Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD44 gene products are potential markers of aggressiveness in different tumour models, a result which prompted us to study clinical neuroblastoma (NB) specimens. CD44 expression was determined by immunostaining of 52 tumour samples from newly diagnosed NB with a monoclonal antibody (J173) directed against an epitope common to all CD44 isoforms. CD44 immunoreactivity was detected in 37 of the tumours (71%). CD44 was expressed in all 22 NBs with favourable prognoses (stages 1, 2 or 4S), but only 50% (15/30) of advanced NB (stages 3 and 4) (P < 10(-4)), suggesting that the absence, rather than the overexpression, of CD44 is a signal of tumour aggressiveness. The cumulative progression-free survival was significantly longer in patients with CD44 positive tumours compared with patients with CD44 negative tumours (P < 10(-5)). More importantly, progression-free survival was also significantly higher in CD44 positive patients within the high-risk group (P < 0.01). In univariate analysis, we tested the prognostic value of tumour expression of CD44 in comparison with tumour stage, age, tumour histology, and presence or absence of amplification of the MYCN protooncogene. All five measures had significant prognostic value. The expression of CD44 and the absence of MYCN amplification were the most powerful predictors of a favourable outcome. In a multivariate analysis of these measures, CD44 expression and tumour stage were the only independent prognostic factors for the prediction of patient survival. NB is the first clinical model described in which tumour aggressiveness correlates with repression rather than stimulation of CD44 expression. We recommend the use of CD44 as an additional biological marker in the initial staging of NB.
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PMID:Evaluation of CD44 prognostic value in neuroblastoma: comparison with the other prognostic factors. 757 64

Cell-cell and cell-extracellular matrix interactions mediated by cell adhesion molecules (for example CD44) play an important role in the cascade of metastasis and the progression of human malignant tumours. The most important aim of this review was, on the basis of our results and the literature, to show the correlation between the expression of CD44s and differentiation and prognosis of neuroblastoma. Surprisingly and in contrast to most other malignant tumours, neuroblastomas exhibited an inverse correlation between CD44s expression and tumour progression. It can be stated that CD44s is a prognostic marker in neuroblastoma which correlates significantly with the grade of tumour cell differentiation, but not with clinical stage. Moreover, there exists a statistically significant correlation between MYCN oncogene amplification and the lack of CD44s expression.
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PMID:Differentiation and prognosis of neuroblastoma in correlation to the expression of CD44s. 757 65

Knowledge about genetic alterations specific to the metastatic process and chemoresistance in neuroblastoma is progressing steadily. Low or no CD44 expression, increased NM23 expression and specific mutations of the 5' coding regions of NM23 are distinct features of aggressive, metastatic neuroblastoma. MYCN down-regulates Class I HLA antigen expression in many neuroblastoma cell lines and, in turn, may be regulated by a suppressor gene. The MYCN amplified human neuroblastoma cell line, IGR-N-91, established in vitro, metastasises in the nude mouse and has exhibited co-activation of MYCN and PGY1, resulting from direct activation of the oncoprotein on the PGY1 promoter. In this model, the MYCN product activates angiogenesis, the dissemination process and chemoresistance via specific genes (PGY1 and GST3). MYCN, like the BCL-2 and TP53 products, may also play a key role in apoptosis. The implication of these genes in the potential for metastasis and chemoresistance in neuroblastoma is discussed.
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PMID:Genetic alterations associated with metastatic dissemination and chemoresistance in neuroblastoma. 757 68

Neuroblastoma is the second commonest malignancy in childhood. The prognosis of the disease is largely dependent on the extension of the tumour at diagnosis. For disseminated disease the survival rate is very low. The question as to whether mass screening in infants can improve the prognosis of the disease was first addressed in Japan more than 20 years ago. Since then, more than 7 million children have been screened in Japan and over 650 cases of neuroblastoma have been detected. However, the available data are compromised by an inadequate cancer registry and conclude that screening at 6 months of age seems to double the incidence of neuroblastoma. This result has been verified by a Canadian study conducted from 1989 to 1994 in the province of Quebec. The incidence of neuroblastoma appeared to have tripled, and there was no decrease in the rate of advanced disease. Mass screening pilot studies have also been conducted in the U.K., France, Austria, Australia, U.S.A., Italy, Norway and Germany. Analysis of the results shows that neuroblastoma screening before the age of 6 months is feasible, but no significant reduction in mortality could be shown until now. Moreover, most of the cases diagnosed by screening have favourable biological markers. Only a few with unfavourable parameters, such as amplification of proto-oncogene MYCN, diploidy and/or del 1p36 could be detected. A screening programme that includes 1.25-2 million screened and unscreened children at 1 year of age monitored by an almost complete national cancer registry should show whether mass screening for early detection of neuroblastoma is worthwhile.
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PMID:Neuroblastoma mass screening: the arguments for and against. 757 69

The use of new strategies for dose intensification using peripheral blood stem cell or autologous purged bone marrow rescue has raised expectations for cure in advanced neuroblastoma, although conflicting reports exist regarding the efficacy of these approaches. Using risk groups based on both biological and clinical staging, the Children's Cancer Group (CCG) has conducted a series of pilot studies to test new induction, consolidation and myeloablative regimens to attempt to improve outcome. We summarise below the outcome and prognostic factor analysis for the pilot chemotherapy trial, CCG-(CCG-321P2), and the use of high dose myeloablative chemoradiotherapy with allogeneic (CCG-321P1) or autologous purged bone marrow rescue (CCG-321P3) for high risk neuroblastoma patients who were progression-free at the end of induction chemotherapy. After autologous bone marrow transplantation (ABMT), progression-free survival (PFS) at 4 years was 38% (median follow-up 4 years). Prognostic factors for relapse after ABMT included pre-BMT disease status, bone marrow tumour content at harvest, extent of primary resection at diagnosis, and time to ABMT. MYCN amplification, age, stage, and pre-BMT myeloablative regimen were not significant. Allogeneic BMT did not have a better outcome than ABMT. In a retrospective, non-randomised comparison of ABMT and chemotherapy, there was a significant difference in PFS for stage IV patients. High risk subgroups possibly benefiting from ABMT could be identified, including those with tumour MYCN amplification, over 2 years at diagnosis, and those not in complete remission at the end of induction. A randomised prospective trial comparing myeloablative therapy with ABMT to continuous infusion consolidation chemotherapy is currently underway in CCG to determine the relative benefit.
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PMID:Role of myeloablative therapy in improved outcome for high risk neuroblastoma: review of recent Children's Cancer Group results. 757 71

The role of single drugs in the treatment of neuroblastoma is poorly defined. We, therefore, tested neuroblastoma cell survival after a 72 h exposure to one of 19 cytostatic drugs by monolayer proliferation assay. 6 cell lines (IMR-5, Kelly, SK-N-SH, GI-CA-N, CHP-100, CHP-134) were selected on the basis of MYCN amplification and PGY1 overexpression. ED50 drug concentrations were related to plasma levels achievable in patients during chemotherapy. More effective substances were mitoxantrone, doxorubicin, hydroxyurea, bleomycin, dactinomycin, cisplatinum, thiotepa, melphalan, carboplatinum, etoposide, vincristine, cytarabine, 6-thioguanine, cyclophosphamide, ifosfamide and zilascorb. Parental drugs (cyclophosphamide, cisplatinum) appeared more cytotoxic on a molar basis than derived drugs (ifosfamide, carboplatinum). Less effective drugs included 5-fluorouracil, 6-mercaptopurine, CCNU and procarbazine. Fractional application of a given dose was more efficient than a single dose of cyclophosphamide, ifosfamide and cisplatinum. The tested neuroblastoma cell lines showed distinct sensitivities to cytostatic drugs. Cell lines with MYCN amplification appeared more sensitive than PGY1 overexpressing cells. In conclusion, comparative in vitro testing of cytostatic drugs may provide a rationale for their clinical evaluation. Investigation of drug combinations and application of the monolayer proliferation assay to tumour biopsy material for preclinical chemosensitivity testing are clearly warranted.
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PMID:Antiproliferative potential of cytostatic drugs on neuroblastoma cells in vitro. 757 81

Human neuroblastoma cells often have deletions of the distal short arm of chromosome 1 (1p). Earlier studies using chromosome analysis had suggested that the 1p deletion is correlated with a poor survival chance for the patient. We have reevaluated this possibility by analyzing 51 neuroblastomas for loss of heterozygosity (LOH) at 1p. We detected LOH in 32% of the cases. LOH did not correlate with the age of the patients at diagnosis or with tumor stage but was correlated significantly with amplification of the MYCN proto-oncogene. Nine of 10 MYCN-amplified tumors had deletions in 1p (P < 0.001). Survival chances of patients with tumors carrying MYCN amplification together with the deletion at 1p were decreased significantly (eight of nine affected patients died) compared with a patient group without any of these aberrations (P < 0.001). However, the deletion of 1p alone without MYCN amplification was not associated with a poor outcome compared with patients who had neither deletion nor amplification (only two of eight affected patients died; P = 0.803). From these data we conclude that 1p deletions are not reliable markers to determine a patient's prognosis. They may, however, identify a subgroup of neuroblastomas in which MYCN is amplified readily, resulting in rapid tumor progression.
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PMID:The 1p deletion is not a reliable marker for the prognosis of patients with neuroblastoma. 758 2

The neuroblastoma cell line NGP contains two homogeneously staining regions (hsr). One of these hsrs contains MYCN sequences. Reverse painting experiments demonstrated that the second HSR consisted of two chromosome 12-derived amplification units, located at 12q14-15 and 12q24. Southern blot and fluorescence in situ hybridization (FISH) analysis showed amplification of genes located at 12q14-15: SAS, MDM2, and CDK4, GLI, CHOP, CDK2, and A2MR were found not to be amplified. FISH further demonstrated amplification of RSN, a gene located at 12q24. The finding of two distinct chromosome 12 amplification units in a neuroblastoma cell line NGP is reminiscent of recent findings in well-differentiated liposarcoma (WDLPS) and other sarcomas. The second amplification unit on chromosome 12 in NGP is located more distal (12q24) than the one observed in WDLPS (12q21). The mechanism and biologic significance of this amplification process in neuroblastoma and WDLPS remain to be elucidated.
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PMID:Identification of two distinct chromosome 12-derived amplification units in neuroblastoma cell line NGP. 766 45

We characterized differences in the structural organization of the MYCN amplicons of a number of neuroblastomas by analyzing 8 contigs spanning 330 kb cloned from the MYCN amplicon of a neuroblastoma cell line. Some regions were amplified in almost all specimens, the conserved regions (CRs), and others were differentially amplified in some subsets, the non-conserved regions (NCRs). CRs constituted only 20% of the 330 kb region, with the remainder being NCRs. The regions that inevitably co-segregate with the MYCN gene make up the core, whereas flanking regions are retained at random. If a histogram of the frequency with which the amplified NCR sequences from one specimen match those of the cell line MC-NB-I shows a random distribution, the NCRs would co-segregate with MYCN as a result of random events. However, both the tumors and cell lines/xenografts showed a distribution with two distinct peaks; one from a group containing a small number of sequences with a fairly high degree of homology to the NCRs of MC-NB-I, and the other from a group containing a large number of sequences with little homology. These results indicate that the flanking segments are preferentially co-segregated with MYCN by a non-random mechanism.
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PMID:Structural organization of MYCN amplicons of neuroblastoma tumors, xenografts, and cell lines characterized by the sequences encompassing the MYCN amplicons in a human neuroblastoma cell line. 769 Nov 54

Amplification of the MYCN gene is a well documented genetic alteration of aggressively growing human neuroblastomas. Through cytogenetic studies we have identified neuroblastoma cell lines which, in addition to amplified MYCN, carry amplified DNA not harbouring MYCN. In situ hybridization of biotinylated total genomic DNA to metaphase chromosomes of normal human lymphocytes by reverse genomic hybridization revealed the amplified DNA to be derived from chromosome 12 band q13-14. Subsequent filter analyses showed a 20- to 40-fold amplification of the MDM2 gene, located at 12q13-14, both in three cell lines and in an original tumor, in addition to amplified MYCN. As the apparent consequence of amplification abundant MDM2 protein was present, a part of which was complexed with p53.
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PMID:Non-syntenic amplification of MDM2 and MYCN in human neuroblastoma. 770 Jun 32


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