| 1: Cancer Res. 2006 Jul
1;66(13):6756-62. |
|
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HDJ-2 as a Target for Radiosensitization of Glioblastoma
Multiforme Cells by the Farnesyltransferase Inhibitor R115777 and the Role
of the p53/p21 Pathway.
Wang CC, Liao YP, Mischel PS, Iwamoto KS, Cacalano
NA, McBride WH.
Departments of Radiation Oncology and Pathology and Laboratory Medicine,
University of California at Los Angeles School of Medicine, Los Angeles,
California and Department of Radiation Oncology, Chang Gung Memorial
Hospital, Taipei, Taiwan.
Resistance of glioblastoma multiforme to radiotherapy poses a major clinical
challenge. Farnesyltransferase inhibitors (FTI), such as R115777, have
potential to increase radiotherapeutic benefit in this disease, although
their mechanism of action is unclear. In our study with eight glioblastoma
multiforme cell lines, the most sensitive ones underwent cell cycle arrest
in response to FTI treatment. Radiosensitization by FTIs, however, seemed to
involve other pathways. If R115777 treatment was initiated <6 hours
before irradiation, all eight glioblastoma multiforme lines were
radiosensitized. However, if the time between drug and radiation was
extended to 24 hours, cells harboring wild type but not mutated p53 were
able to counteract drug-induced radiosensitization. The involvement of the
p53/p21 pathway in the development of resistance was confirmed by showing
that U87 cells transfected with human papillomavirus E6 to block p53 or
interfering RNA to inhibit p21 stayed radiosensitive for 24 hours after drug
treatment. The time dependency of R115777-induced radiosensitization
suggested that the initial FTI target for early radiosensitization was
short-lived, and that a p21-directed pathway restored resistance.
Consideration of prenylated molecules that could potentially be involved led
us to consider HDJ-2, a co-chaperone of heat shock protein 70. This
hypothesis was strengthened by finding that cellular radiosensitivity was
increased by genetic inhibition of HDJ-2, whereas overexpression conferred
radioresistance. Importantly, irradiation of cells caused HDJ-2 to migrate
from the cytoplasm to the nucleus, and this migration was inhibited by prior
FTI treatment. These results have clinical relevance in that they help
explain the variability in responses to FTIs that occurs following
radiotherapy and elucidate some of the reasons for the complexity underlying
FTI-induced radiosensitization. (Cancer Res 2006; 66(13): 6756-62).
PMID: 16818651 [PubMed - in process]
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| 2: Cancer Res. 2006 Jul
1;66(13):6665-74. |
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Genome-Wide Analysis of Epigenetic Silencing Identifies
BEX1 and BEX2 as Candidate Tumor Suppressor Genes in Malignant Glioma.
Foltz G, Ryu GY, Yoon JG, Nelson T, Fahey J,
Frakes A, Lee H, Field L, Zander K, Sibenaller
Z, Ryken TC, Vibhakar R, Hood L, Madan A.
Neurogenomic Research Laboratory, Department of Neurosurgery.
Promoter hypermethylation and histone deacetylation are common epigenetic
mechanisms implicated in the transcriptional silencing of tumor suppressor
genes in human cancer. We treated two immortalized glioma cell lines, T98
and U87, and 10 patient-derived primary glioma cell lines with trichostatin
A (TSA), a histone deacetylase inhibitor, or 5-aza-2'-deoxycytidine
(5-AzaC), a DNA methyltransferase inhibitor, to comprehensively identify the
cohort of genes reactivated through the pharmacologic reversal of these
distinct but related epigenetic processes. Whole-genome microarray analysis
identified genes induced by TSA (653) or 5-AzaC treatment (170). We selected
a subset of reactivated genes that were markedly induced (greater than
two-fold) after treatment with either TSA or 5-AzaC in a majority of glioma
cell lines but not in cultured normal astrocytes. We then characterized the
degree of promoter methylation and transcriptional silencing of selected
genes in histologically confirmed human tumor and nontumor brain specimens.
We identified two novel brain expressed genes, BEX1 and BEX2, which were
silenced in all tumor specimens and exhibited extensive promoter
hypermethylation. Viral-mediated reexpression of either BEX1 or BEX2 led to
increased sensitivity to chemotherapy-induced apoptosis and potent tumor
suppressor effects in vitro and in a xenograft mouse model. Using an
integrated approach, we have established a novel platform for the
genome-wide screening of epigenetically silenced genes in malignant glioma.
This experimental paradigm provides a powerful new method for the
identification of epigenetically silenced genes with potential function as
tumor suppressors, biomarkers for disease diagnosis and detection, and
therapeutically reversible modulators of critical regulatory pathways
important in glioma pathogenesis. (Cancer Res 2006; 66(13): 6665-74).
PMID: 16818640 [PubMed - in process]>>>
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| 3: Cancer Res. 2006 Jul
1;66(13):6473-6. |
|
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Association of Mutant TP53 with Alternative Lengthening
of Telomeres and Favorable Prognosis in Glioma.
Chen YJ, Hakin-Smith V, Teo M, Xinarianos GE, Jellinek
DA, Carroll T, McDowell D, Macfarlane MR, Boet R,
Baguley BC, Braithwaite AW, Reddel RR, Royds JA.
Department of Pathology, University of Otago.
The molecular basis for alternative lengthening of telomeres (ALT), a
prognostic marker for glioma patients, remains unknown. We examined TP53
status in relation to telomere maintenance mechanism (TMM) in 108 patients
with glioblastoma multiforme and two patients with anaplastic astrocytoma
from New Zealand and United Kingdom. Tumor samples were analyzed with
respect to telomerase activity, telomere length, and ALT-associated
promyelocytic leukemia nuclear bodies to determine their TMM. TP53 mutation
was analyzed by direct sequencing of coding exons 2 to 11. We found an
association between TP53 mutation and ALT mechanism and between wild-type
TP53 and telomerase and absence of a known TMM (P < 0.0001). We suggest
that TP53 deficiency plays a permissive role in the activation of ALT.
(Cancer Res 2006; 66(13): 6473-6).
PMID: 16818615 [PubMed - in process]>>>
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| 4: Cancer Res. 2006 May
1;66(9):4687-92. |
|
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Dynamic imaging of emerging resistance during cancer
therapy.
Lee KC, Hall DE, Hoff BA, Moffat BA, Sharma S,
Chenevert TL, Meyer CR, Leopold WR, Johnson TD, Mazurchuk
RV, Rehemtulla A, Ross BD.
Department of Biological Chemistry, University of Michigan Medical School,
Ann Arbor, MI 48109, USA.
One of the greatest challenges in developing therapeutic regimens is the
inability to rapidly and objectively assess tumor response due to treatment.
Moreover, tumor response to therapeutic intervention in many cases is
transient, and progressive alterations within the tumor may mask the
effectiveness of an initially successful therapy. The ability to detect
these changes as they occur would allow timely initiation of alternative
approaches, maximizing therapeutic outcome. We investigated the ability of
diffusion magnetic resonance imaging (MRI) to provide a sensitive measure of
tumor response throughout the course of treatment, possibly identifying
changes in sensitivity to the therapy. Orthotopic 9L gliomas were subjected
to two separate therapeutic regimens, with one group receiving a single
5-day cycle (1omega) of low-dose 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)
and a second group receiving two cycles at the same dose, bisected with 2
days of rest (2omega). Apparent diffusion coefficient maps were acquired
before and throughout treatment to observe changes in water mobility, and
these observations were correlated to standard measures of therapeutic
response and outcome. Our results showed that diffusion MRI was indeed able
to detect the emergence of a drug-resistant tumor subpopulation subsequent
to an initially successful cycle of BCNU therapy, leading to minimal gains
from a second cycle. These diffusion MRI findings were highly correlated
with tumor growth delay, animal survival, and ex vivo growth inhibition
assays showing emerging resistance in excised tumors. Overall, this study
highlights the ability of diffusion MRI to provide sensitive dynamic
assessment of therapy-induced response, allowing early opportunities for
optimization of therapeutic protocols.
PMID: 16651420 [PubMed - indexed for MEDLINE]>>>
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| 5: Clin
Cancer Res. 2006 Jul 1;12(13):3935-41. |
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Prognostic associations of activated mitogen-activated
protein kinase and akt pathways in glioblastoma.
Pelloski CE, Lin E, Zhang L, Yung WK, Colman
H, Liu JL, Woo SY, Heimberger AB, Suki D, Prados
M, Chang S, Barker FG 3rd, Fuller GN, Aldape KD.
Authors' Affiliations: Departments of Radiation Oncology, Biostatistics and
Applied Mathematics, Neuro-Oncology, Neurosurgery, and Pathology, University
of Texas M.D. Anderson Cancer Center, Houston, Texas.
PURPOSE: Activation of mitogen-activated protein kinase (MAPK) and members
of the Akt pathway have been shown to promote cell proliferation, survival,
and resistance to radiation. This study was conducted to determine whether
any of these markers are associated with survival time and response to
radiation in glioblastoma. EXPERIMENTAL DESIGN: The expression of
phosphorylated (p-)Akt, mammalian target of rapamycin (p-mTOR), p-p70S6K,
and p-MAPK were assessed by immunohistochemical staining in 268 cases of
newly diagnosed glioblastoma. YKL-40, a prognostic marker previously
examined in these tumors, was also included in the analysis. Expression data
were tested for correlations with response to radiation therapy in 131
subtotally resected cases and overall survival (in all cases). Results were
validated in an analysis of 60 patients enrolled in clinical trials at a
second institution. RESULTS: Elevated p-MAPK expression was most strongly
associated with poor response to radiotherapy, a finding corroborated in the
validation cohort. For survival, higher expressions of p-mTOR, p-p70S6K, and
p-MAPK were associated with worse outcome (all P < 0.03). YKL-40
expression was associated with the expressions of p-MAPK, p-mTOR, and
p-p70S6K (all P < 0.02), with a trend toward association with p-Akt
expression (P = 0.095). When known clinical variables were added to a
multivariate analysis, only age, Karnofsky performance score, and p-MAPK
expression emerged as independent prognostic factors. CONCLUSIONS: p-MAPK
and activated members of the Akt pathway are markers of outcome in
glioblastoma. Elevated expression of p-MAPK is associated with increased
radiation resistance and represents an independent prognostic factor in
these tumors.
PMID: 16818690 [PubMed - in process]>>>
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| 6: Int
J Radiat Oncol Biol Phys. 2006 Jun 29; [Epub ahead of print] |
|
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Outcome and prognostic factors in cerebellar glioblastoma
multiforme in adults: A retrospective study from the Rare Cancer Network.
Weber DC, Miller RC, Villa S, Hanssens P, Baumert
BG, Castadot P, Varlet P, Abacioglu U, Igdem S,
Szutowicz E, Nishioka H, Hofer S, Rutz HP, Ozsahin
M, Taghian A, Mirimanoff RO.
University Hospital of Geneva, Geneva, Switzerland; Paul Scherrer Institute,
Villigen, Switzerland.
PURPOSE: The aim of this study was to assess the outcome in patients with
cerebellar glioblastoma (GBM) treated in 15 institutions of the Rare Cancer
Network. METHODS AND MATERIALS: Data from a series of 45 adult patients with
cerebellar GBM were collected in a retrospective multicenter study. Median
age was 50.3 years. Brainstem invasion was observed in 9 (20%) patients.
Radiotherapy (RT) was administered to 36 patients (with concomitant
chemotherapy, 7 patients). Adjuvant chemotherapy after RT was administered
in 8 patients. Median RT dose was 59.4 Gy. Median follow-up was 7.2 months
(range, 3.4-39.0). RESULTS: The 1-year and 2-year actuarial overall survival
rate was 37.8% and 14.7%, respectively, and was significantly influenced by
salvage treatment (p = 0.048), tumor volume (p = 0.044), extent of
neurosurgical resection (p = 0.019), brainstem invasion (p = 0.0013),
additional treatment after surgery (p < 0.001), and completion of the
initial treatment (p < 0.001) on univariate analysis. All patients
experienced local progression: 8 and 22 had progression with and without a
distant failure, respectively. The 1- and 2-year actuarial progression free
survival was 25% and 10.7%, respectively, and was significantly influenced
by brainstem invasion (p = 0.002), additional treatment after surgery (p =
0.0016), and completion of the initial treatment (p < 0.001). On
multivariate analysis, survival was negatively influenced by the extent of
surgery (p = 0.03) and brainstem invasion (p = 0.02). CONCLUSIONS: In this
multicenter retrospective study, the observed pattern of failure was local
in all cases, but approximately 1 patient of 4 presented with an
extracerebellar component. Brainstem invasion was observed in a substantial
number of patients and was an adverse prognostic factor.
PMID: 16814953 [PubMed - as supplied by publisher]>>>
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| 7: Int
J Radiat Oncol Biol Phys. 2006 Jun 29; [Epub ahead of print] |
|
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A pathology-based substrate for target definition in
radiosurgery of brain metastases.
Baumert BG, Rutten I, Dehing-Oberije C, Twijnstra A,
Dirx MJ, Debougnoux-Huppertz RM, Lambin P, Kubat B.
Department of Radiation Oncology (MAASTRO), GROW, University Hospital
Maastricht, Maastricht, The Netherlands.
PURPOSE: To investigate the need of a margin other than for accuracy reasons
in stereotactic radiosurgery (SRS) of brain metastases by means of
histopathology. METHODS AND MATERIALS: Evaluation of 45 patients from two
pathology departments having had brain metastases and an autopsy of the
brain. Growth patterns were reviewed with a focus on infiltration beyond the
metastases boundary and made visible with immunohistochemical staining: the
metastasis itself with tumor-specific markers, surrounding normal brain
tissue with a glial marker, and a possible capsule with a soft tissue
marker. Measurements were corrected by a tissue-shrinkage correction factor
taken from literature. Outcomes parameters for infiltration were mean and
maximum depths of infiltration and number of measured infiltration sites.
RESULTS: In 48 of 76 metastases, an infiltration was present. The largest
group of metastases was lung cancer. Small-cell lung cancer (SCLC) and
melanoma showed a maximum depth of infiltration of >/=1 mm, and other
histologies <1 mm. For non-small-cell lung cancer (NSCLC), melanoma, and
sarcoma, the highest number of infiltrative sites were observed (median, 2;
range, 1-8). SCLC showed significantly larger infiltrative growth, compared
with other diagnostic groups. In NSCLC, the highest percentage of
infiltration was present (70%). CONCLUSIONS: Infiltrative growth beyond the
border of the brain metastasis was demonstrated in 63% of the cases
evaluated. Infiltrative growth, therefore, has an impact in defining the
clinical target volume for SRS of brain metastases, and a margin of
approximately 1 mm should be added to the visible lesion.
PMID: 16814946 [PubMed - as supplied by publisher]>>>
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| 8: J
Clin Oncol. 2006 Jun 20;24(18):2715-22. |
|
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Comment in:
- J Clin Oncol. 2006 Jun 20;24(18):2689-90.
Adjuvant procarbazine, lomustine, and vincristine
improves progression-free survival but not overall survival in newly
diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized
European Organisation for Research and Treatment of Cancer phase III trial.
van den Bent MJ, Carpentier AF, Brandes AA, Sanson M,
Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold
W, Sipos L, Haaxma-Reiche H, Kros JM, van
Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia
T.
Departments of Neurology and Pathology, Daniel den Hoed Cancer
Center/Erasmus University Hospital, Rotterdam, The Netherlands. m.vandenbent@erasmusmc.nl
PURPOSE: Anaplastic oligodendrogliomas are more responsive to chemotherapy
than high-grade astrocytomas. We investigated, in a multicenter randomized
controlled trial, whether adjuvant procarbazine, lomustine, and vincristine
(PCV) chemotherapy improves overall survival (OS) in newly diagnosed
patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas.
PATIENTS AND METHODS: The primary end point of the study was OS; secondary
end points were progression-free survival (PFS) and toxicity. Patients were
randomly assigned to either 59.4 Gy of radiotherapy (RT) in 33 fractions
only or to the same RT followed by six cycles of standard PCV chemotherapy (RT/PCV).
1p and 19q deletions were assessed with fluorescent in situ hybridization.
RESULTS: A total of 368 patients were included. The median follow-up time
was 60 months, and 59% of patients have died. In the RT arm, 82% of patients
with tumor progression received chemotherapy. In 38% of patients in the RT/PCV
arm, adjuvant PCV was discontinued for toxicity. OS time after RT/PCV was
40.3 months compared with 30.6 months after RT only (P = .23). RT/PCV
increased PFS time compared with RT only (23 v 13.2 months, respectively; P
= .0018). Twenty-five percent of patients were diagnosed with combined
1p/19q loss; 74% of this subgroup was still alive after 60 months. RT/PCV
did not improve survival in the subgroup of patients with 1p/19q loss.
CONCLUSION: Adjuvant PCV chemotherapy does not prolong OS but does increase
PFS in anaplastic oligodendroglioma. Combined loss of 1p/19q identifies a
favorable subgroup of oligodendroglial tumors. No genetic subgroup could be
identified that benefited with respect to OS from adjuvant PCV.
Publication Types:
- Clinical Trial, Phase III
- Multicenter Study
- Randomized Controlled Trial
PMID: 16782911 [PubMed - indexed for MEDLINE]
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| 9: J
Clin Oncol. 2006 Jun 20;24(18):2707-14. |
|
-
Comment in:
- J Clin Oncol. 2006 Jun 20;24(18):2689-90.
Phase III trial of chemotherapy plus radiotherapy
compared with radiotherapy alone for pure and mixed anaplastic
oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402.
Intergroup Radiation Therapy Oncology Group Trial 9402; Cairncross
G, Berkey B, Shaw E, Jenkins R, Scheithauer B,
Brachman D, Buckner J, Fink K, Souhami L, Laperierre
N, Mehta M, Curran W.
University of Calgary, Calgary, Alberta, Canada; e-mail: jgcairnx@ucalgary.ca
PURPOSE: Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA)
are treated with surgery and radiotherapy (RT) at diagnosis, but they also
respond to procarbazine, lomustine, and vincristine (PCV), raising the
possibility that early chemotherapy will improve survival. Furthermore,
better outcomes in AO have been associated with 1p and 19q allelic loss.
PATIENTS AND METHODS: Patients with AO and AOA were randomly assigned to PCV
chemotherapy followed by RT versus postoperative RT alone. The primary end
point was overall survival. The status of 1p and 19q alleles was assessed by
fluorescence in situ hybridization. RESULTS: Two hundred eighty-nine
eligible patients were randomly assigned to either PCV plus RT (n = 147) or
RT alone (n = 142). At progression, 80% of patients randomly assigned to RT
had chemotherapy. With 3-year follow-up on most patients, the median
survival times were similar (4.9 years after PCV plus RT v 4.7 years after
RT alone; hazard ratio [HR] = 0.90; 95% CI, 0.66 to 1.24; P = .26).
Progression-free survival time favored PCV plus RT (2.6 years v 1.7 years
for RT alone; HR = 0.69; 95% CI, 0.52 to 0.91; P = .004), but 65% of
patients experienced grade 3 or 4 toxicity, and one patient died. Patients
with tumors lacking 1p and 19q (46%) compared with tumors not lacking 1p and
19q had longer median survival times (> 7 v 2.8 years, respectively; P
< or = .001); longer progression-free survival was most apparent in this
subset. CONCLUSION: For patients with AO and AOA, PCV plus RT does not
prolong survival. Longer progression-free survival after PCV plus RT is
associated with significant toxicity. Tumors lacking 1p and 19q alleles are
less aggressive or more responsive or both.
Publication Types:
- Clinical Trial, Phase III
- Multicenter Study
- Randomized Controlled Trial
PMID: 16782910 [PubMed - indexed for MEDLINE]
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| 10: J
Clin Oncol. 2006 Jun 20;24(18):2689-90. |
|
-
Comment on:
- J Clin Oncol. 2006 Jun 20;24(18):2707-14.
- J Clin Oncol. 2006 Jun 20;24(18):2715-22.
Anaplastic oligodendroglial tumors: a tale of two trials.
Gilbert MR, Lang FF.
Publication Types:
PMID: 16782906 [PubMed - indexed for MEDLINE]
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| 11: J Neurooncol.
2006 Jul 5; [Epub ahead of print] |
|
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PTEN inhibits adrenomedullin expression and function in
brain tumor cells.
Betchen SA, Musatov S, Roberts J, Pena J, Kaplitt
MG.
Department of Neurosurgery, Weill Medical College of Cornell University, New
York, NY, USA.
Adrenomedullin is a vasoactive peptide that is upregulated in higher-grade
gliomas and promotes tumor cell proliferation. Since reduced activity of the
anti-oncogene PTEN seems to also correlate with higher tumor grade, this
suggests an inverse association between PTEN activity and adrenomedullin
expression. PC12 pheochromocytoma and human U251 glioma cell lines were
stably transfected with human PTEN or control plasmid. Adrenomedullin
expression was analyzed using quantitative PCR and Western blotting. A cell
proliferation assay was used to assess adrenomedullin effects on U251 cells
overexpressing PTEN. PC12 and U251 cells overexpressing PTEN had 17- and
8-fold decreases in adrenomedullin mRNA levels, respectively, compared to
control cells. Cellular and secreted adrenomedullin peptide was similarly
reduced. Addition of adrenomedullin to medium of controlled cells induced
proliferation, as described previously, but U251 cells overexpressing PTEN
did not respond to exogenous adrenomedullin. Further exploration revealed
that PTEN also inhibits expression of the gliomas receptor for
adrenomedullin, which accounts for this effect. These data were all
replicated with an inducible PTEN construct confirming that these effects
are not exclusively secondary to chronic overexpression. Given the profound
effects of adrenomedullin on tumor cells, this is a novel and previously
unidentified mechanism by which alterations in PTEN levels or function may
influence tumor growth.
PMID: 16821090 [PubMed - as supplied by publisher]
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| 12: J Neurooncol.
2006 Jul 5; [Epub ahead of print] |
|
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HER2-positive Breast Cancer Brain Metastases: Multiple
Responses to Systemic Chemotherapy and Trastuzumab-a Case Report.
Church DN, Bahl A, Jones A, Price CG.
Department of Medical Oncology, Bristol Haematology and Oncology Centre,
Horfield Road, BS2 8ED, Bristol, UK, chris.price@ubht.swest.nhs.uk.
Brain metastases from metastatic breast cancer typically occur in 10-15% of
patients and are associated with survival of 3-6 months. Recent series have
shown that women with HER2-postive metastatic breast cancer receiving the
drug trastuzumab develop brain metastases more frequently than this, but
also that continuation of trastuzumab after diagnosis of brain metastases in
such patients is associated with extended survival. Authors have speculated
that this is due to improved systemic control of disease; however, a
possibility is that trastuzumab may have a beneficial effect on cerebral
metastases themselves. We report the case of a woman with HER2-positive
metastatic breast cancer who developed multiple brain metastases while on
trastuzumab, in whom the addition of systemic chemotherapy to continued
trastuzumab has produced multiple treatment responses associated with
prolonged survival. This is the first report of its kind.
PMID: 16821088 [PubMed - as supplied by publisher]>>>
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| 13: J
Nucl Med. 2006 May;47(5):776-82. |
|
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18F-FET PET differentiation of ring-enhancing brain
lesions.
Floeth FW, Pauleit D, Sabel M, Reifenberger G, Stoffels
G, Stummer W, Rommel F, Hamacher K, Langen KJ.
Department of Neurosurgery, Heinrich-Heine-University, Dusseldorf, Germany.
The aim of this study was to explore the differential diagnostic value of
PET using the amino acid O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) in
patients with newly diagnosed solitary intracerebral lesions showing ring
enhancement on contrast-enhanced MRI. METHODS: (18)F-FET PET analyses were
performed on 14 consecutive patients with intracerebral ring-enhancing
lesions. Eleven of the patients were additionally studied with (18)F-FDG
PET. In all patients, the main differential diagnosis after MRI was a
malignant lesion, in particular glioblastoma multiforme, versus a benign
lesion, in particular brain abscess. A malignant tumor was suspected for
lesions showing increased (18)F-FET uptake on PET images with a mean
lesion-to-brain ratio of at least 1.6 ((18)F-FET PET positive). A
nonneoplastic lesion was suspected in cases of minimal or absent (18)F-FET
uptake, with a mean lesion-to-brain ratio of less than 1.6 ((18)F-FET PET
negative). Histologic diagnosis was obtained by serial biopsies in 13 of the
14 patients. One patient refused the biopsy, but follow-up indicated an
abscess because his lesion regressed under antibiotic therapy. RESULTS:
Histology and clinical follow-up showed high-grade malignant gliomas in 5
patients and nonneoplastic lesions in 9 patients. The findings of (18)F-FET
PET were positive in all 5 glioma patients and in 3 of 9 patients with
nonneoplastic lesions, including 2 patients with brain abscesses and 1
patient with a demyelinating lesion. The findings of (18)F-FDG PET were
positive (mean lesion-to-gray matter ratio > or = 0.7) in 4 of 4 glioma
patients and 3 of 7 patients with nonneoplastic lesions. CONCLUSION:
Although (18)F-FET PET has been shown to be valuable for the diagnostic
evaluation of brain tumors, our data indicate that, like (18)F-FDG PET,
(18)F-FET PET has limited specificity in distinguishing between neoplastic
and nonneoplastic ring-enhancing intracerebral lesions. Thus, histologic
investigation of biopsy specimens remains mandatory to make this important
differential diagnosis.
PMID: 16644747 [PubMed - indexed for MEDLINE]>>>
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| 14: Neurology. 2006 Jun
13;66(11):1763-5. |
|
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Primary dural lymphomas: a clinicopathologic study of
treatment and outcome in eight patients.
Iwamoto FM, DeAngelis LM, Abrey LE.
Department of Neurology and Neuroscience, Weill Medical College of Cornell
University, New York, NY, USA.
The authors report eight patients with primary dural lymphoma (PDL). All
patients had extra-axial masses on MRI that diffusely enhanced after
gadolinium. Pathology revealed low-grade non-Hodgkin lymphoma (marginal zone
lymphoma of MALT [mucosa-associated lymphoid tissue] type) in all patients.
All patients underwent radiation therapy, and three received chemotherapy.
Complete response was achieved in 100% of patients, but three developed
systemic relapse.
PMID: 16769960 [PubMed - indexed for MEDLINE]>>>
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| 15: Neurology. 2006 Jun
13;66(11):1661-7. |
|
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Clinical use of genotype to predict chemosensitivity in
oligodendroglial tumors.
Walker C, Haylock B, Husband D, Joyce KA, Fildes
D, Jenkinson MD, Smith T, Broome J, du Plessis
DG, Warnke PC.
J.K. Douglas Laboratories, Clatterbridge Hospital, Bebington, Wirral, UK.
carol.walker@ccrt.nhs.uk
BACKGROUND: The -1p/-19q genotype has been associated with prolonged
survival and chemosensitivity in oligodendroglial neoplasms, but the
predictive and prognostic significance of genotype in the routine clinic is
not established. METHODS: The authors investigated allelic imbalance in
1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in a cohort
representative of clinical practice at their center (50 primary, 26
recurrent cases) given PCV chemotherapy between 2000 and 2003 and compared
with response and outcome following PCV. RESULTS: 1p/19q loss was found in
12/19 OII, 10/23 OAII, 11/13 OIII, and 6/21 OAIII. Response, seen in 92%
with 1p/19q loss, was associated with the -1p/-19q genotype (Fisher exact: p
< 0.001) regardless of WHO grade or whether primary or recurrent. 1p/19q
loss was an independent prognostic factor associated with longer
progression-free (PFS) and overall survival (OS) (Cox regression: PFS and OS
p < 0.001), with greater impact on PFS than OS in primary tumors, and OS
at recurrence. 17p13 loss and p53 mutation were associated with poor
prognosis in recurrent tumors and chromosome 10 loss was associated with
short PFS and OS in primary tumors. Histologic subtype did not influence
outcome in tumors of equivalent genotype. Genotype had greater association
with response and outcome than conventional clinical factors. A total of 29%
with intact 1p/19q and a variety of genetic or clinicopathologic
characteristics responded in association with increased PFS and OS.
CONCLUSIONS: The -1p/-19q genotype predicted response and favorable outcome
following PCV chemotherapy corroborating genetic analysis to guide routine
clinical management. However, some cases with intact 1p/19q also had
clinical benefit.
PMID: 16769937 [PubMed - indexed for MEDLINE]>>>
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| 16: Oncogene. 2006 Jul 3; [Epub
ahead of print] |
|
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Apoptosis in malignant glioma cells triggered by the
temozolomide-induced DNA lesion O(6)-methylguanine.
Roos WP, Batista LF, Naumann SC, Wick W, Weller
M, Menck CF, Kaina B.
1Department of Toxicology, University of Mainz, Mainz, Germany.
Methylating drugs such as temozolomide (TMZ) are widely used in the
treatment of brain tumours (malignant gliomas). The mechanism of TMZ-induced
glioma cell death is unknown. Here, we show that malignant glioma cells
undergo apoptosis following treatment with the methylating agents
N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and TMZ. Cell death determined
by colony formation and apoptosis following methylation is greatly
stimulated by p53. Transfection experiments with O(6)-methylguanine-DNA
methyltransferase (MGMT) and depletion of MGMT by O(6)-benzylguanine showed
that, in gliomas, the apoptotic signal originates from O(6)-methylguanine
(O(6)MeG) and that repair of O(6)MeG by MGMT prevents apoptosis. We further
demonstrate that O(6)MeG-triggered apoptosis requires Fas/CD95/Apo-1
receptor activation in p53 non-mutated glioma cells, whereas in p53 mutated
gliomas the same DNA lesion triggers the mitochondrial apoptotic pathway.
This occurs less effectively via Bcl-2 degradation and caspase-9, -2, -7 and
-3 activation. O(6)MeG-triggered apoptosis in gliomas is a late response
(occurring >120 h after treatment) that requires extensive cell
proliferation. Stimulation of cell cycle progression by the Pasteurella
multocida toxin promoted apoptosis whereas serum starvation attenuated it.
O(6)MeG-induced apoptosis in glioma cells was preceded by the formation of
DNA double-strand breaks (DSBs), as measured by gammaH2AX formation. Glioma
cells mutated in DNA-PK(cs), which is involved in non-homologous
end-joining, were more sensitive to TMZ-induced apoptosis, supporting the
involvement of DSBs as a downstream apoptosis triggering lesion. Overall,
the data demonstrate that cell death induced by TMZ in gliomas is due to
apoptosis and that determinants of sensitivity of gliomas to TMZ are MGMT,
p53, proliferation rate and DSB repair.Oncogene advance online publication,
3 July 2006; doi:10.1038/sj.onc.1209785.
PMID: 16819506 [PubMed - as supplied by publisher]>>>
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Volume 5, Number 28 - 10 July 2006