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  • 1
    Language: English
    In: International journal of cancer, 01 October 2013, Vol.133(7), pp.1624-30
    Description: The differentiation between hereditary and sporadic microsatellite-unstable (MSI-H) colorectal cancer is a crucial step in Lynch syndrome diagnostics. Within MSI-H colorectal cancers, the BRAF V600E mutation is strongly associated with sporadic origin. Here, we asked whether BRAF V600E-specific immunohistochemistry (clone VE1) is helpful in separating sporadic from Lynch syndrome-associated MSI-H colorectal cancers. To that end, we performed VE1 immunohistochemistry and BRAF sequencing in a series of 91 MSI-H colorectal cancer specimens from patients tested for Lynch syndrome. Concordance of VE1 immunohistochemistry and molecular BRAF mutation status was observed in 90 of 91 (98.9%) MSI-H samples. All 11 tumors classified as BRAF V600E mutation-positive by Sanger sequencing were immunopositive, and 79 (98.8%) of 80 tumors classified as BRAF wild type showed negative staining. All VE1-positive tumors were MLH1- and PMS2-negative by immunohistochemistry. None of the tumors from mismatch repair (MMR) gene germline mutation carriers (n = 28) displayed positive VE1 staining, indicating that BRAF V600E mutation-specific immunostaining has a low risk of excluding Lynch syndrome patients from germline mutation analysis. In conclusion, implementation of VE1 immunohistochemistry was able to detect BRAF-mutated MSI-H colorectal cancers with a sensitivity of 100% and a specificity of 98.8%. Among MLH1-negative colorectal cancers, the rate of VE1-positive lesions was 21%, offering the exclusion of these patients from MMR germline testing. Therefore, we suggest the integration of VE1 immunohistochemistry into the diagnostic panel of Lynch syndrome.
    Keywords: Braf V600e ; Lynch Syndrome ; Colorectal Cancer ; Hereditary Nonpolyposis Colorectal Cancer ; Microsatellite Instability ; Microsatellite Instability ; Adaptor Proteins, Signal Transducing -- Genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis -- Diagnosis ; Nuclear Proteins -- Genetics ; Proto-Oncogene Proteins B-Raf -- Genetics
    ISSN: 00207136
    E-ISSN: 1097-0215
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  • 2
    Language: English
    In: Journal of the National Cancer Institute, June 19, 2013, Vol.105(12), p.917(3)
    Description: [BRAF.sup.V600E] mutations are frequent in melanomas originating from intermittently sun-exposed skin and also in common acquired melanocytic nevi, suggesting that BRAF mutation is an early event in melanocytic neoplasia. All neoplastic melanocytes within such a nevus would be expected to carry the BRAF mutation, and thus we evaluated the frequency of cells with [BRAF.sup.V600E] mutations within acquired nevi by droplet digital polymerase chain reaction. In BRAF-mutant nevi the number of BRAF mutant alleles equaled the number of wild-type (WT) alleles in the neoplastic cell population, consistent with a fully clonal heterozygous BRAF mutation. The allelic ratio of [BRAF.sup.V600E] to [BRAF.sup.WT] in the eight VE1-positive nevi, adjusted for degree of stromal contamination, ranged from 0.84 to 1.12 with an average ratio of 1.01. This was confirmed by immunohistochemistry with an antibody specific for [BRAF.sup.V600E], which uniformly labeled the neoplastic cells without any evidence of heterogeneity. We found [BRAF.sup.V600E] mutations in the melanocytic nevi to be fully clonal, strongly suggesting that BRAF-activating mutations typically are early initiating events in melanocytic neoplasia. J Natl Cancer Inst;2013;105:917-919 DOI:10.1093/jnci/djt119
    Keywords: Gene Mutation -- Research ; Melanoma -- Research ; Melanoma -- Genetic Aspects ; Polymerase Chain Reaction -- Usage
    ISSN: 0027-8874
    E-ISSN: 14602105
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  • 3
    In: Nature, 2011, Vol.478(7368), p.197
    Description: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
    Keywords: Sciences (General) ; Physics;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 4
    Language: English
    In: Journal of the American Academy of Dermatology, September 2012, Vol.67(3), pp.488-491
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jaad.2012.03.022 Byline: Alexander Skorokhod (a), David Capper (b)(c), Andreas von Deimling (b)(c), Alexander Enk (a), Peter Helmbold (a) Author Affiliation: (a) Department of Dermatology, Heidelberg University Hospital, Heidelberg, Germany (b) Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany (c) Clinical Cooperation Unit Neuropathology, German Cancer Research Center (Deutsches Krebsforschungszentrum), Heidelberg, Germany Article Note: (footnote) Supported by Deutsche Krebshilfe DKH108856., Disclosure: Drs Capper and von Deimling declare shared inventorship of BRAF V600E specific antibody clone VE1; a patent for diagnostic application of VE1 is pending. Drs Skorokhod, Enk, and Helmbold have no conflicts of interest to declare.
    Keywords: Medicine
    ISSN: 0190-9622
    E-ISSN: 1097-6787
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  • 5
    Language: English
    In: International Journal of Radiation Oncology, Biology, Physics, 2011, Vol.81(5), pp.1415-1421
    Description: To evaluate the correlation between the 1993 and 2000/2007 World Health Organization (WHO) classification with the outcome in patients with high-grade meningiomas. Between 1985 and 2004, 73 patients diagnosed with atypical or anaplastic meningiomas were treated with radiotherapy. Sections from the paraffin-embedded tumor material from 66 patients (90%) from 13 different pathology departments were re-evaluated according to the first revised WHO classification from 1993 and the revised classifications from 2000/2007. In 4 cases, the initial diagnosis meningioma was not reproducible (5%). Therefore, 62 patients with meningiomas were analyzed. All 62 tumors were reclassified according to the 1993 and 2000/2007 WHO classification systems. Using the 1993 system, 7 patients were diagnosed with WHO grade I meningioma (11%), 23 with WHO grade II (37%), and 32 with WHO grade III meningioma (52%). After scoring using the 2000/2007 system, we found 17 WHO grade I meningiomas (27%), 32 WHO grade II meningiomas (52%), and 13 WHO grade III meningiomas (21%). According to the 1993 classification, the difference in overall survival was not statistically significant among the histologic subgroups ( = .96). Using the 2000/2007 WHO classifications, the difference in overall survival became significant ( = .02). Of the 62 reclassified patients 29 developed tumor progression (47%). No difference in progression-free survival was observed among the histologic subgroups ( = .44). After grading according to the 2000/2007 WHO classifications, significant differences in progression-free survival were observed among the three histologic groups ( = .005). The new 2000/2007 WHO classification for meningiomas showed an improved correlation between the histologic grade and outcome. This classification therefore provides a useful basis to determine the postoperative indication for radiotherapy. According to our results, a comparison of the published data for future treatment decision-making remains difficult when the histologic diagnosis has not been based on the new improved classification system.
    Keywords: Medicine
    ISSN: 0360-3016
    E-ISSN: 1879-355X
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  • 6
    In: Journal Of The National Cancer Institute, 2013, Vol. 105(12), pp.917-919
    Description: BRAF V600E mutations are frequent in melanomas originating from intermittently sun-exposed skin and also in common acquired melanocytic nevi, suggesting that BRAF mutation is an early event in melanocytic neoplasia. All neoplastic melanocytes within such a nevus would be expected to carry the BRAF mutation, and thus we evaluated the frequency of cells with BRAF V600E mutations within acquired nevi by droplet digital polymerase chain reaction. In BRAF -mutant nevi the number of BRAF mutant alleles equaled the number of wild-type (WT) alleles in the neoplastic cell population, consistent with a fully clonal heterozygous BRAF mutation. The allelic ratio of BRAF V600E to BRAF WT in the eight VE1-positive nevi, adjusted for degree of stromal contamination, ranged from 0.84 to 1.12 with an average ratio of 1.01. This was confirmed by immunohistochemistry with an antibody specific for BRAF V600E , which uniformly labeled the neoplastic cells without any evidence of heterogeneity. We found BRAF V600E mutations in the melanocytic nevi to be fully clonal, strongly suggesting that BRAF -activating mutations typically are early initiating events in melanocytic neoplasia.
    Keywords: Medicine;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, Sept 3, 2013, Vol.110(36), p.14735(6)
    Description: Disruption of the blood--brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase C[beta], which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase C[beta] in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS. EAE | enzastaurin | CNS www.pnas.org/cgi/doi/10.1073/pnas.1302569110
    Keywords: Protein Kinases -- Physiological Aspects ; Protein Kinases -- Health Aspects ; Blood-brain Barrier -- Physiological Aspects ; Blood-brain Barrier -- Health Aspects ; Encephalomyelitis -- Physiological Aspects
    ISSN: 0027-8424
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.409-14
    Description: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
    Keywords: Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Cell Cycle Proteins -- Metabolism ; Glioblastoma -- Drug Therapy ; Glioma -- Drug Therapy ; Intracellular Signaling Peptides and Proteins -- Metabolism ; O(6)-Methylguanine-DNA Methyltransferase -- Pharmacology ; Tor Serine-Threonine Kinases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: Brain Pathology, Jan, 2011, Vol.21(1), p.74(14)
    Description: To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1750-3639.2010.00454.x Byline: Andreas von Deimling, Andrey Korshunov, Christian Hartmann Keywords: biomarker; BRAF; glioma; IDH1; MGMT Abstract: Abstract For some, glioma biomarkers have been expected to solve common diagnostic problems in routine neuropathology service caused by insufficient material, technical shortcomings or lack of experience. Further, biomarkers should predict patient outcome and direct optimal therapy for the individual patient. Unfortunately, current biomarkers still fall somewhat short of these grand expectations. While there has been some progress, it has generally been slow and in small steps. In this review, the newest set of glioma biomarkers: O.sup.6-methylguanine-DNA methyltransferase (MGMT) methylation, BRAF fusion and IDH1 mutation are discussed. MGMT methylation is well established as a prognostic/predictive marker for glioblastoma; however, technical questions regarding testing remain, it is not currently utilized widely in guiding patient management, and it has proven to be of no assistance in diagnostics. In contrast, BRAF fusion and IDH1 mutation analyses promise to be very helpful for classifying and grading gliomas, while their potential predictive value has yet to be established. Article History: Received 11 October 2010; accepted 11 October 2010. Article note: Professor Dr. Andreas von Deimling, MD, Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universitat Heidelberg, Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany (E-mail: andreas.vondeimling@med.uni-heidelberg.de)
    Keywords: Gliomas -- Genetic Aspects ; Biological Markers ; Methylation
    ISSN: 1015-6305
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  • 10
    Language: English
    In: PLoS ONE, 2012, Vol.7(3), p.e33449
    Description: Hypermethylation in the promoter region of the MGMT gene encoding the DNA repair protein O 6 -methylguanine-DNA methyltransferase is among the most important prognostic factors for patients with glioblastoma and predicts response to treatment with alkylating agents like temozolomide. Hence, the MGMT status is widely determined in most clinical trials and frequently requested in routine diagnostics of glioblastoma. Since various different techniques are available for MGMT promoter methylation analysis, a generally accepted consensus as to the most suitable diagnostic method remains an unmet need. Here, we assessed methylation-specific polymerase chain reaction (MSP) as a qualitative and semi-quantitative method, pyrosequencing (PSQ) as a quantitative method, and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a semi-quantitative method in a series of 35 formalin-fixed, paraffin-embedded glioblastoma tissues derived from patients treated in a prospective clinical phase II trial that tested up-front chemoradiotherapy with dose-intensified temozolomide (UKT-05). Our goal was to determine which of these three diagnostic methods provides the most accurate prediction of progression-free survival (PFS). The MGMT promoter methylation status was assessable by each method in almost all cases ( n  = 33/35 for MSP; n  = 35/35 for PSQ; n  = 34/35 for MS-MLPA). We were able to calculate significant cut-points for the continuous methylation signals at each CpG site analysed by PSQ (range, 11.5 to 44.9%) and at one CpG site assessed by MS-MLPA (3.6%) indicating that a dichotomisation of continuous methylation data as a prerequisite for comparative survival analyses is feasible. Our results show that, unlike MS-MLPA, MSP and PSQ provide a significant improvement of predicting PFS compared with established clinical prognostic factors alone (likelihood ratio tests: p 〈0.001). Conclusively, taking into consideration prognostic value, cost effectiveness and ease of use, we recommend pyrosequencing for analyses of MGMT promoter methylation in high-throughput settings and MSP for clinical routine diagnostics with low sample numbers.
    Keywords: Research Article ; Medicine ; Oncology ; Pathology
    E-ISSN: 1932-6203
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