Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    facet.materialart.
    facet.materialart.
    German Medical Science GMS Publishing House; Düsseldorf
    In:  Gemeinsame Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaft für Thoraxchirurgie; 20131024-20131026; Basel, Schweiz; DOCHT4.3 /20131014/
    Publication Date: 2013-10-15
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Keywords: CANCER ; KINASE ; ACTIVATION ; metastases ; MELANOMA ; SIGNALING PATHWAY ; MUTATIONS ; KRAS ; RAF ; SEROUS CARCINOMAS
    Abstract: BACKGROUND: Genetic analyses have identified BRAF V600E mutations in a subset of ovarian carcinomas. The aim of this study was to investigate the expression of BRAF V600E aberrant protein using a novel mutation-specific antibody in epithelial ovarian tumors. METHODS: We immunohistochemically analyzed expression of V600E-mutant BRAF protein in archival formalin-fixed, paraffin-embedded tissue specimens of 142 epithelial ovarian tumors [98 invasive carcinomas and 44 tumors of low malignant potential (LMP)] using monoclonal antibody VE1. BRAF mutation status was validated in all immunopositive cases and in 6 immunonegative control cases by gene sequencing. RESULTS: We found anti-BRAF V600E immunolabeling in 4 serous carcinomas and 5 serous LMP. Presence of a BRAF V600E mutation was confirmed by sequencing analysis in 6 of the 9 cases (3 LMP tumors, 3 low-grade carcinomas). In 2 partially VE1-positive tumors deriving from 1 patient (1 LMP and 1 contralateral invasive high-grade serous carcinoma), genetic analysis repeatedly resulted in BRAF wild-type, arguing for false-positive immunostaining results. One immunopositive case was repeatedly inconclusive in genetic analysis. In all 6 genetically confirmed cases, BRAF V600E mutant protein expression was homogenous throughout the tumor tissue. CONCLUSIONS: We found BRAF V600E mutations in 13% (4/31) of serous LMP and 5% (3/62) of invasive serous carcinomas. No BRAF V600E mutations were detected in nonserous epithelial ovarian tumors. For reliable assessment of the BRAF V600E status in ovarian epithelial tumor samples, an integrated approach using immunohistochemistry and genetic analysis seems advisable, as both methods lead to incorrect results in some cases.
    Type of Publication: Journal article published
    PubMed ID: 22820660
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Keywords: carcinoma ; COLORECTAL-CANCER ; BRAF MUTATIONS ; adenoma ; HYPERPLASTIC POLYPS ; NEGATIVE COLONOSCOPY ; MALIGNANT MELANOCYTIC LESIONS ; METHYLATOR PHENOTYPE ; BORDERLINE VARIANT ; NEOPLASIA PATHWAY
    Abstract: BRAF V600E mutation in serrated lesions of the colon has been implicated as an important mutation and as a specific marker for the serrated carcinogenic pathway. Recent findings point to microvesicular hyperplastic polyps that have similar histologic and molecular features to sessile serrated adenomas/polyps, as potential colorectal carcinoma precursors. The aim of this study was to evaluate BRAF V600E mutation status by immunohistochemistry in serrated lesions of the colon with regard to histomorphology. We investigated 194 serrated lesions of the colon, comprising 42 sessile serrated adenomas/polyps, 16 traditional serrated adenomas, 136 hyperplastic polyps and 20 tubular/tubulovillous adenomas (conventional adenomas) with the novel BRAF V600E mutation-specific antibody VE1. In addition, BRAF exon 15 and KRAS exon 2 status was investigated by capillary sequencing in selected cases. All sessile serrated adenomas/polyps (42/42, 100%), 15/16 (94%) traditional serrated adenomas and 84/136 (62%) hyperplastic polyps were VE1+. None of the VE1- serrated lesions showed BRAF V600E mutation. Forty out of 42 (95%) sessile serrated adenomas/polyps displayed areas with microvesicular hyperplastic polyp-like features. In microvesicular hyperplastic polyps, VE1 positivity was significantly associated with nuclear atypia (P = 0.003); however, nuclear atypia was also present in VE1- cases. Immunostaining with VE1 allows not only the detection of BRAF V600E mutation but also the correlation with histomorphology on a cellular level in serrated lesions. VE1 enables a subclassification of microvesicular hyperplastic polyps according to the mutation status. This improved classification of serrated lesions including immunohistochemical evaluation of BRAF V600E mutation may be the key to identify lesions with higher potential to progression into sessile serrated adenoma/polyp, and further to BRAF V600E-mutated colorectal cancer.
    Type of Publication: Journal article published
    PubMed ID: 23887306
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Abstract: BACKGROUND: Increased incidence of brain metastases (BM) in non-small cell lung cancer (NSCLC) with ALK translocations was postulated, however, ALK gene aberrations in NSCLC-BM have not been investigated so far. METHODS: We investigated ALK and EML4 gene aberrations (amplifications, translocations, inversions) by fluorescent in situ hybridization (FISH) (n=175) and ALK and EML4 protein expression by immunohistochemistry (n=221) in NSCLC BM and corresponding primary tumors. RESULTS: ALK translocations were found in 4/151 (2.6%; 3 of them involving EML4) of BM of adenocarcinomas (AC), 1/9 (11.1%) of adenosquamous carcinomas (ASC), 0/5 of squamous cell carcinomas (SCC) and 0/10 of large cell carcinomas (LCC). Rearrangement of ALK without involvement of EML4 was seen in 1 AC-BM and rearrangement of EML4 without involvement of ALK in 3 AC-BM, 1 ASC-BM and 1 LCC. ALK amplifications without gene rearrangements were found in BM of 16/151 (10.6%) AC, 2/5 (40%) SCC, 0/9 ASC and one LCC. ALK translocation status was constant between BM and primary tumors in 16 evaluable cases including two cases with ALK-EML4 translocations Among these 16 cases ALK amplification was seen in two BM and none of the primary tumors. All cases with translocations but not with amplifications of ALK showed protein expression. We found no association of ALK gene status with patient age, gender or overall survival time. CONCLUSIONS: ALK translocations and amplifications are found in approximately 3% and 11% of NSCLC-BM, respectively. While ALK translocations appear to be constant between primary tumors and BM, amplifications seem to be more prevalent in BM. ALK translocation, but not ALK amplification is associated with ALK protein overexpression. Further studies are needed to determine whether NSCLC-BM patients with ALK gene aberrations may benefit from specific inhibitor therapy.
    Type of Publication: Journal article published
    PubMed ID: 23453647
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: RECEPTOR ; CELL CARCINOMA
    Abstract: OBJECTIVES: FGFR1 amplifications are common in squamous cell carcinoma and rare in adenocarcinoma of the lung, but have not been investigated in brain metastases of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We performed fluorescent in situ hybridization (FISH) for FGFR1 and immunohistochemistry for pAKT, PI3K, HIF1a and Ki67 in 175 NSCLC brain metastases and 11 matched primary tumors. ALK gene rearrangement status was available from a previous study. We performed statistical correlations of clinical, histopathological and molecular data. RESULTS: FGFR1 amplifications were found in a total of 30/175 (17%) brain metastases: 4/21 (19%) squamous cell carcinomas, 20/130 (15.3%) adenocarcinomas, 2/12 (16.6%) adenosquamous carcinomas, 4/9 (44.4%) large cell carcinomas and 0/3 neuroendocrine large cell carcinoma. FGFR1 gene status was identical between primary tumors and brain metastases in 9/11 evaluable cases. In 2/11 cases (1 adenosquamous and 1 large cell carcinoma), FGFR1 amplifications were present only in the brain metastasis and not in the primary tumor. Furthermore, we found a significant positive correlation of ALK and FGFR1 gene amplification status in brain metastases (p〈0.001, Chi square test). Patients with high-level FGFR1 amplifications had significantly higher number of visceral metastases (p〈0.001, Chi square test). CONCLUSION: Our findings argue for an enrichment of FGFR1 amplifications in brain metastases of adenocarcinomas (where they were 5-fold more frequent than reported for primary tumors) and possibly also of other non-squamous carcinomas, but not in squamous cell carcinomas of the lung. These results may be relevant for targeted therapy and prophylaxis of NSCLC brain metastases.
    Type of Publication: Journal article published
    PubMed ID: 24183471
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: EXPRESSION ; IN-VIVO ; PATHWAY ; DIFFERENTIATION ; TUMORS ; MUTATIONS ; PHENOTYPE ; GLIOBLASTOMA-MULTIFORME ; PODOPLANIN ; CHALLENGES
    Abstract: BACKGROUND: Recently, isocitrate dehydrogenase 1 (IDH1) was identified as a major participant in glioma pathogenesis. At present, the enzymatic activity of the protein has been the main topic in investigating its physiological function, but its signaling pathway allocation was unsuccessful. Interestingly, proteins regulated by phosphoinositide 3-kinase (PI3K)/Akt signaling, are among the top downregulated genes in gliomas associated with high percentage of IDH1 and IDH2 mutations. The aim of this study was to investigate a hypothetical relation between IDH1 and PI3K signaling. METHODS: The presence of mutant IDH1 and markers for active PI3K/Akt signaling, present as phosphorylated Akt and podoplanin (PDPN), were investigated in a discovery cohort of 354 patients with glioma. In vitro experiments were used to confirm functional links. RESULTS: This study shows an inverse correlation between mutant IDH1 and markers for active PI3K/Akt signaling. In support of a functional link between these molecules, in vitro expression of mutant IDH1 inhibited Akt phosphorylation in a 2-hydroxyglutarate-dependent manner. CONCLUSIONS: This study provides patient tumor and in vitro evidence suggesting that mutant IDH1 inhibits PI3K/Akt signaling. Cancer 2014;120:2440-2447. (c) 2014 American Cancer Society.
    Type of Publication: Journal article published
    PubMed ID: 24771584
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: SURVIVAL ; carcinoma ; ACTIVATION ; protein expression ; EGFR ; C-MET ; GENE COPY NUMBER ; ALK ; TUMOR REGISTRY
    Abstract: BACKGROUND: CMET represents an emerging therapy target for monoclonal antibodies and tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). METHODS: We investigated CMET gene amplification status by fluorescence in-situ hybridization (FISH) and CMET protein expression by immunohistochemistry in a large series of 209 NSCLC brain metastases (BM; 165 adenocarcinoma, 20 squamous cell carcinoma, 11 adenosquamous carcinomas, 11 large cell carcinomas and two large cell neuroendocrine carcinomas) and correlated our results to clinic-pathological parameters and molecular data from previous studies. RESULTS: We found CMET gene amplification in 36/167 (21.6%) and CMET protein expression in 87/196 (44.4%) of evaluable BM. There was a strong correlation between the presence of CMET gene amplification and CMET protein expression (P 〈 0.001, chi-square test). Furthermore, presence of CMET amplification correlated positively with presence of ALK amplifications (P = 0.039, chi-square test) and high HIF1 alpha index (P = 0.013, Mann-Whitney U-test). Neither CMET expression nor CMET gene amplification status correlated with patient outcome parameters or known prognostic factors. CONCLUSIONS: CMET overexpression and CMET amplification are commonly found in NSCLC BM and may represent a promising therapeutic target.
    Type of Publication: Journal article published
    PubMed ID: 25039982
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Keywords: CELL LUNG-CANCER ; FOLLOW-UP ; brain metastases ; ADJUVANT CHEMOTHERAPY ; EGFR MUTATIONS ; TARGETED THERAPIES ; CLINICAL-PRACTICE GUIDELINES ; OPEN-LABEL ; HER2-POSITIVE BREAST-CANCER ; MUTATION-POSITIVE MELANOMA
    Abstract: Metastases to the central nervous system (CNS) are common in several cancer types. For most primary tumors that commonly metastasize to the CNS, molecular biomarker analyses are recommended in the clinical setting for selection of appropriate targeted therapies. Therapeutic efficacy of some of these agents has been documented in patients with brain metastases, and molecular testing of CNS metastases should be considered in the clinical setting. Here, we summarize the clinically relevant biomarker tests that should be considered in neurosurgical specimens based on the current recommendations of the European Society of Medical Oncology (ESMO) or the National Comprehensive Cancer Network (NCCN) for the most relevant primary tumor types: lung cancer (EGFR mutations, ALK rearrangement, BRAF mutations), breast cancer (HER2 amplification, steroid receptor overexpression), melanoma (BRAF mutations), and colorectal cancer (RAS mutations). Furthermore, we discuss emerging therapeutic targets including novel oncogenic alterations (ROS1 rearrangements, FGFR1 amplifications, CMET amplifications, and others) and molecular features of the tumor microenvironment (including immune-checkpoint molecules such as CTLA4 and PD-1/PD-L1). We also discuss the potential role of advanced biomarker tests such as next-generation sequencing and "liquid biopsies" for patients with CNS metastases.
    Type of Publication: Journal article published
    PubMed ID: 25287912
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Abstract: In primary melanoma, ETV1 transcription factor was suggested to be activated mainly by gene amplification and to promote tumor growth in cooperation with BRAF (V600E) . Aim of this study was to investigate ETV1 expression in human melanoma with a focus on brain metastases. We investigated ETV1 in 68 human melanoma brain metastases using FISH for ETV1 gene (located at chromosome 7p21) and centromere chromosome 7 and immunohistochemistry for ETV1, BRAF (V600E) , and ETV1/BRAF associated proteins pMSK1, pRSK1, pp38, pMEK1/2, MAPKAP kinase 2, CIC, HIF-1alpha and Ki-67. We further studied ETV1 copy number variations in 32 melanoma cell lines from primary and metastatic lesions using array CGH. The influence of the MAP kinase pathway activity on ETV1 mRNA and protein expression under BRAF wild-type and BRAF (V600E) conditions were determined in melanoma cell lines using qRT-PCR and Western Blot. No ETV1 high grade amplifications were observed in tissue samples, but low grade ETV1 gene amplifications were found in 7 (10.3 %) melanoma brain metastases. ETV1 protein expression in tissue samples (15 %) correlated with BRAF (V600E) status (p = 0.007) and HIF-1alpha expression (p = 0.049), but not with ETV1 gene dose. Application of the BRAF(V600E)-specific inhibitor vemurafenib and the BRAF(V6ooE/V600K)-inhibitor dabrafenib revealed predominant regulation of ETV-1 mRNA and protein via MAPK-pathway. ETV1 expression is a rare event in human melanoma and seems to be rather based on hyperactivation of MAPK signals, by BRAF (V600E) mutation, than on ETV1 gene amplification. Consequently, therapeutic inhibition of BRAF and the downstream MAPK pathway also down-regulates oncogenic ETV1 expression.
    Type of Publication: Journal article published
    PubMed ID: 25073704
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Abstract: The mutated BRAF oncogene represents a therapeutic target in malignant melanoma. Because BRAF mutations are also involved in the pathogenesis of other human malignancies, the use of specific BRAF inhibitors might also be extended to other diseases in the future. A prerequisite for the clinical application of BRAF inhibitors is the reliable detection of activating BRAF mutations in routine histopathological samples. In a multicenter approach, we evaluated a novel and fully automated PCR-based system (Idylla) capable of detecting BRAF V600 mutations in formalin-fixed, paraffin-embedded tissue within 90 minutes with high sensitivity. We analyzed a total of 436 samples with the Idylla system. Valid results were obtained in 421 cases (96.56%). Its performance was compared with conventional methods (pyrosequencing or Sanger sequencing). Concordant results were obtained in 406 cases (96.90%). Reanalysis of eight discordant samples by next-generation sequencing and/or pyrosequencing with newly extracted DNA and the BRAF RGQ Kit confirmed the Idylla result in seven cases, resulting in an overall agreement of 98.57%. In conclusion, the Idylla system is a highly reliable and sensitive platform for detection of BRAF V600 mutations in formalin-fixed, paraffin-embedded material, providing an efficient alternative to conventional diagnostic methods, particularly for routine diagnostics laboratories with limited experience in molecular pathology.
    Type of Publication: Journal article published
    PubMed ID: 26921540
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...