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NCI CANCERLIT® Search: Neuroblastoma - January 2002
National Cancer Institute®
Last Modified: January 1, 2002
Table of Contents
1
UI - 11414640
AU - Wolff M; Schoning M; Niemann G; Krageloh-Mann I
TI -
Late detection of neuroblastoma in a patient with prolonged cerebellar
ataxia without opsoclonus.
SO - Neuropediatrics 2001 Apr;32(2):101-3
AD - Department of Child Neurology, University Children's Hospital, Tubingen,
Germany. Markus.Wolff@med.uni-tuebingen.de
A 19-month-old boy presented with acute-onset cerebellar ataxia
following immunisation. Ataxia was prolonged with a fluctuating course
over a period of two years. Opsoclonus was never observed. Extensive
diagnostic studies were negative during this time. Finally, a
neuroblastoma was discovered. Ataxia disappeared completely during
polychemotherapy. This report suggests that occult neuroblastoma must be
considered in any child with unexplained prolonged cerebellar ataxia.
Specific investigations are recommended for such cases.
2
UI - 11450908
AU - Cackett P; Weir C
TI -
Olfactory neuroblastoma--an unusual presentation.
SO - J Neuroophthalmol 2001 Jun;21(2):90-1
AD - Tennent Institute of Ophthalmology, Gartnavel General Hospital, Glasgow,
Scotland. pdcackett@hotmail.com
3
UI - 11448079
AU - Okuyama C; Ushuima Y; Nakamura T; Kikkawa M; Nishimura T
TI -
Thallium-201 scintigraphy of neuroblastoma: different results for
primary tumors and skeletal lesions.
SO - Ann Nucl Med 2001 Apr;15(2):171-7
AD - Department of Radiology, Kyoto Prefectural University of Medicine,
Japan. cokuyama@rad.kpu-m.ac.jp
Thallium-201 scintigraphy was performed in 8 children with
neuroblastoma, and uptake by the tumors was evaluated in comparison with
the results of 123I-MIBG scintigraphy. No primary tumors or metastatic
lymph nodes showed 201Tl accumulation, but in 4 cases of bone marrow
metastases accompanied by focal cortical invasion, the metastatic lesion
was demonstrated more clearly on the early image than on the delayed
image. In another case of bone metastases infiltrating cortical bone
revealed by 123I-MIBG scintigraphy and biopsy before treatment, 201Tl
scintigraphy performed after chemotherapy showed abnormal accumulation
in the tibia, but the second 123I-MIBG scintigraphy performed 1 week
after the 201Tl scintigraphy showed no abnormal uptake. 201Tl does not
appear to have good affinity for neuroblastoma, but it accumulates in
metastatic skeletal lesions. A reactive hypermetabolic bone marrow,
and/or inflammatory process and periosteal reaction due to the presence
of metastatic foci may have induced the 201Tl accumulation. It seems
that 201Tl is not useful for the diagnosis. Nevertheless, the
discordance between 201Tl uptake in primary tumors and skeletal lesions
allows speculation on the mechanism of 201Tl accumulation in skeletons.
4
UI - 11456333
AU - Sanfeliu C; Sebastia J; Ki SU
TI -
Methylmercury neurotoxicity in cultures of human neurons, astrocytes,
neuroblastoma cells.
SO - Neurotoxicology 2001 Jun;22(3):317-27
AD - Department of Neurology, University of British Columbia, Vancouver,
Canada.
Neurotoxic effects of methylmercury, were investigated in vitro in
primary cultures of human neurons and astrocytes isolatedfrom human
fetal brain and in the human neuroblastoma cell line SH-SY5Y. The
protection provided by agents with antioxidant properties was tested in
these cultures to examine the oxidative stress mechanism of
methylmercury poisoning. After 24 h of exposure to methylmercury, LC50
values were 6.5, 8.1 and 6.9 microM for human neurons, astrocytes and
neuroblastoma cells, respectively, and the degree of cell damage
increased at longer exposure times. Depletion of the cellular pool of
reduced glutathione (GSH) by treatment with buthionine sulfoximine
potentiated methylmercury cytotoxicity in all three cell types;
neuroblastoma cells were the most sensitive. Addition of GSH
extracellularly blocked methylmercury neurotoxicity in all cell types.
The major beneficial effect of GSH could be attributed to its capacity
to form conjugates with methylmercury, which reduces the availability of
these organometallic molecules to the cells and facilitates their
efflux. Cysteine protected astrocytes and neuroblastoma cells from
methylmercury neurotoxicity, while selenite, Vitamin E and catalase
produced some minor protective effects in three cell types, particularly
in neurons. The present study showed that the human neural cells tested
had differential responses to methylmercury: astrocytes were resistant
to methylmercury neurotoxicity and neurons were more most responsive to
protection afforded by antioxidants among the three cell types.
5
UI - 11475582
AU - Lindner W; Behnisch W; Kunz U; Debatin KM; Pohlandt F
TI -
Congenital neuroblastoma mimicking early onset sepsis.
SO - Eur J Pediatr 2001 Jul;160(7):436-8
AD - Department of Paediatrics, University of Ulm, Prittwitzstrasse 43, 89070
Ulm, Germany. wolfgang.lindner@medizin.uni-ulm.de
A newborn girl presented with symptoms of severe early onset sepsis but
also with systemic hypertension (SH) at age 3 h. Plasma catecholamine
(CAT) levels were extremely elevated, reflecting increased release of
CAT from a congenital neuroblastoma (NB). Clinical symptoms at time of
admission were: prolonged capillary refill (5 s), tachycardia,
tachydyspnoea, metabolic acidosis (pH 7.17, lactate 11.8 mmol/l), fever
(38.4 degrees C) and SH: 90/50/65 mmHg (systolic/diastolic/mean). The
infant experienced organ failure (lung, heart, liver). A retroperitoneal
dumbbell tumour was detected. Plasma CAT levels at age 15 h were:
noradrenaline 219 nmol/l; adrenaline 13 nmol/l; and dopamine 65.3
nmol/l. SH responded to intermittent alpha-adrenergic blockage.
CAT-related symptoms ceased within 1 week. The intraspinal NB was
surgically removed when cord compression became symptomatic. The
neurological and developmental state is normal at age 17 months. The
abdominal NB regressed spontaneously. CONCLUSION: A neuroblastoma should
be considered in newborn infants presenting with a shock-like condition
together with systemic hypertension.
6
UI - 11483248
AU - Roseboom PH; Urben CM; Kalin NH
TI -
Persistent corticotropin-releasing factor(1) receptor desensitization
and downregulation in the human neuroblastoma cell line IMR-32.
SO - Brain Res Mol Brain Res 2001 Aug 15;92(1-2):115-27
AD - Department of Psychiatry, University of Wisconsin-Madison, 6001 Research
Park Boulevard, Madison, WI 53719, USA. roseboom@facstaff.wisc.edu
Brain corticotropin-releasing factor (CRF) systems integrate various
responses to stress. Pathological responses to stress may result from
errors in CRF receptor regulation in response to changes in synaptic CRF
levels. To establish an in vitro model to study brain CRF receptors, we
characterized the CRF-induced modulation of CRF(1) receptors in the
human neuroblastoma cell line, IMR-32. Treatment with CRF decreased
CRF(1) receptor binding and desensitized CRF-induced increases in cAMP.
The decrease in binding had an EC(50) of approximately 10 nM, was
maximal by 30 min, and was blocked by the CRF receptor antagonist
[D-Phe(12), Nle(21,38), C(alpha)-MeLeu(37)]CRF(12-41). The
desensitization was homologous as vasoactive intestinal
polypeptide-induced increases in cAMP were unchanged, and elevation of
cAMP did not alter CRF(1) receptor binding. Treatment with CRF for up to
24 h did not alter CRF(1) receptor mRNA levels, suggesting that a
posttranscriptional mechanism maintains the decrease in receptor
binding. Interestingly, recovery of CRF receptor binding and
CRF-stimulated cAMP production was only partial following exposure to
100 nM CRF. In contrast, receptor binding recovered to control levels
following exposure to 10 nM CRF. These data suggest that exposure to
high doses of CRF result in permanent changes characterized by only
partial recovery. Identifying the mechanisms underlying this partial
recovery may provide insights into mechanisms underlying the acute and
chronic effects of stress on CRF receptor regulation.
7
UI - 11547111
AU - Koyle MA; Hatch DA; Furness PD 3rd; Lovell MA; Odom LF; Kurzrock EA
TI -
Long-term urological complications in survivors younger than 15 months
of advanced stage abdominal neuroblastoma.
SO - J Urol 2001 Oct;166(4):1455-8
AD - Department of Pediatric Urology, Children's Hospital and University of
Colorado School of Medicine, Denver, Colorado, USA.
PURPOSE: We evaluated the long-term urological complications in
survivors of infant advanced stage abdominal neuroblastoma. MATERIALS
AND METHODS: The records of patients who presented during an 8-year
period with surgical problems related to the kidney and who had survived
advanced stage (IV and IV-S) neuroblastoma were reviewed. RESULTS: Of 7
patients identified 3 had complications of obstruction from
retroperitoneal fibrosis and 4 had renal cell carcinoma. In the renal
cell carcinoma group 3 patients had synchronous, multifocal, bilateral
tumors and 1 had a tumor in a solitary kidney. Pathological examination
of renal cell carcinoma revealed oncocytoidy with solid and papillary
patterns. One patient underwent bilateral nephrectomy but in the
remaining 3 renal preservation surgery was performed. All 7 patients
have no progression of secondary complications 2 to 8 years after
initial presentation. CONCLUSIONS: Survivors of advanced stage abdominal
neuroblastoma may be predisposed to long-term urological complications
well after initial diagnosis. Because of the risk of renal damage from
obstruction secondary to retroperitoneal fibrosis, and the propensity to
have renal cell carcinoma, close long-term followup using abdominal
imaging is recommended.
8
UI - 11571626
AU - Kong XT; Choi SH; Bessho F; Kobayashi M; Hanada R; Yamamoto K; Hayashi Y
TI -
Codon 201(Gly) polymorphic type of the DCC gene is related to
disseminated neuroblastoma.
SO - Neoplasia 2001 Jul-Aug;3(4):267-72
AD - Department of Pediatrics, Graduate School of Medicine, University of
Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
The deleted in colorectal carcinoma (DCC) gene is a potential
tumor-suppressor gene on chromosome 18q21.3. The relatively high
frequency of loss of heterozygosity (LOH) and loss of expression of this
gene in neuroblastoma, especially in the advanced stages, imply the
possibility of involvement of the DCC gene in progression of
neuroblastoma. However, only few typical mutations have been identified
in this gene, indicating that other possible mechanisms for the
inactivation of this gene may exist. A polymorphic change (Arg to Gly)
at DCC codon 201 is related to advanced colorectal carcinoma and
increases in the tumors with absent DCC protein expression. In order to
understand whether this change is associated with the development or
progression of neuroblastoma, we investigated codon 201 polymorphism of
the DCC gene in 102 primary neuroblastomas by polymerase chain reaction
single-strand conformation polymorphism. We found no missense or
nonsense mutations, but a polymorphic change from CGA (Arg) to GGA (Gly)
at codon 201 resulting in three types of polymorphism: codon 201(Gly)
type, codon 201(Arg/Gly) type, and codon 201(Arg) type. The codon
201(Gly) type occurred more frequently in disseminated (stages IV and
IVs) neuroblastomas (72%) than in localized (stages I, II, and III)
tumors (48%) (P=.035), and normal controls (38%) (P=.024). In addition,
the codon 201(Gly) type was significantly more common in tumors found
clinically (65%) than in those found by mass screening (35%) (P=.002).
The results suggested that the codon 201(Gly) type of the DCC gene might
be associated with a higher risk of disseminating neuroblastoma.
9
UI - 11550280
AU - Van Roy N; Van Limbergen H; Vandesompele J; Van Gele M; Poppe B; Salwen
TI -
H; Laureys G; Manoel N; De Paepe A; Speleman F
Combined M-FISH and CGH analysis allows comprehensive description of
genetic alterations in neuroblastoma cell lines.
SO - Genes Chromosomes Cancer 2001 Oct;32(2):126-35
AD - Centre for Medical Genetics, Ghent University Hospital, De Pintelaan
185, 9000 Ghent, Belgium.
Cancer cell lines are essential gene discovery tools and have often
served as models in genetic and functional studies of particular tumor
types. One of the future challenges is comparison and interpretation of
gene expression data with the available knowledge on the genomic
abnormalities in these cell lines. In this context, accurate description
of these genomic abnormalities is required. Here, we show that a
combination of M-FISH with banding analysis, standard FISH, and CGH
allowed a detailed description of the genetic alterations in 16
neuroblastoma cell lines. In total, 14 cryptic chromosome rearrangements
were detected, including a balanced t(2;4)(p24.3;q34.3) translocation in
cell line NBL-S, with the 2p24 breakpoint located at about 40 kb from
MYCN. The chromosomal origin of 22 marker chromosomes and 41
cytogenetically undefined translocated segments was determined.
Chromosome arm 2 short arm translocations were observed in six cell
lines (38%) with and five (31%) without MYCN amplification, leading to
partial chromosome arm 2p gain in all but one cell line and loss of
material in the various partner chromosomes, including 1p and 11q. These
2p gains were often masked in the GGH profiles due to MYCN
amplification. The commonly overrepresented region was chromosome
segment 2pter-2p22, which contains the MYCN gene, and five out of eleven
2p breakpoints clustered to the interface of chromosome bands 2p16 and
2p21. In neuroblastoma cell line SJNB-12, with double minutes (dmins)
but no MYCN amplification, the dmins were shown to be derived from
16q22-q23 sequences. The ATBF1 gene, an AT-binding transcription factor
involved in normal neurogenesis and located at 16q22.2, was shown to be
present in the amplicon. This is the first report describing the
possible implication of ATBF1 in neuroblastoma cells. We conclude that a
combined approach of M-FISH, cytogenetics, and CGH allowed a more
complete and accurate description of the genetic alterations occurring
in the investigated cell lines. Copyright 2001 Wiley-Liss, Inc.
10
UI - 11555782
AU - Volter C; Baier G; Hoppe F; Schwager K; Helms J
TI -
[Diagnosis, treatment and results of malignant skull base tumours]
SO - Laryngorhinootologie 2001 Sep;80(9):512-6
AD - Univ.-HNO-Klinik Wurzburg, Germany. c.voelter@mail.uni-wuerzburg.de
BACKGROUND: Malignant tumours of the cranial base are rare and present
usually in advanced tumour stage due to the lack of early clinical
symptoms. PATIENTS AND METHODS: Sixty patients with malignant tumours
infiltrating the skull base were treated at the Department of
Otorhinolaryngology Head and Neck Surgery, University of Wurzburg
between 1987 and 1999. Most of the tumours (n = 51) originated from the
nose or paranasal sinuses, the epipharynx, the outer ear canal or the
middle ear. Seven tumours were malignant brain tumours infiltrating the
bony structures of the skull base or originated from the cranial base
itself. Two patients suffered from metastases of an adenocarcinoma of
the prostata. The histological diagnosis was confirmed in 53 patients
preoperatively and in seven patients during tumour resection. Squamous
cell carcinoma (n = 24), adenocarcinoma (n = 10) and sarcoma (n = 7)
were the most common histologies found. RESULTS: A radical en bloc
resection of the tumour was only possible in 26 out of 60 cases. A
surgical tumour reduction with postoperative radiation therapy was
performed in seven patients as a palliative approach. Eight patients
underwent a combined radio- and chemotherapy according to the
histological diagnosis. Primary radiotherapy was the treatment of choice
in eleven patients, where the tumours were located in the central area
of the cranial base. Palliative radiotherapy or solely medical pain
control were applied to eight patients who presented either with distant
metastases or an advanced tumour growth. The mean postoperative survival
following radical surgery was 48 months and after primary radiotherapy
27 months. DISCUSSION: A statistical analysis of the results is not
applicable due to the great variety of the disease concerning the
histological diagnosis, the tumour size and the location as well as the
small number of patients.
11
UI - 11557304
AU - Fried U; Kotarsky K; Alling C
TI -
Chronic ethanol exposure enhances activating protein-1 transcriptional
activity in human neuroblastoma cells.
SO - Alcohol 2001 Jul;24(3):189-95
AD - Department of Medical Neurochemistry, Institute of Laboratory Medicine,
Lund University Hospital, 221 85, Lund, Sweden.
ulrik.fried@neurokemi.lu.se
This study demonstrates a method for studying the effects of ethanol on
transcription mediated by activating protein-1 (AP-1). The effects of
ethanol on AP-1 activity and on the signaling cascades in this process
were investigated by using a reporter gene technique with secreted
alkaline phosphatase as the reporter gene coupled to nine DNA
AP-1-binding elements. Long-term ethanol exposure (48-72 h) dose
dependently enhanced AP-1 transcriptional activity in SH-SY5Y cells.
Shorter exposure periods with ethanol did not influence AP-1
transcriptional activity compared with findings for control cells.
Inhibition of protein kinase C (PKC) dramatically decreased AP-1
activity in both control and ethanol-exposed cells and abolished the
ethanol enhancement. This finding suggests a pivotal role for
PKC-coupled signaling in AP-1 transcriptional activity. Phorbol ester
stimulation of AP-1 transcriptional activity was not influenced by
long-term ethanol exposure. This finding indicates that signaling events
upstream of PKC are the targets for ethanol. Mitogen-activated protein
kinases ERK and p38 may play a role in ethanol-enhanced AP-1 activity
because inhibitors of both enzymes partly reduced the enhancement. The
inhibitors also partly blocked phorbol ester-induced AP-1 activation,
which demonstrates a function of these mitogen-activated protein kinases
downstream of PKC.
12
UI - 11568913
AU - Garaventa A
TI -
Does a "false-negative" MIBG scan predict a better outcome in
neuroblastoma patients?
SO - Med Pediatr Oncol 2001 Oct;37(4):418
13
UI - 11593707
AU - Ichino M; Tsuruta T; Ogawa A; Ichikawa T; Ishii K; Tomita Y
TI -
[A case of adult neuroblastoma arising in the retroperitoneal space]
SO - Nippon Hinyokika Gakkai Zasshi 2001 Sep;92(6):632-5
AD - Department of Urology, Shinsyu University School of Medicine.
Neuroblastoma, common in children, rarely develops in adults. We
recently treated a patient with adult neuroblastoma. A 34-year-old man
complained of a swelling in right inguinal region. CT scan showed
swelling of retroperitoneal and inguinal lymph nodes, and bone
scintigram by 99mTc-HMDP showed an abnormal uptake in the swollen lymph
nodes. Chemotherapy with CDDP (cisplatinum), VP-16 (etoposide), BLM
(bleomycin), ADM (adriamycin) was not effective. Histopathological
examination of a biopsy specimen revealed neuroblastoma. Another
chemotherapy with CPM (cyclophosphamide), VCR (vincristine), ADM, DTIC
(dacarbazine), CDDP, VP-16 was effective in decreasing the tumor size.
Further high dose chemotherapy with CPM, ADM, CDDP, VP-16 combined with
peripheral blood stem cell transplantation led to almost complete
disappearance of the tumor and normalization of blood tumor markers
(neuron specific enolase and immunosuppressive acidic protein).
Retroperitoneal lymph node dissection demonstrated well-differentiated
neuroblastoma in the excised tissue. Six months postoperatively, the
tumor recurred in the pelvic cavity. Although chemotherapy and
radiotherapy were given, he died of the disease 12 months
postoperatively.
14
UI - 11599009
AU - Popescu BO; Cedazo-Minguez A; Popescu LM; Winblad B; Cowburn RF;
TI -
Ankarcrona M
Caspase cleavage of exon 9 deleted presenilin-1 is an early event in
apoptosis induced by calcium ionophore A 23187 in SH-SY5Y neuroblastoma
cells.
SO - J Neurosci Res 2001 Oct 1;66(1):122-34
AD - Karolinska Institute, NEUROTEC, Division of Geriatric Medicine, KFC,
NOVUM, Huddinge, Sweden.
Presenilins (PSs) are mutated in a majority of familial Alzheimer
disease (FAD) cases. Mutated PSs may cause FAD by a number of
pro-apoptotic mechanisms, or by regulating gamma-secretase activity, a
protease involved in beta-amyloid precursor protein processing to the
neurotoxic beta-amyloid peptide. Besides their normal endoproteolytic
processing, PSs are substrates for caspases, being cleaved to
alternative N-terminal and C-terminal fragments. So far little is known
about the role of PSs cleavage in the apoptotic machinery. Here, we used
SH-SY5Y neuroblastoma cells stably transfected with wild-type or exon 9
deleted presenilin 1 (PS1) in a time-course study after the exposure to
the calcium ionophore A23187. During and after exposure to A 23187,
intracellular calcium levels were higher in exon 9 deleted PS1 cells as
compared with non-transfected and wild-type PS1 transfected cells. Cell
death and the enrichment of apoptotic cells after A23187 exposure were
increased by overexpression of exon 9 deleted PS1 as compared with the
control cell lines. Wild-type PS1 cells were compared with exon 9
deleted PS1 cells and the temporal relationship between PS1 and other
caspase substrates cleavages was analyzed. Exon 9 deleted PS1 cells
exhibited a higher caspase-3 activation and a greater cleavage of PS1
and poly(ADP-ribose) polymerase (PARP) compared with wild-type PS1
cells. Exon 9 deleted PS1 cleavage occurred earlier than other caspase
substrate cleavages (i.e., PARP and gelsolin), simultaneous with minimum
detectable caspase-3 activation. Therefore, alternative cleavage of PS1
may play an important role for the regulation of the proteolytic cascade
activated during apoptosis. Copyright 2001 Wiley-Liss, Inc.
15
UI - 11598603
AU - Hayward K; Jeremy RJ; Jenkins S; Barkovich AJ; Gultekin SH; Kramer J;
TI -
Crittenden M; Matthay KK
Long-term neurobehavioral outcomes in children with neuroblastoma and
opsoclonus-myoclonus-ataxia syndrome: relationship to MRI findings and
anti-neuronal antibodies.
SO - J Pediatr 2001 Oct;139(4):552-9
AD - Department of Pediatrics, the Pediatric Clinical Research Center,
University of California San Francisco, USA.
OBJECTIVES: Opsoclonus-myoclonus-ataxia (OMA) syndrome affects 2% to 3%
of patients with neuroblastoma. This study examined relationships
between long-term neurobehavioral outcomes and potential biologic
markers of OMA, including chronic changes on magnetic resonance imaging
(MRI) brain scanning and prevalence of late antineuronal antibodies.
STUDY DESIGN: Children with neuroblastoma and OMA were identified
through medical record review of patients treated at the University of
California at San Francisco Medical Center from 1979 to 1999. Eleven
patients with a mean follow-up time of 7.6 years underwent standard
neurologic, neurocognitive, developmental/behavioral, and academic
assessments. Consenting patients underwent MRI brain scanning and a
blood draw. Sera were analyzed for the presence of antineuronal
immunoreactivity. RESULTS: Two (18%) patients had no observed neurologic
abnormalities, 7 (64%) demonstrated mild deficits, and 2 (18%) had
severe neurologic deficits. However, on neurocognitive, behavioral, and
academic assessments, 6 (55%) children performed within the average
range, 1 (9%) was moderately below average and 4 (36%) had severe
cognitive and behavioral deficiencies. Brain MRI in 5 of 5 patients was
notable for cerebellar atrophy without supratentorial involvement.
Antineuronal activity was detected in sera of 0 of 10 children at
follow-up. CONCLUSIONS: Certain patients with neuroblastoma associated
OMA may achieve average-range neurobehavioral function in spite of
residual neurologic abnormalities, with suggestion of continued
improvement over time. Late cerebellar atrophy appears to be a common
finding regardless of neurologic outcome, whereas antineuronal immune
reactivity does not appear to be a long-term feature of OMA.
16
UI - 11677271
AU - Shankar SL; Mani S; O'Guin KN; Kandimalla ER; Agrawal S; Shafit-Zagardo
TI -
B
Survivin inhibition induces human neural tumor cell death through
caspase-independent and -dependent pathways.
SO - J Neurochem 2001 Oct;79(2):426-36
AD - Department of Pathology, Albert Einstein College of Medicine, Bronx, New
York 10461, USA.
Survivin inhibits apoptosis during development and carcinogenesis and is
absent in differentiated cells. To determine whether survivin inhibition
induces cell death in neural tumor cells, survivin antisense
oligonucleotides (SAO) were administered to a human neuroblastoma (MSN)
and an oligodendroglioma (TC620) resulting in a dose-dependent reduction
in survivin protein. Although 74% of the SAO-treated MSN cells were
trypan blue(+), PARP cleavage or activated caspase-3 was not observed.
However nuclear translocation of AIF occurred and XIAP increased
dramatically. Co-administration of z-Val-Ala-Asp(OMe)-fluoromethyl
ketone (zVAD-fmk) with SAO did not inhibit cell death suggesting a
caspase-independent mechanism of cell death. Propidium iodide (PI)
staining revealed multiple large macronuclei with no apoptotic bodies
supporting a role for survivin in cell division. By contrast, while 70%
of the SAO-treated TC620 cells were trypan blue(+), PARP was cleaved,
cells were TUNEL(+) and PI-staining revealed macronuclei and numerous
apoptotic bodies. Co-treatment of the TC620 cells with SAO and zVAD-fmk
blocked cell death. While no macronuclei or apoptotic bodies were
observed there was a two-fold increase in metaphase cells. Our results
suggest that survivin inhibition decreases the viability of human neural
tumor cells and as a result of mitotic catastrophe, cell death can be
initiated by either a classic apoptotic mechanism or a
caspase-independent mechanism.
17
UI - 11675134
AU - McConville CM; Dyer S; Rees SA; Luttikhuis ME; McMullan DJ; Vickers SJ;
TI -
Ramani P; Redfern D; Morland BJ
Molecular cytogenetic characterization of two non-MYCN amplified
neuroblastoma cell lines with complex t(11;17).
SO - Cancer Genet Cytogenet 2001 Oct 15;130(2):133-40
AD - Division of Medical and Molecular Genetics, University of Birmingham,
Birmingham B15 2TT, UK. c.mcconville@bham.ac.uk
The pediatric tumor neuroblastoma is characterized by a very variable,
and at times unpredictable, pattern of clinical behavior, ranging from a
benign localized tumor to an aggressive malignancy with poor prognosis.
Standard clinical and pathological assessments do not always
differentiate reliably between tumor subtypes and, therefore, genetic
markers are now playing an increasingly important role in treatment
decisions. MYCN oncogene amplification, for example, provides a useful
marker of poor prognosis. However, less than one-half of all patients
who present with, or who later develop, metastatic disease show MYCN
amplification. Consequently, the identification of characteristic
patterns of genetic alteration in the remaining tumors is of importance.
In this report, we describe two new cell lines that we have established
from metastatic, non-MYCN amplified, advanced stage neuroblastomas.
These cell lines show a number of features in common, including
unbalanced translocation between 11q and 17q, loss of 3p, 4p and 11q and
gain of 17q. Therefore, they provide a valuable resource for the
characterization of genetic pathways leading to aggressive tumor growth
in non-MYCN amplified neuroblastomas.
18
UI - 11677110
AU - Catchpoole DR; Lock RB
TI -
The potential tumour suppressor role for caspase-9 (CASP9) in the
childhood malignancy, neuroblastoma.
SO - Eur J Cancer 2001 Nov;37(17):2217-21
AD - Children's Cancer Institute Australia for Medical Research, PO Box 81,
Randwick, NSW 2031, Australia. danielc@chw.edu.au
The clinical aggressiveness of neuroblastoma, a childhood embryonal
tumour of neuroectodermal cells derived from the neural crest, is
considered to be dictated by the competitive interactions between cell
proliferation, differentiation and apoptosis. Caspase-9 is a central
effector enzyme in the apoptotic mechanism. Recent studies with
caspase-9 (CASP9) knockout mice indicate a primary defect in the brain
caused by decreased apoptosis during the early stages of nervous system
development. It is our hypothesis that silencing of CASP9 through
genetic mutations may promote neuroblastoma tumorigenesis. Here, we
report the outcome of screening neuroblastoma tumours for silencing
mutations in CASP9. cDNA prepared from RNA isolated from 22
neuroblastoma tumours representing the full range of neuroblastoma
clinicopathological disease stages was sequenced. Single nucleotide
changes were detected in all neuroblastoma tumours, but were found not
to represent silencing mutations, but rather sequence polymorphisms.
These polymorphisms did not associate with the clinicopathological
stages of disease or the predicted clinical outcomes of the patients.
Silencing mutations of CASP9 are therefore unlikely to be causal to
neuroblastoma tumorigenesis.
19
UI - 11689596
AU - Sato Y; Sasaki H; Kondo S; Fukai I; Kiriyama M; Yamakawa Y; Fujii Y
TI -
Expression of the cdc25B mRNA correlated with that of N-myc in
neuroblastoma.
SO - Jpn J Clin Oncol 2001 Sep;31(9):428-31
AD - Department of Surgery II, Nagoya City University Medical School, Nagoya,
Japan.
BACKGROUND: Neuroblastoma is one of the most common solid tumors in
early childhood. Overexpression of the proto-oncogene N-myc has been
reported to be correlated with more malignant course of the disease.
cdc25B is reported to be a target of myc and elevated in several
malignant cells and tissues. METHODS: Expression of cdc25B and N-myc
messenger RNAs were evaluated by real-time reverse transcription
polymerase chain reaction (RT-PCR) assay in 20 tumor samples from
neuroblastoma using LightCycler. The data were analyzed with reference
to clinicopathological factors. Immunohistochemistry for cdc25B was also
performed. RESULTS: There was no significant difference in the cdc25B
expression between patient groups according to age, gender and clinical
stage. The cdc25B mRNA expression levels were significantly correlated
with N-myc mRNA levels (y = -0.445 + 20.577x, p < 0.0001). CONCLUSION:
We could not establish the clinical significance to determine the cdc25B
mRNA level from neuroblastoma. However, we suggest that cdc25B may play
an active role as a target of N-myc in neuroblastoma, although the
biological function of cdc25B in neuroblastoma remains to be clarified.
20
UI - 11691808
AU - Adachi Y; Reynolds PN; Yamamoto M; Wang M; Takayama K; Matsubara S;
TI -
Muramatsu T; Curiel DT
A midkine promoter-based conditionally replicative adenovirus for
treatment of pediatric solid tumors and bone marrow tumor purging.
SO - Cancer Res 2001 Nov 1;61(21):7882-8
AD - The Division of Human Gene Therapy, Department of Medicine, University
of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Yasuo.Adachi@ccc.uab.edu
The treatment of advanced neuroblastoma (NB) or Ewing's sarcoma (ES) is
one of the major challenges in pediatric oncology. Both malignancies are
refractory to conventional therapies and have an extremely poor
prognosis. High-dose myeloablative radiochemotherapy with autologous
bone marrow or peripheral blood stem cell rescue is one of the most
aggressive treatments attempted for these diseases but is often
undermined by residual tumor cells contaminating the graft. Thus, in
this approach, purging of tumor cells from the graft is key to the
prevention of relapse after transplantation. We investigated a novel
approach to eliminate tumor cells from the bone marrow or peripheral
blood stem cell graft without causing stem cell damage through the use
of a conditionally replicative adenovirus (Ad). ES and NB are sensitive
to Ad infection, and advanced NBs express a high level of the
growth/differentiation factor midkine (MK). We confirmed in this study
that ES cell lines (SK-ES-1 and RD-ES) are also sensitive to Ad
infection and express high levels of MK. In contrast, CD34+ stem cells
are refractory to Ad infection and express very little MK. A
conditionally replicative Ad in which the expression of E1 is controlled
by the MK promoter achieved good levels of viral replication in NB or ES
and induced remarkable tumor cell killing. On the other hand, this virus
caused no damage to CD34+ cells even after 3 h of infection at a dose of
1000 multiplicity of infection. We concluded that application of this
replication-competent Ad to hematopoietic grafts could be a simple but
effective procedure to achieve complete tumor cell purging.
21
UI - 11696453
AU - Krams M; Claviez A; Heidorn K; Krupp G; Parwaresch R; Harms D; Rudolph P
TI -
Regulation of telomerase activity by alternate splicing of human
telomerase reverse transcriptase mRNA in a subset of neuroblastomas.
SO - Am J Pathol 2001 Nov;159(5):1925-32
AD - Department of Pathology, University of Kiel, Kiel, Germany.
mkrams@path.uni-kiel.de
It has been proposed that the regulation of telomerase takes place at
the transcriptional level, the expression of the catalytic subunit human
telomerase reverse transcriptase (hTERT) being crucial for telomerase
activity (TA). Recently, differential splicing of hTERT mRNA has been
demonstrated in various tissues during embryonal development, and it has
been suggested that only full-length transcripts translate into
functionally active telomerase. With this in view, we analyzed the
different hTERT transcripts by reverse transcriptase-polymerase chain
reaction in neuroblastic tumors and compared the results with the TA,
the tumor growth fraction, and the MYCN status. In a series of 38
neuroblastic tumors, high TA and full-length hTERT transcripts were
found in nine samples, whereas nine samples showed absence of both
enzymatic activity and hTERT transcripts. Interestingly, in another
eight samples, low or absent TA coincided with a lack of full-length
hTERT transcripts. Eleven samples contained hTERT transcripts with low
or undetectable TA and one sample had low TA but no hTERT transcripts.
TA correlated with MYCN amplification and was weakly associated with the
proliferative activity. Moreover, a significant correlation with tumor
progression was observed. Our findings point at a posttranscriptional
regulation of TA in a subset of neuroblastic tumors. Because high TA was
detected only in tumors with full-length hTERT transcripts, reverse
transcriptase-polymerase chain reaction analysis of archival
neuroblastic tumor samples might help to appraise the malignant
potential in individual cases.
22
UI - 11696644
AU - Matthay KK; Panina C; Huberty J; Price D; Glidden DV; Tang HR; Hawkins
TI -
RA; Veatch J; Hasegawa B
Correlation of tumor and whole-body dosimetry with tumor response and
toxicity in refractory neuroblastoma treated with (131)I-MIBG.
SO - J Nucl Med 2001 Nov;42(11):1713-21
AD - Department of Pediatrics, University of California, San Francisco, San
Francisco, California 94143-0106, USA.
The purpose of our study was to determine the effect of tumor-targeted
radiation in neuroblastoma by correlating administered
(131)I-metaiodobenzylguanidine (MIBG) activity to tumor and whole-body
dosimetry, tumor volume change, overall response, and hematologic
toxicity. METHODS: Eligible patients had MIBG-positive lesions and
tumor-free, cryopreserved hematopoietic stem cells. Activity was
administered according to body weight and protocol as part of a phase I
and phase II study. The whole-body radiation dose was derived from daily
1-m exposure measurements, the tumor self-absorbed radiation dose
(TSARD) was determined from scintillation-camera conjugate views, and
the tumor volume was measured using CT or MRI. RESULTS: Forty-two
patients with refractory neuroblastoma (16 with prior hematopoietic stem
cell transplant) received a median activity of 555 MBq/kg (15 mCi/kg)
(range, 93-770 MBq/kg) and a median total activity of 11,470 MBq (310
mCi) (range, 3,330-30,969 MBq). The median whole-body radiation dose was
228 cGy (range, 57-650 cGy) and the median TSARD was 3,300 cGy (range,
312-30,500 cGy). Responses among evaluable patients included 16 partial
response, 3 mixed response, 14 stable disease, and 9 progressive
disease. Higher TSARD values predicted better overall disease response
(P < 0.01). The median decrease in tumor volume was 19%; 18 tumors
decreased, 4 remained stable, and 5 increased in size. Correlation was
seen between administered activity per kilogram and whole-body dose as
well as hematologic toxicity (assessed by blood platelet and neutrophil
count nadir) (P < 0.05). The median whole-body dose was higher in the 11
patients who required hematopoietic stem cell infusion for prolonged
neutropenia versus the 31 patients who did not (323 vs. 217 cGy; P =
0.03). CONCLUSION: Despite inaccuracies inherent in dosimetry methods,
(131)I-MIBG activity per kilogram correlated with whole-body radiation
dose and hematologic toxicity. The TSARD by conjugate planar imaging
predicted tumor volume decrease and also correlated with overall tumor
response.
23
UI - 11709726
AU - Meyer GE; Shelden E; Kim B; Feldman EL
TI -
Insulin-like growth factor I stimulates motility in human neuroblastoma
cells.
SO - Oncogene 2001 Nov 8;20(51):7542-50
AD - Neuroscience Program, University of Michigan, 4414 Kresge III, 200 Zina
Pitcher Place, Ann Arbor, MI 48109, USA.
Motility is an important process that contributes to cancer cell spread.
Growth factors are key regulators of motility in many cell types.
Insulin-like growth factor I (IGF-I) causes SH-SY5Y human neuroblastoma
cells to undergo dynamic morphological changes, leading to the extension
of lamellipodia. IGF-I stimulated lamellipodia extension requires
signaling through both phosphatidylinositol 3-kinase (PI3-K) and MAP
kinase pathways. IGF-I, over a period of hours, stimulates SH-SY5Y and
SHEP neuroblastoma cells to become more motile. While SH-SY5Y and SHEP
cells use different insulin receptor substrate (IRS) isoforms to
transduce signals from the IGF-I receptor, IGF-I has the same relative
effect on the motility of both cell lines. Blocking the PI3-K and MAP
kinase pathways attenuates the ability of IGF-I to increase motility.
Overexpression of PTEN also attenuates IGF-I mediated motility. These
results delineate some of the proximal events in the signaling mechanism
utilized by IGF-I to stimulate cell motility.
24
UI - 11709729
AU - Astuti D; Agathanggelou A; Honorio S; Dallol A; Martinsson T; Kogner P;
TI -
Cummins C; Neumann HP; Voutilainen R; Dahia P; Eng C; Maher ER; Latif F
RASSF1A promoter region CpG island hypermethylation in
phaeochromocytomas and neuroblastoma tumours.
SO - Oncogene 2001 Nov 8;20(51):7573-7
AD - Section of Medical and Molecular Genetics, Department of Paediatrics and
Child Health, University of Birmingham, The Medical School, Edgbaston,
Birmingham, B15 2TT, UK.
Deletions of chromosome 3p are frequent in many types of neoplasia
including neural crest tumours such as neuroblastoma (NB) and
phaeochromocytoma. Recently we isolated several candidate tumour
suppressor genes (TSGs) from a 120 kb critical interval at 3p21.3
defined by overlapping homozygous deletions in lung and breast tumour
lines. Although mutation analysis of candidate TSGs in lung and breast
cancers revealed only rare mutations, expression of one of the genes
(RASSF1A) was absent in the majority of lung tumour cell lines analysed.
Subsequently methylation of a CpG island in the promoter region of
RASSF1A was demonstrated in a majority of small cell lung carcinomas and
to a lesser extent in non-small cell lung carcinomas. To investigate the
role of 3p TSGs in neural crest tumours, we (a) analysed
phaeochromocytomas for 3p allele loss (n=41) and RASSF1A methylation
(n=23) and (b) investigated 67 neuroblastomas for RASSF1A inactivation.
46% of phaeochromocytomas showed 3p allele loss (38.5% at 3p21.3).
RASSF1A promoter region hypermethylation was found in 22% (5/23) of
sporadic phaeochromocytomas and in 55% (37/67) of neuroblastomas
analysed but RASSF1A mutations were not identified. In two neuroblastoma
cell lines, methylation of RASSF1A correlated with loss of RASSF1A
expression and RASSF1A expression was restored after treatment with the
demethylating agent 5-azacytidine. As frequent methylation of the CASP8
gene has also been reported in neuroblastoma, we investigated whether
RASSF1A and CASP8 methylation were independent or related events. CASP8
methylation was detected in 56% of neuroblastomas with RASSF1A
methylation and 17% without RASSF1A methylation (P=0.0031). These
results indicate that (a) RASSF1A inactivation
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