| 1: Br J Cancer. 2005 Jan 18; [Epub ahead of print] |
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Survivin, Survivin-2B, and Survivin-deItaEx3 expression
in medulloblastoma: biologic markers of tumour morphology and clinical
outcome.
Fangusaro JR, Jiang Y, Holloway MP, Caldas H, Singh V, Boue DR, Hayes J,
Altura RA.
[1] 1Center for Childhood Cancer Research, Columbus Children's Research
Institute (CCRI), College of Medicine and Public Health, The Ohio State
University, 700 Children's Drive, Columbus, OH 43205, USA [2] 2Department of
Pediatrics, College of Medicine and Public Health, The Ohio State
University, Columbus, OH, USA.
Survivin is an apoptotic inhibitor that is expressed at high levels in a
variety of malignancies. Survivin has four known alternative splice forms
(Survivin, Survivin-2B, Survivin-deltaEx3, and Survivin-3B), and the recent
literature suggests that these splice variants have unique functions and
subcellular localisation patterns. We evaluated 19 fresh-frozen paediatric
medulloblastomas for the expression of three Survivin isoforms by
quantitative PCR. Survivin was most highly expressed when compared with
normal cerebellar tissue. We also investigated Survivin protein expression
in 40 paraffin-embedded paediatric medulloblastoma tumours by
immunohistochemistry. We found a statistically significant association
between the percentage of Survivin-positive cells and histologic subtype,
with the large-cell-anaplastic variant expressing Survivin at higher levels
than the classic subtype. We also found a statistically significant
relationship between the percent of Survivin-positive cells in the tumours
and clinical outcome, with higher levels of Survivin correlating with a
worse prognosis. In summary, our study demonstrates a role for Survivin as a
marker of tumour morphology and clinical outcome in medulloblastoma.
Survivin may be a promising future prognostic tool and potential biologic
target in this malignancy.British Journal of Cancer advance online
publication, 18 January 2005; doi:10.1038/sj.bjc.6602317 www.bjcancer.com.
PMID: 15655550 [PubMed - as supplied by publisher]
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| 2: Int J Cancer. 2005 Jan 20;113(3):379-85. |
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Frequent promoter hypermethylation and low expression of
the MGMT gene in oligodendroglial tumors.
Mollemann M, Wolter M, Felsberg J, Collins VP, Reifenberger G.
Department of Neuropathology, Heinrich-Heine-University, Dusseldorf,
Germany.
Allelic losses on the chromosome arms 1p and 19q have been associated with
favorable response to chemotherapy and good prognosis in anaplastic
oligodendroglioma patients, but the molecular mechanisms responsible for
this relationship are as yet unknown. The DNA repair enzyme
O(6)-methylguanine DNA methyltransferase (MGMT) may cause resistance to
DNA-alkylating drugs commonly used in the treatment of anaplastic
oligodendrogliomas and other malignant gliomas. We report on the analysis of
52 oligodendroglial tumors for MGMT promoter methylation, as well as mRNA
and protein expression. Using sequencing of sodium bisulfite-modified DNA,
we determined the methylation status of 25 CpG sites within the MGMT
promoter. In 46 of 52 tumors (88%), we detected MGMT promoter
hypermethylation as defined by methylation of more than 50% of the sequenced
CpG sites. Real-time reverse transcription-PCR showed reduced MGMT mRNA
levels relative to non-neoplastic brain tissue in the majority of tumors
with hypermethylation. Similarly, immunohistochemical analysis showed either
no or only small fractions of MGMT positive tumor cells. MGMT promoter
hypermethylation was significantly more frequent and the percentage of
methylated CpG sites in the investigated MGMT promoter fragment was
significantly higher in tumors with loss of heterozygosity on chromosome
arms 1p and 19q as compared to tumors without allelic losses on these
chromosomes arms. Taken together, our data suggest that MGMT
hypermethylation and low or absent expression are frequent in
oligodendroglial tumors and likely contribute to the chemosensitivity of
these tumors.
PMID: 15455350 [PubMed - indexed for MEDLINE]
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| 3: J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):296-8. |
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Acute aspiration pneumonia due to bulbar palsy: an
initial manifestation of posterior fossa convexity meningioma.
Shenoy SN, Raja A.
Department of Neurosurgery, Kasturba Medical College and Hospital,
MANIPAL-576 119, UDUPI, Karnataka, India. shenoysn@yahoo.com.
PMID: 15654062 [PubMed - in process]
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| 4: J Nucl Med. 2005 Jan;46(1 Suppl):151S-6S. |
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Current status of therapy of solid tumors: brain tumor
therapy.
Zalutsky MR.
Departments of Radiology and Biomedical Engineering, Duke University Medical
Center, Durham, North Carolina.
Treatment of malignant brain tumors with conventional approaches is largely
unsuccessful because curative doses generally cannot be delivered without
excessive toxicity to normal brain. Radioimmunotherapy is emerging as an
attractive alternative for glioma therapy because of the potential for more
selectively irradiating tumor cells while sparing normal tissues. Several
institutions are engaged in phase I and phase II trials investigating the
therapeutic potential of monoclonal antibodies (mAbs) labeled with the
beta-emitters (131)I and (90)Y and the alpha-emitter (211)At in patients
with recurrent and newly diagnosed brain tumors. The current status of these
trials will be discussed with regard to efficacy, toxicity, and future
directions.
PMID: 15653663 [PubMed - in process]
| 5: J Clin Oncol. 2004 Dec 1;22(23):4727-34. |
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Second-line chemotherapy with irinotecan plus carmustine
in glioblastoma recurrent or progressive after first-line temozolomide
chemotherapy: a phase II study of the Gruppo Italiano Cooperativo di
Neuro-Oncologia (GICNO).
Brandes AA, Tosoni A, Basso U, Reni M, Valduga F, Monfardini S, Amista P,
Nicolardi L, Sotti G, Ermani M.
Department of Medical Oncology, University Hospital of Padova, Padova,
Italy. aabrandes@unipd.it
PURPOSE: Glioblastoma multiforme (GBM), the most frequent brain tumor in
adults, is not considered chemosensitive. Nevertheless, there is widespread
use of first-line chemotherapy, often with temozolomide, as a therapeutic
option in patients with progressive disease after surgery and radiotherapy.
However, at the time of second recurrence and/or progression, active and
noncross-resistant chemotherapy regimens are required. The aim of the
present multicenter phase II trial, therefore, was to ascertain the efficacy
of second-line carmustine (BCNU) and irinotecan chemotherapy. PATIENTS AND
METHODS: Patients with histologically confirmed GBM, recurring or
progressing after surgery, standard radiotherapy and a first-line
temozolomide-based chemotherapy, were considered eligible. The primary
end-point was progression-free survival at 6 months (PFS-6), and secondary
end-points included response rate, toxicity, and survival. All patients were
on enzyme-inducing antiepileptic prophylaxis. Chemotherapy consisted of BCNU
(100 mg/m2 on day 1) plus irinotecan (175 mg/m2/weekly for 4 weeks), every 6
weeks, for a maximum of eight cycles. In the absence of grade 2 toxicity,
the irinotecan dose was increased to 200 mg/m2. RESULTS: A total of 42
patients (median age, 53.4 years; median Karnofsky performance status, 80;
range, 60 to 90) were included in the study. PFS-6 was 30.3% (95% CI, 18.5%
to 49.7%). Median time to progression was 17 weeks (95% CI, 11.9 to 23.9).
Nine partial responses (21.4%; 95% CI, 9% to 34%) were obtained. Toxicity
was manageable. CONCLUSION: The BCNU plus irinotecan regimen seems active
and non-cross-resistant in patients with GBM with recurrence after
temozolomide-based chemotherapy.
Publication Types:
- Clinical Trial
- Clinical Trial, Phase II
- Multicenter Study
PMID: 15570079 [PubMed - indexed for MEDLINE]
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| 6: Oncology. 2004;67(2):174-8. |
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Brain metastasis responding to gefitinib alone.
Poon AN, Ho SS, Yeo W, Mok TS.
Department of Clinical Oncology, The Chinese University of Hong Kong, Hong
Kong, China.
A woman with stage IIIb non-small cell lung cancer (NSCLC) developed disease
progression with brain metastases during chemotherapy. Due to unusual
circumstances, the patient received gefitinib alone, without the use of
corticosteroid treatment or radiotherapy. There was a dramatic clinical
improvement within 1 week. Follow-up magnetic resonance imaging of the brain
1 month later showed decreases in both the size and number of brain
metastases. The patient remains well 9 months after initiation of gefitinib.
It is proposed that gefitinib may have a role in treatment of brain
metastases from NSCLC. 2004 S. Karger AG, Basel.
Publication Types:
- Case Reports
- Review
- Review of Reported Cases
PMID: 15539923 [PubMed - indexed for MEDLINE]
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| 7: Nature. 2004 Nov 18;432(7015):281-2. |
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Comment on:
Neurobiology: at the root of brain cancer.
Clarke MF.
Publication Types:
PMID: 15549078 [PubMed - indexed for MEDLINE]
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| 8: No Shinkei Geka. 2004 Aug;32(8):827-34. |
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[Cancer stem cells in pediatric brain tumors]
[Article in Japanese]
Nakano I, Hemmati HD, Kornblum HI.
Department of Molecular and Medical Pharmacology, David Geffen School of
Medicine at UCLA, Los Angeles, CA 90095, USA. inakano@mednet.ucla.edu
Cancers are formed by heterogeneous cell types from immature highly
proliferative cells to lineage-committed differentiated cells.
Transplantation studies have suggested the existence of "cancer stem
cells", individual cells capable of producing an entire tumor. Recent
advances in stem cell research have allowed for the demonstration of the
existence of cancer stem cells in acute myeloid leukemia, breast cancer,
and, most recently, in pediatric brain tumors. Each of these has some
similarities with the normal stem cells in the corresponding organs. For
example, leukemia stem cells express some, but not all, markers of
hematopoietic stem cells. Regarding pediatric brain tumors, putative cancer
stem cells were identified from medulloblastoma and also from glioma. These
tumor-derived cells self-renew under clonal conditions, and differentiate
into neurons and glia as well as into abnormal cells with mixed phenotypes.
Interestingly, the tumor stem/progenitors, enriched in culture, maintained
proliferation after 4 weeks from transplantation into neonatal rat brain. In
this review, we discuss the difference as well as the similarity between
tumor and normal stem cells, and also the possible clinical implication of
cancer stem cells.
Publication Types:
PMID: 15478649 [PubMed - indexed for MEDLINE]
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| 9: Neurosurgery. 2004 Oct;55(4):977-8. |
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Possible oncogenicity of subventricular zone neural stem
cells: case report.
Uchida K, Mukai M, Okano H, Kawase T.
Department of Neurosurgery, School of Medicine, Keio University, Tokyo,
Japan.
OBJECTIVE: The origin of brain tumors has attracted much controversy. Recent
advances in neural stem cell biology coupled with the new concepts of
central nervous system development have raised interesting possibilities
regarding the oncogenic properties of neural stem/progenitor cells. To
elucidate these putative properties further, the clinical materials from an
infant brain tumor were analyzed, focusing on the relation with the neural
stem/progenitor cells. METHODS: The expression of neural stem/progenitor
cell markers in the tumor cells and the cellular components of the infant
brain tumor were examined using immunohistochemistry. The tumor cell biology
was analyzed both in culture and in the grafted brain environment. RESULTS:
Three main bodies of evidence were demonstrated indicating that the tumor
was of possible subventricular zone postnatal or adult normal neural stem
cell origin. First, in the tumor specimen we demonstrated the strong
positive expression of the neural stem/progenitor cell markers, nestin and
Musashi-1. Second, immunohistochemistry revealed the presence of neuronal,
astrocytic, and immature precursor cells in the tumor tissue, similar to the
cellular components of the subventricular zone, thereby pointing to the
subventricular zone as the possible origin of the tumor. The subventricular
zone also is one of the strong candidates for the location of
postnatal/adult neural stem cells. This cellular evidence was strengthened
further by the clinicoradiological findings that demonstrated the
involvement of the subventricular zone of the lateral ventricle by the
tumor. Third, in the in vitro and in vivo experiments, a dynamic shift in
expression patterns between neural stem cells (nestin, Musashi-1) and
differentiated cells (glial fibrillary acidic protein, neuron-specific Class
III beta-tubulin) markers was seen, similar to the proposed behavior of
postnatal/adult neural stem cells in situ. CONCLUSION: These findings
suggest that this brain tumor originated from neural stem cells located in
the subventricular zone, and the further possibility of the general
oncogenic potential of neural stem cells.
PMID: 15458607 [PubMed - in process]
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| 10: Orv Hetil. 2004 Jun 20;145(25):1307-13. |
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[Embryonic stem cell therapy in experimental stroke:
host-dependent malignant transformation]
[Article in Hungarian]
Erdo F, Trapp T, Buhrle C, Fleischmann B, Hossmann KA.
Experimentelle Neurologie, Max-Planck Institut fur neurologische Forschung,
Koln, Nemetorszag. franciska.erdo@idri.hu
INTRODUCTION: Therapeutic application of embryonic stem cells in
neurodegenerative disorders like stroke is widely investigated in
preclinical animal models. AIM: The authors studied the therapeutic
potential of murine embryonic stem cells in two rodent models of stroke.
METHODS: Undifferentiated and predifferentiated stem cells were implanted
into the non-ischemic hemisphere of mice and rats following focal brain
ischemia. The brains were analysed by immunohistochemistry and histology.
The in vitro differentiation of the cells was checked by immunocytochemistry
and Western-blot. RESULTS: After xenotransplantation in rats
undifferentiated cells migrated along the corpus callosum towards the
ischemic injury. Later stem cells differentiated into neurons in the border
zone of the lesion. In the homologous mouse brain, the same murine embryonic
stem cells did not migrate, but produced highly malignant teratocarcinomas
at the site of implantation, independent of whether they were
predifferentiated in vitro to neural progenitor cells. These experiments
demonstrated a hitherto unrecognized adverse outcome after
xenotransplantation and homologous transplantation of embryonic stem cells.
CONCLUSION: This observation raises serious concerns about safety provisions
when the therapeutic potential of human embryonic stem cells is tested in
preclinical animal models. The clinical trials are based on the positive
outcome of the xenologous experiments.
PMID: 15285148 [PubMed - indexed for MEDLINE]
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Volume 4, Number 5 - 25 January 2005