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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