Table of Contents
1
UI - 11642491
AU - Shields JA; Shields CL; Brotman HK; Carvalho C; Perez N; Eagle RC Jr
TI -
Cancer metastatic to the orbit: the 2000 Robert M. Curts Lecture.
SO - Ophthal Plast Reconstr Surg 2001 Sep;17(5):346-54
AD - Oncology Service, Wills Eye Hospital, Thomas Jefferson University,
Philadelphia, Pennsylvania 19107, USA.
PURPOSE: To report the demographics and clinical features of a large
series of patients with orbital metastasis. METHODS: Retrospective chart
review on 100 consecutive patients and a literature review on orbital
metastasis. RESULTS: Of 100 patients, the primary tumor site was breast
in 53 (53%), prostate gland in 12 (12%), lung in 8 (8%), skin (melanoma)
in 6 (6%), kidney in 5 (5%), gastrointestinal tract in 5 (5%), choroid
(melanoma) in 2 (2%), parotid gland in 1 (1%), and adrenal gland
(neuroblastoma) in 1 (1%). Of patients in whom a detailed history was
available, there was no history of cancer at the time of presentation in
19%. In 10%, the primary tumor remained undetected despite systemic
evaluation. There were 36 male patients and 64 female patients whose
mean age at diagnosis was 62 years (median 60 years, range 5 to 91
years). Both the right and left orbits were affected equally, and 4
cases (4%) were bilateral. The most frequent clinical findings were
limited ocular motility (54%), proptosis (50%), and palpable mass (43%).
The diagnoses were established by history, systemic survey, imaging
studies, and biopsy. Treatment included chemotherapy, hormone therapy,
irradiation, surgical excision, or observation, depending on clinical
circumstances. Among patients with sufficient follow-up, 95% died of
metastasis, with overall mean survival of 15 months (median 15 months;
range 3 to 96 months) after orbital diagnosis. CONCLUSIONS: The most
common primary cancers that metastasize to the orbit are breast,
prostate gland, and lung cancer. In 19%, there is no history of cancer
when the patient presents with ophthalmic symptoms and in 10% the
primary site remains obscure despite systemic evaluation. The systemic
prognosis is generally poor.
2
UI - 11601682
AU - Bellincampi L; Ballerini S; Bernardini S; Inserra A; Marchetti P;
TI -
Boglino C; Donfrancesco A; Federici G
Glutathione transferase P1 polymorphism in neuroblastoma studied by
endonuclease restriction mapping.
SO - Clin Chem Lab Med 2001 Sep;39(9):830-5
AD - Department of Internal Medicine, University of Rome Tor Vergata, Rome,
Italy.
Several members of the different glutathione transferase (GST) gene
classes are polymorphic. Particular interest has been focused on the
GSTP class because this gene class is up-regulated during the early
stage of oncogenesis and is significantly overexpressed in many human
tumors. It has also been shown that high levels of GSTP1 expression are
associated directly with tumor drug resistance and with poor patient
survival. Our aim was to understand the possible association between
GSTP1 polymorphism and cellular response to chemotherapeutic drugs in
neuroblastoma. In fact, several antineoplastic drugs used in the
neuroblastoma high-risk chemotherapeutic protocol are potential
substrates of GSTP1-1 (etoposide, adriamycin and carboplatin). The GSTP1
genotype homozygote *A/*A was identified in 11 patients independent of
their response to the chemotherapeutic treatment. Only four patients had
a heterozygote genotype A*/B*. Therefore, based on our preliminary data,
we were not able to conclude that GSTP1 polymorphism had an impact on
patient response to treatment in neuroblastoma.
3
UI - 11723749
AU - Yamaguchi S; Wada T; Oba K; Yoshihiro S; Naito K
TI -
Oral etoposide following combination chemotherapy and radiation therapy
in a patient with advanced adult neuroblastoma led to long survival.
SO - Int J Clin Oncol 2001 Oct;6(5):259-61
AD - Department of Urology, Yamaguchi University School of Medicine, 1-1-1
Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
Although neuroblastoma is a common tumor of early childhood, it is rare
in adults. In spite of the poor prognosis of advanced neuroblastoma in
adults, there is still no effective treatment for this condition in
adults. Here we report that oral etoposide salvage chemotherapy was able
to prolong the survival of an adult patient with advanced neuroblastoma.
A 26-year-old man had advanced neuroblastoma that was resistant to
combination intravenous chemotherapy and radiation therapy. He was then
treated with oral etoposide, at a dose of 50 mg daily for 5 days in a
21-day course. Toxicity was very mild and he was followed as an
outpatient while he received 76 courses of this oral etoposide salvage
chemotherapy. Seventy months after diagnosis, this patient is still
alive and has no new distant metastases.
4
UI - 11750901
AU - Nguyen HN; Wang C; Perry DC
TI -
Depletion of intracellular calcium stores is toxic to SH-SY5Y neuronal
cells.
SO - Brain Res 2002 Jan 11;924(2):159-66
AD - Department of Pharmacology, George Washington University Medical Center,
2300 I St. NW, 20037, Washington, DC, USA
Inhibiting Ca(2+) uptake by the sarcoendoplasmic reticular Ca(2+)-ATPase
pump (SERCA) causes release of Ca(2+) from the endoplasmic reticulum
(ER), increased cytosolic Ca(2+) ([Ca(2+)](cyt)) and depletion of ER
Ca(2+) stores. These studies were designed to test the effects of SERCA
inhibition on neuronal viability, using as a model the human
neuroblastoma cell line, SH-SY5Y. Continuous exposure to the SERCA
inhibitor thapsigargin (TG) decreased SH-SY5Y viability to <30% after 48
h exposure, and produced DNA laddering. Two other SERCA inhibitors, BHQ
and cyclopiazonic acid CPA, were similarly toxic, although at 1000-fold
higher concentrations. BHQ and CPA toxicity was prevented by removing
drug within several hours, whereas TG toxicity was essentially
irreversible. All three SERCA inhibitors caused an increase in
[Ca(2+)](cyt) that was partially blocked by the ryanodine receptor
inhibitors, dantrolene and DHBP. Pretreatment with 40 microM dantrolene
gave substantial protection against TG- or BHQ-induced cell death but it
did not inhibit death from staurosporine, which does not cause release
of ER Ca(2+). DHBP (20-100 microM) also gave partial protection against
TG toxicity, as did ruthenium red (2 microM), but not ryanodine (10
microM). Inhibition of capacitative Ca(2+) entry with EGTA or LaCl(3) or
low extracellular Ca(2+), or chelation of [Ca(2+)](cyt) with BAPTA-AM,
failed to inhibit TG toxicity, although they prevented increases in
[Ca(2+)](cyt) caused by TG. Taken together, these data suggest that
toxicity caused by SERCA inhibition in SH-SY5Y cells is caused by ER
Ca(2+) depletion, which triggers an apparent apoptotic pathway.
5
UI - 11753194
AU - Swischuk LE
TI -
Stomach pain for 3 weeks.
SO - Pediatr Emerg Care 2001 Dec;17(6):449-51
AD - Department of Radiology, The University of Texas Medical Branch,
Galveston, Texas 77550-0709, USA.
6
UI - 11807663
AU - Girgert R; Wittrock J; Schweizer P
TI -
Neuroblastoma: inhibition of progression (Part II). Basic science in
pediatric surgery.
SO - Eur J Pediatr Surg 2001 Dec;11(6):363-7
AD - Department of Pediatric Surgery, University of Tubingen, Germany.
rainer.girgert@medizin.uni-ulm.de
In neuroblastoma, amplification of the protooncogene N-myc is the most
important molecular characteristic predicting a bad outcome for the
patients. Despite the importance of the N-myc gene, little is known
about the mechanisms regulating its expression. We found evidence that
insulin-like growth factor II stimulates the growth of neuroblastoma in
a paracrine fashion. Two neuroblastoma cell lines predominantly
expressed IGF-II whereas two other cell lines expressed the
IGF-receptor. In a receptor-positive cell line, N-myc expression was
enhanced by stimulation with IGF-II. As the growth-stimulating signals
of the IGF receptor are transmitted via Ras proteins, inactivation of
Ras is one promising tool to prevent the induction of N-myc expression
by IGF-II. Treatment of neuroblastoma cells with an inhibitor of the
farnesyl-protein-transferase (FPTase) inactivated H-ras protein
completely and N-ras protein by more than 50 %. Cell growth of
neuroblastoma cells in serum containing medium was clearly diminished by
inhibition of FPTase. The growth-promoting effect of IGF-II was reduced
to exactly half the amount observed in non-inhibited cells.
7
UI - 11807672
AU - Petit T; de Lagausie P; El Ghoneimi A; Garel C; Aigrain Y
TI -
Postnatal management of cystic neuroblastoma.
SO - Eur J Pediatr Surg 2001 Dec;11(6):411-4
AD - Department of Paediatric Surgery, Robert Debre University Hospital,
Paris, France. petit.d@chu-caen.fr
Cystic adrenal neuroblastoma (NB) is highly unusual. We report two cases
of cystic NB, detected antenatally and emphasize postnatal strategy
management. Case 1: a right cystic mass was detected in a foetus in the
34th week of pregnancy, and checked as the same in the 36th week.
Postnatal ultrasonography confirmed the presence of a growing adrenal
cystic mass. MRI and MIBG scintigraphy suggested an isolated adrenal
tumour, without catecholamine secretion. Surgical resection was decided
upon and pathological examination confirmed the diagnosis of cystic NB.
Follow-up found a recurrence at 10 months and the patient underwent
excision after chemotherapy. Histology confirmed the metastatic origin
from NB. Case 2: a right adrenal cystic mass was detected during
pregnancy, with no regression of tumour size on postnatal US. MRI, MIBG
scintigraphy, and catechol plasma and urinalysis led to the conclusion
of an isolated non-secreting lesion. A right adrenalectomy was performed
at 1 month. Pathologic examination diagnosed a cystic NB. We would
suggest serial US examinations and early removal of any cystic mass with
characteristic US signs (thick complex wall) or without regression on
one month follow-up. Prenatal diagnosis may provide the best chances for
neonatal excision and good prognosis.
8
UI - 11821825
AU - Tajiri T; Shono K; Tanaka S; Suita S
TI -
Evaluation of genetic heterogeneity in neuroblastoma.
SO - Surgery 2002 Jan;131(1 Suppl):S283-7
AD - Department of Pediatric Surgery, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan.
BACKGROUND AND METHODS: The prognosis in neuroblastoma, which is the
most common solid tumor in children, tends to vary greatly, and many
studies have demonstrated both clinical and biological factors to be
closely correlated with the outcome. In order to select the optimal
treatment according to the degree of malignancy of neuroblastoma, it is
essential to accurately and rapidly identify any genetic heterogeneity
associated with the prognosis. We assessed the status of some genetic
abnormalities (MYCN amplification, deletion of the short arm of
chromosome 1, DNA ploidy, and a gain of the chromosome 17q region)
associated with the prognosis using several molecular biological
methods. RESULTS AND CONCLUSIONS: The combination of several molecular
biological techniques is thus considered to be useful for elucidating
the degree of malignancy of neuroblastoma. In particular, diagnostic
analyses based on a combination of the fluorescence in situ
hybridization (FISH) method and the quantitative polymerase chain
reaction (PCR) method may be considered to be the most effective methods
for quickly and accurately evaluating any aberrations in the gene
dosages associated with the patients' outcomes.
9
UI - 11685689
AU - Iwanaka T; Yamamoto K; Ogawa Y; Arai M; Ito M; Kishimoto H; Hanada R;
TI -
Imaizumi S
Maturation of mass-screened localized adrenal neuroblastoma.
SO - J Pediatr Surg 2001 Nov;36(11):1633-6
AD - Department of Surgery, Saitama Children's Medical Center, 2100 Magome,
Iwatsuki, Saitama 339-8551, Japan.
BACKGROUND/PURPOSE: In infants, neuroblastoma has been known to
spontaneously differentiate into a benign ganglioneuroma. Although
several investigators have compared mass-screened with unscreened,
disseminated with localized, and adrenal with retroperitoneal
neuroblastoma, there are very few cross-comparisons of the above
parameters. Herein, the authors report the maturation of mass-screened,
localized adrenal neuroblastoma. METHODS: Fifty-one mass-screened
adrenal neuroblastomas were divided into 2 groups. In infants less than
1 year of age (Group A), 45 neuroblastomas were resected, whereas 6
neuroblastomas were resected after observation in 1- to 4-year-old
children (group B). Histopathology of the tumors in the 2 groups was
compared. Data were analyzed by X(2) test, and P <.05 was considered
significant. RESULTS: According to the International Neuroblastoma
Pathological Classification, 41 of 45 tumors of group A were
"differentiating neuroblastoma" and 4 of 6 tumors of group B were
"maturing ganglioneuroma." Maturation toward ganglioneuroblastoma was
observed in 16 neuroblastomas of group A (36%) and 6 neuroblastomas of
group B (100%). In group A, 58% had low mitosis karyorrhexis index
(MKI); all patients in group B had low MKI. CONCLUSIONS: If left
untreated, maturation of mass-screened, localized adrenal neuroblastomas
is a common phenomenon. These children do not need to undergo early
operation. Copyright 2001 by W.B. Saunders Company.
10
UI - 11750845
AU - Eggert A; Grotzer MA; Zuzak TJ; Ikegaki N; Zhao H; Brodeur GM
TI -
Expression of Apo-3 and Apo-3L in primitive neuroectodermal tumours of
the central and peripheral nervous system.
SO - Eur J Cancer 2002 Jan;38(1):92-8
AD - Division of Oncology and Biostatistics, The Children's Hospital of
Philadelphia, PA 19104, USA.
Deregulation of apoptosis has been implicated in the pathogenesis,
spontaneous regression and treatment resistance of neuroblastoma. A
newly recognised member of the tumour necrosis factor (TNF)-family of
death receptors known as Apo-3 has been mapped to human chromosome
1p36.3, a region commonly deleted in aggressive neuroblastoma. Based on
its localisation and function, Apo-3 is a candidate for the putative
neuroblastoma tumour suppressor gene. Therefore we analysed mRNA
expression of the Apo-3 receptor/ligand (Apo-3/Apo-3L) system in a
representative panel of 18 neuroblastoma cell lines, 41 primary
neuroblastoma and 13 ganglioneuromas/ganglioneuroblastomas by
semi-quantitative RT-PCR. We compared the level of expression with the
well-established prognostic factors age, stage, histology,
MYCN-amplification and TrkA expression, as well as outcome. For
comparison, we studied Apo-3/Apo-3L expression in 27 central nervous
system (CNS) primitive neuroectodermal tumours/medulloblastomas
(PNET/medulloblastoma) and in six normal brain samples. Neuroblastoma
cell lines with 1p deletion and MYCN-amplification expressed
significantly lower levels of Apo-3 (P=0.009 and P=0.03, respectively)
compared with neuroblastoma cell lines without 1p deletion or
MYCN-amplification. The mean expression level of Apo-3L was
significantly higher in ganglioneuromas/ganglioneuroblastomas compared
with neuroblastomas (P=0.001) and in normal brain compared with
PNET/medulloblastoma (P<0.0001). Expression of Apo-3L was significantly
associated with survival in neuroblastomas (P<0.049) and in
PNET/medulloblastomas (P=0.01). Expression of Apo-3 was significantly
associated with survival in PNET/medulloblastomas (P=0.03). Thus, the
Apo-3 receptor/ligand system might be involved in the regulation of
apoptosis in neuroblastomas and PNET.
11
UI - 11857022
AU - Perel Y; Amrein L; Dobremez E; Rivel J; Daniel JY; Landry M
TI -
Galanin and galanin receptor expression in neuroblastic tumours:
correlation with their differentiation status.
SO - Br J Cancer 2002 Jan 7;86(1):117-22
AD - Laboratory of Differentiation and Development Biology, EA DRED 483,
University of Bordeaux 2, 146, rue Leo Saignat, 33076 Bordeaux Cedex,
France. yves.perel@chu-bordeaux.fr
Neuroblastoma and its benign differentiated counterpart, ganglioneuroma,
are paediatric neuroblastic tumours arising in the sympathetic nervous
system. Their broad spectrum of clinical virulence is mainly related to
heterogeneous biologic background and tumour differentiation.
Neuroblastic tumours synthesize various neuropeptides acting as
neuromodulators. Previous studies suggested that galanin plays a role in
sympathetic tissue where it could be involved in differentiation and
development. We investigated the expression and distribution of galanin
and its three known receptors (Gal-R1, Gal-R2, Gal-R3) in 19 samples of
neuroblastic tumours tissue by immunohistochemistry, in situ
hybridization and fluorescent-ligand binding. This study provides clear
evidence for galanin and galanin receptor expression in human
neuroblastic tumours. The messengers coding for galanin, Gal-R1 and -R3
were highly expressed in neuroblastoma and their amount dramatically
decreased in ganglioneuroma. In contrast, Gal-R2 levels remained
unchanged. Double labelling studies showed that galanin was mainly
co-expressed with its receptors whatever the differentiation stage. In
neuroblastic tumours, galanin might promote cell-survival or counteract
neuronal differentiation through the different signalling pathways
mediated by galanin receptors. Finally, our results suggest that galanin
influences neuroblastoma growth and development as an
autocrine/paracrine modulator. These findings suggest potential critical
implications for galanin in neuroblastic tumours development.
12
UI - 11857322
AU - Krams M; Hero B; Berthold F; Parwaresch R; Harms D; Rudolph P
TI -
Proliferation marker KI-S5 discriminates between favorable and adverse
prognosis in advanced stages of neuroblastoma with and without MYCN
amplification.
SO - Cancer 2002 Feb 1;94(3):854-61
AD - Department of Pathology, University of Kiel, Kiel, Germany.
mkrams@path.uni-kiel.de
BACKGROUND: The biologic behavior of neuroblastoma is notoriously
variable, and even carefully elaborated prognostic models fail to
predict the clinical course in a portion of cases. Because the
proliferative activity is determined by the sum of all molecular
imbalances that influence cell cycling, the authors investigated the
potential prognostic relevance of the tumor growth fraction in
neuroblastoma. METHODS: A retrospective analysis was conducted on a
cohort of 161 neuroblastoma patients with a median follow-up period of
72.8 months. Tumors were classified according to Hughes typing and
grading criteria. The proliferative index (PI) was assessed
immunohistochemically on archival biopsy specimens using monoclonal
antibody Ki-S5 (Ki-67), and the MYCN status was determined by means of
Southern blot analysis. RESULTS: The PI, MYCN status, International
Neuroblastoma Staging System (INSS) stage, International Neuroblastoma
Pathology Classification grade, Hughes grade, and the patients' age at
diagnosis were all found to be significant predictors of event free
survival by univariate Kaplan-Meier analysis. However, the PI identified
prognostically distinct subsets in higher tumor stages and Grade 2 and 3
neuroblastomas as well as tumors with unfavorable histology, and enabled
risk stratification in tumors with and without MYCN amplification (P =
0.034 and 0.002, respectively). Multivariate Cox regression analysis
selected INSS stage (relative risk [RR], 4.05; P < 0.0001) and the PI
(RR, 2.49; P = 0.007) as the sole independent prognostic indicators,
whereas MYCN entered the selection only after exclusion of the PI.
CONCLUSIONS: It emerges that the PI as a single factor has greater
predictive power than the MYCN status. Proliferation measurements
therefore might significantly improve the accuracy of current prognostic
models for neuroblastoma. Copyright 2002 American Cancer Society. DOI
10.1002/cncr.10256
13
UI - 11565832
AU - Sarkar AK; Burlingame SM; Zang YQ; Dulai V; Hicks MJ; Strother DR;
TI -
Nuchtern JG
Major histocompatibility complex-restricted lysis of neuroblastoma cells
by autologous cytotoxic T lymphocytes.
SO - J Immunother 2001 Jul-Aug;24(4):305-11
AD - DeBakey Department of Surgery, Baylor College of Medicine, and The Texas
Children's Cancer Center, Texas Children's Hospital, Houston, USA.
Vigorous host immune reactivity to neuroblastoma may correlate with
better prognosis, but identification of human cytotoxic T-lymphocyte
(CTL) responses has been relatively unsuccessful. We generated
neuroblastoma-reactive CTL lines from two human leukocyte antigen (HLA)
A2+ neuroblastoma patients by stimulation of peripheral blood
lymphocytes (PBLs) with irradiated autologous tumor cells pretreated
with interferon-gamma in the presence of low concentrations of
interleukin-2 (5 U/mL). These lines lyse autologous tumor cells but do
not kill HLA mismatched allogeneic tumor cells, Epstein-Barr
virus-transformed autologous B cells, or standard natural killer cell
targets. Cytotoxic T lymphocytes generated from one patient recognize
tumor cells from several HLA-A2 matched children, although the other
patient's CTLs do not kill tumor cells from other HLA-A2+ individuals.
Pretreatment of CTLs or target cells with appropriate standard
monoclonal antibodies demonstrates that these CTLs are major
histocompatibility complex class I (HLA-A2) restricted and that the
effector cell population is CD8+. Our findings suggest that these tumor
cells express at least one common HLA-A2 restricted antigen and at least
one unique private epitope. Autologous tumor-specific CTLs can be
readily generated from patients' PBLs and maintained in long-term
culture using standard techniques.
14
UI - 11681538
AU - Eldrup E; Clausen N; Scherling B; Schmiegelow K
TI -
Evaluation of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and plasma
3,4-dihydroxyphenylalanine (DOPA) as tumor markers in children with
neuroblastoma.
SO - Scand J Clin Lab Invest 2001;61(6):479-90
AD - Department of Internal Medicine E. Herlev Hospital, University of
Copenhagen, Denmark. eeldrup@dadlnet.dk
Catecholamines and their metabolites are important in the diagnosis of
neuroblastoma (NB). Plasma (p-) levels of 3,4-dihydroxyphenylalanine
(DOPA) are increased in most NB, probably reflecting decreased DOPA
decarboxylase activity. Urine (u-) homovanillic acid (HVA), a DOPA and
dopamine (DA) metabolite. is also increased in most NB. DOPAC
(3,4-dihydroxyphenylacetic acid) is an important metabolite of DA in
tissues with monoamine oxidase (MAO) activity. Because MAO is expressed
in NB tumor cells, we studied the importance of measuring p-DOPAC and
p-DOPA as compared to u-HVA and u-vanillylmandelic acid (VMA) in the
diagnosis and follow-up of NB. DOPAC, DOPA, dopamine, noradrenaline,
adrenaline, VMA and HVA were measured by reverse-phase HPLC with
electrochemical detection in 106 children (28 with NB (13 newly
diagnosed), 25 with other solid tumors, 28 hospitalized for
nonneoplastic diseases, and 25 healthy children). P-DOPAC or p-DOPA
concentrations were above the upper normal range in 92% of untreated NB
patients, as were u-HVA or u-VMA levels. None of these tumor markers was
correlated to tumor stage or survival. P-DOPA but not p-DOPAC was
correlated to age in NB children. Increased values of p-DOPAC and p-DOPA
were found in one patient surviving NB for 10 years. Plasma DOPAC
concentrations were decreased in children hospitalized for non-NB
diseases, probably reflecting reduced food intake. Plasma analyses of
DOPA and DOPAC seem to be useful alternatives in the diagnosis and
follow-up of NB if urine sampling is to be avoided. Plasma DOPAC may be
an index of nutritional status in various diseases.
15
UI - 11757502
AU - Simpson PB; Bacha JI; Palfreyman EL; Woollacott AJ; McKernan RM; Kerby J
TI -
Retinoic acid evoked-differentiation of neuroblastoma cells predominates
over growth factor stimulation: an automated image capture and
quantitation approach to neuritogenesis.
SO - Anal Biochem 2001 Nov 15;298(2):163-9
AD - Department of Biochemistry and Molecular Biology, Neuroscience Research
Centre, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, United
Kingdom. Peter_Simpsom@merck.com
To facilitate the characterization of compounds that have positive
growth factor mimetic effects on neuritogenesis, we have implemented a
high-throughput functional assay which measures, in a multiparametric
manner, the proliferation and differentiation characteristics of cells
in a microtiter plate. Conditions were established using chronic
incubation of SH-SY5Y human neuroblastoma cells with retinoic acid (RA)
and/or nerve growth factor (NGF) in which discernible alterations in
proliferation, growth, and differentiation of cells were induced.
SH-SY5Y cells were fixed and labeled by immunocytochemistry, and an
automated image acquisition and analysis package on Cellomics
ArrayScanII was utilized to quantify the effects of these treatments on
cell characteristics. NGF and retinoic acid were found to increase
multiple parameters of SH-SY5Y differentiation, including an increased
proportion of cells having neurites and increased extent of branching.
However, marked differences in the effects of these compounds on SH-SY5Y
growth and differentiation were also detected: whereas NGF increased
cell number, RA treatment decreased cell number, and RA but not NGF
caused significant elongation of neurites. This study quantifies and
characterizes the effects of differentiating and proliferating agents on
a human-derived neuroblastoma cell line. The high-content,
rapid-throughput nature of this assay makes it ideal for functional
identification and characterization of compounds regulating cell
behavior.
16
UI - 11738505
AU - Mack TG; Dayanandan R; Van Slegtenhorst M; Whone A; Hutton M; Lovestone
TI -
S; Anderton BH
Tau proteins with frontotemporal dementia-17 mutations have both altered
expression levels and phosphorylation profiles in differentiated
neuroblastoma cells.
SO - Neuroscience 2001;108(4):701-12
AD - Department of Neuroscience and Old Age Psychiatry, Institute of
Psychiatry, De Crespigny Park, London, UK. till.mack@uni-koeln.de
The inherited form of frontotemporal dementia with Parkinsonism linked
to chromosome 17 (FTDP-17) has been attributed to mutations in the tau
gene. Pathologically, affected FTDP-17 brains share tau aggregates with
other tauopathies, the most common being Alzheimer's disease. FTDP-17
mutations may therefore affect tau function leading to tau aggregation
and cell loss. Interaction of tau with microtubules is thought to be
regulated by phosphorylation. Investigating FTDP-17 mutations
transiently expressed as enhanced green fluorescent protein
(EGFP)-tagged proteins for the first time in differentiated neuronal
cells, we found that two out of three missense mutations showed
surprisingly decreased phosphorylation at the pathologically relevant
S202/T205 site, mutant EGFP-tau being completely dephosphorylated in
most cells. Moreover, phosphorylation at the S396/S404 site was
moderately decreased for all mutant isoforms. Although microtubule
integrity was not affected, with all mutants tested we demonstrated an
increase in cellular tau protein level, some of which is
microtubule-bound. Further enhancing this EGFP-tau accumulation by
inhibition of tau degradation resulted in the previously less
phosphorylated mutant EGFP-tau becoming highly phosphorylated.We
conclude that the missense tau mutations primarily result in an excess
of neuronal tau, which may interfere with important cellular functions
such as axonal transport.
17
UI - 11857353
AU - Castino R; Pace D; Demoz M; Gargiulo M; Ariatta C; Raiteri E; Isidoro C
TI -
Lysosomal proteases as potential targets for the induction of apoptotic
cell death in human neuroblastomas.
SO - Int J Cancer 2002 Feb 20;97(6):775-9
AD - Dipartimento di Scienze Mediche, Laboratorio di Patologia Molecolare,
Universita A. Avogadro, Novara, Italy.
Neuroblastoma is the most common type of cancer in infants. In children
this tumor is particularly aggressive; despite various new therapeutic
approaches, it is associated with poor prognosis. Given the importance
of endosomal-lysosomal proteolysis in cellular metabolism, we
hypothesized that inhibition of lysosomal protease would impact
negatively on neuroblastoma cell survival. Treatment with E-64 or
CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a
specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma
cell lines having different degrees of malignancy. Cell death was
associated with condensation and fragmentation of chromatin and
externalization of plasma membrane phosphatidylserine, 2 hallmarks of
apoptosis. Concomitant inhibition of the caspase cascade protected
neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These
data indicate that prolonged inhibition of the lysosomal proteolytic
pathway is incompatible with cell survival, leading to apoptosis of
neuroblastoma cells, and that the cathepsin-mediated and
caspase-mediated proteolytic systems are connected and cooperate in the
regulation of such an event. Since modern antitumor chemotherapy is
aimed at restoring the normal rate of apoptosis in neoplastic tissues,
the demonstration that endosomal-lysosomal cathepsins are involved in
this process may constitute a basis for novel strategies that include
cathepsin inhibitors in the therapeutic regimen. Copyright 2001
Wiley-Liss, Inc.
18
UI - 11839584
AU - Douc-Rasy S; Barrois M; Echeynne M; Kaghad M; Blanc E; Raguenez G;
TI -
Goldschneider D; Terrier-Lacombe MJ; Hartmann O; Moll U; Caput D; Benard
J
DeltaN-p73alpha accumulates in human neuroblastic tumors.
SO - Am J Pathol 2002 Feb;160(2):631-9
AD - Departement de Biologie Clinique, Centre National de Recherche
Scientifique-Unite Mixte de Recherche 1598, Institut Gustave Roussy, 39,
rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Neuroblastic tumors (NTs), occurring in early childhood, display a wide
spectrum of differentiation. Recurrent deletions involving the p73 locus
are frequently observed in undifferentiated NTs. To address the question
of the possible implication of p73 in neuroblastic differentiation, we
investigated the status of the expression of this gene in a panel of
differentiated and undifferentiated tumors. Although mutations were not
found, p73 transcript profiles differed between undifferentiated and
differentiated tumors. The frequency of the transcripts lacking exon 2
(species 1-3) appeared to be higher in undifferentiated than in
differentiating and differentiated NTs. In contrast, products from using
an alternate promoter (DeltaN-p73) were present in all NTs. In addition,
only DeltaN-p73, but not full-length proteins, were detected by
immunoblotting, suggesting a greater stability of N-truncated isoforms.
Importantly, as in the adrenal medulla, most NTs showed p73-positive
immunohistological staining with a cellular distribution and intensity
varying according to the neuronal differentiation. Surprisingly, we
observed redistribution of p73 from the nucleus to the cytoplasm during
neuroblastic differentiation. Our data suggest that, in undifferentiated
NTs, a link may exist between the accumulation of DeltaN-p73alpha
variants and the "nuclear exclusion" of p53.
19
UI - 11594709
AU - Kounami S; Douno S; Matsubara H; Takayama J; Ohira M
TI -
Olfactory neuroblastoma as a second malignant neoplasm in a patient
previously treated for childhood acute leukemia.
SO - Pediatr Hematol Oncol 2001 Oct-Nov;18(7):459-63
AD - Department of Pediatrics, National Cancer Center Hospital, Tokyo, Japan.
Various kinds of second malignant neoplasms after sucessful treatment
for childhood acute leukemia have been reported. The authors describe an
unusual case of an olfactory neuroblastoma in a patient previously
treated for childhood acute leukemia including autologous bone marrow
transplantation. The prophylactic cranial irradiation and the total body
irradiation during autologous bone marrow transplantation may have
induced the development of their patient's olfactory neuroblastoma.
Although a second primary olfactory olfactory neuroblastoma is rare is
rare, it should be added to the list of second malignant neoplasms in
the sinonasal region.
20
UI - 11594710
AU - Iwata A; Hirota T; Konno K; Fujimoto T; Sumida S; Sato K; Hara K
TI -
Osteosarcoma as a second malignancy after treatment for neuroblastoma.
SO - Pediatr Hematol Oncol 2001 Oct-Nov;18(7):465-9
AD - Department of Pediatrics, Aichi Medical University, Japan.
A 4-month old girl was diagnosed as having stage IV neuroblastoma of the
right adrenal gland. Preoperative chemotherapy was given, followed by
local surgical excision. Postoperatively, irradiation of the tumor bed
and adjuvant chemotherapy was given for 11 months. Nine years after
cessation of chemotherapy, the patient developed left hip-joint pain.
Biopsy of the ischium showed chondroblastic osteosarcoma. Limb salvage
surgery was performed after preoperative chemotherapy. Postoperatively,
adjuvant chemotherapy was given for 14 months. Twenty-two months after
treatment for the secondary osteosarcoma, the patient has been remained
in disease-free condition without any evidence of relapse. A second
osteosarcoma occurring outside the radiation field after treatment for
neuroblastoma is quite rare. This unusual case emphasized the need for
close monitoring for development of second malignant neoplasms in
survivors of neuroblastoma even in the absence of a known predisposing
factor, such as radiation therapy.
21
UI - 11878578
AU - Reuland P; Geiger L; Thelen M H; Handgretinger R; Haase B;
TI -
Muller-Schauenburg W; Niethammer D; Bares R
Follow-up in neuroblastoma: comparison of metaiodobenzylguanidine and a
chimeric anti-GD2 antibody for detection of tumor relapse and therapy
response.
SO - J Pediatr Hematol Oncol 2001 Oct;23(7):437-42
AD - Department of Nuclear Medicine, University of Tubingen, FRG, Germany.
Early and correct diagnosis of local tumor recurrence, occurrence of
metastases, and therapy response are essential in patients with
neuroblastoma stage IV. The aim of the study was to evaluate the
diagnostic value of metaiodobenzylguanidine (mIBG) and a chimeric GD2
antibody in the follow-up of patients with neuroblastoma. In a
prospective study, mIBG (N = 31 scans) and immunoscintigraphy were
compared with a chimeric antiganglioside antibody, ch14.18 (MAb) (N = 31
scans), labeled with technetium Tc 99m in the follow-up of 18 patients
with stage IV neuroblastoma. The findings were compared with histologic
findings, other imaging examinations, and clinical changes over the
course of 4 to 6 years. For the diagnosis of local tumor recurrences,
sensitivity was 80% for MAb and 70% for mIBG. Specificity was 93% for
MAb and 72% for mIBG. The MAb was superior for the detection of skeletal
metastases, with a sensitivity of 82% compared with 72% for mIBG.
Specificity was 100% for both techniques. Also, for soft tissue/lymph
node metastases, sensitivity for MAb was higher (50%) than for mIBG
(31%). Specificity was 100% for each technique. In sequential studies,
metastases were detected earlier with MAb (mean: 2.3 m for skeletal
metastases, 3.6 m for soft tissue metastases) than with mIBG. After
therapy, tumor uptake was visualized longer with mIBG (mean 6.3 m) than
with MAb. The chimeric antibody ch14.18 is likely to be valuable for
follow-up examinations and for assessment of therapy response because of
earlier detection of new metastases.
22
UI - 11740055
AU - Candanedo-Gonzalez FA; Alvarado-Cabrero I; Gamboa-Dominguez A;
TI -
Cerbulo-Vazquez A; Lopez-Romero R; Bornstein-Quevedo L; Salcedo-Vargas M
Sporadic type composite pheochromocytoma with neuroblastoma:
clinicomorphologic, DNA content and ret gene analysis.
SO - Endocr Pathol 2001 Fall;12(3):343-50
AD - Department of Pathology, Oncology Hospital, Centro Medico Nacional Siglo
XXI, IMSS. Mexico, D.F. Mexico. fcandanedo@hotmail.com
Composite pheochromocytomas (CP) account for only 3% of all
pheochromocytomas. We analyzed the clinical, immunohistochemical,
ultrastructural, DNA content, and 634 ret mutation features in a
56-year-old Mexican woman with CP localized in the right adrenal gland
and associated to a blood pressure of 140/90 mmHg. Clinical symptoms
were absent after surgery. The tumor showed pheochromocytoma and
neuroblastoma components. This dual phenotype was supported by light
microscopy and corroborated by immunohistochemistry and ultrastructural
findings. Flow cytometric analysis showed that both components were
diploid. A genetic mutational analysis of the ret oncogene in exon 11
showed no 634 mutation. This case demonstrates the indolent behavior of
neuroblastoma associated to a sporadic-type CP in an adult patient.
23
UI - 11748431
AU - Mitjavila M
TI -
Meta-iodobenzylguanidine in neuroblastoma: from diagnosis to therapy.
SO - Nucl Med Commun 2002 Jan;23(1):3-4
24
UI - 11880464
AU - Reynolds CP
TI -
Ras and Seppuku in neuroblastoma.
SO - J Natl Cancer Inst 2002 Mar 6;94(5):319-21
25
UI - 11880474
AU - Kitanaka C; Kato K; Ijiri R; Sakurada K; Tomiyama A; Noguchi K;
TI -
Nagashima Y; Nakagawara A; Momoi T; Toyoda Y; Kigasawa H; Nishi T;
Shirouzu M; Yokoyama S; Tanaka Y; Kuchino Y
Increased Ras expression and caspase-independent neuroblastoma cell
death: possible mechanism of spontaneous neuroblastoma regression.
SO - J Natl Cancer Inst 2002 Mar 6;94(5):358-68
AD - Biophysics Division, National Cancer Center Research Institute, Chuo-ku,
Tokyo, Japan. ckitanak@ncc.go.jp
BACKGROUND: Neuroblastoma undergoes spontaneous regression frequently
during its natural course. Although programmed cell death (PCD) has been
implicated in this process, accumulating evidence suggests that
apoptosis, a form of PCD that is regulated by caspases, may not play a
major role. We examined the mechanism(s) of spontaneous regression of
neuroblastoma, focusing on the role of Ras, a favorable prognostic
marker of neuroblastoma. METHODS: Tumor tissues were analyzed by light
microscopy, electron microscopy, and immunohistochemistry to examine
cell degeneration and expression of Ras and several indicators of PCD.
Cell degeneration was also studied in vitro in neuroblastoma cells
transfected with the H-ras gene. All statistical tests were two-sided.
RESULTS: Immunohistochemical analyses revealed that Ras expression was
increased in areas of cellular degeneration lacking apoptotic
characteristics. The degenerating cells were fragmented without nuclear
condensation and, essentially, lacked caspase-3 activation and apoptotic
DNA fragmentation. These cells had ultrastructural features of
autophagic degeneration, another form of PCD that is distinct from
apoptosis. Focal areas of degeneration associated with Ras expression
were seen more frequently in tumors from patients detected in a
mass-screening program (53 [60.9%] of 87) than in tumors from clinically
detected, advanced-stage patients over 1 year of age (7 [29.2%] of 24)
(P =.006; chi-square test), suggesting a positive relationship between
Ras-associated degeneration and probability of spontaneous
regression/favorable prognosis. The characteristic features of
Ras-associated nonapoptotic degeneration observed in tumor samples were
recapitulated in vitro by transfection-mediated Ras expression, and
Ras-mediated degeneration was augmented by TrkA, another favorable
prognostic marker. CONCLUSIONS: High-level expression of H-Ras in
neuroblastoma cells is associated with caspase cascade-independent,
nonapoptotic PCD. This Ras-mediated nonapoptotic tumor cell death may
play a key role in spontaneous regression of neuroblastoma.
26
UI - 11737230
AU - Huang S; Lichtenauer UD; Pack S; Wang C; Kim AC; Lutchman M; Koch CA;
TI -
Torres-Cruz J; Huang SC; Benz EJ Jr; Christiansen H; Dockhorn-Dworniczak
B; Poremba C; Vortmeyer AO; Chishti AH; Zhuang Z
Reassignment of the EPB4.1 gene to 1p36 and assessment of its
involvement in neuroblastomas.
SO - Eur J Clin Invest 2001 Oct;31(10):907-14
AD - Molecular Pathogenesis Unit, Surgical Neurology Branch, NINDS/NIH,
Building 10/Room 5D32, 9000 Rockville Pike, Bethesda, MD 20892, USA.
OBJECTIVES: EPB4.1 has been previously mapped to human chromosome
1p33-p34.2. In contradiction to this chromosomal location, we have
mapped EPB4.1-1p36 by using fluorescence in situ hybridization and
radiation hybrid mapping. In neuroblastomas, deletions of the telomeric
end of chromosome 1 (1p36) are the most common genetic aberration.
METHODS: We investigated whether genetic aberrations of EPB4.1 can be
detected in some neuroblastomas by analyzing 72 tumours for EPB4.1
mutation, expression, and alternative splicing pattern. Furthermore,
EPB4.1 protein from a neuroblastoma cell line was studied for its
subcellular localization. RESULTS: Sequence changes could be detected in
14 out of 72 neuroblastomas, including missense, silent, and intronic
changes. Duplex RT-PCR analysis revealed a subset of 11 tumours
expressing significantly low levels of EPB4.1. Significant EPB4.1
sequence changes that were detected included an exon 4 G/A missense
mutation (amino acid: V/I) that was shown to be associated with absence
of wild-type EPB4.1 expression (3 tumours), an exon 8 G/A missense
mutation (V/M) (1 tumour), and an intronic sequence change that was
shown to be associated with the presence of an aberrant transcript (1
tumour). Splicing pattern analysis revealed that all EPB4.1 transcripts
from tumours exclude exon 3, a splicing pattern for generating the 135
kDa isoform. EPB4.1 cDNA cloned from a neuroblastoma cell line produced
a 135-kDa protein with a cytoplasm/membrane localization. CONCLUSIONS:
Out of 72 neuroblastomas we have identified 11 tumours with impaired
EPB4.1 expression and 5 tumours with significant sequence changes. We
also found that the 135 kDa isoform is the main EPB4.1 product in
neuroblastoma. EPB4.1 cDNA from a neuroblastoma cell line produced a
135-kDa protein and displayed a cytoplasm/membrane localization in
transfected cells.
27
UI - 11847429
AU - Truckenmiller ME; Vawter MP; Cheadle C; Coggiano M; Donovan DM; Freed
TI -
WJ; Becker KG
Gene expression profile in early stage of retinoic acid-induced
differentiation of human SH-SY5Y neuroblastoma cells.
SO - Restor Neurol Neurosci 2001;18(2-3):67-80
AD - Cellular Neurobiology Research Branch, Intramural Research Program,
National Institute on Drug Abuse, National Institutes of Health, 5500
Nathan Shock Drive, Baltimore, MD 21224, USA.
etrucken@intra.nida.nih.gov
PURPOSE: The human SH-SY5Y cell line is an established model for
retinoic acid (RA)-induced neural differentiation. We employed a broad
human 15K microarray (15,000 genes) and focused Neuroarray (1152 genes)
to examine changes in gene expression early in the process of
differentiation (6 hr), before morphology or growth changes are
observed. METHODS: 33 P-labeled CDNA probes prepared from RNA extracts
of RA-treated and control cultures were hybridized to array membranes,
and levels of expression were quantified and compared. RESULTS: In the
15K array, 19 % of the genes were decreased (0.4 % were named genes and
the remainder were expressed sequence tags (ESTs) or unknowns), and 9 %
were increased (4.2 % named genes). In the Neuroarray, 3 % were
decreased and 8 % were increased. CONCLUSIONS: Summary gene profiles are
presented, which include transcription factors, genes associated with
cell cycle, cell shape, neurotransmission, intermediary filaments, and
others. The prevalence of down-regulated genes in the broad 15K array
and up-regulated genes in the neuro-focused array suggests a pattern
shift in gene expression associated with differentiation. The
predominance of ESTs among the down-regulated genes indicates a great
number of as-yet-unidentified genes are repressed in early stage neural
differentiation.
28
UI - 11878777
AU - Anderson C P; Seeger R C; Satake N; Monforte-Munoz H L; Keshelava N;
TI -
Bailey H H; Reynolds C P
Buthionine sulfoximine and myeloablative concentrations of melphalan
overcome resistance in a melphalan-resistant neuroblastoma cell line.
SO - J Pediatr Hematol Oncol 2001 Nov;23(8):500-5
AD - Division of Hematology-Oncology, Children's Hospital Los Angeles,
California 90027, USA.
BACKGROUND: Alkylator resistance contributes to treatment failure in
high-risk neuroblastoma. Buthionine sulfoximine (BSO) can deplete
glutathione and synergistically enhance in vitro sensitivity to the
alkylating agent melphalan (L-PAM) for many neuroblastoma cell lines,
but optimal use of this combination needs to be defined because clinical
responses have been less frequent and not durable. PATIENTS AND METHODS:
The authors established and characterized a neuroblastoma cell line
(CHLA-171) from a patient who died of progressive disease after
treatment with BSO and low-dose L-PAM. RESULTS: CHLA-171 lacks MYCN
amplification, expresses PGP (P-glycoprotein) 9.5 RNA, and shows cell
surface antigen expression (human leukocyte antigen class I weakly
positive, but HSAN 1.2 (hybridoma, SAN 1.2) and anti-GD2
(anti-ganglioside GD2 antibody) strongly positive) characteristic of
neuroblastoma cell lines. Twenty-four hours of BSO treatment (0-1,000
micromol/L) maximally depleted CHLA-171 glutathione to 36% of baseline.
The cytotoxic response of CHLA-171 to BSO and L-PAM, alone and in
combination, was measured by digital image microscopy (DIMSCAN) over a
range of drug concentrations and compared with drug levels obtained in
the patient during BSO/L-PAM therapy. As single agents, CHLA-171 was
highly resistant to L-PAM (LD90 = 42 micromol/L; peak plasma
concentration in the patient equals 3.9 micromol/L) and moderately
resistant to BSO (LD90 = 509 micromol/L; steady-state concentration in
the patient equals 397 micromol/L). Treatment with a 10:1 (BSO:L-PAM)
fixed ratio combination synergistically overcame resistance (3-4 logs of
cell kill, combination index <1) at clinically achievable levels of BSO
(100-400 micromol/L) and levels of L-PAM (10-40 micromol/L) clinically
achievable only with hematopoietic stem cell support. CONCLUSIONS: The
in vitro results obtained for CHLA-171 suggest that BSO/L-PAM therapy
may be optimally effective for drug-resistant neuroblastoma using
myeloablative doses of L-PAM.
29
UI - 11836721
AU - Yoon G; Graham G; Weksberg R; Gaul HP; DeBaun MR; Coppes MJ
TI -
Neuroblastoma in a patient with the Beckwith-Wiedemann syndrome (BWS).
SO - Med Pediatr Oncol 2002 Mar;38(3):193-9
AD - Alberta Children's Hospital, Calgary, Alberta, Canada.
30
UI - 11836726
AU - Pumberger W; Pomberger G; Wiesbauer P
TI -
Postoperative intussusception: an overlooked complication in pediatric
surgical oncology.
SO - Med Pediatr Oncol 2002 Mar;38(3):208-10
AD - Division of Pediatric Surgery, University of Vienna, Vienna / Wien,
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