Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LFA-3, ICAM-1, HLA.ABC and HLA.DR expression was analyzed on 66 neuroblastoma specimens. HLA.ABC was expressed on 26 specimens, HLA.DR on 2, LFA-3 on 20 and ICAM-1 on 10. HLA.ABC and LFA-3 were positive on ganglioneuroblastoma or ganglioneuroma, but they were negative on neuroblastoma, independently of the clinical staging; HLA.ABC and LFA-3 were induced in vivo by chemotherapy in parallel with tumoral cell differentiation, in both the primary and the metastases. The expression of ICAM-1 was restricted to 5 of the 10 low-grade stage-1 or stage-2 specimens, 1 stage-3 specimen, and the primary tumors of 2 patients with stage-4 disease, analyzed hence at diagnosis and after chemotherapy (4 specimens); metastatic cells obtained in 1 of these patients were negative. HLA.ABC and LFA-3 expressed on both mycN-negative and -positive specimens, whereas ICAM-1 was restricted to MYCN-negative specimens. LFA-3 diffusely stained partially differentiated neuroblasts, Schwann cells and ganglion cells. The expression of HLA.ABC on differentiated neuroblasts varied from one sample to another and within the same tumor; Schwann cells were strongly positive, but ganglion cells were negative. In positive samples, ICAM-1 was expressed on differentiated neuroblasts and Schwann cells, but negative on ganglion cells; however, most of the differentiated tumors were ICAM-1-negative, suggesting ICAM-1 induction by unknown local signal. The 4 markers were negative on undifferentiated neuroblasts. The distribution of these 4 markers on clinical specimens was in agreement with their reactivity on fetal tissues, as well as with results obtained on neuroblastoma cell lines before and after in vitro treatment with IFN-gamma.
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PMID:Expression of leucocyte adhesion molecules on 66 clinical neuroblastoma specimens. 171 Jun 8

Tumors of the peripheral nervous system include neuroblastomas, pheochromocytomas, and neuroepitheliomas. Neuroblastomas and pheochromocytomas are adrenergic in origin and share certain genetic features, whereas neuroepitheliomas are thought to be cholinergic and are characterized by distinct genetic features. Neuroblastomas are characterized by deletion of the short arm of chromosome 1 (1p), amplification of the MYCN proto-oncogene, and hyperdiploidy in subsets of tumors. All three of these genetic features have prognostic value in subsets of patients. Allelic loss of 14q also occurs with increased frequency, but the prognostic importance of this abnormality is not known yet. Pheochromocytomas have not been studied as extensively, but allelic loss for 1p appears to be a frequent change, and no clear examples of oncogene activation have been identified to date. Neuroepitheliomas are characterized by translocation between chromosomes 11 and 22. Although they have a characteristic pattern of proto-oncogene expression, it is not clear that any of these oncogenes are activated specifically, and no sites of allelic loss have been identified to date. Thus, cytogenetic and molecular analysis of neuroblastomas, pheochromocytomas, and neuroepitheliomas are useful in distinguishing them from each other and from other tumors in selected cases. Furthermore, certain genetic markers are useful in predicting clinical behavior, especially for neuroblastoma.
Cancer Metastasis Rev 1991 Dec
PMID:Biology of tumors of the peripheral nervous system. 178 33

An experimental model of advanced human neuroblastoma, IGR-N-91, which is able to disseminate in the nude mouse, has been described. The present study was designed to ascertain which cell population from the IGR-N-91 primary tumour actually disseminates throughout the animals. In s.c. IGR-N-91 tumour xenografts, 3 areas, called pearly, vascularized and haemorrhagic, depending on the presence of blood vessels and haemorrhagic suffusions, were consistently observed and independently resected. Molecular analysis of tumour materials revealed a significant increase in MYCN and max gene transcript levels in the haemorrhagic area, as compared with the pearly and vascularized areas. Given the growth kinetics observed both in vitro and in vivo, and the DNA flow-cytometry profiles of tumour cells obtained from the haemorrhagic area, this transcriptional increase did not appear to be associated with enhanced proliferation. In this area of the tumours, multidrug-resistance-related genes, i.e., MDRI, MRP, GST-pi and topoisomerase II alpha were activated concomitantly with MYCN and max genes. The same observations were made, except for the topoisomerase-II alpha gene, when sub-lines derived from metastases were compared with that derived from the primary tumour. These data demonstrate that over-expression of several genes determining the multi-drug-resistance phenotype precedes the metastatic spread of IGR-N-91 NB tumour cells in the nude mouse. Data also suggest that the cell sub-population exhibiting this pleiotropic over-expression within the primary tumour undergoes selection during metastatic dissemination.
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PMID:Pleiotropic over-expression of multidrug-resistance-related genes is correlated to MYCN and max mRNA accumulation during tumour progression in the IGR-N-91 human neuroblastoma model. 903 51

The effects of nerve growth factor, a neurotrophin mediating growth and differentiation of neural crest-derived cells, are mediated by the receptor TrkA. TrkA mRNA expression has been associated with a good prognosis in human neuroblastoma (NB). We describe the use of monoclonal antibody 5C3 in detecting TrkA expression by immunohistochemistry in NB and other malignant tumors. A murine anti-TrkA IgG1 monoclonal antibody, 5C3, was generated against the extracellular domain of human p140(TrkA). 5C3 detected a 140-kDa band on Western blots. 5C3 was optimized for immunostaining and used to detect p140(TrkA) on 113 frozen NB samples and 42 samples from nine other malignancies. MOPC21 IgG1 antibody was used as a control. Results by immunohistochemistry were compared to TrkA expression assessed by reverse transcription-PCR and Western analysis. The prognostic value of TrkA expression by these methods was evaluated and compared to other known prognostic variables, including stage, age, and MYCN copy number. TrkA expression was detected by immunohistochemistry in 73 of the 113 NB tumor specimens and strongly correlated with nonmetastatic disease. TrkA expression was specific for NB among small round blue cell tumors. Both TrkA expression by immunohistochemistry and localized/4s disease correlated with survival. Tumors from 55 of 60 patients with localized/4s NB exhibited homogeneous or a mixed pattern of TrkA immunohistochemistry, whereas only 18 of 53 patients with stage 4 NB were immunoreactive. Detection of TrkA by reverse transcription-PCR and Western analysis was much more sensitive and no longer correlated with survival. 5C3 enables rapid detection of p140(TrkA) by immuno-histochemistry and identifies patients more likely to have localized NB with a favorable clinical outcome. Lack of TrkA expression is correlated with metastatic, malignant NB. A subset of patients with NB, however, died of aggressive metastatic disease despite TrkA expression. As a mimic of nerve growth factor, 5C3 may be useful in the study of TrkA-expressing tumors.
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PMID:Prognostic value of TrkA protein detection by monoclonal antibody 5C3 in neuroblastoma. 981 8

Angiogenesis plays an important role in the growth and metastasis of malignant tumors. We have previously reported that in children with neuroblastoma (NB), tumor vascularity directly correlates with metastatic disease, MYCN amplification, and poor outcome. The angiogenesis inhibitor TNP-470 has been shown to reduce the rate of NB growth in rodents with macroscopic tumors without ultimately impacting survival. To investigate whether TNP-470 could more effectively inhibit NB growth in animals with a low tumor burden, we treated 30 nude mice with minimal disease with this angiogenesis inhibitor (supplied by TAP Pharmaceuticals, Inc.). Therapy was initiated before tumors were clinically evident after s.c. inoculation of 5 x 10(6) cells from the MYCN-amplified NB cell line NBL-W-N. TNP-470 was administered 3 days/week, and after 12 weeks of treatment, 53% of the treated mice remained tumor free, whereas 100% of the control mice developed tumors (P < 0.0001). To further assess the relationship between the efficacy of TNP-470 treatment and tumor burden, TNP-470 was also administered s.c., 3 days/week, to mice with clinically evident small (<400 mm3; n = 15) and large (>400 mm3; n = 11) tumors. For animals with small tumors, the mean rate of growth was significantly decreased in the treated mice compared to the controls (P = 0.02). In contrast, there was no difference in the mean rate of tumor growth between animals with large tumors treated with TNP-470 and controls (P = 0.64). Our studies demonstrate that the effectiveness of TNP-470 inversely correlates with tumor burden. We speculate that TNP-470 may most effectively inhibit NB tumor growth in children with a low tumor burden.
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PMID:Effectiveness of the angiogenesis inhibitor TNP-470 in reducing the growth of human neuroblastoma in nude mice inversely correlates with tumor burden. 1063 70

To assess the relevance of MYCN amplification and bone lesions in stage 4 neuroblastoma (NB) in infants aged <1 year, 51 infants with stage 4 NB were enrolled. Three groups of patients were defined according to the type of metastases and the resectability of the primary tumour. Group I comprised 21 infants with radiologically detectable bone lesions, Group II 22 patients with an unresectable primary tumour and Group III eight patients with only metaiodobenzylguanidine (MIBG) skeletal uptake. MYCN oncogene content was assayed in 47/51 tumours and found to be amplified in 17 (37%). The 5-year event-free survival (EFS) rate of these 51 infants was 64.1% (+/- 7.1%). In a univariate analysis, bone lesions, MYCN amplification, urinary vanillylmandelic/homovanillic acid ratio and serum ferritin levels adversely influenced outcome. In the multivariate analysis, radiologically detectable bone lesions were the most powerful unfavourable prognostic indicator: the EFS rate was 27.2% for these infants compared to 90% for infants without bone lesions (P<0.0001). Our data emphasize the poor prognosis of infants affected by stage 4 NB with bone lesions, especially when associated with MYCN amplification. Given the poor results in this group whatever the treatment, new therapeutic approaches need to be investigated in the future.
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PMID:Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology. 1099 41

The pediatric tumor neuroblastoma is characterized by a very variable, and at times unpredictable, pattern of clinical behavior, ranging from a benign localized tumor to an aggressive malignancy with poor prognosis. Standard clinical and pathological assessments do not always differentiate reliably between tumor subtypes and, therefore, genetic markers are now playing an increasingly important role in treatment decisions. MYCN oncogene amplification, for example, provides a useful marker of poor prognosis. However, less than one-half of all patients who present with, or who later develop, metastatic disease show MYCN amplification. Consequently, the identification of characteristic patterns of genetic alteration in the remaining tumors is of importance. In this report, we describe two new cell lines that we have established from metastatic, non-MYCN amplified, advanced stage neuroblastomas. These cell lines show a number of features in common, including unbalanced translocation between 11q and 17q, loss of 3p, 4p and 11q and gain of 17q. Therefore, they provide a valuable resource for the characterization of genetic pathways leading to aggressive tumor growth in non-MYCN amplified neuroblastomas.
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PMID:Molecular cytogenetic characterization of two non-MYCN amplified neuroblastoma cell lines with complex t(11;17). 1167 34

Neuroblastoma is the most frequent solid extracranial neoplasm of childhood, with a median age of presentation of under 2 years. This tumour is highly malignant in patients older than 12 months of age with metastatic disease. Clinical studies have confirmed that amplification of the MYCN proto-oncogene is one of the best prognostic indicators of poor outcome. Approximately 30% of neuroblastoma tumours present MYCN amplification at diagnosis. Far less is known about the incidence and consequences of overrepresentation of the gene due to duplication or rearrangement of the chromosome arm in which the gene is situated. This study has analysed 110 neuroblastomas by FISH and has detected a gain of 1-3 copies per cell of MYCN in 8% of MYCN-non-amplified tumours. In these primary tumours, cells gained small numbers of additional MYCN genes by two mechanisms: formation of an isochromosome 2p, or an unbalanced translocation involving the short arm of chromosome 2 (with MYCN) and various partner chromosomes. Quantitative RT-PCR showed three- to seven-fold elevated MYCN expression in three tumours. Although the follow-up time to date is still short, clinical outcome suggests that low-level overexpression of the MYCN gene does not enhance tumour aggressiveness and rapidity of disease progression, as is often seen in neuroblastoma with MYCN amplification. It is hypothesized that the small elevation in MYCN expression could alter the regulation of apoptosis, as has been shown in experimental models.
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PMID:MYCN gene overrepresentation detected in primary neuroblastoma tumour cells without amplification. 1243 19

During the last two decades new diagnostic and therapeutic tools have been utilized to improve the poor survival chances of children with stage 4 neuroblastoma. This study reviews the risk profiles and the long-term outcome of patients from five consecutive German neuroblastoma trials. A total of 96% of all German patients registered at the German childhood cancer registry with neuroblastoma stage 4 over 1 year of age at diagnosis entered one of the trials during 1979-2001. Eight hundred and twenty-eight consecutive children were analyzed retrospectively. In spite of having significantly improved diagnostic tools like bone marrow superstaging and mIBG scintigraphy the stage 4 incidence did not increase after reaching completeness of the registry (5.4 cases/100,000 children at 1-14 years of age; P=0.52). The distribution of the primary tumors and of metastases was constant over the periods. The amount of bone marrow infiltration did not change with time. The risk factors lactate dehydrogenase, ferritin and MYCN, and the clinical risk groups 4A, 4B, 4C also remained constant over the trials with a few exceptions for NB97. The 5-year event free survival increased from 0.01+/-0.01 (NB79) to 0.14+/-0.03 (NB85), 0.16+/-0.04 (NB82), 0.27+/-0.02 (NB90), and 0.33+/-0.04 (NB97). The overall survival rates improved similarly from 0.04 (NB79) to 0.44 (NB97). In conclusion, the improved survival was associated with better treatment and not caused by lower risk profiles in stage 4 neuroblastoma patients.
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PMID:Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. 1288 Sep 54

Regional genomic alterations resulting from single-copy allelic loss or gain have been well characterized in many human cancers and are often of prognostic relevance. Unbalanced gain of 17q material is common in malignant human neuroblastomas and typically results from unbalanced translocations. Unbalanced 17q gain may be an independent predictor of disease outcome, but technical difficulties with quantifying such gain using fluorescent in situ hybridization gives this method limited clinical applicability. We now describe a duplex genomic DNA-based quantitative polymerase chain reaction assay to determine the presence or absence of unbalanced gain of chromosome 17q in primary neuroblastoma specimens. The technique was first refined and validated in a panel of nine human neuroblastoma-derived cell lines by direct comparison with dual-color fluorescent in situ hybridization. Prospective blinded comparison of quantitative polymerase chain reaction and fluorescence in situ hybridization in 40 human neuroblastoma primary tumor samples showed a sensitivity of 96% and 100% specificity for detecting unbalanced 17q gain when a relative 17q copy number ratio of 1.3 was used to define unbalanced gain. Tumors with ratios >1.3 were highly associated with malignant tumor phenotypic features such as metastatic disease (P <.0001) and tumor MYCN amplification (P =.008). These data suggest that quantitative polymerase chain reaction determination of 17q status is feasible and highly specific in primary tumor samples. Sensitivity may be limited because of the inherent complexity of both the chromosomal rearrangements and heterogeneity of some tumor samples. Taken together, quantitative polymerase chain reaction can be used as a high-throughput screening tool for 17q aberrations, but a subset of samples may also require fluorescence in situ hybridization analysis in an attempt to conclusively determine 17q allelic status.
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PMID:Detection of single-copy chromosome 17q gain in human neuroblastomas using real-time quantitative polymerase chain reaction. 1468 26


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