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Abramson Cancer CenterNCI CANCERLIT® Search: Neuroblastoma - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
1
UI - 11894520
AU - Herman TE
TI -
Cervical neuroblastoma, stage IV-S.
SO - J Perinatol 2001 Oct-Nov;21(7):470-2
AD - Mallinckrodt Institute of Radiology, Washington University School of
Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, USA.
2
UI - 11870152
AU - Woods WG
TI -
Substitute "prostate cancer" for "neuroblastoma"?
SO - J Clin Oncol 2002 Mar 1;20(5):1154-5
3
UI - 11870162
AU - Yamamoto K; Ohta S; Ito E; Hayashi Y; Asami T; Mabuchi O; Higashigawa M;
TI -
Tanimura M
Marginal decrease in mortality and marked increase in incidence as a
result of neuroblastoma screening at 6 months of age: cohort study in
seven prefectures in Japan.
SO - J Clin Oncol 2002 Mar 1;20(5):1209-14
AD - Saitama Children's Medical Center, Division of Hematology/Oncology,
Iwatsuki, Saitama, Japan. a0126966@pref.saitama.jp
PURPOSE: To determine the usefulness of 6-month screening for
neuroblastoma. PATIENTS AND METHODS: The cumulative incidence rates
(IRs) and cumulative mortality rates (MRs) of neuroblastoma in children
younger than 60 months of age were analyzed for control (n = 713,025),
qualitative screening (Qual Screen, n = 1,142,519), and quantitative
screening (Quan Screen, n = 550,331) cohorts, and for Screened and
Unscreened subgroups within screening cohorts. RESULTS: IRs (per
100,000) for infants aged 6 to 11 months were 1.12 in Control, 5.69 in
Qual Screen (P <.0001), and 17.81 in Quan Screen (P <.0001); IRs for
children aged 12 to 59 months were 7.29 in Control, 5.86 in Qual Screen
(P =.28), and 6.36 in Quan Screen (P =.60). IRs for children aged 12 to
59 months in Unscreened or Screened subgroups remained at the same
level. When patients diagnosed at younger than 6 months of age were
excluded, the MR (per 100,000) under 60 months for Control was 4.21;
those in Unscreened and Screened subgroups were 3.84 and 2.53 in Qual
Screen (P =.30), and 3.20 and 1.97 in Quan Screen (P =.73),
respectively; MRs between Control and Unscreened subgroups revealed no
significant differences (P =.89 in Qual Screen, P =.85 in Quan Screen).
CONCLUSION: Six-month screening resulted in a marked increase in
incidence for infants with no significant decrease in incidence for
children older than 1 year of age. A decrease in mortality was observed,
but it was not significant. The usefulness of screening is questionable,
because the decrease of mortality should be balanced against the adverse
effect of overdiagnosis and the psychological burden on parents and
children.
4
UI - 11888202
AU - Verstraeten SV; Erlejman AG; Zago MP; Oteiza PI
TI -
Aluminum affects membrane physical properties in human neuroblastoma
(IMR-32) cells both before and after differentiation.
SO - Arch Biochem Biophys 2002 Mar 15;399(2):167-73
AD - Department of Biological Chemistry, IQUIFIB (UBA-CONICET), School of
Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires,
Argentina.
The capacity of Al(3+) to induce changes in the physical properties of
plasma membrane from human neuroblastoma cells (IMR-32) was
investigated, and the magnitude of the changes was compared with that
obtained after cell differentiation to a neuronal phenotype. Similarly
to our previous results in liposomes, Al(3+) (10 to 100 microM) caused a
significant loss of membrane fluidity, being the differentiated cells
more affected than the nondifferentiated cells. Al(3+) also increased
the relative content of lipids in gel phase and promoted lipid
rearrangement through lateral phase separation, with the magnitude of
this effect being similar in nondifferentiated and differentiated cells.
Since membrane physical properties depend on bilayer composition, we
characterized the content of proteins, phospholipids, cholesterol, and
fatty acids in the IMR-32 cells before and after differentiation.
Differentiated cells had a significantly higher content of unsaturated
fatty acids, creating an environment that favors Al(3+)-mediated effects
on the bilayer fluidity. The neurotoxic effects of Al(3+) may be, at
least in part, due to alterations of neuronal membrane physical
properties, with potential consequences on the normal functioning of
membrane-related cellular processes.
5
UI - 11902539
AU - Dulguerov P; Allal A S; Calcaterra T C
TI -
Esthesioneuroblastoma: a meta-analysis and review.
SO - Lancet Oncol 2001 Nov;2(11):683-90
AD - Division of Head and Neck Surgery, Geneva University Hospital,
Switzerland. pavel.dulguerov@hcuge.ch
Our objective was to review recent developments in diagnosis, staging,
and treatment of esthesioneuroblastoma (ENB). A meta-analysis of
publications between 1990 and 2000 was carried out, and studies were
classified according to their main subject: origin/aetiology of ENB,
histopathological diagnosis, and treatment. Data so far point to the
basal progenitor cells of the olfactory epithelium as the origin of ENB.
Histopathological diagnosis remains difficult and is based on results of
antigen expression detected through a panel of antibodies by
immunohistochemistry. RT-PCR of HASH expression could be a specific
marker of ENB. Overall and disease-free survival at 5 years averaged 45%
(SD 22) and 41% (SD 21) in the studies included in the meta-analysis.
Survival in Hyams' grades I-II was 56% (SD 20) compared with 25% (SD 20)
in grades III-IV (odds ratio 6.2). In patients with metastases in
cervical lymph nodes (on average 5% of the total) survival was 29%,
compared with 64% for patients with N0 disease (odds ratio 5.1).
Survival according to treatment modalities was 65% for surgery plus
radiotherapy, 51% for radiotherapy and chemotherapy, 48% for surgery,
47% for surgery plus radiotherapy and chemotherapy, and 37% for
radiotherapy alone. The histopathological grading according to Hyams and
the presence of cervical lymph-node metastases emerged as prognostic
factors. A combination of surgery and radiotherapy seems to be the
optimum approach to treatment. The exact role of chemotherapy in
treatment protocols is still unclear. The role of elective neck
dissection is unclear.
6
UI - 11877669
AU - Beierle EA; Strande LF; Chen MK
TI -
VEGF upregulates Bcl-2 expression and is associated with decreased
apoptosis in neuroblastoma cells.
SO - J Pediatr Surg 2002 Mar;37(3):467-71
AD - University of Florida, Gainesville, FL, USA.
BACKGROUND/PURPOSE: Both the expression of Bcl-2 and the amount of
vascular endothelial growth factor (VEGF) are increased in neuroblastoma
cells cocultured with hepatocytes. The authors hypothesize that VEGF
upregulates Bcl-2 expression by the neuroblastoma cells and protects
them from apoptotic stimuli. METHODS: To determine whether VEGF will
induce Bcl-2 expression in neuroblastoma cells, the cells are plated
with standard media (control) or media supplemented with VEGF. After 24
hours, Bcl-2 expression is measured. To determine whether VEGF protects
neuroblastoma cells from apoptosis, the cells are subjected to tumor
necrosis factor alpha (TNF-alpha) or serum starvation to induce
apoptosis either with or without VEGF added to the culture media. The
cells are collected and apoptosis measured using the
deoxynucleotidyltransferase-mediated dUTP neck end labeling (TUNEL)
method. RESULTS: VEGF increases Bcl-2 expression by 33% over cells
cultured in standard media. Serum starving the tumor cells or adding
TNF-alpha significantly increases the percentage of apoptotic cells. The
addition of VEGF significantly protects the neuroblastoma cells from the
apoptotic effects of both serum starvation and TNF-alpha. CONCLUSIONS:
VEGF increases the expression of Bcl-2 and also abrogates TNF-alpha and
serum starvation-induced apoptosis in neuroblastoma cells in vitro. VEGF
may promote neuroblastoma survival not only through angiogenesis, but
also by altering apoptosis and its regulating proteins. Copyright 2002
by W.B. Saunders Company.
7
UI - 11877670
AU - Beierle EA; Strande LF; Chen MK
TI -
Insulin-like growth factor-I protects neuroblastoma against
starvation-induced apoptosis and is associated with increased Bcl-2
expression.
SO - J Pediatr Surg 2002 Mar;37(3):472-6
AD - University of Florida, Gainesville, FL, USA.
BACKGROUND/PURPOSE: Aggressive neuroblastomas avoid apoptosis and have
increased expression of the antiapoptotic protein, Bcl-2. Insulin-like
growth factor-I (IGF-I) is mitogenic and may promote tumor survival by
inhibiting apoptosis. The authors hypothesize that IGF-I may protect
neuroblastoma cells from apoptosis by upregulating their Bcl-2
expression. METHODS: Human neuroblastoma cells (IMR-32) are cultured,
and 3 experimental groups are established: 1 group with cells cultured
in standard growth media (control), 1 with cells grown in serum-depleted
media (starvation), and 1 with neuroblastoma cells cultured in
starvation media plus IGF-I. The cells are harvested at 14 and 24 hours,
and cytospin slides are made. Bcl-2 expression is measured by
immunohistochemistry. Apoptosis is detected with the TUNEL method.
RESULTS: Bcl-2 expression is decreased 90% in the serum starved
neuroblastoma cells. In addition, apoptosis is 150 times higher in the
starved neuroblastoma cells. These changes are abrogated by the addition
of IGF-I, where apoptosis is decreased 50% and Bcl-2 is 14-fold higher
in the IGF-I-treated group. These changes are most apparent at 24 hours.
CONCLUSIONS: IGF-I protects neuroblastoma cells from apoptosis and
increases Bcl-2 expression. Growth factors may have a direct role in
promoting tumorigenesis by inducing the expression of antiapoptotic
proteins by the tumor. Copyright 2002 by W.B. Saunders Company.
8
UI - 11877677
AU - Sandler A; Scott D; Azuhata T; Takamizawa S; O'Dorisio S
TI -
The survivin:Fas ratio is predictive of recurrent disease in
neuroblastoma.
SO - J Pediatr Surg 2002 Mar;37(3):507-11
AD - Department of Surgery, Department of Pediatrics, The University of Iowa
Hospitals and Clinics, Iowa City, IA, USA.
BACKGROUND/PURPOSE: Several clinical and biologic features of
neuroblastoma (NB) are used to predict the risk of recurrent disease.
The balance between antiapoptotic and proapoptotic factors within a
tumor may affect its ability to survive. Survivin is an antiapoptotic
factor expressed in highly proliferative NB, whereas Fas is a
proapoptotic factor that portends a favorable prognosis. The authors
determined whether the ratio of survivin to Fas (S:F ratio) is
predictive of recurrent disease in patients with NB. The authors
previously have shown the S:F ratio is predictive of recurrent disease
in pediatric renal tumors. METHODS: The authors quantified the levels of
9 different apoptotic mRNA species using Rnase Protection assay (RPA,
Riboquant, PharMingen, San Diego, CA). Twenty-eight primary tumor
specimens were evaluated from patients with ganglioneuroma (n = 3),
ganglioneuroblastoma (n = 2), and neuroblastoma (n = 23) from tumors of
all clinical stages obtained at the time of diagnosis. mRNA levels were
calculated as a percentage of L32 for each specimen assayed, and
positive expression was assumed to be greater than 10% of L32. RESULTS:
Survivin was expressed in 90% of tumors that went on to recur and only
in 27.7% of those that were cured. The S:F ratio was significantly
greater in tumors that went on to recur (n = 10) compared with those
from patients that were cured (n = 18) (median S:F ratio, 3.3 v 0.75; P
=.0002, Wilcoxon rank-sum test). A cutoff ratio of 2.3 was highly
predictive of tumor recurrence irrespective of clinical stage of disease
(area under ROC curve = 0.906). Sensitivity was 80% (CI, 44.4% to
97.5%), specificity was 94.4% (CI, 72.7% to 99.9%), positive predictive
value was 88.9% (CI, 51.8% to 99.7%), and negative predictive value was
89.5% (66.9% to 98.7%). Twenty-five of 28 (89.3%) tumor ratios were
correct in predicting outcome. CONCLUSIONS: The survivin:Fas ratio in
primary tumors may be used to predict the risk for recurrent disease in
patients with NB. The S:F ratio appears to be a more sensitive predictor
of recurrent disease than survivin expression alone. Determining this
ratio may not only be helpful in guiding follow-up of patients with NB,
but also may aid in stratifying patients for more aggressive therapeutic
strategies. Copyright 2002 by W.B. Saunders Company.
9
UI - 11877684
AU - Thomas PB; Delatte SJ; Sutphin A; Frankel AE; Tagge EP
TI -
Effective targeted cytotoxicity of neuroblastoma cells.
SO - J Pediatr Surg 2002 Mar;37(3):539-44
AD - Division of Pediatric Surgery, Department of Surgery, Medical University
of South Carolina, Charleston, SC, USA.
BACKGROUND/PURPOSE: Despite aggressive treatment with surgery,
chemotherapy, and radiotherapy, the prognosis for many children with
neuroblastoma remains poor. Targeted toxins represent novel cancer
therapeutics designed to selectively target and kill cancer cells. The
authors have developed a novel fusion toxin, DT5F11, consisting of
truncated diphtheria toxin (DT(A)) linked to a single chain antibody
(sc5F11) targeting the GD(2) antigen found on most neuroblastoma cells.
This report describes the construction, expression, and in vitro
function of DT5F11. METHODS: Utilizing restriction enzyme digestion,
polymerase chain reaction amplification, and gel electrophoresis, the
prkDTL5F11 plasmid was created by the fusion of distinct coding
sequences for a single-chain GD(2) targeting antibody (sc5F11) and
truncated diphtheria toxin (DT(A)). DH5alpha Escherichi coli-competent
cells were transformed with prkDTL5F11; DNA was amplified, isolated, and
sequenced. The fusion protein was expressed and assayed by Western blot.
Targeted cytotoxicity was analyzed on GD(2)-positive (SK-N-AS, IMR-32,
SK-N-MC, LAN-1) and GD(2)-negative (HeLa) cells. RESULTS: Fluorescent
dye-labeled cycle sequencing identified the constructed fusion toxin
gene. Western blot analysis using a mouse antihuman DT(A) antibody
showed a 69-kD band identifying the fusion toxin, DT5F11. Targeted cell
killing with DT5F11 was seen only in GD(2) positive cells. CONCLUSIONS:
This study demonstrates creation of a novel fusion toxin with effective
GD(2)-targeted cellular toxicity. Further investigation of this fusion
toxin as a therapeutic agent in the management of neuroblastoma is
warranted. Copyright 2002 by W.B. Saunders Company.
10
UI - 11896617
AU - Teitz T; Wei T; Liu D; Valentine V; Valentine M; Grenet J; Lahti JM;
TI -
Kidd VJ
Caspase-9 and Apaf-1 are expressed and functionally active in human
neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN.
SO - Oncogene 2002 Mar 14;21(12):1848-58
AD - Department of Tumor Cell Biology, St. Jude Children's Research Hospital,
Memphis, Tennessee, TN 38105, USA.
Important roles have been suggested for caspase-8, caspase-9 and Apaf-1
in controlling tumor development and their sensitivity to
chemotherapeutic agents. Methylation and deletion of Apaf-1 and CASP8
results in the loss of their expression in melanoma and neuroblastoma,
respectively, while CASP9 localization to 1p36.1 suggests it is a good
candidate tumor suppressor. The status of CASP9 and Apaf-1 expression in
numerous neuroblastoma cell lines with/without amplified MYCN and
chromosome 1p36 loss-of-heterozygosity (LOH) was therefore examined to
test the hypothesis that one or both of these genes are tumor
suppressors in neuroblastoma. Although CASP9 is included in the region
encompassing 1p36 LOH in all neuroblastoma cell lines examined, the
remaining CASP9 allele(s) express a functional caspase-9 enzyme. Apaf-1
is also expressed in all neuroblastoma tumor cell lines examined. Thus,
the CASP9 or Apaf-1 genes do not appear to function as tumor suppressors
in MYCN amplified neuroblastomas. However, approximately 20% of the
neuroblastoma cell lines with methylated CASP8 alleles are also highly
resistant to staurosporine (STS)- and radiation-induced cell death,
presumably because cytochrome c is not released from mitochondria. This
suggests that a second, smaller sub-group of MYCN amplified
neuroblastoma tumors exists with defect(s) in apoptotic signaling
components upstream of caspase-9 and Apaf-1. Since no consistent
differences in Bcl-2, Bcl-x(L) or Bax expression were seen in the STS-
and radiation-resistant neuroblastomas, it suggests that a unique
mitochondrial signaling factor(s) is responsible for the defect in
cytochrome c release in this sub-group of tumors.
11
UI - 11920516
AU - Ambros IM; Hata J; Joshi VV; Roald B; Dehner LP; Tuchler H; Potschger U;
TI -
Shimada H
Morphologic features of neuroblastoma (Schwannian stroma-poor tumors) in
clinically favorable and unfavorable groups.
SO - Cancer 2002 Mar 1;94(5):1574-83
AD - Children's Cancer Research Institute, St. Anna Kinderspital, Vienna,
Austria. ambros@ccri.univie.ac.at
BACKGROUND: After the establishment of the International Neuroblastoma
Pathology Classification system, the authors studied retrospectively the
prognostic impact of morphologic features in a series of two clinically
distinct subsets of patients with peripheral neuroblastic tumors (NTs),
i.e., tumors in the neuroblastoma category. METHODS: Forty-seven NTs
categorized into either clinically favorable or unfavorable subgroups
were selected randomly from 100 NTs for a histologic review that
included the evaluation of 14 morphologic characteristics. The review
was performed individually followed by a group review. The correlations
of the prognostic significance of the individual morphologic features
and the correlations among them were determined by use of odds ratios
(ORs) with corresponding 95% confidence intervals (95%CIs). The
inter-rater agreement was determined by using the Cohen kappa
coefficient. RESULTS: Ten of 14 morphologic features, including nuclear
size, cellularity, prominent nucleoli in undifferentiated or poorly
differentiated neuroblasts, and the number of mitotic and karyorrhectic
cells (MKI), showed a significant correlation with the clinical groups
(ORs between 36.9 and 10.5 and P values between < 0.001 and 0.002). In
addition to the patient's age at diagnosis (OR, 7.4; 95%CI, 1.9-28.9; P
= 0.002), 8 of 14 features also provided prognostic information (ORs
between 35.1 and 7.9 and P values between < 0.001 and 0.039).
CONCLUSIONS: This study again confirmed the prognostic impact of the
criteria used in the Shimada system and revealed that some other
morphologic features, such as prominent nucleoli in undifferentiated and
poorly differentiated neuroblasts, identify unfavorable tumor biology,
partly independent from the patient's age at diagnosis. However, the
prognostic impact of these features needs to be confirmed by analysis of
a large series of neuroblastic tumors. Copyright 2002 American Cancer
Society.
12
UI - 11844067
AU - Miura K; Mineta H; Yokota N; Tsutsui Y
TI -
Olfactory neuroblastoma with epithelial and endocrine differentiation
transformed into ganglioneuroma after chemoradiotherapy.
SO - Pathol Int 2001 Dec;51(12):942-7
AD - Division of Pathology, Second Department of Pathology, Hamamatsu
University School of Medicine, Japan. kmiura@hama-med.ac.jp
We report a 56-year-old man in whom an olfactory neuroblastoma with
epithelial and endocrine differentiation transformed into a mature
ganglioneuroma after chemoradiotherapy. The tumor arising from the
sphenoidal and maxillary sinuses showed rapid growth into the frontal
lobe and metastasis to the cervical lymph nodes. The patient showed
signs of a syndrome of inappropriate secretion of antidiuretic hormone
(SIADH). A radical craniofacial resection of the primary tumor was
performed after 16 Gy of local irradiation and systemic chemotherapy.
Three months after the operation, the patient died of mediastinal
metastasis. The biopsy before chemoradiotherapy showed a neuroblastoma
with Homer-Wright rosettes, fibrillary matrix, Flexner-Wintersteiner
rosettes and antidiuretic hormone production. After chemoradiotherapy,
the histology changed to that of a ganglioneuroma consisting of large
ganglion cells and Schwann cells without immature neuroblastoma
components. Although transformation to ganglioneuroma in an adrenal
neuroblastoma is common, an olfactory neuroblastoma showing
ganglioneuronal maturation after chemoradiotherapy has not been
reported. The pluripotent progenitor cells of the olfactory neurons may
be the origin and their existence explains why various neoplasms with
neuronal and epithelial differentiation arise from the olfactory mucosa.
13
UI - 11692651
AU - DeMonte F
TI -
Functional outcomes in skull base surgery. What is acceptable?
SO - Clin Neurosurg 2001;48():340-50
AD - Department of Neurosurgery, University of Texas M.D. Anderson Cancer
Center, Houston, Texas, USA.
14
UI - 11850545
AU - De Preter K; Speleman F; Combaret V; Lunec J; Laureys G; Eussen BH;
TI -
Francotte N; Board J; Pearson AD; De Paepe A; Van Roy N; Vandesompele J
Quantification of MYCN, DDX1, and NAG gene copy number in neuroblastoma
using a real-time quantitative PCR assay.
SO - Mod Pathol 2002 Feb;15(2):159-66
AD - Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Amplification of the proto-oncogene MYCN is a strong adverse prognostic
factor in neuroblastoma patients in all tumor stages. The status of the
MYCN gene has become an important factor in clinical decision making and
therapy stratification. Consequently, fast and accurate assessment of
MYCN gene copy number is of the utmost importance and the use of two
independent methods to determine MYCN status is recommended. For these
reasons we have developed and evaluated a real-time quantitative PCR
(Q-PCR) assay as an alternative for time-consuming Southern blot
analysis (SB), and as a second independent technique in parallel with
fluorescence in situ hybridization (FISH) analysis. Advantages of Q-PCR
are a large dynamic range of quantification, no requirement for post-PCR
sample handling and the need for very small amounts of starting
material. The accuracy of the assay was illustrated by measurement of
MYCN single gene copy changes in DNA samples of two patients with 2p
deletion and duplication, respectively. Two different detection
chemistries i.e., a sequence specific TaqMan probe and a generic DNA
binding dye SYBR Green I were evaluated and shown to yield similar
results. Also, two different calculation methods for copy number
determination were used i.e., the kinetic method and the comparative
C(T) method, and shown to be equivalent. In total, 175 neuroblastoma
samples with known MYCN status, as determined by FISH and/or SB, were
examined. Q-PCR data were highly concordant with FISH and SB data. In
addition to MYCN copy number evaluation, DDX1 and NAG gene copy numbers
were determined using a similar Q-PCR strategy. Survival analysis
pointed out that DDX1 and/or NAG amplification has no additional adverse
effect on prognosis.
15
UI - 11901819
AU - Dotsch J; Repp R; Rascher W; Christiansen H
TI -
Diagnostic and scientific applications of TaqMan real-time PCR in
neuroblastomas.
SO - Expert Rev Mol Diagn 2001 Jul;1(2):233-8
AD - Klinik fur Kinder und Jugendliche, Friedrich-Alexander-University,
Erlangen, Loschgestrasse 15 91054 Erlangen, Germany.
JoergWDoetsch@yahoo.com
This review summarizes the present data on the diagnostic and scientific
applications of TaqMan real-time PCR in neuroblastomas, a novel
fluorescence-based method for quantitation of gene expression and gene
copy number variations as gene amplification and locus
haploinsufficiencies. Particular emphasis is spent on precision and
accuracy and the comparison of TaqMan real-time PCR with more
traditional methods for quantitative PCR. Provided a proper assessment
for each new marker, this method has been shown to be an easy, fast and
reliable alternative to the more traditional methods for the
determination of MYCN amplification and neuropeptide Y gene expression.
The combination with single cell picking in the neuroblastoma tissue may
be a future target of the application of real-time PCR.
16
UI - 11733907
AU - Azuhata T; Scott D; Takamizawa S; Wen J; Davidoff A; Fukuzawa M; Sandler
TI -
A
The inhibitor of apoptosis protein survivin is associated with high-risk
behavior of neuroblastoma.
SO - J Pediatr Surg 2001 Dec;36(12):1785-91
AD - Department of Surgery, University of Iowa, Iowa City, IA 52242, USA.
BACKGROUND/PURPOSE: Apoptotic factors inducing or preventing cell death
may intrinsically govern the behavior of some tumors. Survivin is a
recently described member of the inhibitor of apoptosis protein (IAP)
family, that is expressed in a cell cycle-dependent manner and is found
in tumors of unfavorable histology. This study examines the presence of
several apoptotic factors, including survivin, in neuroblastoma (NB)
tumors. Clues to survivin's function in NB are provided by examining its
association with behavior and cell dynamics in tumors and cell lines.
METHODS: Expression of a panel of apoptosis factors were quantified in
15 NB and related tumors before chemotherapy and in 3 NB cell lines
(NB7, NB10, and NB16). Survivin and other apoptotic factors, as well
N-myc amplification in primary tumors was correlated with recurrent
disease and outcome. Proliferation rate, apoptosis assays, cell cycle
analysis, and drug- or immune-mediated cell death were assessed in cell
lines and evaluated in the context of differential survivin and
apoptosis gene expression. RESULTS: All 7 tumors that went on to recur
expressed survivin, whereas expression was absent in all 8 tumors that
went into remission. N-myc was amplified in 4 (57.1%) of the 7 recurrent
tumors. Of the 8 tumors that were cured, Fas was expressed in 3 (38%),
TRAIL-R1 in 6 (75%) and tumor necrosis factor (TNF)-R1 in 8 (100%),
whereas these pro-apoptotic receptors were present in only 1 (14%), 1
(14%), and 4 (57%) of the 7 tumors that went on to recur, respectively.
Of the 3 cell lines, NB10 expressed the least survivin, displayed the
lowest proliferation index, and had the fewest number of cells in the
G2/M (mitotic) phase of the cell cycle. Furthermore, NB10 also was most
sensitive to TNF-related apoptosis-inducing ligand (TRAIL) or
etoposide-induced cell death. CONCLUSIONS: In primary NB tumors,
survivin expression was associated with tumors of high risk and
unfavorable prognosis, whereas pro-apoptotic receptor expression was
more abundant in tumors of favorable prognosis. In this small series,
survivin expression appeared to be more predictive of recurrent disease
than N-myc amplification. In cell lines, survivin expression was cell
cycle dependent, and its expression was associated with greater
proliferation rates and greater resistance to drug- or immune-mediated
cell death. Survivin expression may become a useful prognostic marker in
NB and could be a potential target for the treatment of this tumor. J
Pediatr Surg 36:1785-1791. Copyright 2001 by W.B. Saunders Company.
17
UI - 11733935
AU - Trobs RB; Korholz D; Bennek J
TI -
Outcome of paratesticular involvement in infants with neuroblastoma.
SO - J Pediatr Surg 2001 Dec;36(12):E23
AD - Department of Pediatric Surgery, University of Leipzig, Germany.
The authors report on 3 infants suffering from disseminated
neuroblastoma (NB) involving the testes or paratesticular structures.
INSS stage 4 in 2 cases, and "biological" INSS stage 4S were considered,
respectively. One patient with a stage 4 NB died of tumor progression;
one patient is under therapy. The patient with NB 4S was cured with
preservation of both testes after antineoplastic chemotherapy and
reduction of the retroperitoneal primary. J Pediatr Surg 36:E23.
Copyright 2001 by W.B. Saunders Company.
18
UI - 11891459
AU - Hosalkar HS; Pill SG; Sun PP; Drummond DS
TI -
Progressive spinal lordosis after laminoplasty in a child with thoracic
neuroblastoma.
SO - J Spinal Disord Tech 2002 Feb;15(1):79-83
AD - Division of Orthopaedic Surgery The Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania 19104, USA.
Laminoplasty has been advocated increasingly after spinal tumor excision
in children. Results have shown that it offers the required
decompression, while maintaining spinal stability and the integrity of
the posterior vertebral elements. To the authors' knowledge, there has
been no description of a progressive lordotic deformity of the thoracic
spine after this procedure. A case of an 8-year-old boy with thoracic
neuroblastoma developing progressive thoracic lordosis after
laminoplasty is reviewed, and a possible cause is suggested. Discussing
this potential complication with parents and the patient, and following
up with regular clinical and radiographic assessments is advised.
19
UI - 11932470
AU - Woods WG; Gao RN; Shuster JJ; Robison LL; Bernstein M; Weitzman S; Bunin
TI -
G; Levy I; Brossard J; Dougherty G; Tuchman M; Lemieux B
Screening of infants and mortality due to neuroblastoma.
SO - N Engl J Med 2002 Apr 4;346(14):1041-6
AD - AFLAC Cancer Center, Emory University and Children's Healthcare of
Atlanta, GA 30322, USA. william.woods@choa.org
BACKGROUND: Neuroblastoma, the most common extracranial solid tumor that
occurs in early childhood, can be identified in the preclinical stages
by the detection of catecholamines in the urine. However, it is unknown
whether routine screening for neuroblastoma reduces mortality due to
this disease. METHODS: Through their parents, we offered screening for
neuroblastoma at three weeks and six months of age to all 476,654
children born in the province of Quebec, Canada, during a five-year
period (May 1, 1989, through April 30, 1994). The participation rate was
92 percent. The rate of death due to neuroblastoma was determined and
compared with the rates in several unscreened control populations born
during the same period. RESULTS: Among children younger than eight years
of age in the Quebec cohort, there were 22 deaths due to neuroblastoma;
the cumulative (+/-SE) mortality rate due to neuroblastoma was
4.78+/-1.14 per 100,000 children over a period of nine years. The
standardized incidence ratios for death due to neuroblastoma for the
Quebec cohort were 1.11 (95 percent confidence interval, 0.64 to 1.92)
as compared with a control group in Ontario, Canada; 0.90 (95 percent
confidence interval, 0.48 to 1.70) as compared with a control group in
Minnesota; 1.40 (95 percent confidence interval, 0.81 to 2.41) as
compared with a control group in Florida; and 0.96 (95 percent
confidence interval, 0.56 to 1.66) as compared with a control group in
the Greater Delaware Valley. The standardized mortality ratio for the
Quebec cohort as compared with the rest of Canada was 1.39 (95 percent
confidence interval, 0.85 to 2.30); the odds ratio for the comparison
with a cohort born in Quebec before the screening program began was 0.98
(95 percent confidence interval, 0.54 to 1.77). CONCLUSIONS: Screening
infants for neuroblastoma does not appear to reduce mortality due to
this disease.
20
UI - 11932471
AU - Schilling FH; Spix C; Berthold F; Erttmann R; Fehse N; Hero B; Klein G;
TI -
Sander J; Schwarz K; Treuner J; Zorn U; Michaelis J
Neuroblastoma screening at one year of age.
SO - N Engl J Med 2002 Apr 4;346(14):1047-53
AD - Klinikum Stuttgart, Olgahospital, Child and Adolescent Health,
Pediatrics 5, Stuttgart, Germany. f.schilling@olgahospital.de
BACKGROUND: Neuroblastoma is the second most common type of childhood
tumor. It is not known whether screening for neuroblastoma at one year
of age reduces the incidence of metastatic disease or mortality due to
neuroblastoma. METHODS: We offered urine screening for neuroblastoma at
approximately one year of age to 2,581,188 children in 6 of 16 German
states from 1995 to 2000. A total of 2,117,600 eligible children in the
remaining states served as controls. We compared the two groups in terms
of the incidence of disseminated disease and mortality from
neuroblastoma. RESULTS: A total of 1,475,773 children (61.2 percent of
those who were born between July 1, 1994, and October 31, 1999)
underwent screening. In this group, neuroblastoma was detected by
screening in 149 children, of whom 3 have died. Fifty-five children who
had negative screening tests were subsequently given a diagnosis of
neuroblastoma; 14 of these children have died. The screened group and
children in the control area had a similar incidence of stage 4
neuroblastoma (3.7 cases per 100,000 screened children [95 percent
confidence interval, 2.7 to 4.7] and 3.8 per 100,000 controls [95
percent confidence interval, 2.9 to 4.6]) and a similar rate of death
among children with neuroblastoma (1.3 deaths per 100,000 screened
children [95 percent confidence interval, 0.7 to 1.8] and 1.2 per
100,000 controls [95 percent confidence interval, 0.7 to 1.7]).
Comparison of the screened group and the children in the control area
revealed substantial overdiagnosis in the former group (an estimated
rate of 7 cases per 100,000 children [95 percent confidence interval,
4.6 to 9.2]); the overdiagnosis rate represents children who had
neuroblastoma that was diagnosed by screening but who would not benefit
from earlier diagnosis and treatment. CONCLUSIONS: The present findings
do not support the usefulness of general screening for neuroblastoma at
one year of age.
21
UI - 2983884
AU - Ross RA; Biedler JL
TI -
Presence and regulation of tyrosinase activity in human neuroblastoma
cell variants in vitro.
SO - Cancer Res 1985 Apr;45(4):1628-32
The human neuroblastoma cell line SK-N-SH comprises cells that undergo
morphological and biochemical interconversion between a primitive
sympathoblast and a variant, epithelial-like cell type which does not
express the neuronal characteristics of the SK-N-SH cell line. Since
neural crest cells, from which neuroblastomas are presumed to arise, can
undergo transdifferentiation in culture from a neuronal phenotype into
other cellular phenotypes, particularly into neurilemmal cells and
melanocytes, the present study was undertaken to determine whether this
capacity is preserved in malignant cells of the peripheral nervous
system. Activities for tyrosinase, a melanocyte marker enzyme, and
2':3'-cyclic nucleotide phosphohydrolase, a Schwann-cell marker enzyme,
were measured in clones of the two cell types. While no significant
differences in 2':3'-cyclic nucleotide phosphohydrolase activity were
measurable, tyrosinase activity was detectable only in the flattened
neuroblastoma variant cell lines and was comparable to that in some
human melanoma cell lines. The tyrosinase activity in neuroblastoma cell
variants increased with cell density and was significantly elevated by
melanocyte-stimulating hormone and 8-bromo-cyclic adenosine
monophosphate, similar to that seen in melanoma cells in culture. Thus,
our findings show that human neuroblastoma cells can undergo
bidirectional transdifferentiation in vitro between a neuronal and a
melanocyte phenotype, possibly reflecting a process which occurs in the
patient.
22
UI - 2888312
AU - Tsokos M; Scarpa S; Ross RA; Triche TJ
TI -
Differentiation of human neuroblastoma recapitulates neural crest
development. Study of morphology, neurotransmitter enzymes, and
extracellular matrix proteins.
SO - Am J Pathol 1987 Sep;128(3):484-96
Differentiation of human neuroblastoma (NB) was studied in vitro with
five NB cell lines treated with dibutyryl cyclic adenosinemonophosphate
and retinoic acid. Although the above agents induced different responses
in the various cell lines, three overall morphologic phenotypes emerged:
a neuronal, characterized by cell processes and neurosecretory granules,
a flat cell without pigment, which displayed basal lamina pertinent to
Schwann cells, and a flat pigmented cell which exhibited melanosomes,
similarly to melanocytes. The activity of the Schwann cell enzyme cyclic
nucleotidyl phosphohydrolase increased considerably in one condition,
after induction of a predominantly flat cell phenotype. All studied NB
cell lines were capable of synthesizing and expressing the extracellular
matrix proteins laminin (LM), fibronectin (FN), and Type IV collagen;
but a specific pattern of expression emerged after differentiation,
which was proportional to normal tissue equivalents: neuronal--none;
melanocytic--FN only; and Schwann cell--large amounts of FN, LM, and
Type IV collagen.
23
UI - 2535691
AU - Ciccarone V; Spengler BA; Meyers MB; Biedler JL; Ross RA
TI -
Phenotypic diversification in human neuroblastoma cells: expression of
distinct neural crest lineages.
SO - Cancer Res 1989 Jan 1;49(1):219-25
AD - Department of Biological Sciences, Fordham University, Bronx, New York
10458.
Previous studies of the human neuroblastoma cell line SK-N-SH had
demonstrated the presence of and phenotypic interconversion
(transdifferentiation) between two morphologically and biochemically
distinct cell types: N (neuroblastic) cells with properties of
noradrenergic neurons and S (substrate-adherent) cells with properties
of melanocytes. Current studies have sought to test the generality of
these findings among other cultured human neuroblastoma cell lines and
to define further the S-cell phenotype and that of a newly identified,
morphologically intermediate, I-type cell. Morphologically homogeneous
populations (clonal sublines or subpopulations) of N, S, and I cells
were isolated from five additional neuroblastoma cell lines and analyzed
biochemically for neuronal, glial, and melanocytic marker enzyme
activities and norepinephrine uptake. Immunoblot techniques were used to
detect intermediate filament proteins (neurofilament protein, vimentin,
glial fibrillary acidic protein) and fibronectin. All N-type cells
exhibited neuronal marker enzyme activities, specific uptake of
norepinephrine, and presence of one or more neurofilament proteins.
S-type cells generally lacked neuronal characteristics but contained,
instead, tyrosinase activity (a melanocytic marker enzyme), vimentin,
and fibronectin. This combination of attributes is suggestive of a
multipotent embryonal precursor cell of the neural crest. I-type cells
differentially expressed both S- and N-cell properties and could
represent either a stem cell or an intermediate in the
transdifferentiation process. Studies of the biological significance of
human neuroblastoma cell transdifferentiation and the molecular
mechanisms underlying this process may be of relevance to the biological
and clinical behavior of this tumor in the patient.
24
UI - 2573830
AU - Bates SE; Mickley LA; Chen YN; Richert N; Rudick J; Biedler JL; Fojo AT
TI -
Expression of a drug resistance gene in human neuroblastoma cell lines:
modulation by retinoic acid-induced differentiation.
SO - Mol Cell Biol 1989 Oct;9(10):4337-44
AD - Division of Cancer Treatment, National Cancer Institute, Bethesda,
Maryland 20892.
Expression of a multidrug resistance gene (mdr1) and its protein
product, P-glycoprotein (Pgp), has been correlated with the onset of
multidrug resistance in vitro in human cell lines selected for
resistance to chemotherapeutic agents derived from natural products.
Expression of this gene has also been observed in normal tissues and
human tumors, including neuroblastoma. We therefore examined total RNA
prepared from human neuroblastoma cell lines before and after
differentiation with retinoic acid or sodium butyrate. An increase in
the level of mdr1 mRNA was observed after retinoic acid treatment of
four neuroblastoma cell lines, including the SK-N-SH cell line. Western
blot (immunoblot) analysis demonstrated concomitant increases in Pgp.
However, studies of 3H-vinblastine uptake failed to show a concomitant
Pgp-mediated decrease in cytotoxic drug accumulation. To provide
evidence that Pgp was localized on the cell surface, an immunotoxin
conjugate directed against Pgp was added to cells before and after
treatment with retinoic acid. Incorporation of [3H]leucine was decreased
by the immunotoxin in the retinoic acid-treated cells compared with the
undifferentiated cells. These results demonstrate that whereas
expression of the mdr1 gene can be modulated by differentiating agents,
increased levels of expression are not necessarily associated with
increased cytotoxic drug accumulation.
25
UI - 9183650
AU - MacManus JP; Rasquinha I; Walker T; Chakravarthy B
TI -
Apoptotic human SH-SY5Y neuroblastoma cells have regularly spaced single
strand DNA breaks and increased DNA-dependent protein kinase activity.
SO - Hum Cell 1996 Sep;9(3):197-204
AD - Institute for Biological Sciences, Montreal Road Laboratories, National
Research Council Ottawa, ON Canada. John.MacManus@NRC.CA
SH-SY5Y human neuroblastoma cells died by apoptosis when treated with
staurosporine or ceramide. The treated cells had both the nuclear
morphology and patterns of DNA fragmentation which are characteristic of
apoptosis. Higher order DNA fragments separable by pulse field gel
electrophoresis were shown to contain regularly spaced single-strand
nicks by producing a laddered pattern upon alkali treatment. Further
evidence of DNA damage in treated cells was shown by increased activity
of DNA-dependent protein kinase. This human cell model may prove useful
in delineating the role of a cellular repair response to DNA damage
prior to the irreversible steps of the cell death program.
26
UI - 10037464
AU - Chakravarthy BR; Walker T; Rasquinha I; Hill IE; MacManus JP
TI -
Activation of DNA-dependent protein kinase may play a role in apoptosis
of human neuroblastoma cells.
SO - J Neurochem 1999 Mar;72(3):933-42
AD - Institute for Biological Sciences, National Research Council of Canada,
Ottawa, Ontario.
Treating SH-SY5Y human neuroblastoma cells with 1 microM staurosporine
resulted in a three- to fourfold higher DNA-dependent protein kinase
(DNA-PK) activity compared with untreated cells. Time course studies
revealed a biphasic effect of staurosporine on DNA-PK activity: an
initial increase that peaked by 4 h and a rapid decline that reached
approximately 5-10% that of untreated cells by 24 h of treatment.
Staurosporine induced apoptosis in these cells as determined by the
appearance of internucleosomal DNA fragmentation and punctate nuclear
morphology. The maximal stimulation of DNA-PK activity preceded
significant morphological changes that occurred between 4 and 8 h (40%
of total number of cells) and increased with time, reaching 70% by 48 h.
Staurosporine had no effect on caspase-1 activity but stimulated
caspase-3 activity by 10-15-fold in a time-dependent manner, similar to
morphological changes. Similar time-dependent changes in DNA-PK
activity, morphology, and DNA fragmentation occurred when the cells were
exposed to either 100 microM ceramide or UV radiation. In all these
cases the increase in DNA-PK activity preceded the appearance of
apoptotic markers, whereas the loss in activity was coincident with cell
death. A cell-permeable inhibitor of DNA-PK, OK-1035, significantly
reduced staurosporine-induced punctate nuclear morphology and DNA
fragmentation. Collectively, these results suggest an intriguing
possibility that activation of DNA-PK may be involved with the induction
of apoptotic cell death.
27
UI - 10100712
AU - Hiyama E; Hiyama K; Yokoyama T; Fukuba I; Yamaoka H; Shay JW; Matsuura Y
TI -
Rapid detection of MYCN gene amplification and telomerase expression in
neuroblastoma.
SO - Clin Cancer Res 1999 Mar;5(3):601-9
AD - Department of General Medicine, Hiroshima University School of Medicine,
Hiroshima, Japan. eiso@mcai.med.hiroshima-u.ac.jp
Amplification of the MYCN gene and high telomerase activity predict a
poor prognosis for the patients with neuroblastoma. We used PCR
techniques for rapid detection of MYCN gene amplification and human
telomerase reverse transcriptase (hTERT) expression in neuroblastoma
specimens. The detection of MYCN gene amplification is based on
differential PCR in which three primer pairs were used to coamplify a
178-bp fragment of target MYCN gene with two reference gene fragments, a
237-bp of p53 exon 7 and a 120-bp of beta-globin exon 3, in a single
tube of 40 surgically resected tumor samples. MYCN amplification was
identified by this differential PCR in all 10 samples carrying more than
10 copies (already known to have MYCN gene amplification by Southern
blot analysis). There were no false-negative or false-positive cases,
and the relative intensity of MYCN bands in the differential PCR
correlated significantly with the copy number determined by Southern
blot analysis (y = 0.99, P<0.0001). This protocol was also applicable in
the biopsy or aspirated samples, as well as the paraffin-embedded
tissues, and in detecting intratumoral heterogeneity. Using RT-PCR
procedures, hTERT mRNA expression was detectable in all 13 tumors with
high telomerase activity. These nonradioisotopic PCR-based protocols for
detecting MYCN gene amplification and hTERT mRNA expression are rapid
and reliable and are likely to be useful to determine the biological
behavior of neuroblastoma.
28
UI - 10763829
AU - De Rosa M; Fasano C; Panariello L; Scarano MI; Belli G; Iannelli A;
TI -
Ciciliano F; Izzo P
Evidence for a recessive inheritance of Turcot's syndrome caused by
compound heterozygous mutations within the PMS2 gene.
SO - Oncogene 2000 Mar 23;19(13):1719-23
AD - Dipartimento di Biochimica e Biotecnologie Mediche, CEINGE-Biotecnologie
Avanzate, Universita di Napoli Federico II, Italy.
Turcot's syndrome is a genetic disease characterized by the concurrence
of primary brain tumors and colon cancers and/or multiple colorectal
adenomas. We report a Turcot family with no parental consanguinity, in
which two affected sisters, with no history of tumors in their parents,
died of a brain tumor and of a colorectal tumor, respectively, at a very
early age. The proband had a severe microsatellite instability (MIN)
phenotype in both tumor and normal colon mucosa, and mutations in the
TGFbeta-RII and APC genes in the colorectal tumor. We identified two
germline mutations within the PMS2 gene: a G deletion (1221delG) in exon
11 and a four-base-pair deletion (2361delCTTC) in exon 14, both of which
were inherited from the patient's unaffected parents. These results
represent the first evidence that two germline frameshift mutations in
PMS2, an MMR gene which is only rarely involved in HNPCC, are not
pathogenic per se, but become so when occurring together in a compound
heterozygote. The compound heterozygosity for two mutations in the PMS2
gene has implications for the role of protein PMS2 in the mismatch
repair mechanism, as well as for the presymptomatic molecular diagnosis
of at-risk family members. Furthermore, our data support and enlarge the
notion that high DNA instability in normal tissues might trigger the
development of cancer in this syndrome.
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