| 1: Ann Neurol. 2005 Jan;57(1):34-41. |
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Glioma therapy and real-time imaging of neural precursor
cell migration and tumor regression.
Shah K, Bureau E, Kim DE, Yang K, Tang Y, Weissleder R, Breakefield XO.
Department of Neurology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA.
Despite many refinements in current therapeutic strategies, the overall
prognosis for a patient with glioblastoma is dismal. Neural precursor cells
(NPCs) are capable of tracking glioma tumors and thus could be used to
deliver therapeutic molecules. We have engineered mouse NPCs to deliver a
secreted form of tumor necrosis factor-related apoptosis-inducing ligand
(S-TRAIL); S-TRAIL is optimized to selectively kill neoplastic cells.
Furthermore, we have developed means to simultaneously monitor both the
migration of NSCs toward gliomas and the changes in glioma burden in real
time. Using a highly malignant human glioma model expressing Renilla
luciferase (Rluc), intracranially implanted NPC-FL-sTRAIL expressing both
firefly luciferase (Fluc) and S-TRAIL was shown to migrate into the tumors
and have profound antitumor effects. These studies demonstrate the potential
of NPCs as therapeutically effective delivery vehicles for the treatment of
gliomas and also provide important tools to evaluate the migration of NPCs
and changes in glioma burden in vivo. Ann Neurol 2005;57:34-41.
PMID: 15622535 [PubMed - in process]
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| 2: Ann Neurol. 2005 Jan;57(1):128-31. |
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Essential language function of the right hemisphere in
brain tumor patients.
Thiel A, Habedank B, Winhuisen L, Herholz K, Kessler J, Haupt WF, Heiss
WD.
Department of Neurology, University of Cologne.
Neuroimaging studies of language networks in patients with brain lesions of
the left language-dominant hemisphere have shown activation in the right
inferior frontal gyrus (IFG). We tested the functional relevance of right
IFG activation using neuroimaging-guided repetitive transcranial magnetic
stimulation (rTMS) to disturb language function over bilateral IFG in
right-handed patients with brain tumors and controls. All subjects were
susceptible to TMS over the left IFG. In patients, this susceptibility
correlated with left-sided the degree of language lateralization to the
left. Those patients with lowest dominance were also susceptible to
right-sided TMS proving relevant language function of the right IFG. Ann
Neurol 2005;57:128-131.
PMID: 15622534 [PubMed - in process]
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| 3: Ann Neurol. 2005 Jan;57(1):119-27. |
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Natural history of neurofibromatosis 1-associated optic
nerve glioma in mice.
Bajenaru ML, Garbow JR, Perry A, Hernandez MR, Gutmann DH.
Department of Neurology, Washington University School of Medicine, St.
Louis, MO.
Children affected with the inherited tumor predisposition syndrome,
neurofibromatosis 1 (NF1), are prone to the development of low-grade
astrocytic optic pathway tumors (optic pathway glioma [OPG]). Previously, we
developed a model of NF1-associated astrocytoma (GFAPCre; Nf1(flox/mut)
mice) in which mice develop optic nerve and chiasm glioma. To define the
molecular pathogenesis of OPG, we used this mouse model to study the natural
history of OPG formation using immunohistological and radiographic
approaches. We observed that whereas astrocyte hyperplasia is present in the
optic nerves associated with gross optic nerve thickening at 3 weeks of age,
overt neoplastic changes were not seen until 2 months of age. Astrocyte
proliferation was maximal between 3 weeks and 2 months of age, suggesting
that the most rapid period of growth occurs early. Mouse OPG tumors were
detected by magnetic resonance imaging at 2 months of age and exhibited
contrast enhancement, as seen in human OPG. In addition, the mouse OPG
tumors exhibited expression of proteins associated with astroglial
progenitors, including nestin and brain lipid binding protein. Last, we
observed neovascularization and microglial cell infiltration by 3 weeks of
age before overt neoplastic transformation, suggesting that these cellular
changes participate in the early stages of tumor formation. Ann Neurol
2005;57:119-127.
PMID: 15622533 [PubMed - in process]
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| 4: Cancer. 2004 Dec 15;101(12):2900-1; author reply 2901-2. |
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Comment on:
Immunochemotherapy with rituximab and temozolomide for
central nervous system lymphomas.
Pitini V, Arrigo C, Righi M.
Publication Types:
PMID: 15529311 [PubMed - indexed for MEDLINE]
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| 5: Cancer. 2004 Dec 1;101(11):2614-21. |
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Expression of the pro-apoptotic protein ARTS in
astrocytic tumors: correlation with malignancy grade and survival rate.
Gottfried Y, Voldavsky E, Yodko L, Sabo E, Ben-Itzhak O, Larisch S.
Department of Pathology, Rambam Medical Center, Haifa, Israel.
BACKGROUND: Apoptosis (i.e., programmed cell death) plays a major role in
the development of astrocytic tumors, which are the most common tumors of
the central nervous system. ARTS, a proapoptotic protein that is localized
in the mitochondria, promotes apoptosis by functioning as an XIAP antagonist
and a caspase activator. METHODS: To investigate the role of ARTS in
astrocytoma, the authors examined protein expression and apoptotic activity
in 72 astrocytic tumors, which included low-grade astrocytomas, anaplastic
astrocytomas, and glioblastomas. RESULTS: Whereas normal astrocytes did not
express the ARTS protein, astrocytoma cells strongly expressed ARTS, and the
expression of this protein increased with increasing tumor grade.
Furthermore, increased levels of ARTS were significantly associated with
higher rates of apoptosis (as measured using the terminal
deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick
end-labeling [TUNEL] assay as well as an immunohistochemical staining assay
for active caspase-3) in these tumors. Levels of two other apoptosis-related
proteins, p53 and Bcl-2, also were examined using immunohistochemical
methods; ARTS expression was found to be positively correlated with
expression of the former and negatively correlated with expression of the
latter, which is known to possess antiapoptotic activity. CONCLUSIONS: The
results of the current study suggest that ARTS levels reliably reflect the
ability of cells to undergo apoptosis, which serves as a defense mechanism
against the development and progression of astrocytoma. Furthermore, ARTS
expression, when taken into consideration in combination with tumor grade,
was the only independent predictor of survival identified in the current
analysis. Thus, the authors conclude that ARTS may possess utility as a
prognostic marker, as well as a therapeutic tool, for patients with
astrocytoma. (c) 2004 American Cancer Society
PMID: 15517578 [PubMed - indexed for MEDLINE]
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| 6: Cancer. 2004 Dec 1;101(11):2622-8. |
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Parathyroid hormone-related protein expression is
correlated with clinical course in patients with glial tumors.
Pardo FS, Lien WW, Fox HS, Efird JT, Aguilera JA, Burton DW, Deftos LJ.
Division of Radiation Oncology, Department of Radiology, University of
California-San Diego School of Medicine, San Diego, California, USA.
fpardo@ucsd.edu
BACKGROUND: Parathyroid hormone-related protein (PTHrP) expression modulates
cell survival in a number of human solid tumors. Although PTHrP is expressed
in normal developing and neoplastic central nervous system tissue, clinical
data indicating the importance of this protein with respect to local control
and/or survival in patients with glial tumors are scarce. METHODS: Using a
standard immunoperoxidase technique, the authors examined PTHrP expression
in a population of 51 patients with Daumas-Duport Grade II-IV astrocytomas
over a 15-year period. Both local control and survival were calculated from
the date of definitive irradiation to the last time of known follow-up
examination using the actuarial method. PTHrP expression was scored on
examination under 40x magnification, with the incidence of cellular staining
averaged over 10 high-power fields. The intensity and extent of staining
were characterized semiquantitatively using the standard World Health
Organization classification criteria. The median follow-up duration was
approximately 5.5 years. Multivariate analyses were performed to ascertain
the statistical significance of several standard clinicohistopatholgic
factors (Karnofsky functional status, age, gender, extent of surgical
resection, radiotherapy dose, grade, and PTHrP expression) with respect to
local control and survival. P < 0.05 was considered indicative of
statistical significance. RESULTS: Patients with high levels of PTHrP
expression had significantly lower glial tumor local control rates and
corresponding decreases in progression-free and overall actuarial survival
after definitive irradiation (P < 0.01). In a Cox 3-variable model, the
PTHrP staining score was independent of tumor grade or Karnofsky functional
status. It is notable that the strongest predictor of survival was tumor
grade (P < 0.001). CONCLUSIONS: PTHrP may be an important adjunct to
standard immunopathologic criteria in the determination of glial tumor
responses. A number of mechanisms were explored to derive a more mechanistic
understanding of these translational results. Subsequent prospective studies
involving larger patient populations will be necessary before findings can
be translated to clinical practice. (c) 2004 American Cancer Society
PMID: 15517575 [PubMed - indexed for MEDLINE]
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| 7: Cancer. 2004 Dec 1;101(11):2605-13. |
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Carcinoid metastasis to the brain.
Hlatky R, Suki D, Sawaya R.
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer
Center, Houston, Texas, USA.
BACKGROUND: Carcinoid tumors rarely metastasize to the brain. The objectives
of the current study were to assess the frequency of brain metastasis from
carcinoid tumors, determine correlates of survival, and describe treatment
modalities and their outcomes. METHODS: Between January 1977 and December
2003, 1633 patients with a carcinoid tumor were registered at The University
of Texas M. D. Anderson Cancer Center. Of those, 24 patients (1.5%) had a
diagnosis of brain metastasis. The authors collected demographic and
clinical data and performed a statistical analysis. RESULTS: The median age
at the time patients were diagnosed with brain metastasis was 60 years. The
metastases were treated with whole-brain radiotherapy (WBRT) alone in 7
patients (29%), and 12 patients (50%) underwent surgical resection, 7 of
whom (29%) also received WBRT. The median survival time for the entire
cohort after diagnosis of the primary tumor was 2.3 years (95% confidence
interval [CI], 0.5-4.1 years), and the median survival time after the
diagnosis of brain metastasis was 10.0 months (95% CI, 4.0-16.0 months). The
longest median survival observed after the diagnosis of brain metastasis
(3.2 years) occurred in patients who underwent resection and received WBRT.
In the multivariate analysis, the adjusted rate ratio for comparison of all
treatments versus combination of neurosurgical intervention and WBRT was 5.7
(95% CI, 1.3-26.1; P = 0.024). A positive effect of surgery followed by WBRT
on the duration of survival was detected in patients with a single
metastasis (P = 0.084) as well as in those with multiple metastases (P =
0.018). CONCLUSIONS: Prolonged survival was observed in patients < 65
years old as well as in those who underwent surgery and received WBRT in
comparison with other treatments. Whenever feasible, neurosurgical resection
followed by WBRT seems to be the indicated treatment in patients with brain
metastases from carcinoid tumors. (c) 2004 American Cancer Society
PMID: 15495181 [PubMed - indexed for MEDLINE]
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| 8: Cancer. 2004 Dec 1;101(11):2629-32. |
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Defining the best available treatment for neurocytomas in
children.
Rades D, Schild SE, Fehlauer F.
Department of Radiation Oncology, University Hospital Hamburg-Eppendorf,
Hamburg, Germany. Rades.Dirk@gmx.net
BACKGROUND: In children, neurocytomas are extremely rare tumors in the
central nervous system. Since this entity was introduced in 1982,
approximately 60 cases have been reported among patients age </= =18
years of age. The current analysis was performed to define the best
available neurocytoma therapy in children. METHODS: All reported neurocytoma
cases were reviewed for age, extent of resection, radiotherapy, radiotherapy
dose, local control, and survival. Data were obtained from the literature
and the authors. Statistical analysis was performed with the Kaplan-Meier
method and log-rank test. RESULTS: Fifty-nine children were categorized by
therapy: complete tumor resection (CTR; n = 20), complete tumor resection
plus radiotherapy (CTR-RT; n = 11), incomplete tumor resection (ITR; n =
14), and incomplete tumor resection plus radiotherapy (ITR-RT; n = 14).
Local control rates were better after CTR, CTR-RT, and ITR-RT than after
ITR, at 5 years (86%, 100%, and 100% vs. 60%; P < 0.001) and at 10 years
(86%, 100%, and 100% vs. 45%; P < 0.001). The 5-year and 10-year survival
rates were 100% after CTR, 100% after CTR-RT, 100% after ITR-RT, and 93%
after ITR (P = 0.4). In the ITR-RT group, no difference was observed between
doses </= 50 gray (Gy) and >/= 54 Gy when compared for local control
(P = 1.0) and survival rates (P = 1.0). Radiotherapy-related psychomotor
retardation or secondary brain tumors were not reported. CONCLUSIONS: The
prognosis of children with neurocytomas is extremely good. CTR was
associated with better local control and survival rates than ITR. After ITR,
radiotherapy improves local control, but not survival. If postoperative
radiotherapy is considered, a dose of 50 Gy was appropriate for long-term
local control in children, whereas higher doses were required in adults. (c)
2004 American Cancer Society
PMID: 15494975 [PubMed - indexed for MEDLINE]
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| 9: Cancer. 2004 Dec 1;101(11):2687-92. |
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A prospective evaluation of two radiotherapy schedules
with 10 versus 20 fractions for the treatment of metastatic spinal cord
compression: final results of a multicenter study.
Rades D, Fehlauer F, Stalpers LJ, Wildfang I, Zschenker O, Schild SE,
Schmoll HJ, Karstens JH, Alberti W.
Department of Radiation Oncology, University Hospital Hamburg, Hamburg,
Germany. Rades.Dirk@gmx.net
BACKGROUND: The optimal treatment of patients with metastatic spinal cord
compression (MSCC) is still being debated. The current observational
multicenter study, performed prospectively by the authors, evaluated two
radiotherapy (RT) schedules and prognostic factors with respect to
functional outcome METHODS: In the current study, 214 patients with MSCC
were irradiated between April 2000 and September 2003 with 30 gray (Gy) per
10 fractions per 2 weeks (n = 110) or with 40 Gy per 20 fractions per 4
weeks (n = 104). Motor function and ambulatory status were evaluated before
RT and until 6 months after RT. The following potential prognostic factors
were investigated: RT schedule, performance status, age, number of
irradiated vertebrae, type of primary tumor, pretreatment ambulatory status,
and length of time developing motor deficits before RT. RESULTS: Both groups
were balanced for patient characteristics and potential prognostic factors.
Motor function improved in 43% of patients after 30 Gy and in 41% of
patients after 40 Gy (P = 0.799). Posttreatment ambulatory rates were 60%
and 64% (P = 0.708), respectively. A multivariate analysis demonstrated that
a slower progression of motor deficits before RT (P < 0.001), a favorable
histology of the primary tumor (P < 0.001), and being ambulatory before
RT (P = 0.035) were associated with a better functional outcome. RT schedule
(P = 0.269) and other variables had no significant impact. Acute toxicity
was mild, and late toxicity was not observed during the period of follow-up.
Follow-up was 12 (6-28) months in patients surviving >/= 6 months.
CONCLUSIONS: Thirty gray per 10 fractions was preferable to 40 Gy per 20
fractions, because it was associated with similar outcome, less treatment
time, and lower costs. The type of tumor, pretreatment ambulatory status,
and length of time developing motor deficits before RT were relevant
prognostic factors and should be considered in future studies. (c) 2004
American Cancer Society
Publication Types:
- Clinical Trial
- Multicenter Study
PMID: 15493037 [PubMed - indexed for MEDLINE]
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| 10: Cancer. 2004 Nov 15;101(10):2303-8. |
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Measuring circulating neuroblastoma cells by quantitative
reverse transcriptase-polymerase chain reaction analysis.
Cheung IY, Sahota A, Cheung NK.
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York,
New York.
BACKGROUND: Histologic examination of bone marrow (BM) is an accepted
clinical standard for the detection of metastatic neuroblastoma (NB).
Circulating tumor cells in peripheral blood (PB) derive from depots other
than BM, and its measurement may provide additional information in the
management of patients with NB. METHODS: One hundred twenty patients with
Stage 4 NB were evaluated for tumor cell content in PB by quantitative
reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis of GD2
synthase mRNA with a sensitivity of 1 NB cell in 10(6) normal cells. These
findings were correlated with qRT-PCR analysis of their simultaneously
sampled BM aspirates and 5 standard modalities of disease detection
(histology, computed tomography/magnetic resonance imaging, bone scan,
metaiodobenzylguanidine scan, and urinary homovanillic acid/vanillylmandelic
acid levels). RESULTS: Detection of GD2 synthase transcript was found in 62
patients: Eleven patients had positive (+) samples in their BM and PB
(BM+PB+), 38 patients had BM+PB-negative (BM+PB-) specimens, and 13 patients
had BM-PB+ samples. BM+PB+ paired samples had the highest transcript levels.
When the extent of disease was scored (from 0 to 5) according to the number
of positive disease detection modalities, the magnitude of the transcript
level correlated with disease score. Ninety-one percent of patients with
BM+PB+ samples had evidence of disease in >/= 3 modalities, whereas 97%
of patients with BM-PB- samples and 100% of patients with BM-PB+ samples had
low disease scores </= 2. Marker positivity in BM correlated with disease
score. Patients who had positive marker in BM or PB had higher rates of
relapse and death compared with patients who had negative marker.
Kaplan-Meier analysis demonstrated a significantly greater risk of death for
patients who had BM+PB+ specimens compared with patients who had BM-PB-
samples (P = 0.03). CONCLUSIONS: BM monitoring should continue to be an
integral part of disease follow-up for patients with Stage 4 NB. PB
monitoring to complement tumor surveillance in the BM can be informative.
(c) 2004 American Cancer Society
PMID: 15484213 [PubMed - indexed for MEDLINE]
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| 11: Cancer. 2004 Dec 15;101(12):2788-801. |
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Long-term follow-up results of hyperfractionated
cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD),
a dose-intensive regimen, in adult acute lymphocytic leukemia.
Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos
CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ.
Department of Leukemia, The University of Texas M. D. Anderson Cancer
Center, Houston, Texas 77030, USA. hkantarj@mdanderson.org
BACKGROUND: Modern intensive chemotherapy regimens have improved the
prognosis for patients with adult acute lymphocytic leukemia (ALL). With
these regimens, the complete response rates are now reported to be > 80%,
and the long-term survival rates range from 30% to 45%. The current analysis
updated the long-term results with the original hyperfractionated
cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD)
program, with a median follow-up time of 63 months. METHODS: Between 1992
and 2000, 288 patients were treated with Hyper-CVAD. The median age of the
patients was 40 years, and 59 patients (20%) were > or = age 60 years.
The incidence of Philadelphia chromosome (Ph)-positive ALL was 17%, and the
incidence of of T-cell ALL was 13%. RESULTS: A complete response (CR) was
achieved in 92% of patients. The induction mortality rate was 5% (2% if the
patient's age was < 60 years, and 15% if the patient's age was > or =
60 years). With a median follow-up time of 63 months, the 5-year survival
rate was 38% and the 5-year CR duration rate was 38%. Multivariate analysis
of prognostic factors for CR duration identified the following adverse
factors: age > or = 45 years, leukocytosis > or = 50 x 10(9)/L, poor
performance status (an Eastern Cooperative Oncology Group score of 3-4),
Ph-positive disease, French-American-British L2 morphology, > 1 course to
achieve CR, and Day 14 bone marrow blasts > 5%. Patients were divided
into low-risk (risk score 0-1; 37%), intermediate risk (risk score 2-3;
36%), and poor-risk groups (risk score > or = 4; 27%) with 5-year CR
duration rates of 52%, 37%, and 10%, respectively. CONCLUSIONS: Compared
with the previous VAD regimens, Hyper-CVAD was associated with significantly
better CR rates, CR duration, and survival. The long-term follow-up results
of Hyper-CVAD were favorable. Comparison of Hyper-CVAD with other
established adult ALL regimens is warranted.
Publication Types:
PMID: 15481055 [PubMed - indexed for MEDLINE]
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| 12: Cancer. 2004 Nov 15;101(10):2318-26. |
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Small cell astrocytoma: an aggressive variant that is
clinicopathologically and genetically distinct from anaplastic
oligodendroglioma.
Perry A, Aldape KD, George DH, Burger PC.
Division of Neuropathology, Department of Pathology and Immunology,
Washington University School of Medicine, St. Louis, Missouri 63110-1093,
USA. aperry@wustl.edu
BACKGROUND: Small cell glioblastoma (GBM) is a variant with monomorphous,
deceptively bland nuclei that often is misdiagnosed as anaplastic
oligodendroglioma. METHODS: To elucidate its clinicopathologic and genetic
features, the authors studied 71 adult patients (median age, 57 years),
including 22 patients who were identified from a set of 229 GBMs (10%) that
had been characterized previously by epidermal growth factor receptor
(EGFR)/EGFR-vIII variant immunohistochemistry. Tumors also were analyzed by
fluorescence in situ hybridization for 1p, 19q, 10q, and EGFR copy numbers.
RESULTS: Radiologically, 37% of tumors that were not selected for grade
showed minimal to no enhancement. Similarly, 33% of tumors had no
endothelial hyperplasia or necrosis histologically, qualifying only as
anaplastic astrocytoma (Grade III) using World Health Organization criteria.
Nevertheless, such tumors progressed rapidly, with mortality rates that were
indistinguishable from their Grade IV counterparts. The median survival for
37 patients who were followed until death was 11 months.
Oligodendroglioma-like histology included chicken-wire vasculature (86%),
haloes (73%), perineuronal satellitosis (58%), and microcalcifications
(45%), although mucin-filled microcystic spaces were lacking. No small cell
astrocytomas had 1p/19q codeletions, whereas EGFR amplification and 10q
deletions were present in 69% and 97% of small cell astrocytomas,
respectively. The tumors expressed EGFR and EGFR-vIII more commonly than
nonsmall cell GBMs (83% vs. 35% [P < 0.001]; 50% vs. 21% [P < 0.001]
respectively). CONCLUSIONS: Small cell astrocytoma is an aggressive
histologic variant that behaved like primary GBM, even in the absence of
endothelial hyperplasia and necrosis. Despite considerable morphologic
overlap with anaplastic oligodendroglioma, clinicopathologic and genetic
features were distinct. Fifty percent of small cell astrocytomas expressed
the constitutively activated vIII mutant form of EGFR, and molecular testing
for 10q deletion improved the diagnostic sensitivity over EGFR alone. (c)
2004 American Cancer Society
PMID: 15470710 [PubMed - indexed for MEDLINE]
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| 13: Cancer. 2004 Nov 15;101(10):2300-2. |
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Invasive aspergillosis in patients with solid tumors.
Ohmagari N, Raad II, Hachem R, Kontoyiannis DP.
Department of Infectious Diseases, Infection Control and Employee Health,
The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,
USA.
Invasive aspergillosis (IA) has been reported only rarely among patients
with solid tumors. In the current study, the authors retrospectively
identified 13 episodes of definite or probable IA (using European
Organization for Research and Treatment of Cancer criteria) occurring in
patients with solid tumors who were treated between 1994-2003. Nine patients
had pulmonary IA and three patients were found to have IA of the brain.
Seven patients (54%) had primary or metastatic brain tumors and 6 patients
(46%) received systemic steroids within 30 days prior to the diagnosis of
IA. The majority of patients (69%) had a lymphocyte count < 500/microL
but only 1 patient was neutropenic within the 30 days before the diagnosis
of IA was made. Nodular infiltrates and cavities were the most common
radiologic findings. Seven patients (54%) responded to antifungal treatment.
(c) 2004 American Cancer Society
PMID: 15452832 [PubMed - indexed for MEDLINE]
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| 14: Clin Cancer Res. 2004 Dec 15;10(24):8250-65. |
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Characterization of gastrin-induced proangiogenic effects
in vivo in orthotopic U373 experimental human glioblastomas and in vitro in
human umbilical vein endothelial cells.
Lefranc F, Mijatovic T, Mathieu V, Rorive S, Decaestecker C, Debeir O,
Brotchi J, Van Ham P, Salmon I, Kiss R.
Department of Neurosurgery, Erasmus University Hospital.
PURPOSE: This study aims to investigate the role of gastrin-17 (G17) on
angiogenesis features in gliomas both in vitro and in vivo. EXPERIMENTAL
DESIGN: The influences of G17 and G17 receptor antagonists were
characterized in vitro in terms of angiogenesis on human umbilical vein
endothelial cell (HUVEC) tubulogenesis processes on Matrigel and in vivo
with respect to U373 orthotopic glioma xenografts. The influence of
phosphatidylinositol 3'-kinase, protein kinase C, and nuclear factor-kappaB
inhibitors was characterized in vitro on G17-mediated HUVEC tubulogenesis.
G17-mediated release of interleukin (IL)-8 from HUVECs and G17-induced
modifications in nuclear factor-kappaB DNA binding activity were
characterized by means of specific enzyme-linked immunosorbent assays. The
influence of G17 on E- and P-selectin expression was determined by means of
computer-assisted microscopy, whereas the influence of E- and P-selectin on
HUVEC migration was approached by means of antisense oligonucleotides. The
chemotactic influence of G17 and IL-8 on HUVEC migration was characterized
by means of computer-assisted videomicroscopy with Dunn chambers. RESULTS:
Messenger RNAs for cholecystokinin (CCK)A, CCKB, and CCKC receptors were
present in HUVECs and microvessels dissected from a human glioblastoma.
Whereas G17 significantly increased the levels of angiogenesis in vivo in
the U373 experimental glioma model and in vitro in the HUVECs, the CCKB
receptor antagonist L365,260 significantly counteracted the G17-mediated
proangiogenic effects. G17 chemoattracted HUVECs, whereas IL-8 failed to do
so. IL-8 receptor alpha (CXCR1) and IL-8 receptor beta (CXCR2) mRNAs were
not detected in these endothelial cells. Gastrin significantly (but only
transiently) decreased the level of expression of E-selectin, but not
P-selectin, whereas IL-8 increased the expression of E-selectin. Specific
antisense oligonucleotides against E- and P-selectin significantly decreased
HUVEC tubulogenesis processes in vitro on Matrigel. CONCLUSIONS: The present
study shows that gastrin has marked proangiogenic effects in vivo on
experimental gliomas and in vitro on HUVECs. This effect depends in part on
the level of E-selectin activation, but not on IL-8 expression/release by
HUVECs.
PMID: 15623601 [PubMed - in process]
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| 15: Clin Cancer Res. 2004 Dec 15;10(24):8220-8. |
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Noninvasive magnetic resonance spectroscopic imaging
biomarkers to predict the clinical grade of pediatric brain tumors.
Astrakas LG, Zurakowski D, Tzika AA, Zarifi MK, Anthony DC, De Girolami
U, Tarbell NJ, Black PM.
Nuclear Magnetic Resonance Surgical Laboratory, Department of Surgery,
Massachusetts General Hospital, Shriners Burns Institute, Harvard Medical
School, Boston, Massachusetts 02114, USA.
The diagnosis and therapy of childhood brain tumors, most of which are low
grade, can be complicated because of their frequent adjacent location to
crucial structures, which limits diagnostic biopsy. Also, although new
prognostic biomarkers identified by molecular analysis or DNA microarray
gene profiling are promising, they too depend on invasive biopsy. Here, we
test the hypothesis that combining information from biologically important
intracellular molecules (biomarkers), noninvasively obtained by proton
magnetic resonance spectroscopic imaging, will increase the diagnostic
accuracy in determining the clinical grade of pediatric brain tumors. We
evaluate the proton magnetic resonance spectroscopic imaging exams for 66
children with brain tumors. The intracellular biomarkers for
choline-containing compounds (Cho), N-acetylaspartate, total creatine, and
lipids and/or lactate were measured at the highest Cho region and normalized
to the surrounding healthy tissue total creatine. Neuropathological grading
was done with WHO criteria. Normalized Cho and lipids and/or lactate were
elevated in high-grade (n = 23) versus low-grade (n = 43) tumors, which
multiple logistic regression confirmed are independent predictors of tumor
grade (for Cho, odds ratio 24.8, P < 0.001; and for lipids and/or
lactate, odds ratio 4.4, P < 0.001). A linear combination of normalized
Cho and lipids and/or lactate that maximizes diagnostic accuracy was
calculated by maximizing the area under the receiver operating
characteristic curve. Proton magnetic resonance spectroscopic imaging,
although not a proxy for histology, provides noninvasive, in vivo biomarkers
for predicting clinical grades of pediatric brain tumors.
PMID: 15623597 [PubMed - in process]
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| 16: Clin Cancer Res. 2004 Dec 15;10(24):8177-84. |
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Hypoxia is important in the biology and aggression of
human glial brain tumors.
Evans SM, Judy KD, Dunphy I, Jenkins WT, Hwang WT, Nelson PT, Lustig RA,
Jenkins K, Magarelli DP, Hahn SM, Collins RA, Grady MS, Koch CJ.
Department of Radiation Oncology, School of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6072, USA.
sydevans@mail.med.upenn.edu
We investigated whether increasing levels of tissue hypoxia, measured by the
binding of EF5
[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] or
by Eppendorf needle electrodes, were associated with tumor aggressiveness in
patients with previously untreated glial brain tumors. We hypothesized that
more extensive and severe hypoxia would be present in tumor cells from
patients bearing more clinically aggressive tumors. Hypoxia was measured
with the 2-nitroimidazole imaging agent EF5 in 18 patients with
supratentorial glial neoplasms. In 12 patients, needle electrode
measurements were made intraoperatively. Time to recurrence was used as an
indicator of tumor aggression and was analyzed as a function of EF5 binding,
electrode values and recursive partitioning analysis (RPA) classification.
On the basis of EF5 binding, WHO grade 2 tumors were characterized by modest
cellular hypoxia (pO2s approximately 10%) and grade 3 tumors by
modest-to-moderate hypoxia (pO2s approximately 10%- 2.5%). Severe hypoxia
(approximately 0.1% oxygen) was present in 5 of 12 grade 4 tumors. A
correlation between more rapid tumor recurrence and hypoxia was demonstrated
with EF5 binding, but this relationship was not predicted by Eppendorf
measurements.
PMID: 15623592 [PubMed - in process]
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| 17: Clin Cancer Res. 2004 Jun 1;10(11):3667-77. |
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Intravenous RNA interference gene therapy targeting the
human epidermal growth factor receptor prolongs survival in intracranial
brain cancer.
Zhang Y, Zhang YF, Bryant J, Charles A, Boado RJ, Pardridge WM.
Departments of Medicine and Neurology, University of California Los Angeles,
Los Angeles, California 90024, USA.
PURPOSE: The human epidermal growth factor receptor (EGFR) plays an
oncogenic role in solid cancer, including brain cancer. The present study
was designed to prolong survival in mice with intracranial human brain
cancer with the weekly i.v. injection of nonviral gene therapy causing RNA
interference (RNAi) of EGFR gene expression. EXPERIMENTAL DESIGN: Human U87
gliomas were implanted in the brain of adult scid mice, and weekly i.v. gene
therapy was started at day 5 after implantation of 500000 cells. An
expression plasmid encoding a short hairpin RNA directed at nucleotides
2529-2557 within the human EGFR mRNA was encapsulated in pegylated
immunoliposomes. The pegylated immunoliposome was targeted to brain cancer
with 2 receptor-specific monoclonal antibodies (MAb), the murine 83-14 MAb
to the human insulin receptor and the rat 8D3 MAb to the mouse transferrin
receptor. RESULTS: In cultured glioma cells, the delivery of the RNAi
expression plasmid resulted in a 95% suppression of EGFR function, based on
measurement of thymidine incorporation or intracellular calcium signaling.
Weekly i.v. RNAi gene therapy caused reduced tumor expression of
immunoreactive EGFR and an 88% increase in survival time of mice with
advanced intracranial brain cancer. CONCLUSIONS: Weekly i.v. nonviral RNAi
gene therapy directed against the human EGFR is a new therapeutic approach
to silencing oncogenic genes in solid cancers. This is enabled with a
nonviral gene transfer technology that delivers liposome-encapsulated
plasmid DNA across cellular barriers with receptor-specific targeting
ligands.
PMID: 15173073 [PubMed - indexed for MEDLINE]
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| 18: J Neuropathol Exp Neurol. 2004 Dec;63(12):1274-83. |
|
Human endosialin (tumor endothelial marker 1) is
abundantly expressed in highly malignant and invasive brain tumors.
Brady J, Neal J, Sadakar N, Gasque P.
Brain Inflammation and Immunity Group, Department of Medical Biochemistry
and Immunology, University of Wales College of Medicine, Heath Park,
Cardiff, United Kingdom.
Endosialin (tumor endothelial marker 1) is expressed preferentially by tumor
endothelial cells but not by normal endothelium. Its protein domain
architecture is homologous to that of CD93 and thrombomodulin (CD141),
suggesting a similar function in mediating cell-cell interactions. The aim
of this study was to investigate the expression pattern of endosialin in
human brain tumors in a bid to decipher its contribution to tumor
angiogenesis. We generated an antibody specifically recognizing human
endosialin and used it to study endosialin expression in 30 human brain
tumor specimens by immunoblotting and immunohistochemistry. Twenty of 30
tumors expressed endosialin in a heterogeneous manner. The largest
proportion of endosialin-expressing tumors was found in highly invasive
glioblastoma multiforme, anaplastic astrocytomas, and metastatic carcinomas.
Endosialin was localized to the endothelium of small and large vessels
strongly stained for CD31 and was also expressed by Thy-1-positive
fibroblast-like cells close to the meninges and alpha-smooth muscle
actin-positive cells in some vessels. Endosialin colocalized with
thrombomodulin, suggesting the proteins may have complementary functions in
tumor progression.
PMID: 15624764 [PubMed - in process]
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| 19: Neurosurgery. 2005 Jan;56(1):155-62. |
|
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Anti-epidermal growth factor receptor monoclonal antibody
cetuximab augments radiation effects in glioblastoma multiforme in vitro and
in vivo.
Eller JL, Longo SL, Kyle MM, Bassano D, Hicklin DJ, Canute GW.
Department of Neurosurgery, State University of New York Upstate Medical
University, Syracuse, New York.
OBJECTIVE: Previously, we demonstrated that the anti-epidermal growth factor
receptor (EGFR) antibody cetuximab alone was effective against
EGFR-amplified glioblastoma multiforme (GBM) cells in vivo and in vitro. The
purpose of the present work was to study further the effectiveness of
cetuximab as a monotherapy as well as combining it with radiation therapy or
chemotherapy. METHODS: EGFR-amplified GBM cells were implanted either in the
flanks of nude mice to determine the effectiveness of cetuximab on larger
tumor burden or intracranially to assess the ability of cetuximab to cross
the blood-brain barrier. Cells were also exposed to cetuximab in combination
with radiation in vivo or chemotherapeutic agents in vitro. RESULTS:
Increasing tumor burden in the flanks of mice decreased the amount of tumor
growth inhibition. For the first two intracranial models using cetuximab for
5 weeks, the treated mice had a significant increase in median survival
compared with controls. When cetuximab was given indefinitely, the results
were encouraging, with an increase in median survival for the treated group
not yet reached but at least 900%. Mice with flank GBM exposed to cetuximab
and radiation had a larger increase in median survival than those with
either treatment alone. Preliminary in vitro experiments using cetuximab and
chemotherapeutic agents showed increased cytotoxicity. CONCLUSION: These
results were encouraging, demonstrating the effectiveness of cetuximab
against EGFR-amplified GBM. Surprisingly, cetuximab was effective when
administered systemically in an intracranial model. Radiation augmented the
effect of cetuximab on GBM in vitro and in vivo. In vitro analysis
demonstrated additive effects for chemotherapeutic agents as well. These
results confirm EGFR blockade with cetuximab as a potential treatment
against human GBM.
PMID: 15617598 [PubMed - in process]
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| 20: Neurosurgery. 2005 Jan;56(1):146-54. |
|
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Oncolytic Virotherapy of Meningiomas in Vitro with
Replication-competent Adenovirus.
Grill J, Lamfers ML, van Beusechem VW, van der Valk P, Huisman A, Sminia
P, Alemany R, Curiel DT, Vandertop WP, Gerritsen WR, Dirven CM.
Department of Medical Oncology, Division of Gene Therapy, Vrije Universiteit
Medical Center, Amsterdam, The Netherlands, and Department of Pediatric
Oncology, Institut Gustave Roussy, Villejuif, France.
OBJECTIVE: To evaluate the efficacy of the conditionally replicating
adenovirus (Ad) Ad.d24 for oncolysis of benign and malignant meningiomas.
METHODS: Primary meningioma cells and organotypic spheroids were cultured
from tumor biopsies of 12 consecutive unselected patients. Four different
Ads were constructed and tested on meningioma cells and spheroids: a
replication-deficient Ad encoding the luciferase marker gene (Ad.Luc), a
replication-competent Ad with complete E1 region (Ad.E1+), a
replication-competent Ad encoding the luciferase gene in the E3 region
(Ad.E1Luc), and a conditionally replicating Ad with an E1ACR2 deletion
(Ad.d24). Replication of the latter is restricted to cells with a defective
retinoblastoma pathway, whereas Ad.E1+ and Ad.E1Luc can replicate in all
human cells like a wild-type Ad. Their oncolytic activity was compared in
primary meningioma cells and spheroids by use of viability and outgrowth
assays. RESULTS: Adenoviral penetration into organotypic meningioma
spheroids was detected with the replication-competent Ad.E1Luc, whereas
infection with the replication-deficient Ad.Luc was limited to the outer
layer of the spheroid. Replication of the Ads and oncolysis was demonstrated
in primary cell cultures of meningioma cells at high dose, i.e., greater
than 50 plaque-forming units per cell. At a lower dose of 5 plaque-forming
units per cell, Ad.d24 kills meningioma cells more efficiently than Ad.E1+.
Infection of organotypic meningioma spheroids with Ad.d24 resulted in
decreased viability and suppression of outgrowth as compared with untreated
control spheroids. CONCLUSION: Infection of meningioma cells and spheroids
with replication-competent Ads results in efficient oncolysis. The Ad
modified to replicate selectively in retinoblast-mutant cells, Ad.d24,
seemed to be an efficient oncolytic agent in benign, atypical, and malignant
meningiomas.
PMID: 15617597 [PubMed - in process]
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| 21: Neurosurgery. 2005 Jan;56(1):130-8. |
|
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Preoperative and Intraoperative Diffusion Tensor
Imaging-based Fiber Tracking in Glioma Surgery.
Nimsky C, Ganslandt O, Hastreiter P, Wang R, Benner T, Sorensen AG,
Fahlbusch R.
Department of Neurosurgery, University Erlangen-Nurnberg, Erlangen, Germany.
OBJECTIVE: To investigate the intraoperative displacement of major white
matter tracts during glioma resection by comparing preoperative and
intraoperative diffusion tensor imaging-based fiber tracking. METHODS: In 37
patients undergoing glioma surgery, preoperative and intraoperative
diffusion tensor imaging was performed with a 1.5-T magnetic resonance
scanner applying an echo-planar imaging sequence with six diffusion
directions. For three-dimensional tractography, we implemented a
knowledge-based multiple-region-of-interest approach applying user-defined
seed regions in the color-coded maps of fractional anisotropy. Tracking was
initiated in both the retrograde and orthograde directions according to the
direction of the principal eigenvector in each voxel of the region of
interest. The tractography results were also assigned color, applying the
convention used in color-coded fractional anisotropy maps. RESULTS:
Preoperative and intraoperative fiber tracking was technically feasible in
all patients. Fiber tract visualization gave a quick and intuitive overview
of the displaced course of white matter tracts in three-dimensional space.
Comparison of preoperative and intraoperative tractography depicted a marked
shifting of major white matter tracts during glioma removal. Maximum white
matter tract shifting ranged from -8 to +15 mm (+2.7 +/- 6.0 mm; mean +/-
standard deviation); in 29.7%, an inward and in 62.2%, an outward shifting
was detected. CONCLUSION: Comparing preoperative and intraoperative fiber
tracking visualizes a marked shifting and deformation of major white matter
tracts because of tumor removal. This shifting emphasizes the need for an
intraoperative update of navigation systems during resection of deep-seated
tumor portions near eloquent brain areas. Fiber tracking is a method not
only for preoperative neurosurgical visualization but also for further
intraoperative planning.
PMID: 15617595 [PubMed - in process]
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| 22: Surg Neurol. 2004 Dec;62(6):522-9; discussion 529-30. |
|
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Major venous sinus resection in the surgical treatment of
recurrent aggressive dural based tumors.
Buster WP, Rodas RA, Fenstermaker RA, Kattner KA.
Division of Neurological Surgery, Central Illinois Neuroscience Foundation,
Bloomington, IL 61701, USA.
BACKGROUND: Despite gross total resection, aggressive dural based tumors
invading major venous sinuses have high recurrence rates with poor long-term
survivability. Options for aggressive surgical management of dural sinus
invasion may be limited by the inherently high risk of morbidity and
mortality. METHODS: Between July 1996 and July 2002, 5 cases of recurrent
aggressive dural based tumors were operated on. Gross total resection had
been previously performed in 4 cases, and near total resection in 1 case.
Tumor pathology included 2 malignant meningiomas, 1 hemangiopericytoma, 1
atypical meningioma, and 1 benign meningioma with atypical features. All
tumors recurred within 3 to 47 months and occluded a major venous sinus
(four superior sagittal and one dominant right transverse sinus). Gross
total resection of tumor and involved venous sinus was accomplished in each
case. RESULTS: Three patients had no signs of clinical or radiographic
recurrence at 10, 18, and 53 months of follow up. One patient who developed
a fatal pulmonary embolism 10 months postoperatively had evidence of tumor
progression on autopsy. One patient had tumor recurrence at 10 months, but
is alive at 38 months and receiving adjunctive therapy. CONCLUSION: For
aggressive dural based tumors that recur with invasion of a major venous
sinus, radical resection of tumor and occluded sinus can be performed safely
and may improve long-term survival.
Publication Types:
PMID: 15576120 [PubMed - indexed for MEDLINE]
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Volume 4, Number 2 - 5 January 2005