Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroblastoma is known for its peculiar cellular kinetics, which has provoked some controversy regarding surgical treatment. Highly sensitive exploration systems using reverse transcription polymerase chain reaction (RT-PCR) methods have been developed to detect neuroblastoma cells. In our series of 49 patients with advanced neuroblastoma, circulating tumor cells (CTC) were detected by this system in 55.6% of the stage 4 patients who were examined, suggesting that the primary lesion may release tumor cells into the peripheral blood. The Kaplan-Meier survival rate was significantly lower among the patients with CTC or chemotherapy-insensitive bone marrow micrometastasis, compared with those without detectable micrometastasis (33.8 vs. 87.5%, P < 0.05). In contrast, a stage 3 patient with MYCN amplification exhibited drastic local relapse without systemic dissemination of the disease. Two patients were positive for CTC without an identifiable primary site. These observations indicate that the local growth of the primary tumor and tumor cell dissemination may be regulated by different molecular mechanisms in neuroblastomas. MYCN amplification seemed to be more closely associated with localized tumor growth but was minimally correlated with CTC positivity. High-risk neuroblastoma may include two separate subgroups characterized by different cellular kinetics: a local risk cohort and a systemic risk cohort. Surgical strategies for neuroblastoma should be determined with taking this cellular kinetics into consideration.
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PMID:Cellular kinetics of neuroblastoma and the role of surgery. 2176 82

Although more than 110 neuroblastoma (NB) cell lines have been established, there have been neither reports on the rate of success to establish NB cell lines, nor well-documented NB cell lines from long-term-survivors. We attempted to establish NB cell lines from 114 patients. Sixteen NB cell lines were established from 12 patients. The success rates to establish cell lines were 1.4% (1/70) from patients in early stages, 25.0% (11/44) from those in advanced stages, and 10.5% (12/114) from those in all stages respectively. Eleven of these 12 patients eventually died. The surviving patient, who was in stage 4 with MYCN-amplification, has been event-free for 19 years after completing therapy. The serum MYCN DNA level in patient TK was very high before therapy, decreased after chemotherapy, and has remained at the normal levels until now. The gene expression profiling of the primary tumor and the K-N-TK cell line was analyzed with an NB-specific cDNA microarray, and indicated that the probability of 5-year survival was extremely low. Microarray-based comparative genomic hybridization (CGH) analysis indicated that genomic aberration profiles of the cell line were uncommon, with MYCN amplification, 17q gain and 11q loss. A unique KP-N-TK cell line, established from an event-free survivor, will be a useful tool for investigating how a patient can survive a tumor with an extremely poor prognosis.
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PMID:A MYCN-amplified cell line derived from a long-term event-free survivor among our sixteen established neuroblastoma cell lines. 2326 33

We describe neuroblastoma (NB) in monozygotic twins whose ages at the onset of the disease had a 3-year interval. The primary tumor site of twin 1 was the adrenal gland, whereas that of twin 2 was the jejunum/mesentery. MYCN amplification, DNA index, ALK mutation, and copy number alterations of DNA were different between each primary tumor. NB in ectopic sites may have resulted from twin-to-twin metastasis through vascular anastamoses in the placenta. The pathogenesis of this NB involved a premalignant stage of NB during the fetal development and subsequent molecular alterations after birth, resulting in NBs that were phenotypically similar but genetically different.
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PMID:Ectopic neuroblastoma in monozygotic twins with different ages of onset: possible twin-to-twin metastasis in utero with distinct genetic alterations after birth. 2366 22

We report two cases of high-risk metastatic neuroblastoma, comprising two biologically distinct components in the adrenal primary tumor, which showed clear differences not only histologically but also in MYCN amplification and HA-RAS/TRKA immunoreactivity (Case 1), anaplastic lymphoma kinase (ALK) immunoreactivity (Case 2). These two cases with multiple separated components were similar to cases classified as ganglioneuroblastoma, nodular subtype (GNBn), in terms of composite tumor. Comparable to the GNBn category, the prognosis of the patients described here may depend on the components with unfavorable histology according to International Neuroblastoma Pathology Classification. Further analyses of such composite neuroblastoma cases are important for assessing disease prognosis.
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PMID:Two cases of neuroblastoma comprising two distinct clones. 2410 45

Patients with non-muscle invasive bladder cancer (NMIBC) generally have a high risk of relapsing locally after primary tumor resection. The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease. We studied the copy number variations (CNVs) of 24 oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR and BRAF) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence. Formalin-fixed paraffin-embedded tissue samples from 43 patients who underwent transurethral resection of the bladder (TURB) were used; 23 patients had relapsed and 20 were disease-free after 5 years. Amplification frequencies were analyzed for all genes and MDM4 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones (0.65 vs. 0.3; Fisher's test p=0.023). Recurrence-free survival analysis confirmed the predictive role of MDM4 (log-rank test p=0.041). Our preliminary results indicate a putative role for the MDM4 gene in predicting local recurrence of bladder cancer. Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients.
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PMID:Copy number analysis of 24 oncogenes: MDM4 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer. 2502 75

Aberrant expression of the simple mucin-type carbohydrate antigens such as Tn antigen is associated with malignant transformation and cancer progression. N-acetylgalactosaminyltransferase 2 (GALNT2), one of the enzymes that mediate the initial step of mucin-type O-glycosylation, is responsible for forming Tn antigen. GALNT2 is expressed differentially in nervous tissues during mouse embryogenesis; however, the role of GALNT2 in neuroblastoma (NB) remains unclear. Here we showed that increased GALNT2 expression evaluated using immunohistochemistry in NB tumor tissues correlated well with the histological grade of differentiation as well as younger age at diagnosis, early clinical stage, primary tumor originated from the extra-adrenal site, favorable INPC histology, and MYCN non-amplification. Multivariate analysis showed that GALNT2 expression is an independent prognostic factor for better survival for NB patients. GALNT2 overexpression suppressed IGF-1-induced cell growth, migration, and invasion of NB cells, whereas GALNT2 knockdown enhanced these NB phenotypes. Mechanistic investigations demonstrated that GALNT2 overexpression modified O-glycans on IGF-1R, which suppressed IGF-1-triggered IGF-1R dimerization and subsequent downstream signaling events. Conversely, these properties were reversed by GALNT2 knockdown in NB cells. Our findings suggest that GALNT2 regulates malignant phenotypes of NB cells through the IGF-1R signaling pathway, suggesting a critical role for GALNT2 in the pathogenesis of NB.
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PMID:GALNT2 suppresses malignant phenotypes through IGF-1 receptor and predicts favorable prognosis in neuroblastoma. 2536 49

Neuroblastoma prognosis varies tremendously based on the stage and biologic features of the tumor. Treatment varies depending on the risk group and can range from surgery alone for stage 1 tumors to aggressive multimodality treatment for MYCN-amplified tumors. Although surgery plays a role in the diagnosis and management of all stages of neuroblastoma, the importance of that role, especially the extent of resection, in high-risk neuroblastoma continues to evolve. In the past five years, there have been several advances in neuroblastoma surgery. Studies have demonstrated that patients with low-risk disease can be treated with surgery alone, and in a subset of patients who are neonatally diagnosed with adrenal tumors, surgery can be avoided in 80%. Recent abstracts have supported a role for >90% resection of the primary tumor in high-risk patients. This article also reviews the surgical approaches to difficult thoracic and abdominal tumors, as well as the role for minimally invasive surgery in the management of localized neuroblastoma.
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PMID:Advances in the surgical treatment of neuroblastoma: a review. 2548 13

In around half of the patients with neuroblastoma (NBL), the primary tumor is located in one of the adrenal glands. We have previously reported on a transplantable TH-MYCN model of subcutaneous (SC) growing NBL in C57Bl/6 mice for immunological studies. In this report, we describe an orthotopic TH-MYCN transplantable model where the tumor cells were injected intra-adrenally (IA) by microsurgery. Strikingly, 9464D cells grew out much faster in IA tumors compared to the subcutis. Tumors were infiltrated by equal numbers of lymphocytes and myeloid cells. Within the myeloid cell population, however, tumor-infiltrating macrophages were more abundant in IA tumors compared to SC tumors and expressed lower levels of MHC class II, indicative of a more immunosuppressive phenotype. Using 9464D cells stably expressing firefly luciferase, enhanced IA tumor growth could be confirmed using bioluminescence. Collectively, these data show that the orthotopic IA localization of TH-MYCN cells impacts the NBL tumor microenvironment, resulting in a more stringent NBL model to study novel immunotherapeutic approaches for NBL.
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PMID:Intra-adrenal murine TH-MYCN neuroblastoma tumors grow more aggressive and exhibit a distinct tumor microenvironment relative to their subcutaneous equivalents. 2568 36

MYCN amplification occurs in 20% of neuroblastomas and is strongly related to poor clinical outcome. We have identified folate-mediated one-carbon metabolism as highly upregulated in neuroblastoma tumors with MYCN amplification and have validated this finding experimentally by showing that MYCN amplified neuroblastoma cell lines have a higher requirement for folate and are significantly more sensitive to the antifolate methotrexate than cell lines without MYCN amplification. We have demonstrated that methotrexate uptake in neuroblastoma cells is mediated principally by the reduced folate carrier (RFC; SLC19A1), that SLC19A1 and MYCN expression are highly correlated in both patient tumors and cell lines, and that SLC19A1 is a direct transcriptional target of N-Myc. Finally, we assessed the relationship between SLC19A1 expression and patient survival in two independent primary tumor cohorts and found that SLC19A1 expression was associated with increased risk of relapse or death, and that SLC19A1 expression retained prognostic significance independent of age, disease stage and MYCN amplification. This study adds upregulation of folate-mediated one-carbon metabolism to the known consequences of MYCN amplification, and suggests that this pathway might be targeted in poor outcome tumors with MYCN amplification and high SLC19A1 expression.
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PMID:MYCN amplification confers enhanced folate dependence and methotrexate sensitivity in neuroblastoma. 2586 Sep 40

The MYCN oncogene is a strong genetic marker associated with poor prognosis in neuroblastoma (NB). Therefore, MYCN gene amplification and subsequent overexpression provide a possible target for new treatment approaches in NB. We first identified an inverse correlation of MYCN expression with CD45 mRNA in 101 NB tumor samples. KEGG mapping further revealed that MYCN expression was associated with immune-suppressive pathways characterized by a down-regulation of T cell activation and up-regulation of T cell inhibitory gene transcripts. We then aimed to investigate whether DNA vaccination against MYCN is effective to induce an antigen-specific and T cell-mediated immune response. For this purpose, we generated a MYCN-expressing syngeneic mouse model by MYCN gene transfer to NXS2 cells. MYCN-DNA vaccines were engineered based on the pCMV-F3Ub plasmid backbone to drive ubiquitinated full-length MYCN-cDNA and minigene expression. Vaccines were delivered orally with attenuated S. typhimurium strain SL7207 as a carrier. Immunization with both MYCN-DNA vaccines significantly reduced primary tumor growth of MYCN-expressing NB cells in contrast to negative controls. The immune response was mediated by tumor-infiltrating T cells in vivo, which revealed MYCN-specific and MHC class I-restricted lysis of inducible MYCN-expressing NB target cells in vitro. Finally, these antigen-specific T cells also killed MYCN-negative mammary carcinoma cells pulsed with MYCN peptides in contrast to controls. In summary, we demonstrate proof of concept that MYCN can be targeted by DNA vaccination, which may provide an approach to overcoming MYCN immune-suppressive activities in patients with MYCN-amplified disease.
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PMID:Targeting of MYCN by means of DNA vaccination is effective against neuroblastoma in mice. 2607 66


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