confirm APC as a safe and beneficial tool for coagulation of human brain
tissue. However, further clinical studies are required to evaluate the
suitability and indications of this method in brain tumor treatment.
PMID: 15584209 [PubMed - in process]
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| 6: Clin Neuropathol. 2004 Sep-Oct;23(5):241-4. |
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Co-occurrence of Wilson's disease and glioblastoma
multiforme--is it a chance association?
Sinha S, Prashanth LK, Mahadevan A, Satish S, Ravishankar S, Arunodaya
GR, Taly AB, Shankar SK.
Department of Neurology, National Institute of Mental Health and
Neurosciences, Bangalore, India.
We report a patient with glioblastoma multiforme who was subsequently
diagnosed to have Wilson's disease. Immunohistochemical studies of the tumor
revealed high (> 60%) labeling index for p53 and Rb retinoblastoma
protein. Whether this association is like the co-occurrence of
retinoblastoma and Wilson's disease due to possible somatic mutation in
chromosome 13 needs to be explored.
PMID: 15581028 [PubMed - in process]
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| 7: Clin Neuropathol. 2004 Sep-Oct;23(5):238-40. |
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Algorithm for the standardized assessment of vascular
patterns in glioblastoma specimens.
Preusser M, Birner P, Hainfellner JA.
Institute of Neurology, AKH, Medical University of Vienna, Austria.
In a recent study, the existence of distinct vascular patterns with
prognostic impact has been described in glioblastomas. The bizarre
angiogenic subtype was associated with shorter postoperative survival times
whereas the classic angiogenic subtype ("microvascular sprouting";
evenly distributed branching capillaries in major tumor parts resembling
classic angiogenesis) was associated with a significantly more favorable
outcome. Evaluation of angiogenic subtypes of glioblastomas may be relevant
for anti-angiogenic therapy strategies. To this end, a method is needed for
standardized evaluation of vascular patterns in glioblastomas. Here, we
provide a simple algorithm for the standardized assessment of angiogenic
patterns in anti-CD34-immunostained glioblastoma specimens, which can be
used for research and in the routine diagnostic setting.
PMID: 15581027 [PubMed - in process]
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| 8: Clin Neuropathol. 2004 Sep-Oct;23(5):209-17. |
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Molecular abnormalities in pediatric embryonal brain
tumors--analysis of loss of heterozygosity on chromosomes 1, 5, 9, 10, 11,
16, 17 and 22.
Zakrzewska M, Rieske P, Debiec-Rychter M, Zakrzewski K, Polis L, Fiks T,
Liberski PP.
Department of Molecular Pathology and Neuropathology, Medical University of
Lodz, Poland. madziazakrzewska@wp.pl
Embryonal tumors, the most common group of malignant brain tumors in
childhood, are heterogeneous and have been associated with a large number of
genetic abnormalities. The aim of this study was to comprehensively analyze
loss of heterozygosity (LOH) on regions harboring suppressor genes (PTCH2,
PTCH1, APC, PTEN, DMBT1, SUFU, AXIN1, hSNF5/INI1) and to study chromosomal
regions in which deletions have been described most frequently (1p, 1q, 11p,
16p, 17p). Twenty-nine children (17 male and 12 female), aged from 1 year 13
years were included in this study. There were 24 medulloblastomas (MB) and 5
supratentorial primitive neuroectodermal tumors (sPNET). Tissue samples from
29 primary and 11 recurrent tumors were analyzed according to the LOH
standard procedures, which were extended to include fluorescence in situ
hybridization for detection of isochromosome 17q (i(17q)) and direct
sequencing ofTP53 exon 4. LOH on 17p was found in 15 out of 29 tumors. FISH
analysis identified the presence of i(17q) in 16 tumors. Comparison of LOH
analysis and the FISH data indicated that alterations of 17p were related to
be the introduction of an i(17q) formation. LOH on 10q and 9q was observed
in 4 and 2 cases, respectively, and was associated with alterations of
chromosome 17. These results indicated a connection between alterations of
PTCH/SHH genes and abnormalities of chromosome 17. A deleted region on 22q,
covering the hSNF5/INI1 locus, was observed in 3 tumors. Progression of the
molecular changes occurred in 1 case of recurrent medulloblastoma. LOH on
10q and 17p was found in both primary and recurrent tumor, while losses on
11p, 16p, and 16q occurred only in the recurrent tumor. No evidence of
alteration in TP53 exon 4 was identified.
PMID: 15581023 [PubMed - in process]
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| 9: Clin Neuropathol. 2004 Sep-Oct;23(5):204-8. |
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Isolated intracranial Rosai-Dorfman disease mimicking
meningioma.
Kayali H, Onguru O, Erdogan E, Sirin S, Timurkaynak E.
Department of Neurosurgery, Gulhane Military Medical Academy, Ankara,
Turkey. hkayali@gata.edu.tr
Sinus histiocytosis with massive lymphadenopathy (SHML), also known as
Rosai-Dorfman disease (RDD), is an idiopathic histiocytic proliferation
affecting lymph nodes. It is typically characterized by painless cervical
lymphadenopathy, fever and weight loss. Although extranodal involvement has
been reported in diverse sites, intracranial presentation, particularly in
the absence of nodal disease is uncommon. To the best of our knowledge, 48
patients with intracranial masses have been reported previously. A
31-year-old man was admitted to our clinic with a 4-month history of
progressive headache. His medical history was unremarkable except for
occasional fever. There were not any neurological deficit and weight loss.
No lymphadenopathy (particularly bilateral cervical) and extranodal
involvement in diverse sites were revealed by physical and radiological
examinations. Routine hematological and biochemical studies were normal
except for mild leukocytosis and elevated erythrocyte sedimentation rate.
The patient underwent magnetic resonance imaging (MRI) testing that revealed
an enhancing mass in the left temporal lobe. Preoperative diagnosis was
meningioma. The patient underwent a left frontotemporal craniotomy with
complete resection of the mass. Histopathology was compatible with RDD.
Extranodal RDD is rarely found intracranially. Prognosis is benign
especially in the absence of nodal disease. It is clinically and
radiologically difficult to distinguish from meningioma, and histological
examination is essential for a definitive diagnosis.
PMID: 15581022 [PubMed - in process]
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| 10: J Neurochem. 2004 Dec;91(6):1275-83. |
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BCL-2-induced glioma cell invasiveness depends on
furin-like proteases.
Wick W, Wild-Bode C, Frank B, Weller M.
Laboratory of Molecular Neuro-Oncology, Department of General Neurology and
Hertie Institute for Clinical Brain Research, University of Tubingen,
Medical School, Tubingen, Germany.
Abstract Migration and invasion are prerequisites for the neoplastic
phenotype of malignant glioma. Ectopic expression of BCL-2 enhances
migration and invasion of glioma cells and promotes their synthesis of
transforming growth factor-beta(2) (TGF-beta(2)). We here report that
BCL-2-expressing cells show enhanced expression and activity of the
proprotein convertase, furin, which processes metalloproteinases (MMP) and
TGF-beta. Consistent with a biological role for a BCL-2-dependent increase
in furin-like protease (FLP) activity, BCL-2-expressing cells exhibit
enhanced MMP activity. Both a pseudosubstrate furin inhibitor,
decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk), or alpha
1-anti-trypsin Portland (PDX), a recombinant furin-inhibitory protein,
suppress constitutive and BCL-2-mediated MMP activity and invasion. This
inhibition is not overcome by TGF-beta or hepatocyte growth factor (HGF). A
neutralizing TGF-beta antibody attenuates, but not abrogates, the invasive
properties conferred by exogenous expression of BCL-2, whereas the MMP
inhibitor o-phenantroline (o-PA) abolishes the pro-invasive action of BCL-2.
Exogenous HGF results in enhanced, and expression of dominant-negative ezrin
in reduced, FLP activity, and dec-RVKR-cmk blunts the HGF-induced expression
of mature TGF-beta(2). Consequently, HGF and BCL-2 family proteins use a
furin-dependent pathway to promote invasion via TGF-beta and MMP in human
malignant glioma cells and the pro-invasive properties of TGF-beta require
furin- dependent MMP activity.
PMID: 15584904 [PubMed - in process]
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| 11: Neuroradiology. 2004 Dec 4; [Epub ahead of print] |
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Value of petrosal sinus sampling: coexisting acromegaly,
empty sella and meningioma.
Yarman S, Minareci O.
Division of Endocrinology, Metabolism and Nutrition, Department of Internal
Medicine, Medical Faculty of Istanbul University, 34390, Istanbul, Turkey.
Simultaneous occurrence of an intracranial meningioma and a growth hormone
(GH)-producing pituitary adenoma is exceedingly rare, as is coexistence of
an empty sella and acromegaly. We report all these rare entities in the same
patient. We evaluated the role of inferior petrosal sinus sampling for
lateralisation of an adenoma in this patient.
PMID: 15580492 [PubMed - as supplied by publisher]
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| 12: Oncogene. 2004 Dec 06; [Epub ahead of print] |
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RNA interference against a glioma-derived allele of EGFR
induces blockade at G(2)M.
Fan QW, Weiss WA.
[1] 1Department of Neurology, University of California, San Francisco, CA,
USA [2] 2Department of Pediatrics, University of California, San Francisco,
CA, USA [3] 3Department of Neurological Surgery, University of California,
San Francisco, CA, USA [4] 4Brain Tumor Research Center, University of
California, San Francisco, CA, USA.
Amplification and mutation of the epidermal growth factor receptor (EGFR) is
common in astrocytoma. The most frequently occurring mutation (DeltaEGFR,
EGFRvIII) deletes exons 2-7 from this receptor tyrosine kinase (RTK), and
signals constitutively in the absence of ligand. DeltaEGFR is not found in
normal tissue, and therefore represents an attractive therapeutic target.
Here, we show that a small interfering RNA (siRNA) directed against the
unique exon 1/exon 8 junction sequence of DeltaEGFR efficiently suppressed
expression of DeltaEGFR in rodent fibroblasts and in two human glioblastoma
cell lines. SiRNA-mediated depletion of DeltaEGFR led to reduction in the
levels of phosphorylated Akt in glioma cells, was associated with increased
apoptosis, and induced partial arrest at the G(2)M phase of the cell cycle.
Inhibitors of PI3 kinase cooperated with siRNA treatment, leading to further
increases in both cell cycle blockade and apoptosis. Importantly, cell cycle
blockade could be reversed, and apoptosis rescued using a conditional allele
of Akt, implicating Akt as a primary target of combination therapy. This
study demonstrates the therapeutic potential of siRNA to impact DeltaEGFR as
a glioma-specific target, and offers a mechanistic rationale for combining
siRNA and small molecule inhibitor therapies against distinct components in
the EGFR signaling pathway.Oncogene advance online publication, 6 December
2004; doi:10.1038/sj.onc.1208227.
PMID: 15580296 [PubMed - as supplied by publisher]
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Volume 3, Supplement 18 - 15 December 2004