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  • 1
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; THERAPY ; TYROSINE KINASE ; GENE ; GENES ; HYBRIDIZATION ; PROTEIN ; DRUG ; TUMORS ; LINES ; PATIENT ; LIGAND ; prognosis ; REDUCTION ; CONTRAST ; CELL-LINES ; GROWTH-FACTOR RECEPTOR ; PHOSPHORYLATION ; chromosome ; TARGET ; NO ; IN-SITU ; LESIONS ; AMPLIFICATION ; MUTATION ; METASTASIS ; PROSTATE-CANCER ; CELL-LINE ; LINE ; MUTATIONS ; HOMOLOG ; US ; LIGANDS ; TARGETS ; FLUORESCENCE ; POOR-PROGNOSIS ; SARCOMA ; fluorescence in situ hybridization ; PTEN ; TP53 ; EPIDERMAL-GROWTH-FACTOR ; ONCOLOGY ; TUMOR-SUPPRESSOR ; THERAPIES ; INCREASE ; EGFR ; cell proliferation ; LEVEL ; analysis ; SUPPRESSOR ; tumor suppressor gene ; NERVE ; USA ; DRUGS ; KINASE INHIBITOR ; epidermal growth factor receptor ; GROWTH-FACTOR-RECEPTOR ; receptor tyrosine kinase ; SOMATIC MUTATIONS ; comparison ; ErbB2 ; neurofibromatosis ; TARGETED THERAPY ; tumor suppressor ; EGF ; TRASTUZUMAB ; FACTOR-RECEPTOR ; growth factor ; MPNST ; NEU PROTOONCOGENE ; SCHWANN-CELLS
    Abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n=37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor a and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients. Neuro-Oncology 10, 946-957, 2008 (Posted to Neuro-Oncology [serial online], Doc. D07-00250, July 23, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-053)
    Type of Publication: Journal article published
    PubMed ID: 18650488
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  • 2
    Keywords: CELLS ; EXPRESSION ; proliferation ; tumor ; CELL ; IN-VIVO ; PATHWAY ; VIVO ; SUPPORT ; DEATH ; SAMPLE ; SAMPLES ; cell line ; TUMORS ; LINES ; MICE ; ACTIVATION ; cell signaling ; MARKER ; REDUCTION ; DOMAIN ; animals ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; signal transduction ; treatment ; TYPE-1 ; PROGRESSION ; HUMANS ; CELL-DEATH ; CYCLE PROGRESSION ; CELL-LINE ; MARKERS ; SIGNALING PATHWAY ; OUTCOMES ; ABNORMALITIES ; cell lines ; Ras ; signaling ; PERIPHERAL-NERVE ; RNA INTERFERENCE ; cell proliferation ; LEVEL ; TRANSCRIPTIONAL ACTIVATION ; cell death ; NERVE ; USA ; INVASIVENESS ; Male ; Cell Line,Tumor ; outcome ; neurofibromatosis ; MESENCHYMAL TRANSITION ; STATE ; MPNST ; SCHWANN-CELLS ; Schwann cell ; ras Proteins/metabolism ; Base Sequence ; Mice,SCID ; Neoplasm Invasiveness ; Nerve Sheath Neoplasms/genetics/*metabolism/pathology ; ral GTP-Binding Proteins/antagonists & inhibitors/genetics/*metabolism ; RNA,Small Interfering/genetics ; Schwann Cells/metabolism
    Abstract: Ras leads an important signaling pathway that is deregulated in neurofibromatosis type 1 and malignant peripheral nerve sheath tumor (MPNST). In this study, we show that overactivation of Ras and many of its downstream effectors occurred in only a fraction of MPNST cell lines. RalA, however, was overactivated in all MPNST cells and tumor samples compared to nontransformed Schwann cells. Silencing Ral or inhibiting it with a dominant-negative Ral (Ral S28N) caused a significant reduction in proliferation, invasiveness, and in vivo tumorigenicity of MPNST cells. Silencing Ral also reduced the expression of epithelial mesenchymal transition markers. Expression of the NF1-GTPase-related domain (NF1-GRD) diminished the levels of Ral activation, implicating a role for neurofibromin in regulating RalA activation. NF1-GRD treatment caused a significant decrease in proliferation, invasiveness, and cell cycle progression, but cell death increased. We propose Ral overactivation as a novel cell signaling abnormality in MPNST that leads to important biological outcomes with translational ramifications.
    Type of Publication: Journal article published
    PubMed ID: 19414599
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  • 3
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; proliferation ; CELL ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; MODEL ; THERAPY ; TYROSINE KINASE ; VITRO ; VIVO ; DRUG ; MICE ; COMPLEX ; COMPLEXES ; TYPE-1 ; TYROSINE KINASE INHIBITOR ; ALPHA ; TARGET ; MOUSE ; PATTERNS ; EFFICACY ; PLEXIFORM NEUROFIBROMAS ; TARGETS ; inflammation ; NERVE SHEATH TUMORS ; FEATURES ; ONCOLOGY ; PATTERN ; XENOGRAFTS ; IMATINIB MESYLATE ; SIZE ; KIT ; FRAGMENT ; INHIBIT ; PDGFR ; neurofibromatosis ; tumours ; Type ; RECEPTOR-TYROSINE-KINASE ; Glivec
    Abstract: Plexiform neurofibromas (PNF), one of the major features of neurofibromatosis type 1 (NF1), are characterized by complex cellular composition and mostly slow but variable growth patterns. In this study, we examined the effect of imatinib mesylate, a receptor tyrosine kinase inhibitor, on PNF-derived Schwann cells and PNF tumour growth in vitro and in vivo. In vitro, PNF-derived primary Schwann cells express platelet-derived growth factors receptors (PDGFR) alpha and beta, both targets of imatinib, and cell viability was reduced by imatinib mesylate, with 50% inhibition concentration (IC50) of 10 mu M. For in vivo studies, PNF tumour fragments xenografted onto the sciatic nerve of athymic nude mice were first characterized. The tumours persisted for at least 63 days and maintained typical characteristics of PNFs such as complex cellular composition, low proliferation rate and angiogenesis. A transient enlargement of the graft size was due to inflammation by host cells. Treatment with imatinib mesylate at a daily dose of 75 mg/kg for 4 weeks reduced the graft size by an average of 80% (n = 8), significantly different from the original sizes within the group and from sizes of the grafts in 11 untreated mice in the control group (P 〈 0.001). We demonstrated that grafting human PNF tumour fragments into nude mice provides an adequate in vivo model for drug testing. Our results provide in vivo and in vitro evidence for efficacy of imatinib mesylate for PNF
    Type of Publication: Journal article published
    PubMed ID: 19921098
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  • 4
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; Germany ; DIAGNOSIS ; NEW-YORK ; TUMORS ; TIME ; PATIENT ; prognosis ; BIOLOGY ; TYPE-1 ; DIFFERENCE ; RECURRENCE ; TRANSFORMATION ; ONCOLOGY ; INTERVAL ; USA ; VARIABLES ; soft-tissue sarcoma ; DES ; YOUNGER ; histopathology ; malignant peripheral nerve sheath tumor ; neurofibromatosis ; NEUROFIBROMATOSIS 1 ; neurofibromatosis type 1 ; pathomechanism
    Abstract: The differences in the clinical course and histopathology of sporadic and neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) were investigated retrospectively. The collective comprised 38 NF1 patients and 14 sporadic patients. NF1 patients were significantly younger at diagnosis (p 〈 0.001) and had a significantly shorter survival time than sporadic patients (median survival 17 months vs. 42 months, Breslow p 〈 0.05). The time interval to local recurrence and metastatic spread was also significantly shorter in NF1 patients (9.4 months vs. 30.0 months, p 〈 0.01; 9.1 months vs. 33.2 months, p 〈 0.001, respectively). In patients with the original histopathological data available (22 NF1 patients, 14 sporadic cases), NF1-associated MPNST showed a significantly higher cellularity compared to sporadic tumors (p 〈 0.001) whereas sporadic MPNST featured a significantly higher pleomorphism (p 〈 0.01). Most importantly, while histopathological variables correlated with French Federation Nationale des Centres de Lutte Contre le Cancer grading in sporadic MPNST, this was not the case for NF1-associated tumors. The differences between NF1-associated and sporadic MPNST in regard to the clinical course and histopathology may reflect some fundamental differences in biology and pathomechanism of the two tumor groups. Our findings indicate the necessity for a separate grading scheme which takes into account the genetic background in NF1 patients
    Type of Publication: Journal article published
    PubMed ID: 17111191
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; Germany ; GENE-EXPRESSION ; PROTEIN ; TUMORS ; PATIENT ; MARKER ; prognosis ; CONTRAST ; treatment ; TYPE-1 ; ASSOCIATION ; polymorphism ; TARGET ; MUTANT ; NO ; IDENTIFICATION ; NEOPLASIA ; PROGRESSION ; MUTATION ; TUMOR PROGRESSION ; METASTASIS ; p53 ; MUTATIONS ; SOFT-TISSUE SARCOMAS ; CARCINOMAS ; RECURRENT ; POOR-PROGNOSIS ; TP53 ; MMP ; WILD-TYPE P53 ; MATRIX ; ONCOLOGY ; GRADE ; MALIGNANT PROGRESSION ; LEVEL ; NEUROFIBROMATOSIS TYPE-1 ; USA ; matrix metalloproteinase ; METALLOPROTEINASE ; MATRIX-METALLOPROTEINASE ; malignant peripheral nerve sheath tumor ; neurofibromatosis type 1 ; HUMAN COLLAGENASE-3 MMP-13 ; matrix metalloproteinase 13 ; POLYMORPHIC VARIANTS ; TP53 MUTATIONS
    Abstract: 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
    Type of Publication: Journal article published
    PubMed ID: 17786186
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  • 6
    Keywords: MRI ; MAGNETIC-RESONANCE ; magnetic resonance imaging ; AGE ; NERVE SHEATH TUMORS ; NF1
    Abstract: Objectives To define the frequency and clinical features of plexiform neurofibromas (PN) in children with neurofibromatosis type 1. Study design Sixty-five children received whole-body magnetic resonance imaging (MRI) and clinical-neurologic examination. Tumor sizes were calculated volumetrically with the program MedX v3.42.X(2) test, Fisher exact test, t test, and Spearman rank correlation were used for statistical analysis. Results Seventy-three tumors were detected in 37 of these 65 children. The mean volume of the tumors was 145.4 mL or 4.8 mL/kg body weight. Eighteen of the 73 PNs caused clinical deficits in 17 children, and the other 56 PNs in 20 children were asymptomatic. Symptomatic tumors were larger than asymptomatic ones (9.6 vs 3.3 mUkg body weight; P = .01). However, in certain body regions, for example, the head, small tumors also caused clinical deficits. Ten of 18 children 〉= 11.5 years (median age of the 37 children with PNs) had symptomatic PNs compared with 7 of 19 who were 〈11.5 years (P = .25). Conclusion PNs cause clinical deficits in young children. Early detection and regular MRI monitoring help to estimate growth and possible upcoming complications, and are thus beneficial for optimizing treatment and management.
    Type of Publication: Journal article published
    PubMed ID: 21621223
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  • 7
    Keywords: pathology ; THERAPIES ; FAMILIES ; MEMBER ; NEW-YORK ; FAMILY ; EXPRESSION ; THERAPY ; EGFR ; GENETIC ALTERATION ; USA
    Type of Publication: Meeting abstract published
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  • 8
    Keywords: USA ; TYROSINE KINASES ; TYROSINE ; Genetic ; TARGETED THERAPY ; TUMORS ; RECEPTOR ; EXPRESSION ; tumor ; KINASE ; THERAPY ; TYROSINE KINASE ; pathology ; PERIPHERAL-NERVE ; THERAPIES
    Type of Publication: Meeting abstract published
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  • 9
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary Schwannomas are benign solitary tumours of the peripheral nerve sheaths. The occurrence of multiple schwannomas usually implies hereditary disease. The most frequent syndrome associated with multiple schwannomas is neurofibromatosis type 2 (NF2), which is defined by bilateral vestibular schwannomas. Schwannomatosis is a distinct disease characterized by multiple pathologically proven schwannomas in the absence of vestibular schwannomas. It is not currently known if the presence of multiple schwannomas confined to a limb may represent a mosaic form of NF2 or a distinct disease, because mutation analysis of these tumours is not routinely performed. We report a 31-year-old patient who presented with multiple slowly growing subcutaneous tumours on his left arm. His family history was negative for cutaneous tumours or central nervous system disease, and he did not have additional features of NF2. Magnetic resonance tomography and ophthalmological examination excluded vestibular schwannoma and eye stigmata of NF2. After resection of three tumours, histological analysis confirmed the diagnosis of benign schwannomas. Molecular genetic analysis by temperature gradient gel electrophoresis and microsatellite marker analysis demonstrated two distinct mutations of the NF2 gene (NF2) in two different schwannomas, with concomitant loss of heterozygosity in both tumours. In contrast, neither normal skin nor peripheral blood lymphocytes revealed mutations of NF2. The clinical and molecular genetic findings suggest that the diagnosis in our patient is schwannomatosis rather than segmental NF2 because the mutations found in different tumours were not identical. The possibility of a localized predisposition for the acquisition of NF2 mutations is discussed.
    Type of Medium: Electronic Resource
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