Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The natural history and the clinical and neuroimaging features of brainstem tumors in neurofibromatosis type 1 (NF1) are poorly understood. Magnetic resonance imaging (MRI) has been useful in NF1 in detecting intracranial abnormalities, especially of the brainstem. Brainstem tumors in NF1 have been confused clinically with non-NF1 brainstem tumors and radiographically with the increased T2 signal abnormalities, also known as "unidentified bright objects" (UBOs), which are common in NF1 and often located in the brainstem. This study, which evaluated 17 NF1 patients with brainstem tumors, is the largest series to date. Fifteen of 17 patients (88%) had neurologic signs and symptoms referable to brainstem dysfunction, including dysarthria, cranial neuropathies, and gross motor incoordination. Tumors were located primarily in the medulla in 14 of 17 NF1 patients (82%), in contrast to the pontine tumor location in the non-NF1 population. Seven NF1 patients (41%) required shunt placement for hydrocephalus at initial diagnosis, more frequent than in non-NF1 brainstem tumor patients. Six of 17 patients (35%) had evidence of radiographic tumor progression, but only three of them (18%) had correlative clinical progression. Two patients with progressive symptoms had partial surgical resection, and pathology revealed either fibrillary or anaplastic astrocytomas. Three patients were treated with radiation therapy, chemotherapy, or both, with two deaths. With a median follow-up of 52 months, 15 of 17 patients remain alive; 14 of them did not require adjuvant therapy. In our series, we describe NF1 brainstem tumors as a distinct clinical entity, much less aggressive than non-NF1 pontine tumors but more symptomatic than brainstem UBOs in NF1.
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PMID:Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. 747 89

Optic gliomas occur in 15% of patients with neurofibromatosis type 1 (NF 1) and are a significant cause of morbidity. Of these tumors, 20-30% become symptomatic, usually before age 10 years. Previous studies have suggested that visual evoked potentials (VEPs) are a sensitive method for the detection of asymptomatic optic gliomas. Because routine neuroimaging of children with NF 1 is currently not recommended, the role of pattern-shift VEPs (PS VEPs) as a screening test for optic gliomas was evaluated. PS VEPs were performed on 10 children with NF 1 and optic gliomas and 20 children with NF 1 and normal visual pathways (as defined on MRI). PS VEPs had 90% sensitivity for detecting optic gliomas, with an increase in sensitivity to 100% when hemifield stimulation was used. The specificity of the test was 60%. Four of 20 children without optic gliomas had thickened optic nerves on computed tomography which represented dural ectasia with normal visual pathways on MRI; PS VEPs were normal in these patients. The efficacy of PS VEPs as a routine screen for optic gliomas is limited by the age at which children will cooperate with the test procedure and the high incidence of false-positive results; however, VEPs do provide a useful adjunct to routine clinical ophthalmologic assessment in the detection of optic gliomas in children with NF 1. Abnormal test results provide a stronger indication for neuroimaging. The early detection of optic gliomas allows for close monitoring of tumor progression and earlier intervention prior to significant visual loss.
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PMID:Optic gliomas in neurofibromatosis type 1: role of visual evoked potentials. 774 70

A case of multifocal malignant peripheral neuroectodermal tumor (PNET) arising from a plexiform neurofibroma in a 4-month-old Chinese boy with neurofibromatosis type 1 (NF-1) is described. Cytogenetic culture demonstrated hypotriploid karyotype with an abnormal clone characterized by 59-60, XY, +2, +3, +6, +8, +8, +12, +i(13)(q10), +der(14)t(1;14)(q21;q32), +16, +19, +20, +mar[cp3] with no apparent abnormality of chromosome 17. The child was treated with combination chemotherapy comprising ifosphamide, vincristine and doxorubicin. Despite initial partial response the child finally died of tumor progression and pulmonary metastases 8 months after diagnosis. We believe this is the first reported case of PNET in a child with NF-1 and may support an association between these two disorders of neural crest origin.
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PMID:Malignant peripheral neuroectodermal tumor in an infant with neurofibromatosis type 1. 854 6

Twenty-eight children (mean age 8 years) with neurofibromatosis type 1 (NF1) and cerebral tumor were studied from 1975 to 1992 (mean follow-up 8.1 years) considering the biological behaviour of the tumor and the patient's quality of life, in order to identify retrospectively the best management. All, except one, tumors were benign gliomas, 76% of the optic nerve/chiasm (NCO), just 10% infratentorial. Sixteen children (57%) did not receive any treatment, 2 radiotherapy (RT) only and 4 symptomatic treatment only; in 6 patients the tumor resection was performed. 92% of the 25 survivors had sufficient autonomy in daily life at last follow-up. Considering the risk of cerebral tumors in patients with NF1, we conclude that cerebral magnetic resonance should be performed also in the asymptomatic ones. If neuroradiological findings are characteristic of benign glioma, histologic confirmation seems unnecessary. Surgical resection is recommended only in tumors confined to a single optic nerve, with severe or progressive symptoms. In chiasmatic tumors we suggest partial resection or symptomatic treatment only with close clinical and radiological observation. RT is only recommended if there is unequivocal evidence of tumor progression. Chemotherapy can delay the use of RT in very young children. Cerebral tumors different from NCO gliomas seem to have a similar natural history in patients with or without NF1 and therefore the management should be the same for both groups.
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PMID:[Cerebral tumors in children with neurofibromatosis type 1]. 876 74

Although most visual pathway tumors are low-grade gliomas their biologic behavior is highly unpredictable. In order to determine whether assessment of proliferative activity can assist in predicting tumor behavior, we studied the MIB-1 labeling indices (MIB-1 LIs) in surgical specimens and monitored tumor growth in 31 consecutive children operated on between 1978 and 1997. The MIB-1 LIs at diagnosis varied from 0-10.6% (mean +/- SD, 3.27 +/- 2.49%). Tumor progression occurred in 19 patients leading to death in seven, three of whom had neurofibromatosis type 1 (NF1). No association between MIB-1 LI at initial diagnosis and both progression free and overall survival was apparent. However, the MIB-1 LIs increased to 15.2% and 18% in two patients with NF1 who developed highly malignant gliomas 6 and 6.5 years after irradiation. In the remaining patients the MIB-1 LIs did not change significantly over time in a total of 17 repeat surgeries. Three patients with LIs of 6.8%, 10.6% and 8.8% are stable after 6, 4.5 and 3.5 years with partial resection, biopsy and subtotal resection, respectively, and no further therapy in the first two and chemotherapy in the latter. Three patients (10%) with LIs of 6.4%, 4.8% and 2.2% either presented with or developed leptomeningeal spread during follow-up. While MIB-1 LI does not appear to assist in clinical decision making patient numbers were too small to find out whether response to chemotherapy varies with proliferative potential.
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PMID:Proliferative activity as measured by MIB-1 labeling index and long-term outcome of visual pathway astrocytomas in children. 1042 Oct 72

We here review the literature on genetics related to pheochromocytoma. About 10 percent of these neuroendocrine tumors are hereditary and are most often associated with multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease, and neurofibromatosis type 1 (NF 1). Hereditary tumor syndromes such as the aforementioned ones, are ideal to study the molecular pathogenesis of tumorigenesis as opposed to sporadic tumors in which genetic alterations often merely represent epigenetic tumor progression phenomena. Recent advances in molecular genetics, especially of RET, VHL, NF1, and SDHD, helped better understand the pathogenesis of pheochromocytoma. In this paper, we not only summarize key points of genetic discoveries related to pheochromocytoma, but also report in table format all known RET germline mutations related to pheochromocytoma.
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PMID:Genetic aspects of pheochromocytoma. 1130 96

We performed an open-label phase II trial of oral pirfenidone in 24 patients with neurofibromatosis type 1 (NF1). Tumors were monitored by three-dimensional MRI. At the end of treatment, four patients had a decrease in tumor volume by 15% or more, three had tumor progression, and 17 remained stable. Pirfenidone warrants further investigation in NF1, which has until now lacked an effective control therapy.
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PMID:Phase II trial of pirfenidone in adults with neurofibromatosis type 1. 1703 76

Defects in genes that control DNA repair, proliferation, and apoptosis can increase genomic instability, and thus promote malignant progression. Although most tumors that arise in humans with neurofibromatosis type 1 (NF1) are benign, these individuals are at increased risk for malignant peripheral nerve sheath tumors (MPNST). To characterize additional mutations required for the development of MPNST from benign plexiform neurofibromas, we generated a mouse model for these tumors by combining targeted null mutations in Nf1 and p53, in cis. CisNf1+/-; p53+/- mice spontaneously develop PNST, and these tumors exhibit loss-of-heterozygosity at both the Nf1 and p53 loci. Because p53 has well-characterized roles in the DNA damage response, DNA repair, and apoptosis, and because DNA repair genes have been proposed to act as modifiers in NF1, we used the cisNf1+/-; p53+/- mice to determine whether a mutator phenotype arises in NF1-associated malignancies. To quantitate spontaneous mutant frequencies (MF), we crossed the Big Blue mouse, which harbors a lacI transgene, to the cisNf1+/-; p53+/- mice, and isolated genomic DNA from both tumor and normal tissues in compound heterozygotes and wild-type siblings. Many of the PNST exhibited increased mutant frequencies (MF=4.70) when compared to normal peripheral nerve and brain (MF=2.09); mutations occurred throughout the entire lacI gene, and included base substitutions, insertions, and deletions. Moreover, the brains, spleens, and livers of these cisNf1+/-; p53+/- animals exhibited increased mutant frequencies when compared to tissues from wild-type littermates. We conclude that a mild mutator phenotype arises in the tumors and tissues of cisNf1+/-; p53+/- mice, and propose that genomic instability influences NF1 tumor progression and disease severity.
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PMID:A mild mutator phenotype arises in a mouse model for malignancies associated with neurofibromatosis type 1. 1720 58

Malignant peripheral nerve sheath tumors (MPNST) are sarcomas with poor prognosis and limited treatment options. Factors contributing to tumor progression are largely unknown. We therefore examined MPNST from 22 neurofibromatosis type 1 (NF1) patients, 14 non-NF1 patients, and 14 neurofibroma patients for matrix metalloproteinase 13 (MMP-13) expression. Because wild-type and mutant p53 were shown to differentially regulate MMP-13 expression, TP53 status and protein levels were also determined. MMP-13 expression was detected in 58% of MPNST and was significantly associated with recurrent MPNST (P = .019). p53 was observed in 78% of MPNST and was found to be strongly associated with MMP-13 expression (P = .005). In contrast, 14 neurofibromas lacked MMP-13 and p53 expressions. TP53 mutations were found in only 11% of MPNST and were associated with high tumor grades (P = .029). No significant association between mutant TP53 and MMP-13 was observed, indicating that other factors drive MMP-13 expression in MPNST. The presence of metastasis was linked to p53Pro(72) polymorphism (P = .041) and shorter survival. In summary, our data suggest that MMP-13 expression in nerve sheath tumors is coupled with malignant progression. Therefore, MMP-13 may serve as a marker for progression and as a therapeutic target.
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PMID:MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. 1778 86

Interactions between tumorigenic cells and their surrounding microenvironment are critical for tumor progression yet remain incompletely understood. Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a common genetic disorder characterized by complex tumors called neurofibromas. Genetic studies indicate that biallelic loss of Nf1 is required in the tumorigenic cell of origin in the embryonic Schwann cell lineage. However, in the physiologic state, Schwann cell loss of heterozygosity is not sufficient for neurofibroma formation and Nf1 haploinsufficiency in at least one additional nonneoplastic lineage is required for tumor progression. Here, we establish that Nf1 heterozygosity of bone marrow-derived cells in the tumor microenvironment is sufficient to allow neurofibroma progression in the context of Schwann cell Nf1 deficiency. Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation.
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PMID:Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. 1898 50


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