| 1: Br J Cancer. 2004 Aug 31;91(5):829-33. |
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A prognostic index that predicts outcome following
palliative whole brain radiotherapy for patients with metastatic malignant
melanoma.
Morris SL, Low SH, A'Hern RP, Eisen TG, Gore ME, Nutting CM, Harrington
KJ.
Melanoma Unit, The Royal Marsden Hospital NHS Trust, 203 Fulham Road, London
SW3 6JJ, UK.
To determine the outcome of patients with metastatic malignant melanoma
(MMM) treated with palliative whole brain radiotherapy (WBRT) and to
identify factors that predict treatment outcome to assist future trial
design, a retrospective study was performed on patients with MMM who
received WBRT at the Royal Marsden Hospital between 1998 and 2003. Data
regarding patient factors, tumour factors and survival were collected. A
total of 112 patients were identified and full data were available for 102
patients. The median age was 53 years (range 25-81 years), 66.7% were male
and 33.3% female. The median dose prescribed was 20 Gy in five fractions as
a mid-plane dose. The median survival after WBRT for the whole group was 51
days (range 3-1386). In an attempt to define prognostic groups, we used the
validated RTOG recursive partitioning analysis (RPA) classification for
brain metastasis (class 1: Karnofsky Performance Score (KPS) >/=70%, age
<65 years with no extracranial metastasis; class 3: KPS <70%; class 2:
all others). The median survivals were 151, 71 and 21 days for RPA class 1,
2 and 3, respectively (P<0.001). Multivariate analysis showed that RPA
class, leptomeningeal involvement, presence and number of extracranial
metastatic sites and progressive disease in the brain on imaging before WBRT
are important independent predictive factors. A prognostic index was derived
from these factors that allowed identification of patients unlikely to
benefit from WBRT. In conclusion, the RTOG RPA classification is valid when
applied to patients with MMM. Patients in RPA class 1 and good prognosis
class 2 are likely to benefit from palliative WBRT and should be considered
for entry into trials that aim to improve duration of response. We
identified that patients with RPA class 3, leptomeningeal involvement or RPA
class 2 with poor prognostic index are unlikely to benefit from palliative
WBRT.
PMID: 15305201 [PubMed - indexed for MEDLINE]
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| 2: Br J Cancer. 2004 Aug 31;91(5):923-8. |
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Educational attainment among survivors of childhood
cancer: a population-based cohort study in Denmark.
Koch SV, Kejs AM, Engholm G, Johansen C, Schmiegelow K.
Department of Psychosocial Cancer Research, Institute of Cancer
Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100
Copenhagen, Denmark.
We identified 2384 patients in the Danish Cancer Register in whom cancer had
been diagnosed in 1960-1996 before they reached the age of 20 and compared
them with 53 143 sex- and age-matched controls identified from the Register
of Population Statistics. Complete education records and demographic and
socioeconomic information for the period 1980-2000 were obtained for both
cohorts from Statistics Denmark. The rate ratio (RR) for educational
attainment was estimated by discrete-time Cox regression analyses. An
overall reduction in attaining basic education was found (RR, 0.90; 95%
confidence interval, 0.83-0.96). Female survivors of central nervous system
(CNS) tumours showed the largest educational deficit (RR, 0.55; 95%
confidence interval, 0.37-0.82). Non-CNS tumour survivors attained education
as controls at most levels. When the analyses were conditioned on completion
of youth education, further educational attainment was not reduced for any
group of survivors. These findings confirm that only survivors of CNS
tumours in childhood experience significant educational deficits. The
deficit was mainly seen among persons whose tumour was diagnosed before they
reached the level of secondary education.
PMID: 15292930 [PubMed - indexed for MEDLINE]
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| 3: Cancer. 2004 Nov 3 [Epub ahead of print] |
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Phase II study of temozolomide without radiotherapy in
newly diagnosed glioblastoma multiforme in an elderly population.
Alliot C.
Hematology/ncology Division, General Hospital of Annemasse, Annemasse,
France.
No abstract.
PMID: 15526295 [PubMed - as supplied by publisher]
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| 4: Cancer. 2004 Oct 15;101(8):1908-18. |
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Development of a chemoresistant orthotopic human nonsmall
cell lung carcinoma model in nude mice: analyses of tumor heterogenity in
relation to the immunohistochemical levels of expression of
cyclooxygenase-2, ornithine decarboxylase, lung-related resistance protein,
prostaglandin E synthetase, and glutathione-S-transferase-alpha (GST)-alpha,
GST-mu, and GST-pi.
Mathieu A, Remmelink M, D'Haene N, Penant S, Gaussin JF, Van Ginckel R,
Darro F, Kiss R, Salmon I.
Pathology Laboratory, Erasmus University Hospital, Universite Libre de
Bruxelles, Brussels, Belgium.
BACKGROUND: Nonsmall cell lung carcinomas (NSCLCs) are associated with very
dismal prognoses, and adjuvant chemotherapy, including irinotecan, taxanes,
platin, and vinca alkaloid derivatives, offer patients only slight clinical
benefits. Part of the chemoresistance of NSCLC results from the expression
in NSCLC cells of a very large set of endogenous proteins, which antagonize
chemotherapy-mediated attacks on these tumor cells. METHODS: The authors set
up an orthotopic model of a human NSCLC by grafting A549 cells into the
lungs of nude mice. They tried treating these A549 NSCLC orthotopic
xenograft-bearing nude mice on the basis of various chemotherapeutic
protocols, including chronic administrations of taxol, oxaliplatin, and
irinotecan. A cyclooxygenase-2 (COX-2) inhibitor (NS-398) also was assayed
in combination with taxol. The immunohistochemical expression levels of
COX-2, prostaglandin E synthetase (PGES), ornithine decarboxylase (ODC), the
lung-related resistance protein (LRP), and glutathione-S-transferase-alpha
(GST-alpha), GST-mu, and GST-pi were quantitatively determined by means of
computer-assisted microscopy in control and drug-treated NSCLC orthotopic
xenografts. RESULTS: The orthotopic A549 xenograft model developed in 100%
of the grafted mice, leading to brain metastases in approximately 61% mice
and to liver metastases in approximately 40% of mice. The model was
resistant to taxol and oxaliplatin and was only weakly sensitive to
irinotecan. High levels of chemoresistant markers (i.e., COX-2, PGES, ODC,
LRP, GST-alpha, GST-mu, and GST-pi) were observed in the nontreated A549
xenografts, although with dramatic variations in individual expression.
Taxol and oxaliplatin significantly increased the levels of expression of
COX-2, PGES, GST-mu, and GST-pi in a number of different experimental
protocols. CONCLUSIONS: The A549 orthotopic xenograft model could be used to
evaluate investigational chemotherapeutic agents to identify drugs rapidly
that are more active than the drugs currently in use in hospitals.
PMID: 15386340 [PubMed - indexed for MEDLINE]
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| 5: Cancer. 2004 Oct 15;101(8):1760-6. |
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Central nervous system metastases in patients with
high-risk breast carcinoma after multimodality treatment.
Gonzalez-Angulo AM, Cristofanilli M, Strom EA, Buzdar AU, Kau SW, Broglio
KR, Smith TL, Hortobagyi GN.
Department of Breast Medical Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas 77030, USA. agonzalez@mdanderson.org
BACKGROUND: The current study was performed to determine the incidence of
central nervous system (CNS) metastases and to examine associated disease
characteristics in a group of patients with locally advanced breast
carcinoma (LABC) or inflammatory breast carcinoma (IBC) treated at The
University of Texas M. D. Anderson Cancer Center (Houston, TX). METHODS:
Seven hundred sixty-eight patients treated with multimodality therapy
between 1982 and 2000 in any of 6 neoadjuvant trials were eligible for the
current study. Five hundred ninety-two patients (77%) had LABC, and 176
(23%) had IBC. CNS disease was defined as the presence of brain metastases
or leptomeningeal disease. Time to detection of CNS disease and overall
survival were estimated using the Kaplan-Meier product-limit method, and
differences were evaluated using log-rank tests. RESULTS: The median patient
age was 48 years. Most tumors were classified as T4 lesions (58%) and
exhibited lymph node involvement (78%). Fifty-one percent of all tumors had
positive hormone receptor status. At a median follow-up duration of 9.5
years, 61 patients (8%) had developed CNS metastases, with the CNS
representing the first site of recurrence for 38 of these 61 (63%).
Characteristics associated with the development of CNS metastases over time
included negative hormone receptor status (P = 0.03), Grade 3 disease (P =
0.01), and larger tumor size (P = 0.02). The median time to detection of CNS
metastases was 2.3 years. Ten patients (16%) remained alive after treatment
for CNS metastases. The median survival from the time of diagnosis of CNS
metastases was 8 months. CONCLUSIONS: CNS metastases from breast carcinoma
were relatively uncommon and were strongly associated with more aggressive
clinical presentation. Survival from the time of diagnosis of such
metastases generally was short.
PMID: 15386311 [PubMed - indexed for MEDLINE]
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| 6: Cancer. 2004 Oct 15;101(8):1843-9. |
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Late-delayed cerebral involvement in systemic non-Hodgkin
lymphoma: a second primary tumor or a tardy recurrence?
Lossos A, Ashhab Y, Sverdlin E, Amir G, Ben-Yehuda D, Siegal T.
Leslie and Michael Gaffin Center for Neuro-Oncology, Hadassah-Hebrew
University Hospital, Jerusalem, Israel. alos@hadassah.org.il
BACKGROUND: Central nervous system involvement is a well recognized
complication of systemic non-Hodgkin lymphoma. Most central nervous system
recurrences occur within the first 2 years after the initial diagnosis and
are considered to represent clonally related recurrence of systemic disease.
The authors attempted to investigate the clonal relation between the
late-delayed central nervous system involvement and the original systemic
tumor. METHODS: The authors studied archival, formalin fixed, paraffin
embedded tissue samples from 8 patients with isolated cerebral involvement
diagnosed > 3 years after their initial presentation with aggressive,
systemic, B-cell non-Hodgkin lymphoma. The rearranged immunoglobulin
heavy-chain variable region genes (VH) from both sites were amplified by
polymerase chain reaction and were sequenced when necessary. RESULTS: In
three of five patients who had interpretable results, a distinct,
monoclonal, VH family-specific band profile was obtained from the cerebral
and systemic lymphoma. In the other two patients, a similar VH band pattern
was observed and also was compared using direct sequencing, which
demonstrated sequence differences between tumors from the two sites.
CONCLUSIONS: Clonal variance between the cerebral and systemic lymphoma in
these patients suggested the possibility that some instances of late-delayed
recurrence in the central nervous system represent a second, new B-cell
lymphoma rather than a true recurrence of the original systemic tumor, a
finding that may have significant clinical and biologic implications.
PMID: 15372481 [PubMed - indexed for MEDLINE]
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| 7: Cancer Res. 2004 Nov 1;64(21):8009-8014. |
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In vivo near-infrared fluorescence imaging of integrin
alphavbeta3 in brain tumor xenografts.
Chen X, Conti PS, Moats RA.
PET Imaging Science Center, University of Southern California Keck School of
Medicine, Los Angeles, California, USA. shawchen@stanford.edu
Noninvasive visualization of cell adhesion molecule alpha(v)beta(3) integrin
expression in vivo has been well studied by using the radionuclide imaging
modalities in various preclinical tumor models. A literature survey
indicated no previous use of cyanine dyes as contrast agents for in vivo
optical detection of tumor integrin. Herein, we report the integrin receptor
specificity of novel peptide-dye conjugate arginine-glycine-aspartic acid
(RGD)-Cy5.5 as a contrast agent in vitro, in vivo, and ex vivo. The
RGD-Cy5.5 exhibited intermediate affinity for alpha(v)beta(3) integrin
(IC(50) = 58.1 +/- 5.6 nmol/L). The conjugate led to elevated
cell-associated fluorescence on integrin-expressing tumor cells and
endothelial cells and produced minimal cell fluorescence when coincubated
with c(RGDyK). In vivo imaging with a prototype three-dimensional
small-animal imaging system visualized subcutaneous U87MG glioblastoma
xenograft with a broad range of concentrations of fluorescent probe
administered via the tail vein. The intermediate dose (0.5 nmol) produces
better tumor contrast than high dose (3 nmol) and low dose (0.1 nmol) during
30 minutes to 24 hours postinjection, because of partial self-inhibition of
receptor-specific tumor uptake at high dose and the presence of significant
amount of background fluorescence at low dose, respectively. The tumor
contrast was also dependent on the mouse viewing angles. Tumor uptake of
RGD-Cy5.5 was blocked by unlabeled c(RGDyK). This study suggests that the
combination of the specificity of RGD peptide/integrin interaction with
near-infrared fluorescence detection may be applied to noninvasive imaging
of integrin expression and monitoring anti-integrin treatment efficacy
providing near real-time measurements.
PMID: 15520209 [PubMed - as supplied by publisher]
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| 8: Cancer Res. 2004 Nov 1;64(21):7954-7961. |
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SD-208, a novel transforming growth factor beta receptor
I kinase inhibitor, inhibits growth and invasiveness and enhances
immunogenicity of murine and human glioma cells in vitro and in vivo.
Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R, Mangadu R,
Liu YW, Platten M, Herrlinger U, Murphy A, Wong DH, Wick W, Higgins LS,
Weller M.
Laboratory of Molecular Neuro-Oncology, Department of General Neurology,
Hertie Institute for Clinical Brain Research, University of Tubingen, School
of Medicine, Tubingen, Germany.
The cytokine transforming growth factor (TGF)-beta, by virtue of its
immunosuppressive and promigratory properties, has become a major target for
the experimental treatment of human malignant gliomas. Here we characterize
the effects of a novel TGF-beta receptor (TGF-betaR) I kinase inhibitor,
SD-208, on the growth and immunogenicity of murine SMA-560 and human LN-308
glioma cells in vitro and the growth of and immune response to intracranial
SMA-560 gliomas in syngeneic VM/Dk mice in vivo. SD-208 inhibits the growth
inhibition of TGF-beta-sensitive CCL64 cells mediated by recombinant
TGF-beta1 or TGF-beta2 or of TGF-beta-containing glioma cell supernatant at
an EC(50) of 0.1 mumol/L. SD-208 blocks autocrine and paracrine TGF-beta
signaling in glioma cells as detected by the phosphorylation of Smad2 or
TGF-beta reporter assays and strongly inhibits constitutive and
TGF-beta-evoked migration and invasion, but not viability or proliferation.
Peripheral blood lymphocytes or purified T cells, cocultured with
TGF-beta-releasing LN-308 glioma cells in the presence of SD-208, exhibit
enhanced lytic activity against LN-308 targets. The release of interferon
gamma and tumor necrosis factor alpha by these immune effector cells is
enhanced by SD-208, whereas the release of interleukin 10 is reduced. SD-208
restores the lytic activity of polyclonal natural killer cells against
glioma cells in the presence of recombinant TGF-beta or of
TGF-beta-containing glioma cell supernatant. The oral bioavailability of
SD-208 was verified by demonstrating the inhibition of TGF-beta-induced Smad
phosphorylation in spleen and brain. Systemic SD-208 treatment initiated 3
days after the implantation of SMA-560 cells into the brains of syngeneic
VM/Dk mice prolongs their median survival from 18.6 to 25.1 days. Histologic
analysis revealed no difference in blood vessel formation, proliferation, or
apoptosis. However, animals responding to SD-208 showed an increased tumor
infiltration by natural killer cells, CD8 T cells, and macrophages. These
data define TGF-beta receptor I kinase inhibitors such as SD-208 as
promising novel agents for the treatment of human malignant glioma and other
conditions associated with pathological TGF-beta activity.
PMID: 15520202 [PubMed - as supplied by publisher]
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| 9: Cancer Res. 2004 Nov 1;64(21):7794-800. |
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The SmoA1 mouse model reveals that notch signaling is
critical for the growth and survival of sonic hedgehog-induced
medulloblastomas.
Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA,
Russell TL, Ellenbogen RG, Bernstein ID, Beachy PA, Olson JM.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle,
Washington 98109, USA.
To develop a genetically faithful model of medulloblastoma with increased
tumor incidence compared with the current best model we activated the Sonic
Hedgehog (Shh) pathway by transgenically expressing a constitutively active
form of Smoothened in mouse cerebellar granule neuron precursors (ND2:SmoA1
mice). This resulted in early cerebellar granule cell hyper-proliferation
and a 48% incidence of medulloblastoma formation. Gene expression studies
showed an increase in the known Shh targets Gli1 and Nmyc that correlated
with increasing hyperplasia and tumor formation. Notch2 and the Notch target
gene, HES5, were also significantly elevated in Smoothened-induced tumors
showing that Shh pathway activation is sufficient to induce Notch pathway
signaling. In human medulloblastomas reverse transcription-PCR for Shh and
Notch targets revealed activation of both of these pathways in most tumors
when compared with normal cerebellum. Notch pathway inhibition with soluble
Delta ligand or gamma secretase inhibitors resulted in a marked reduction of
viable cell numbers in medulloblastoma cell lines and primary tumor
cultures. Treatment of mice with D283 medulloblastoma xenografts with a
gamma secretase inhibitor resulted in decreased proliferation and increased
apoptosis, confirming that Notch signaling contributes to human
medulloblastoma proliferation and survival. Medulloblastomas in ND2:SmoA1
mice and humans have concomitant increase in Shh and Notch pathway
activities, both of which contribute to tumor survival.
PMID: 15520185 [PubMed - in process]
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| 10: Cancer Res. 2004 Nov 1;64(21):7787-93. |
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Notch1 and notch2 have opposite effects on embryonal
brain tumor growth.
Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, Brat DJ, Perry A,
Eberhart CG.
Department of Pathology, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205, USA.
The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an
oncogene in some neoplasms, and a tumor suppressor in others. Here, we show
that different Notch receptors can have opposite effects in a single tumor
type. Expression of truncated, constitutively active Notch1 or Notch2 in
embryonal brain tumor cell lines caused antagonistic effects on tumor
growth. Cell proliferation, soft agar colony formation, and xenograft growth
were all promoted by Notch2 and inhibited by Notch1. We also found that
Notch2 receptor transcripts are highly expressed in progenitor cell-derived
brain tumors such as medulloblastomas, whereas Notch1 is scarce or
undetectable. This parallels normal cerebellar development, during which
Notch2 is predominantly expressed in proliferating progenitors and Notch1 in
postmitotic differentiating cells. Given the oncogenic effects of Notch2, we
analyzed its gene dosage in 40 embryonal brain tumors, detecting an
increased copy number in 15% of cases. Notch2 gene amplification was
confirmed by fluorescence in situ hybridization in one case with extremely
high Notch2 mRNA levels. In addition, expression of the Notch pathway target
gene Hes1 in medulloblastomas was associated with significantly shorter
patient survival (P = 0.01). Finally, pharmacological inhibition of Notch
signaling suppresses growth of medulloblastoma cells. Our data indicate that
Notch1 and Notch2 can have opposite effects on the growth of a single tumor
type, and show that Notch2 can be overexpressed after gene amplification in
human tumors.
PMID: 15520184 [PubMed - in process]
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| 11: Radiology. 2004 Oct;233(1):56-7. |
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The dural tail sign.
Wallace EW.
Department of Radiology, Oakwood Hospital, 18101 Oakwood Blvd, Dearborn, MI
48123, USA. eww21@yahoo.com
PMID: 15454617 [PubMed - indexed for MEDLINE]
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| 12: Radiology. 2004 Oct;233(1):139-48. Epub 2004 Aug 18. |
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Whole-body MR imaging: evaluation of patients for
metastases.
Lauenstein TC, Goehde SC, Herborn CU, Goyen M, Oberhoff C, Debatin JF,
Ruehm SG, Barkhausen J.
Departments of Diagnostic and Interventional Radiology and Obstetrics and
Gynecology, University Hospital Essen, Hufelandstrasse 55, D-45122 Essen,
Germany. thomas.lauenstein@uni-essen.de
PURPOSE: To compare the results of whole-body magnetic resonance (MR)
imaging with staging based on computed tomographic (CT), dedicated MR
imaging, and nuclear scintigraphic results as standard of reference.
MATERIALS AND METHODS: Fifty-one patients with known malignant tumors were
included in the study. Patients were placed on a rolling table platform
capable of moving the patient rapidly through the isocenter of the magnet
bore. The thorax and the abdomen were imaged by using fast breath-hold
T2-weighted sequences in the transverse plane. After intravenous
administration of a paramagnetic contrast agent, three-dimensional
gradient-echo data sets were collected in five stations and covered the body
from the skull to the knees. Location and size of cerebral, pulmonary,
hepatic, and osseous metastases were documented by two experienced
radiologists. Whole-body MR imaging findings were compared with results
obtained at skeletal scintigraphy, CT, and dedicated MR imaging. RESULTS:
The mean examination time for whole-body MR imaging was 14.5 minutes. All
cerebral, pulmonary, and hepatic metastases greater than 6 mm in diameter
could be identified with whole-body MR imaging. Small pulmonary metastases
were missed with MR imaging, which did not change therapeutic strategies,
but MR imaging depicted a single hepatic metastasis that was missed with CT.
Skeletal scintigraphy depicted osseous metastases in 21 patients, whereas
whole-body MR imaging revealed osseous metastases in 24 patients. The
additional osseous metastases seen with MR imaging were confirmed at
follow-up examinations but did not result in a change in therapy. Whole-body
MR imaging performed on a per-patient basis revealed sensitivity and
specificity values of 100%. CONCLUSION: Whole-body MR imaging for the
evaluation of metastases compared well with the reference techniques for
cerebral, pulmonary, and hepatic lesions. Whole-body MR imaging was more
sensitive in the detection of hepatic and osseous metastases than were the
reference techniques. Copyright RSNA, 2004
PMID: 15317952 [PubMed - indexed for MEDLINE]
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| 13: Radiology. 2004 Oct;233(1):67-78. Epub 2004 Aug 18. |
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Intraoperative high-field-strength MR imaging:
implementation and experience in 200 patients.
Nimsky C, Ganslandt O, Von Keller B, Romstock J, Fahlbusch R.
Department of Neurosurgery, University Erlangen-Nurnberg, Schwabachanlage 6,
91054 Erlangen, Germany. nimsky@nch.imed.uni-erlangen.de
PURPOSE: To review the initial clinical experience with intraoperative
high-field-strength magnetic resonance (MR) imaging of brain lesions in 200
patients. MATERIALS AND METHODS: Two hundred patients (mean age, 46.1 years;
range, 7-84 years), most of whom had glioma or pituitary adenoma, were
examined with a 1.5-T MR imager equipped with a rotating operating table and
located in a radiofrequency-shielded operating theater. A navigation
microscope placed inside the 0.5-mT zone and used in combination with a
ceiling-mounted navigation system enabled integrated microscope-based
neuronavigation. The extent of resection depicted at intraoperative imaging,
the surgical consequences of intraoperative imaging, and the clinical
practicability of the operating room setup were analyzed. RESULTS:
Seventy-seven resections with a transsphenoidal approach, 100 craniotomies,
and 23 burr-hole procedures were performed. In 55 (27.5%) of 200 patients,
intraoperative MR imaging had immediate surgical consequences (eg, extension
of resection in 39% of patients with pituitary adenoma or glioma). In 108
patients the navigation system was used, and for 37 of those patients,
functional imaging data were integrated into the navigation system. There
was nearly no difference in quality between pre- and intraoperative images.
Intraoperative workflow with intraoperative patient transport for imaging
was straightforward, and imaging in most cases began less than 2 minutes
after sterile covering of the surgical site. No complications resulted from
high-field-strength MR imaging. CONCLUSION: The high-field-strength MR
imager was successfully adapted for intraoperative use with the integrated
neuronavigation system. Intraoperative MR imaging provided valuable
information that allowed intraoperative modification of the surgical
strategy. Copyright RSNA, 2004
PMID: 15317949 [PubMed - indexed for MEDLINE]
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Volume 3, Supplement 13 - 9 November 2004