Last Modified: November 1, 2001
Table of Contents
CancerMail from the National Cancer Institute
UI - 21261628
AU - Vettenranta K; Aalto Y; Wikstrom S; Knuutila S; Saarinen-Pihkala U
TI - Comparative genomic hybridization reveals changes in DNA-copy number in poor-risk neuroblastoma.
SO - Cancer Genet Cytogenet 2001 Mar;125(2):125-30
AD - Division of Hematology-Oncology and Stem Cell Transplantation, Hospital for Children and Adolescents, University of Helsinki, FIN-00029, Helsinki, Finland. firstname.lastname@example.org
Aggressive neuroblastoma remains a therapeutic challenge, and additional understanding of its biology is of paramount importance. Changes in DNA-copy number were analysed in the neuroblastoma cells of 27 patients using comparative genomic hybridization (CGH). Eighteen of the patients had a poor risk disease (16/18 stage IV) and 9 had a non-poor-risk disease (3/9 stage I-II, 2/9 stage III, and 4/9 stage IVS). Changes in DNA-copy number were detected in 72% of the poor-risk and 22% of the non-poor-risk tumors with gains of chromosomal material being more prevalent than losses. Gains were most common in chromosomes 2, 7, and 17 and losses in chromosome 11. Changes in DNA-copy number were multiple in all but one of the patients with poor-risk disease. The applicability of CGH in studies on the genomic changes in pediatric malignancies is demonstrated by our data also adding weight to the argument of multiple elements with oncogenic and/or tumor suppressor potential being involved in the aggressive phenotype of poor-risk neuroblastoma.
UI - 21261632
AU - Moritake H; Horii Y; Kuroda H; Sugimoto T
TI - Analysis of PTEN/MMAC1 alteration in neuroblastoma.
SO - Cancer Genet Cytogenet 2001 Mar;125(2):151-5
AD - Department of Pediatrics, Miyazaki Medical College, 200 Kihara, Kiyotake-cho, 889-1692, Miyazaki, Japan. email@example.com
Neuroblastoma is the most common extracranial solid tumor in children. Although it has been reported that loss of heterozygosity at various loci, including 10q, frequently occurs in neuroblastoma, a bona fide tumor suppressor gene has not been identified. Recently, a gene mapped to chromosome 10q23, PTEN/MMAC1, was identified as a tumor suppressor gene that inhibits cell survival and cell proliferation by catalyzing the dephosphorylation of phosphatidylinositol 3,4,5-triphosphate. To screen for mutations of this gene in neuroblastoma, we analyzed 11 primary neuroblastoma tumors and 16 neuroblastoma cell lines for PTEN/MMAC1 mutations and deletions. All nine exons of the PTEN/MMAC1 gene were examined using the polymerase chain reaction-single strand conformational polymorphism assay and sequencing. Only one of the cell lines showed a mutation, a 1-bp frameshift deletion in exon 7, and an allelic loss in the opposite allele was revealed by a microsatellite analysis. Our results indicate that the disruption of the PTEN/MMAC1 gene is not a frequent event in neuroblastoma, and suggest that this disruption may be responsible for malignant progression in only a limited proportion of cases of neuroblastoma.
UI - 21378006
AU - Hoon DS; Kuo CT; Wen S; Wang H; Metelitsa L; Reynolds CP; Seeger RC
TI - Ganglioside GM2/GD2 synthetase mRNA is a marker for detection of infrequent neuroblastoma cells in bone marrow.
SO - Am J Pathol 2001 Aug;159(2):493-500
AD - Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA. firstname.lastname@example.org
GalNAcbeta1-4(NeuAcalpha2-3)Galbeta1-4Glcbeta1-Cer (GM2)/GalNAcbeta1-4(NeuAcalpha2-8NeuAcalpha2-3)Galbeta1-4Glcbeta1-1Cer (GD2) synthetase [beta-1,4-N-acetyl-galactosaminyl transferase (GalNAc-T)] mRNA, which encodes a key glycosyltransferase for ganglioside GD2 synthesis, was assessed as a molecular marker for detecting metastatic neuroblastoma cells in bone marrow (BM). GalNAc-T mRNA expression by neuroblastoma cell lines (n = 15), primary untreated neuroblastoma tumors (n = 29), morphologically normal BM (n = 22), peripheral blood stem cells (n = 10) from patients with cancers other than neuroblastoma, and blood mononuclear cells from normal donors (n = 17) was assessed by using reverse transcriptase-polymerase chain reaction (RT-PCR) and electrochemiluminescence detection assay (RT-PCR/ECL). BM harvested from 15 neuroblastoma patients was tested before and after ex vivo immunomagnetic bead purging, and results were compared to immunocytological analysis of the same specimens. All neuroblastoma cell lines (mean, 653 x 10(3) ECL units) and primary tumors (mean, 683 x 10(3) ECL units) were positive for significant expression of GalNAc-T mRNA compared to normal blood and BM cells. The RT-PCR/ECL assay could detect GalNAc-T mRNA in 100 pg of total RNA, and in a mixture of one neuroblastoma cell among 10(7) normal BM or blood cells. Eight of 15 autologous BM cells harvested from patients with neuroblastoma had tumor cells detectable by immunocytology, and all 15 were positive for GalNAc-T mRNA. After ex vivo purging, none of the BM cells was immunocytology-positive, but six remained positive by the RT-PCR/ECL assay. GalNAc-T mRNA provides a specific and sensitive molecular marker for RT-PCR/ECL detection of infrequent neuroblastoma cells in BM.
UI - 21393509
AU - Ueda K
TI - Detection of the retinoic acid-regulated genes in a RTBM1 neuroblastoma cell line using cDNA microarray.
SO - Kurume Med J 2001;48(2):159-64
AD - Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume 830-0011, Japan.
A microarray system is a powerful and very useful technology for analyzing the expression profile of thousands of genes. In this study, we made a cDNA microarray system carrying 2007 cDNAs obtained from primary neuroblastoma cDNA library and identified retinoic acid (RA)-regulated genes in a RTBM1 neuroblastoma cell line. We repeated independent hybridization experiment twice and found that 7 genes were up-regulated, and 5 genes were down-regulated on the cDNA microarray. The semi-quantitative reverse transcriptase (RT)-PCR analysis to confirm the results showed that 4 genes which included amyloid precursor-like protein 2 (APLP2), P311, dihydropyrimidinase related protein3 (DRP3) and RGP4 were up-regulated, while 2 genes, Id-2 and vimentin, were down-regulated. Thus, our neuroblastoma cDNA microarray system is useful to screen the neuronal differentiation- and growth-related genes regulated by RA with high efficiency.
UI - 21397966
AU - Keshelava N; Zuo JJ; Chen P; Waidyaratne SN; Luna MC; Gomer CJ; Triche TJ; Reynolds CP
TI - Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines.
SO - Cancer Res 2001 Aug 15;61(16):6185-93
AD - Division of Hematology-Oncology, Children's Hospital Los Angeles, Los Angeles, California 90027, USA.
Neuroblastomas can acquire a sustained high-level drug resistance during chemotherapy and especially myeloablative chemoradiotherapy. p53 mutations are rare in primary neuroblastomas, but a loss of p53 function could play a role in multidrug resistance. We determined p53 function by measuring induction of p21 and/or MDM2 proteins in response to melphalan (L-PAM) in seven L-PAM-sensitive and 11 L-PAM-resistant neuroblastoma cell lines. p53 was functional in seven/seven drug-sensitive but in only 4/11 drug-resistant cell lines (P = 0.01). In four of the seven cell lines lacking p53 function, mutations of p53 were detected by the microarray GeneChip p53 Assay and automated sequencing, whereas six cell lines with functional p53 had no evidence of p53 mutations. All of the cell lines with wild-type (wt) p53 showed a strong transactivation of the p53-HBS/CAT reporter gene, whereas the four cell lines with mutant p53 failed to transactivate p53 HBS/CAT. Overexpression of MDM2 protein (relative to p53 functional lines) was seen in two p53-nonfunctional cell lines with wt p53; one showed genomic amplification of MDM2. Nonfunctional and mutated p53 was detected in a resistant cell line, whereas a sensitive cell line derived from the same patient before treatment had functional and wt p53. Loss of p53 function was selectively achieved by transduction of human papillomavirus 16 E6 (which degrades p53) into two drug-sensitive neuroblastoma cell lines with intact p53, causing high-level drug resistance to L-PAM, carboplatin, and etoposide. These data obtained with neuroblastoma cell lines suggest that the high-level drug resistance observed in some recurrent neuroblastomas is attributable to p53 mutations and/or a loss of p53 function acquired during chemotherapy. If confirmed in patient tumor samples, these data support development of p53-independent therapies for consolidation and/or salvage of recurrent neuroblastomas.
UI - 21411561
AU - Kim GJ; Park SY; Kim H; Chun YH; Park SH
TI - Chromosomal aberrations in neuroblastoma cell lines identified by cross species color banding and chromosome painting.
SO - Cancer Genet Cytogenet 2001 Aug;129(1):10-6
AD - Graduate School of Biotechnology, Korea University College of Medicine, 126-1, Anam-Dong 5-Ka, Sungbuk-Ku, Seoul 136-705, South Korea.
We have studied cytogenetic rearrangements in karyotypes of five neuroblastoma cell lines [SK-N-AS, SK-N-SH, SH-SY5Y, SK-N-MC, SMS-KCNR] by G-banding, cross species color banding (RxFISH), and fluorescence in situ hybridization (FISH) with chromosome painting probes. Each neuroblastoma cell line had unique modal karyotypic characteristics and showed a variable number of numerical and structural clonal cytogenetic aberrations. The number of rearranged chromosomes in SK-N-AS, SK-N-SH, SH-SY5Y, SK-N-MC, and SMS-KCNR was 11, 3, 7, 14 (tetraploid, 20-21), and 6, respectively. The origins of abnormal chromosomes were effectively analyzed by RxFISH and FISH with multiple chromosome painting probes. The chromosomal origin of the homogeneously staining region in SH-SY5Y was identified as coamplification of chromosome bands 2p13 and 2p24 by chromosome microdissection and FISH. The non-random rearrangements of chromosomes were determined on 1p34 approximately p36, 6q16 approximately q21, 8q24, 9q34, 11q13 approximately q23, 16q23 approximately q24, 17q21, and 22q31. These results may provide useful information for further molecular characterization of neuroblastoma.
UI - 21324671
AU - Bjornland K; Bratland A; Rugnes E; Pettersen S; Johansen HT; Aasen AO; Fodstad O; Ree AH; Maelandsmo GM
TI - Expression of matrix metalloproteinases and the metastasis-associated gene S100A4 in human neuroblastoma and primitive neuroectodermal tumor cells.
SO - J Pediatr Surg 2001 Jul;36(7):1040-4
AD - Institute for Surgical Research and the Department of Pediatric Surgery, The National Hospital, Oslo, Norway.
BACKGROUND: Matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of MMPs; TIMPs) have been shown to correlate with in vitro invasiveness and clinical outcome in several adult malignancies. The importance of MMP and TIMP expression in neuroblastoma (NB) and primitive neuroectodermal tumors (PNET) is incompletely understood. The aim of the current study was to relate in vitro invasion of NB and PNET cell lines with MMP and TIMP expression and evaluate the effect of a synthetic MMP inhibitor. Furthermore, S100A4 levels were determined because recent reports have suggested a possible association between MMPs, TIMPs, and the metastasis-associated gene S100A4. METHODS: Expression of MMPs, TIMPs, and S100A4 was evaluated at both mRNA and protein levels in 2 human NB and 2 PNET cell lines. In vitro invasion and effects of the synthetic MMP inhibitor Marimastat were assessed in the Transwell chamber assay. RESULTS: The most invasive cells expressed the highest levels of MMPs and S100A4. Marimastat reduced invasion by 30%. CONCLUSIONS: In vitro invasion correlated with MMP and S100A4 expression. The fact that Marimastat reduced in vitro invasion is encouraging for further studies on a possible therapeutic application for proteinase inhibitors. Copyright 2001 by W.B. Saunders Company.
UI - 21374479
AU - La Quaglia MP
TI - Surgical management of neuroblastoma.
SO - Semin Pediatr Surg 2001 Aug;10(3):132-9
AD - Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10012, USA.
Neuroblastoma treatment remains challenging but has been advanced by the establishment of clinical and biological variables that determine prognostic risk. Risk-based therapy currently is the hallmark of neuroblastoma treatment. Initially, stage and age were the prime determinants of survival used in clinical practice. The Shimada histopathologic classification added to the former 2 and biochemical markers like the serum ferritin, lactic dehydrogenase, and neuron-specific enolase also provided information regarding prognosis. The current era of neuroblastoma therapy has been influenced heavily by advances in molecular biology, most notably the identification of the MYCN oncogene and the application of recombinant DNA methods to identification of chromosomal deletions. Current risk assessment includes age, stage, histopathology, and biochemical markers but also analyses performed on DNA extracted from fresh tumors. This places the onus of obtaining an adequate quantity and quality of fresh neuroblastoma tissue directly on the pediatric surgeon who performs the initial biopsy. Copyright 2001 by W.B. Saunders Company
UI - 21375703
AU - Willatt LR; Pearson J; Green AJ
TI - Partial trisomy of 2p and neuroblastoma.
SO - Am J Med Genet 2001 Aug 15;102(3):304-5
UI - 21390958
AU - Bi G; Chen YZ
TI - [The rapid effects of steroids on glycine uptake in neuroblastoma cell strain SK-N-SH cells]
SO - Sheng Li Xue Bao 1999 Dec;51(6):603-8
AD - Neuroscience Research Institute, Second Military Medical University, Shanghai 200433.
In the present study, glycine uptake in SK-N-SH cells was determined with liquid scintillation technique, and the rapid effects of steroids on glycine uptake in SK-N-SH cells were investigated. The results were as follows. High-affinity glycine uptake in SK-N-SH cells was dependent on Na+ and Cl-. Corticosterone (CORT), progesterone (P) and dexamethasone (DEX) had rapid effects on the glycine uptake. Since estradiol (E2) and deoxycorticosterone (DOC) had no effects, it was suggested that the rapid effects of steroids were specific. The rapid effects of CORT were concentration-dependent in a range of 10(-9)-10(-6) mol/L. The rapid effects were not affected by the inhibitor of protein synthesis and persisted even when CORT was conjugated with bovine serum album, but attenuated when Ca2+ was absent in the external medium. The results suggest that the steroid effect on glycine uptake in SK-N-SH cells was nongenomicly mediated.
UI - 21385490
AU - Navarra M; Romano C; Lorenzon T; Rotiroti D; Di Renzo G
TI - Ethanol exposure inhibits the cytotoxic effect induced by gp120 in CHP100 human neuroblastoma cells.
SO - J Neurosci Res 2001 Aug 15;65(4):354-61
AD - Department of Pharmacobiological Sciences, Faculty of Pharmacy, University of Catanzaro Magna Graecia & IBAF-CNR, 88021 Roccelletta di Borgia, Catanzaro, Italy. email@example.com
The aim of present study was to investigate the acute effects of ethanol on cytotoxicity induced by HIV-1 coat protein gp120 in CHP100 human neuroblastoma cell line. We demonstrate that ethanol, within a range of clinically relevant concentrations (15-90 mM) prevents cell death elicited by gp120 (10 pM) in a dose dependent manner. This protective action seems to be mediated by a reduction of free intracellular Ca(2+) levels because ethanol, at concentrations ranging from 0.1-0.5%, is able to decrease gp120-stimulated Ca(2+) uptake up to 24%. Furthermore, our data show an involvement of NO/cGMP messenger system pathway, because ethanol is also able to reduce gp120-stimulated NO release (up to 45%) and cyclic GMP accumulation (up to 73%). These findings suggest that the protective effect of ethanol against gp120-induced cytotoxicity in CHP100 cells underlies a Ca(2+)-activated, NO/cGMP-dependent mechanism. Copyright 2001 Wiley-Liss, Inc.
UI - 21253218
AU - Iwanaka T; Arai M; Ito M; Kawashima H; Matoba K; Imaizumi S
TI - Challenges of laparoscopic resection of abdominal neuroblastoma with lymphadenectomy. A preliminary report.
SO - Surg Endosc 2001 May;15(5):489-92
AD - Department of Surgery, Saitama Children's Medical Center, 2100 Magome, Iwatsuki, Saitama 339-8551, Japan. firstname.lastname@example.org
BACKGROUND: The laparoscopic procedure involving total resection of abdominal neuroblastoma combined with lymphadenectomy has not been reviewed in English literature. The aim of this study was to evaluate the significance and accuracy of laparoscopic resection of abdominal neuroblastoma. METHODS: Since July 1997, five patients with abdominal neuroblastoma underwent laparoscopic resection combined with lymphadenectomy or sampling of the lymph nodes. The length of operation, intraoperative blood loss, resectability, and complications were retrospectively reviewed and evaluated. RESULTS: Four cases were managed laparoscopically, but one case was converted to open procedure because of poor visualization around large vessels. The mean operation time was 135 min and the intraoperative blood loss 52 ml. CONCLUSIONS: Good visualization of the primary tumor and large vessels is, arguably, the most important factor for successful completion of this procedure laparoscopically. Precise indicators for laparoscopic resection of abdominal neuroblastoma provide a better prognosis and a good quality of life for children with neuroblastoma.
UI - 21377776
AU - Cliff JF; Newman L; Malone M; Brady G; Crean SJ
TI - Facial features of widespread neuroblastoma: a case report.
SO - Int J Paediatr Dent 2001 May;11(3):215-20
AD - Department of Maxillofacial and Dental Surgery, Great Ormond Street Hospital for Children, London, UK.
A case report of stage IV neuroblastoma which presented with periorbital swelling and ecchymosis originally misdiagnosed as facial trauma. The child soon developed a sinister pancytopenia, which following extensive investigations was revealed to be due to an underlying neuroblastoma. Periorbital ecchymosis associated with neuroblastoma is termed 'raccoon eyes' and is a diagnostic trap for the unwary.
UI - 21303193
AU - Cheung IY; Cheung NK
TI - Quantitation of marrow disease in neuroblastoma by real-time reverse transcription-PCR.
SO - Clin Cancer Res 2001 Jun;7(6):1698-705
AD - Department of Pediatrics, Memorial Sloan-Kettering Cancer Center New York, New York 10021, USA. email@example.com
PURPOSE: GD2 is abundantly expressed in neuroblastoma (NB). GD2 synthesis is dependent on key enzyme beta 1,4-N-acetylgalactosaminyltransferase (GD2 synthase). We explore the potential of GD2 synthase mRNA as a molecular marker of minimal residual disease by first comparing it quantitatively with immunocytology and then testing its clinical utility. EXPERIMENTAL DESIGN: A real-time reverse transcription-PCR assay to quantify mRNA of GD2 synthase was developed. Quantitation was normalized to endogenous control glyceraldehyde-3-phosphate dehydrogenase in a multiplex PCR. RESULTS: The upper limit of normal was defined by 31 normal marrow and blood samples, achieving a sensitivity of one NB cell in 10(6) normal mononuclear cells. When 155 bone marrows from 100 NB patients were studied, GD2 synthase mRNA levels correlated well with the number of GD2-positive cells, as measured by immunocytology using anti-GD2 antibodies (r = 0.96). This is the first demonstration of the quantitative relationship between a specific mRNA and the actual number of tumor cells. In a pilot study, the level of this transcript in sequential marrow samples of five stage 4 NB patients correlated closely with their clinical status. At 24 months after diagnosis, available remission bone marrows from patients with advanced NB diagnosed at >1 year of age initially treated with protocols N6 and N7 at Memorial Sloan-Kettering Cancer Center (n = 44) were analyzed for GD2 synthase mRNA. Positivity was strongly associated with progression-free (P < 0.005) and overall survival (P < 0.001). CONCLUSIONS: Measurement of tumor cells by real-time quantitative reverse transcription-PCR of GD2 synthase has potential clinical utility, especially for the detection of minimal residual disease.
UI - 21349735
AU - Bursztajn S; Feng JJ; Nanda A; Berman SA
TI - Differential responses of human neuroblastoma and glioblastoma to apoptosis.
SO - Brain Res Mol Brain Res 2001 Jul 13;91(1-2):57-72
AD - Department of Pathology, Dartmouth Medical College and VA Medical Center, 215 North Main St. Research Building #44, White River Junction, VT 05009, USA. firstname.lastname@example.org
Staurosporine, a protein kinase and etoposide, a topoisomerase II inhibitor, are known to enhance apoptosis. The differential effects of these agents on T98G glioblastoma and SK-N-SH neuroblastoma, cell lines both derived from human tumors, have not been determined. We assessed cellular viability, DNA fragmentation and laddering, chromatin condensation, and Poly(ADP-ribose) polymerase (PARP) cleavage induced by these agents at a series of concentrations and times. In addition, to gain an understanding of the mechanism by which these agents work, we measured Protein Kinase C (PKC) activity. Staurosporine induced significant alterations in all apoptotic parameters tested in both cell lines. Etoposide induced apoptotic alterations similar to those caused by staurosporine in neuroblastoma but produced no detectable apoptotic changes in glioblastoma cells. Etoposide induced membrane but not cytosolic PKC activity in neuroblastoma but had no effect on PKC activity in glioblastoma. Our results show that the induction of apoptosis is cell type dependent. PKC activity appears to be crucial in the initiation of apoptosis.
UI - 21396091
AU - De Roos AJ; Teschke K; Savitz DA; Poole C; Grufferman S; Pollock BH; Olshan AF
TI - Parental occupational exposures to electromagnetic fields and radiation and the incidence of neuroblastoma in offspring.
SO - Epidemiology 2001 Sep;12(5):508-17
AD - Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA. email@example.com
We examined parental occupational exposures to electromagnetic fields and radiation and the incidence of neuroblastoma in offspring. Cases were 538 children diagnosed with neuroblastoma between 1992 and 1994 in the United States or Canada. Age-matched controls were selected by random-digit dialing. Occupational exposures to electrical equipment and radiation sources were classified by an industrial hygienist, and average exposures to extremely low frequency magnetic fields were estimated using a job exposure matrix. Maternal exposure to a broad grouping of sources that produce radiofrequency radiation was associated with an increased incidence of neuroblastoma (odds ratio = 2.8; 95% confidence interval = 0.9-8.7). Paternal exposure to battery-powered forklifts was positively associated with neuroblastoma (odds ratio = 1.6; 95% confidence interval = 0.8-3.2), as were some types of equipment that emit radiofrequency radiation (odds ratios congruent with 2.0); however, the broad groupings of sources that produce ELF fields, radiofrequency radiation, or ionizing radiation were not associated with neuroblastoma. Paternal average extremely low frequency magnetic field exposure >0.4 microTesla was weakly associated with neuroblastoma (odds ratio = 1.6; 95% confidence interval = 0.9-2.8), whereas maternal exposure was not. Overall, there was scant supportive evidence of strong associations between parental exposures in electromagnetic spectrum and neuroblastoma in offspring.
UI - 21433655
AU - Lo Piccolo MS; Cheung NK; Cheung IY
TI - GD2 synthase: a new molecular marker for detecting neuroblastoma.
SO - Cancer 2001 Aug 15;92(4):924-31
AD - Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
BACKGROUND: Neuroblastomas (NBs) almost ubiquitously express the ganglioside GD2. GD2 synthesis is dependent on the key enzyme GD2 synthase. Thus, GD2 synthase transcript may prove to be a potential molecular marker of NB. METHODS: Seventy-seven NB tumor tissues of all stages, 5 NB cell lines, and 26 normal bone marrows (BMs) and peripheral blood (PBL) samples, as well as 26 non-NB remission-BMs were analyzed for the expression of GD2 synthase by a highly sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) and chemiluminescence detection. One hundred fifty-two NB BMs were tested and comparisons were made among three independent detection techniques, namely GD2 synthase RT-PCR, immunofluorescence (IF), and histology (HIST). RESULTS: GD2 synthase transcript was present in 5 of 5 cell lines and in 77 of 77 tumors tested. Among 116 marrows that were positive by at least 1 of the 3 methods, 78% were detectable by GD2 synthase, 68% by IF, and 46% by HIST. Seventy-six percent of positive BMs that were obtained during treatment and follow-up had GD2 synthase expression, whereas only 29% were HIST positive. Correlation between RT-PCR and IF was high (P = 0.001), and positivity by 3 out of 3 methods was strongly correlated with poor survival (P < 0.01). Of note, marrows tested at the time of chemotherapy were positive by at least 2 out of 3 methods and were associated with adverse outcome (P = 0.01). Serial samples (n = 28) in 5 patients demonstrated close agreement between RT-PCR and patient disease status. CONCLUSIONS: The current study found that molecular detection of GD2 synthase transcript in NB BMs may have potential value in detecting rare tumor cells. Copyright 2001 American Cancer Society.
UI - 21397878
AU - Anderson J; Kempski H; Hill L; Rampling D; Gordon T; Michalski A
TI - Neuroblastoma in monozygotic twins--a case of probable twin-to-twin metastasis.
SO - Br J Cancer 2001 Aug 17;85(4):493-6
AD - Unit of Molecular Haematology, Institute of Child Health, Great Ormond Street Hospital for Children NHS Trust, London, UK.
Concordance for neuroblastoma in monozygotic twins has been reported only rarely, and the cause of the shared pathology has not been established. We describe a case of infant monozygotic twins developing tumours that were morphologically, clinically and molecularly indistinguishable, but with a delay of 6 months between times of presentation. Both tumours were metastatic and had amplification of MYCN and deletion at 1p36. Twin 1, who developed neuroblastoma first, had constitutional karyotype abnormalities in at least 5% of peripheral blood mononuclear cells involving 1p and 3p, and a deletion of 1q44 in 21% of cells. Twin 2 had a normal constitutional karyotype and lacked rearrangement or deletion of these regions. We propose an acquired neuroblastoma predisposition specific for twin 1, and in utero metastatic spread of tumour cells to twin 2 via the shared placental circulation. Copyright 2001 Cancer Research Campaign.
UI - 21397885
AU - Luttikhuis ME; Powell JE; Rees SA; Genus T; Chughtai S; Ramani P; Mann JR; McConville CM
TI - Neuroblastomas with chromosome 11q loss and single copy MYCN comprise a biologically distinct group of tumours with adverse prognosis.
SO - Br J Cancer 2001 Aug 17;85(4):531-7
AD - Division of Medical and Molecular Genetics, University of Birmingham B15 2TT, UK.
Neuroblastoma is a heterogeneous tumour and its effective clinical management is dependent on accurate prognostic evaluation. In approximately 25% of patients amplification of the MYCN oncogene is known to be associated with a poor outcome. In order to identify additional molecular markers with prognostic potential in non-MYCN-amplified neuroblastomas, we looked for a correlation between clinical outcome and loss of heterozygosity (LOH) on four chromosomes that frequently show alteration in neuroblastoma (chromosomes 3, 4, 11 and 14). Chromosome 11q loss (with frequent parallel loss of chromosomes 3p, 4p and/or 14q) was found exclusively in tumours without MYCN amplification and was significantly associated with poor event-free survival. The 2-year event-free survival rate for 11q LOH cases was 30%, compared to 34% for MYCN-amplified cases and 100% for cases without these abnormalities. While 11q LOH was associated predominantly with advanced-stage disease, 2 cases with low-stage disease and 11q LOH both suffered relapses. We conclude that chromosome 11q loss defines a biologically distinct group of tumours without MYCN amplification that appear to have potential for aggressive metastatic growth. Thus this genetic alteration may be an important new prognostic marker in neuroblastoma. Copyright 2001 Cancer Research Campaign.
UI - 21160511
AU - Yamanaka M; Saitoh F; Saitoh H; Nisimura S; Sawada Y; Tsukui A; Kaimori M; Takahashi N
TI - Primary retroperitoneal ganglioneuroblastoma in an adult.
SO - Int J Urol 2001 Mar;8(3):130-2
AD - Japanese Ground Self Defense Force Aomori Clinic, Aomori, Japan.
A case of retroperitoneal ganglioneuroblastoma in a 60-year-old man is reported. This retroperitoneal tumor was surgically removed and pathologic diagnosis was ganglioneuroblastoma. Ganglioneuroblastoma usually occurs in children and is extremely rare in adults. The characteristics are described of an unusual tumor based on the published reports.
UI - 21218708
AU - Miano M; Garaventa A; Pizzitola MR; Piccolo MS; Dallorso S; Villavecchia GP; Bertolazzi C; Cabria M; De Bernardi B
TI - Megatherapy combining I(131) metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma.
SO - Bone Marrow Transplant 2001 Mar;27(6):571-4
AD - Haematology and Oncology Department, G Gaslini Children's Hospital, Genoa, Italy.
Despite the use of aggressive chemotherapy, stage 4 high risk neuroblastoma still has very poor prognosis which is estimated at 25%. Metabolic radiotherapy with I(131) MIBG appears a feasible option to enhance the effects of chemotherapy. Seventeen patients having MIBG-positive residual disease received 4.1-11.1 mCi/kg of I(131) MIBG 7-10 days before initiating the high-dose chemotherapy cycle consisting of busulphan 16 mg/kg and melphalan 140 mg/m(2) followed by PBSC infusion. We compared the toxicity in these patients to that seen in 15 control subjects with neuroblastoma who underwent a PBSC transplant without MIBG therapy. We observed greater toxic involvement of the gastrointestinal system in children treated with I(131) MIBG: grade 2 or 3 mucositis developed in 13/17 patients treated with I(131) MIBG and in 9/15 treated without it. Grade 1-2 gastrointestinal toxicity occurred in 12/17 children given MIBG and in 5/15 of the controls. One child receiving I(131) MIBG developed transient interstitial pneumonia. Another child who also received I(131) MIBG after PBSC rescue developed fatal pneumonia after the third course of metabolic radiotherapy. Our experience indicates that MIBG can be included in the high-dose chemotherapy regimens followed by PBSC rescue for children with residual neuroblastoma taking up MIBG. Attention should be paid to avoiding lung complications. Prospective studies are needed to demonstrate the real efficacy of this treatment.
UI - 21236705
AU - Monsieurs MA; Thierens HM; Vral A; Brans B; De Ridder L; Dierckx RA
TI - Patient dosimetry after 131I-MIBG therapy for neuroblastoma and carcinoid tumours.
SO - Nucl Med Commun 2001 Apr;22(4):367-74
AD - Department of Biomedical Physics & Radiation Dosimetry, University of Ghent, Belgium. firstname.lastname@example.org
AIM: The aim of the study was to determine the equivalent total body dose (ETBD) using the cytokinesis-blocked micronucleus assay in 22 131 I-meta-iodobenzylguanidine (131 I-MIBG) therapies (18 neuroblastoma, mean 5097 MBq, SD 1591; and four carcinoid tumours, mean 7681 MBq, SD 487). The results are correlated with the total body radiation dose according to the Medical Internal Radiation Dosimetry (MIRD) formalism. METHODS: For each patient, blood samples were taken immediately before and 1 week after 131I-MIBG therapy. The first blood sample was irradiated in vitro with 60Co gamma-rays to determine the dose-response curve. Micronuclei were scored in 1000 binucleated cells. By using the dose-response curve the ETBD was derived from the increase in micronuclei after 131I-MIBG therapy (second blood sample). Based on three consecutive biplanar scans taken at 3, 6 and 9 days post-administration respectively, the total body dose following the MIRD formalism was calculated. RESULTS: The micronucleus assay was evaluable in only 14 out of 22 131I-MIBG therapies due to cell division inhibition caused by previous chemotherapy treatments and lymphocyte dilution due to blood transfusions given shortly after 131I-MIBG therapy. For these 14 therapies, the mean micronucleus yield after 131I-MIBG therapy was significantly increased (P < 0.01) with a mean of 92 (SD 77) for neuroblastoma patients and with a mean of 35 (SD 8) for carcinoid patients. The increase observed in the present study is greater than previously observed after 131I therapy and 89Sr therapy but much lower than after external beam radiotherapy. For all patients treated with multiple therapies, the initial increase in micronucleus yield had at least partially recovered by the time of the next therapy. This might be explained by an increased turnover of lymphocytes. A mean ETBD of 0.95 Gy (SD 0.55) for neuroblastoma patients and a mean of 0.46 Gy (SD 0.09) for carcinoid patients was calculated. A reasonable correlation (R = 0.87) between the ETBD and the MIRD dose was obtained. The slope value of 0.75 can be explained by the low dose rate effect. CONCLUSIONS: The observation in the present study of important inter-individual variability in the total body dose, with the possibility of high dose values, suggests the necessity of individual dosimetry when administering 131I-MIBG therapy, especially considering that generally more than one therapy is given to each patient.
UI - 21313756
AU - Mathew P; Valentine MB; Bowman LC; Rowe ST; Nash MB; Valentine VA; Cohn SL; Castleberry RP; Brodeur GM; Look AT
TI - Detection of MYCN gene amplification in neuroblastoma by fluorescence in situ hybridization: a pediatric oncology group study.
SO - Neoplasia 2001 Mar-Apr;3(2):105-9
AD - Department of Experimental Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
To assess the utility of fluorescence in situ hybridization (FISH) for analysis of MYCN gene amplification in neuroblastoma, we compared this assay with Southern blot analysis using tumor specimens collected from 232 patients with presenting characteristics typical of this disease. The FISH technique identified MYCN amplification in 47 cases, compared with 39 by Southern blotting, thus increasing the total number of positive cases by 21%. The major cause of discordancy was a low fraction of tumor cells (< or =30% replacement) in clinical specimens, which prevented an accurate estimate of MYCN copy number by Southern blotting. With FISH, by contrast, it was possible to analyze multiple interphase nuclei of tumor cells, regardless of the proportion of normal peripheral blood, bone marrow, or stromal cells in clinical samples. Thus, FISH could be performed accurately with very small numbers of tumor cells from touch preparations of needle biopsies. Moreover, this procedure allowed us to discern the heterogeneous pattern of MYCN amplification that is characteristic of neuroblastoma. We conclude that FISH improves the detection of MYCN gene amplification in childhood neuroblastomas in a clinical setting, thus facilitating therapeutic decisions based on the presence or absence of this prognostically important biologic marker.
UI - 21313763
AU - Yang HW; Chen YZ; Piao HY; Takita J; Soeda E; Hayashi Y
TI - DNA fragmentation factor 45 (DFF45) gene at 1p36.2 is homozygously deleted and encodes variant transcripts in neuroblastoma cell line.
SO - Neoplasia 2001 Mar-Apr;3(2):165-9
AD - Department of Pediatrics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 13-8655, Japan.
Recently, loss of heterozygosity (LOH) studies suggest that more than two tumor suppressor genes lie on the short arm of chromosome 1 (1p) in neuroblastoma (NB). To identify candidate tumor suppressor genes in NB, we searched for homozygous deletions in 20 NB cell lines using a high-density STS map spanning chromosome 1p36, a common LOH region in NB. We found that the 45-kDa subunit of the DNA fragmentation factor (DFF45) gene was homozygously deleted in an NB cell line, NB-1. DFF45 is the chaperon of DFF40, and both molecules are necessary for caspase 3 to induce apoptosis. DFF35, a splicing variant of DFF45, is an inhibitor of DFF40. We examined 20 NB cell lines for expression and mutation of DFF45 gene by reverse transcription (RT)-polymerase chain reaction (PCR) and RT-PCR-single-strand conformation polymorphism. Some novel variant transcripts of the DFF45 gene were found in NB cell lines, but not in normal adrenal gland and peripheral blood. These variants may not serve as chaperons of DFF40, but as inhibitors like DFF35, thus disrupting the balance between DFF45 and DFF40. No mutations of the DFF45 gene were found in any NB cell line, suggesting that the DFF45 is not a tumor suppressor gene for NB. However, homozygous deletion of the DFF45 gene in the NB-1 cell line may imply the presence of unknown tumor suppressor genes in this region.
UI - 21318978
AU - Xie C; Lovell MA; Xiong S; Kindy MS; Guo J; Xie J; Amaranth V; Montine TJ; Markesbery WR
TI - Expression of glutathione-S-transferase isozyme in the SY5Y neuroblastoma cell line increases resistance to oxidative stress.
SO - Free Radic Biol Med 2001 Jul 1;31(1):73-81
AD - Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.
Glutathione-S-transferases (GSTs) are a superfamily of enzymes that function to catalyze the nucleophilic attack of glutathione on electrophilic groups of a second substrate. GSTs are present in many organs and have been implicated in the detoxification of endogenous alpha, beta unsaturated aldehydes, including 4-hydroxynonenal (HNE). Exogenous GST protects hippocampal neurons against HNE in culture. To test the hypothesis that overexpression of GST in cells would increase resistance to exogenous or endogenous HNE induced by oxidative stress, stable transfectants of SY5Y neuroblastoma cells with GST were established. Stable GST transfectants demonstrated enzyme activities 13.7 times (Clone 1) and 30 times (Clone 2) higher than cells transfected with vector alone. GST transfectants (both Clones 1 and 2) demonstrated significantly (p <.05) increased resistance to ferrous sulfate/hydrogen peroxide (20.9% for Clone 1; 46.5% for Clone 2), amyloid beta-peptide (12.2% for Clone 1; 27.5.% for Clone 2), and peroxynitrite (24.3% for Clone 1; 43.9% for Clone 2), but not to exogenous application of HNE in culture medium. GST transfectants treated with 1,1,4-tris (acetyloxy)nonane, a nontoxic derivative of HNE that is degraded to HNE intracellularly, demonstrated a statistically significant (p <.05) increase in viability in a dose-dependent manner compared with SY5Y cells transfected with vector alone. These results suggest that overexpression of GST increases resistance to endogenous HNE induced by oxidative stress or released in the degradation of 1,1,4-tris (acetyloxy)nonane, but not to exogenous application of HNE.
UI - 21334159
AU - Wheldon LM; Nahorski SR; Willars GB
TI - Inositol 1,4,5-trisphosphate-independent calcium signalling by platelet-derived growth factor in the human SH-SY5Y neuroblastoma cell.
SO - Cell Calcium 2001 Aug;30(2):95-106
AD - Department of Cell Physiology & Pharmacology, University of Leicester, UK. email@example.com
In adherent SH-SY5Y human neuroblastoma cells, activation of G-protein-coupled muscarinic M3 receptors evoked a biphasic elevation of both intracellular [Ca(2+)] ([Ca(2+)]i) and inositol-1,4,5-trisphosphate (D-Ins(1,4,5)P3) mass. In both cases, temporal profiles consisted of rapid transient elevations followed by a decline to a lower, yet sustained level. In contrast, platelet-derived growth factor (PDGF), a receptor tyrosine kinase agonist acting via PDGF receptor b chains in these cells, elicited a slow and transient elevation of [Ca(2+)]i that returned to basal levels within 5 to 10 min with no evidence of inositol phosphate generation. Full responses for either receptor type required intracellular and extracellular Ca(2+) and mobilization of a shared thapsigargin-sensitive intracellular Ca(2+) store. Strategies that affected the ability of D-Ins(1,4,5)P3 to interact with the Ins(1,4,5)P3-receptor demonstrated an Ins(1,4,5)P3-dependency of the muscarinic receptor-mediated elevation of [Ca(2+)]i but showed that PDGF-mediated elevations of [Ca(2+)]i are Ins(1,4,5)P3-independent in these cells. Copyright 2001 Harcourt Publishers Ltd.
UI - 21407671
AU - Mattingly RR; Milstein ML; Mirkin BL
TI - Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells.
SO - Cell Signal 2001 Jul;13(7):499-505
AD - Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA. firstname.lastname@example.org
The mitogen-activated protein kinase (MAPk) signaling pathway, which plays a critical role in the proliferation of mammalian cells, is frequently up-regulated in human tumors and may contribute to the transformed phenotype. Since a major limitation of current cancer chemotherapy is prevalent resistance to cytotoxic drugs, this study determined whether alterations in growth factor signaling through MAPk may contribute to this phenomenon in human neuroblastoma cell lines. Drug-resistant SKNSH cell lines were established by long-term incubation with increasing concentrations to 10(-6) M doxorubicin (SKNSH rDOX6) or MDL 28842 (SKNSH rMDL6). The expression of epidermal growth factor receptor (EGFR) and epidermal growth factor (EGF)-induced EGFR tyrosine phosphorylation were lower in drug-resistant SKNSH cells than their wild-type counterparts. In SKNSH rDOX6 cells, decreased activation and reduced nuclear translocation of MAPk in response to EGF, or lysophosphatidic acid (LPA), or phorbol 12-myristate 13-acetate (PMA), were observed. In SKNSH rMDL6 cells, although MAPk could be activated to wild-type levels by ligand stimulation, the translocation of active MAPk to the nucleus was also reduced. These results suggest that resistance to cytotoxic drugs in human neuroblastoma cell lines is associated with a decrease in growth factor signaling through the MAPk pathway.
UI - 21380384
AU - Unger F; Walch C; Stammberger H; Papaefthymiou G; Haselsberger K; Pendl G
TI - Olfactory neuroblastoma (esthesioneuroblastoma): report of six cases treated by a novel combination of endoscopic surgery and radiosurgery.
SO - Minim Invasive Neurosurg 2001 Jun;44(2):79-84
AD - Department of Neurosurgery, Karl-Franzens University, Graz, Austria. email@example.com
Microsurgical techniques have considerably improved the results of surgical treatment for esthesioneuroblastoma (olfactory neuroblastoma). Nevertheless, these rare tumours of the frontal skull base are still associated with high rates of tumour recurrence and mortality, thus remaining a challenge even for experienced surgeons. A novel therapeutic approach that combines endoscopic sinus surgery and radiosurgery (gamma knife) is presented here. Six patients (3 males, 3 females) aged between 27 and 75 years (median 38 years) were treated between August 1993 and July 1999. Following paranasal and nasal endoscopic sinus surgery, marginal irradiation doses ranging from 16 to 34 Gy were applied radiosurgically involving up to 7 isocentres. At present, the median follow-up period is 57 months (range: 9 - 79 months). Without mortality, tumour control was achieved in all patients. One patient, who had to undergo additional craniotomy because of extensive neoplastic infiltration, developed postoperative liquorrhea. In another case the clinical course was complicated by a bilateral frontal sinusitis. All patients complained of nasal discharge and crusts. However, a preoperative Karnovsky Index ranging from 80 to 100 % remained stable in four patients whereas an improvement was observed in two patients. Based on the favourable results observed so far, the combination of endoscopic sinus surgery and radiosurgery can be considered as promising new option for the treatment of esthesioneuroblastoma that merits further investigation.
UI - 21411581
AU - Zhang J; Spring H; Schwab M
TI - Neuroblastoma tumor cell-binding peptides identified through random peptide phage display.
SO - Cancer Lett 2001 Oct 10;171(2):153-64
AD - Division of Cytogenetics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. firstname.lastname@example.org
Random peptide phage display libraries have been employed widely to identify protein-protein interactions, using as targets either purified proteins, intact cells, or organs. To isolate peptides that bind to human neuroblastoma cells, we have used a phage display approach with the neuroblastoma cell line WAC 2 as the target. In particular, two bacteriophages, t147 and t160, displaying peptides p147 and p160, respectively, were isolated by repeated display cycles. Binding of t147 and t160 to WAC 2 cells was abrogated by pretreatment with the peptides p147 and p160, respectively, which strongly support that cellular binding of both phages is dictated by their displayed peptides. Immunofluorescence analysis by confocal light microscopy revealed that the major proportion of t147 remains on the surface of WAC 2 cells and that only a fraction is taken up into the cells. In contrast, the vast majority of t160 is internalized. K(+) depletion reduced the number of the phages internalized by the cells to approximately 20% for t160 and to 10% for t147, indicating that the phage internalization was through receptor-mediated endocytosis. Phage t147 appears to bind to a range of tumor cell lines, including neuroblastoma, breast cancer, glioblastoma and C-cell carcinoma, but less so to non-tumor lines, such as erythrocytes, lymphocytes, monocytes and epithelial cells. Phage t160 bound to a range of neuroblastoma cell lines and a breast cancer cell line, but not to other tested cell lines. While neither of the displayed peptides conferred a narrow tissue specific binding ability, they do provide a basis for targeted drug delivery in selected experimental or natural tumor systems.