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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  49. Jahrestagung der Deutschen Gesellschaft für Plastische und Wiederherstellungschirurgie (DGPW); 20111006-20111008; Ulm; DOC11dgpw046 /20111207/
    Publication Date: 2011-12-07
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: Germany ; human ; DISEASE ; GENE ; PATIENT ; recombination ; SEQUENCE ; SEQUENCES ; DELETION ; ELEMENT ; PROBE ; PHENOTYPES ; AMPLIFICATION ; AGE ; MUTATION ; genetics ; DELETIONS ; MUTATIONS ; PHENOTYPE ; INDIVIDUALS ; CLINICAL-FEATURES ; HOMOLOGOUS RECOMBINATION ; JUNCTIONS ; SINGLE ; FEATURES ; ONSET ; JUNCTION ; 3 ; Genetic ; MEDICAL-CENTER
    Abstract: In this study, the breakpoints of six large intragenic deletions in the NF2 gene are determined, which had initially been detected by multiplex ligation-dependent probe amplification. While one breakpoint occurred within an exon, the remaining 11 lied in the corresponding flanking introns. Two of the deletions were most likely caused by nonallelic homologous recombination between Alu sequences, while the other four appeared to be the result of nonhomologous endjoining, possibly facilitated by rearrangement-promoting elements at the junctions in some cases. The clinical features of patients with large intragenic deletions and individuals with mutations affecting single or multiple nucleotides of the NF2 gene are relatively similar. However, patients with deletions of the 3' exons 15 and 16 of the NF2 gene did exhibit milder phenotypes, especially with respect to the age of disease onset. (c) 2009 Wiley-Liss, Inc.
    Type of Publication: Journal article published
    PubMed ID: 19924781
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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    Keywords: EXPRESSION ; GROWTH ; CELL ; DISEASE ; GENE ; PROTEIN ; DIFFERENTIATION ; BIOMARKERS ; IN-SITU ; MALIGNANT-MELANOMA ; ORIGIN ; SERUM ; BURDEN ; MELANOMA INHIBITORY-ACTIVITY
    Abstract: Background: Neurofibromatosis type 1 (NF1) is a frequent genetic disease characterized by multiple benign tumours with increased risk for malignancy. There is currently no biomarker for tumour load in NF1 patients. Methods: In situ hybridization and quantitative real-time polymerase reaction were applied to investigate expression of cartilage-specific genes in mice bearing conditional inactivation of NF1 in the developing limbs. These mice do not develop tumours but recapitulate aspects of NF1 bone dysplasia, including deregulation of cartilage differentiation. It has been recently shown that NF1 tumours require for their growth the master regulator of cartilage differentiation SOX9. We thus hypothesized that some of the cartilage-specific genes deregulated in an Nf1Prx1 mouse model might prove to be relevant biomarkers of NF1 tumours. We tested this hypothesis by analyzing expression of the SOX9 target gene product melanoma-inhibitory activity/cd-rap (MIA) in tumour and serum samples of NF1 patients. Results: Increased expression of Mia was found in Nf1-deficient cartilage in mice. In humans, MIA was expressed in all NF1-related tumours and its serum levels were significantly higher in NF1 patients than in healthy controls. Among NF1 patients, MIA serum levels were significantly higher in those with plexiform neurofibromas and in those with large number of cutaneous (〉 1,000) or subcutaneous (〉 100) neurofibromas than in patients without such tumours. Most notably, MIA serum levels correlated significantly with internal tumour burden. Conclusions: MIA is a potential serum biomarker of tumour load in NF1 patients which could be useful in following the disease course and monitoring the efficacy of therapies
    Type of Publication: Journal article published
    PubMed ID: 21726432
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  • 7
    Keywords: GENE ; IDENTIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; DELETIONS ; MUTATIONS ; NERVE SHEATH TUMORS ; MALIGNANT-TUMORS ; NF1 ; CYTOGENETIC CHARACTERIZATION ; VONRECKLINGHAUSEN NEUROFIBROMATOSIS
    Abstract: Benign peripheral nerve sheath tumors (PNSTs) are a characteristic feature of neurofibromatosis type I (NF1) patients. NF1 individuals have an 8-13% lifetime risk of developing a malignant PNST (MPNST). Atypical neurofibromas are symptomatic, hypercellular PNSTs, composed of cells with hyperchromatic nuclei in the absence of mitoses. Little is known about the origin and nature of atypical neurofibromas in NF1 patients. In this study, we classified the atypical neurofibromas in the spectrum of NF1-associated PNSTs by analyzing 65 tumor samples from 48 NF1 patients. We compared tumor-specific chromosomal copy number alterations between benign neurofibromas, atypical neurofibromas, and MPNSTs (low-, intermediate-, and high-grade) by karyotyping and microarray-based comparative genome hybridization (aCGH). In 15 benign neurofibromas (4 subcutaneous and 11 plexiform), no copy number alterations were found, except a single event in a plexiform neurofibroma. One highly significant recurrent aberration (15/16) was identified in the atypical neurofibromas, namely a deletion with a minimal overlapping region (MOR) in chromosome band 9p21.3, including CDKN2A and CDKN2B. Copy number loss of the CDKN2A/B gene locus was one of the most common events in the group of MPNSTs, with deletions in low-, intermediate-, and high-grade MPNSTs. In one tumor, we observed a clear transition from a benign-atypical neurofibroma toward an intermediate-grade MPNST, confirmed by both histopathology and aCGH analysis. These data support the hypothesis that atypical neurofibromas are premalignant tumors, with the CDKN2A/B deletion as the first step in the progression toward MPNST.
    Type of Publication: Journal article published
    PubMed ID: 21987445
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  • 8
    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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  • 9
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    German Medical Science; Düsseldorf, Köln
    In:  104. Jahrestagung der Deutschen Ophthalmologischen Gesellschaft (DOG); 20060921-20060924; Berlin; DOC06dogP144 /20060918/
    Publication Date: 2006-09-19
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 10
    Keywords: SPECTRA ; GROWTH ; tumor ; COMMON ; SUPPORT ; DISEASE ; GENE ; TUMORS ; PATIENT ; COMPLEX ; COMPLEXES ; MECHANISM ; recombination ; mechanisms ; TYPE-1 ; DISORDER ; FORM ; HUMANS ; MUTATION ; genetics ; loss of heterozygosity ; MUTATIONS ; BENIGN ; GERMLINE ; CLINICAL-FEATURES ; TP53 ; FEATURES ; ADULT ; VARIANT ; Male ; CHILD ; Middle Aged ; Genes,p53 ; SOMATIC MUTATIONS ; Child,Preschool ; neurofibromatosis ; UK ; Genetic ; LOSS-OF-HETEROZYGOSITY ; Young Adult ; DNA Mutational Analysis ; Base Sequence ; Adolescent ; Molecular Sequence Data ; *Germ-Line Mutation ; *Neurofibroma/genetics/pathology ; *Neurofibromatosis 1/genetics/pathology ; *Spinal Neoplasms/genetics/pathology
    Abstract: Neurofibromatosis type 1 (NF1) is a common inherited complex multi-system disorder associated with the growth of various benign and malignant tumors. About 40% of NF1 patients develop spinal tumors, of whom some have familial spinal neurofibromatosis (FSNF), a variant form of NF1 in which patients present with multiple bilateral spinal tumors but have few other clinical features of the disease. We have studied 22 spinal neurofibromas derived from 14 unrelated NF1 patients. Seven of these patients satisfied the diagnostic criteria of NF1 while the remaining seven had only few features of NF1. The latter group defined as FSNF harbored significantly higher number of missense or missense and splice-site germline mutations compared to the group with classical NF1. This is the first study to describe NF1 somatic mutations in spinal neurofibromas. Loss-of-heterozygosity (LOH) was identified in 8/22 of the spinal tumors, 75% of LOH observed was found to result from mitotic recombination, suggesting that this may represent a frequent mutational mechanisms in these benign tumors. No evidence for LOH of the TP53 gene was found in these tumors.
    Type of Publication: Journal article published
    PubMed ID: 19221814
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