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  1. Article: Molecular characterization of the evolution of premalignant lesions in the upper aerodigestive tract.

    Lechner, Axel / Kumbrink, Jörg / Walz, Christoph / Jung, Andreas / Baumeister, Philipp / Flach, Susanne

    Frontiers in oncology

    2024  Volume 14, Page(s) 1364958

    Abstract: Introduction: Early relapse and development of metastatic disease are some of the primary reasons for the poor prognosis of patients with head and neck squamous cell carcinoma (HNSCC). HNSCC is a heterogeneous disease which may develop in large ... ...

    Abstract Introduction: Early relapse and development of metastatic disease are some of the primary reasons for the poor prognosis of patients with head and neck squamous cell carcinoma (HNSCC). HNSCC is a heterogeneous disease which may develop in large premalignant fields of genetically altered cells. Yet knowing which individuals will progress and develop clinically significant cancers during their lifetimes remains one of the most important challenges of reducing HNSCC morbidity and mortality. To further elucidate the molecular mechanisms, we performed a focused analysis of the genome and immune microenvironment from multiple, matched normal squamous tissue, premalignant lesions, as well as primary and recurrent tumors from seven patients with p16-negative HNSCC.
    Methods: We performed targeted panel Next Generation Sequencing (161 genes) to analyze somatic variants from sequentially collected, matched formalin-fixed paraffin-embedded tissue (normal, premalignant, HNSCC) from two patients. These samples plus samples from five additional patients were analyzed with the Nanostring PanCancer Immune Panel. In addition, we performed shallow whole genome sequencing (0.5x coverage on average) on samples from three of these patients. Patients were, apart from one case, primarily treated with curative-intent surgery, and received subsequent adjuvant treatment, if indicated.
    Results: The most frequently mutated genes were
    Conclusion: Genomic alterations as well as aberrant immune gene expression can be observed early in the evolution of tumors of the upper aerodigestive tract, highlighting the potential for targeting early mechanisms of disease progression.
    Language English
    Publishing date 2024-04-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2024.1364958
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  2. Article ; Conference proceedings: Tumorbiological behaviour and metastatic spread in lower gastrointestinal (GI) tract malignancies – correlation with gene expression patterns

    Pretzsch, E. / Neumann, J. / Nieß, H. / Werner, J. / Kumbrink, J. / Angele, M.

    Zeitschrift für Gastroenterologie

    2023  Volume 61, Issue 08

    Event/congress Viszeralmedizin 2023 77. Jahrestagung der DGVS mit Sektion Endoskopie Herbsttagung der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie mit den Arbeitsgemeinschaften der DGAV und Jahrestagung der CACP, Erst online. Dann Hamburg., 2023-09-11
    Language German
    Publishing date 2023-08-01
    Publisher Georg Thieme Verlag
    Publishing place Stuttgart ; New York
    Document type Article ; Conference proceedings
    ZDB-ID 201387-3
    ISSN 1439-7803 ; 0044-2771 ; 0172-8504
    ISSN (online) 1439-7803
    ISSN 0044-2771 ; 0172-8504
    DOI 10.1055/s-0043-1771930
    Database Thieme publisher's database

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  3. Article: Clinicopathological characterization of next-generation sequencing detected mutations in lung cancers-a single-center experience.

    Walter, Julia / Tufman, Amanda / Kumbrink, Jörg / Neumann, Jens / Kahnert, Kathrin / Sellmer, Laura / Jung, Andreas / Behr, Jürgen / Kauffmann-Guerrero, Diego

    Translational lung cancer research

    2024  Volume 13, Issue 4, Page(s) 799–810

    Abstract: Background: Despite many advances in molecular procedures many lung cancer patients do not receive full panel testing. This can limit the comprehensive understanding of their disease and potentially hinder personalized treatment options.: Methods: In ...

    Abstract Background: Despite many advances in molecular procedures many lung cancer patients do not receive full panel testing. This can limit the comprehensive understanding of their disease and potentially hinder personalized treatment options.
    Methods: In this retrospective analysis, we used results from next-generation sequencing (NGS) testing of 154 patients with adenocarcinoma (AC) or squamous cell carcinoma (SCC) of the lung treated at the University Hospital, Ludwig-Maximilians Universität (LMU) Munich between 2018 and 2021. We compared different clinicopathological features and patients' baseline characteristics with results of NGS testing. We used
    Results: NGS testing found mutations in 107 (69.5%) patients; 44 patients (28.6%) had more than one mutation. The majority (79.2%) of patients had AC and 64.9% were metastasized at diagnosis. Patients with detected mutations had significantly higher
    Conclusions: Mutation profiles differed by histological type and metastases status and were significantly associated with
    Language English
    Publishing date 2024-04-25
    Publishing country China
    Document type Journal Article
    ZDB-ID 2754335-3
    ISSN 2226-4477 ; 2218-6751
    ISSN (online) 2226-4477
    ISSN 2218-6751
    DOI 10.21037/tlcr-23-751
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  4. Article ; Online: Checkpoint inhibitor-induced bullous pemphigoid differs from spontaneous bullous pemphigoid.

    Kramer, N / Müller, G / Zierold, S / Röckel, M / Fröhlich, W / Schefzyk, M / Kumbrink, J / Hassel, J C / Berking, C / Ziemer, M / Nashan, D / French, L E / Vera, J / Kerl-French, K E / Gutzmer, R / Heinzerling, L

    Journal of the European Academy of Dermatology and Venereology : JEADV

    2024  

    Language English
    Publishing date 2024-02-24
    Publishing country England
    Document type Letter
    ZDB-ID 1128828-0
    ISSN 1468-3083 ; 0926-9959
    ISSN (online) 1468-3083
    ISSN 0926-9959
    DOI 10.1111/jdv.19860
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  5. Article ; Online: Bifunctional effect of Zoledronic Acid (ZA) on human mesenchymal stem cells (hMSCs) based on the concentration level.

    Fliefel, R / El Ashwah, A / Entekhabi, S / Kumbrink, J / Ehrenfeld, M / Otto, S

    Journal of stomatology, oral and maxillofacial surgery

    2020  Volume 121, Issue 6, Page(s) 634–641

    Abstract: Background: Treatment of massive bone defects is a great challenge. Mesenchymal stem cells (MSCs) enhance bone regeneration by differentiating into osteoblasts. Bisphosphonates (BPs) are antiresorptives reducing bone resorption. Despite Medication- ... ...

    Abstract Background: Treatment of massive bone defects is a great challenge. Mesenchymal stem cells (MSCs) enhance bone regeneration by differentiating into osteoblasts. Bisphosphonates (BPs) are antiresorptives reducing bone resorption. Despite Medication-related osteonecrosis of the jaw (MRONJ) is a known side effect of antiresorptives, evidences suggest that BPs have positive effect on bone formation. The aims of this study were to investigate the effect of zoledronic acid (ZA) and geranylgeraniol (GGOH) on human mesenchymal stem cells (hMSCs) being a part of the bone microenvironment and evaluate whether low dose of bisphosphonate has enhanced osteogenic differentiation of hMSCs.
    Materials and methods: The effect of ZA and GGOH on MSCs was investigated in addition to the effect of low doses of ZA on osteogenic differentiation of MSCs and analysed by WST-1, Live/Dead staining and coefficient of drug index (CDI). The osteogenic differentiation of the cells was confirmed by ALP activity, xylenol orange and alizarin red staining, microarray and PCR with levels of statistical significance indicated at *P<0.05, **P<0.01 and ***P<0.0001.
    Main findings: Although, high concentration of ZA had significantly decreased the cell viability in MSCs, GGOH reversed the action of ZA on the cells while at very high concentration; it caused severe reduction in the cell viability. CDI showed antagonism or synergism depending on the concentrations of ZA and GGOH.
    Conclusion: The treatment of cells with ZA has increased the mineralization and osteogenic differentiation of MSCs. Our study supported the hypothesis that zoledronic acid plays a bifunctional role depending on the concentration.
    MeSH term(s) Diphosphonates/adverse effects ; Humans ; Imidazoles/pharmacology ; Mesenchymal Stem Cells ; Osteogenesis ; Zoledronic Acid
    Chemical Substances Diphosphonates ; Imidazoles ; Zoledronic Acid (6XC1PAD3KF)
    Language English
    Publishing date 2020-03-20
    Publishing country France
    Document type Journal Article
    ZDB-ID 2916276-2
    ISSN 2468-7855 ; 2468-8509
    ISSN (online) 2468-7855
    ISSN 2468-8509
    DOI 10.1016/j.jormas.2020.03.004
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  6. Article ; Online: New insights into redox-related risk factors and therapeutic targets in oral squamous cell carcinoma.

    Dewenter, Ina / Kumbrink, Joerg / Poxleitner, Philipp / Smolka, Wenko / Liokatis, Paris / Fliefel, Riham / Otto, Sven / Obermeier, Katharina Theresa

    Oral oncology

    2023  Volume 147, Page(s) 106573

    Abstract: Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral cavity accounting for 90 % of oral cancer with a global incidence of 350.000 new cases per year. Curative resection along with adjuvant radiation therapy or a combination of ... ...

    Abstract Oral squamous cell carcinoma (OSCC) is the most common cancer in the oral cavity accounting for 90 % of oral cancer with a global incidence of 350.000 new cases per year. Curative resection along with adjuvant radiation therapy or a combination of radiotherapy with chemotherapy remain as gold standard in treating OSCC. Still, local recurrence, lymph nodal recurrence, and complications of radiation remain the main cause of tumor-related mortality. Reactive oxygen species are not only correlated to the etiology of OSCC due to oxidative DNA damage, lipid peroxidation or effecting signal transduction cascades that effect cell proliferation and tumorigenesis, but are also of great interest in the therapy of OSCC patients. As induced oxidative stress can be used therapeutically for the induction of tumor cell death, redox targets might be a therapeutic addition to the conventional treatment options. In this review, we discuss markers of impaired redox homeostasis as well as potential redox-related treatment targets in OSCC.
    MeSH term(s) Humans ; Carcinoma, Squamous Cell/pathology ; Squamous Cell Carcinoma of Head and Neck ; Mouth Neoplasms/pathology ; Head and Neck Neoplasms ; Oxidation-Reduction ; Risk Factors ; Cell Line, Tumor
    Language English
    Publishing date 2023-11-09
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1120465-5
    ISSN 1879-0593 ; 0964-1955 ; 1368-8375
    ISSN (online) 1879-0593
    ISSN 0964-1955 ; 1368-8375
    DOI 10.1016/j.oraloncology.2023.106573
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    Zs.A 4869: Show issues Location:
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  7. Article ; Online: TGFβ signalling pathway impacts brain metastases profiles in locally advanced colorectal cancer.

    Jacob, Sven / Balonov, Ilja / Jurinovic, Vindi / Heiliger, Christian / Tschaidse, Tengis / Kumbrink, Jörg / Kirchner, Thomas / Werner, Jens / Angele, Martin K / Michl, Marlies / Neumann, Jens

    Clinical & experimental metastasis

    2024  

    Abstract: Rationale: Colorectal Cancer (CRC) represents the third most common type of cancer in Germany and the second most common cancer-related cause of death worldwide. Distant metastases are still the main limit for patient survival. While liver metastases as ...

    Abstract Rationale: Colorectal Cancer (CRC) represents the third most common type of cancer in Germany and the second most common cancer-related cause of death worldwide. Distant metastases are still the main limit for patient survival. While liver metastases as well as peritoneal carcinomatosis can often either be resected or treated with systemic therapy, little options remain for brain metastases. Additionally, a number of studies has already investigated hepatic, peritoneal, pulmonary as well as continuing distant metastases in colorectal cancer. Yet, with respect to tumor biology and brain metastases, little is known so far.
    Material and methods: Two cohorts, M0 without distant spread and BRA with brain metastases were build. RNA was isolated from paraffin embedded specimen. Gene expression was performed by an RNA NanoString-Analysis using the nCounter® PanCancer Progression Panel by NanoString-Technologies (Hamburg, Germany). Results were analysed by principal component analysis, gene expression and pathway analysis using commonly available databases such as KEGG as benchmark for comparison.
    Results: We were able to determine a gene signature that provides a sophisticated group separation between M0 and BRA using principal component analysis. All genes with strong loading characteristics on principal component 1 were cross-referenced with the subsequently performed accurate gene set enrichment analysis (GSEA). The GSEA revealed a clear dysregulation of the TGFβ pathway in compared cohorts M0 and BRA. Interestingly, the targeted pathways analysis of the identified genes confirmed that in fact almost all strong loading genes of PC1 play a role in the TGFβ pathway.
    Conclusion: Our results suggest the TGFβ pathway as a crucial player in the development of brain metastases in primary CRC. In some types of colorectal cancer, downregulation of the TGFβ pathway might hinder primary colorectal cancer to metastasize to the nervous system. While the paradoxical functioning of the TGFβ pathway is still not fully understood, these shed light on yet another clinical implication of this complex pathway.
    Language English
    Publishing date 2024-03-18
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 604952-7
    ISSN 1573-7276 ; 0262-0898
    ISSN (online) 1573-7276
    ISSN 0262-0898
    DOI 10.1007/s10585-024-10277-3
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  8. Article ; Online: Comparative transcriptomic analyses reveal activation of the epithelial-mesenchymal transition program in non-metastasizing low grade pseudomyxoma peritonei.

    Pretzsch, Elise / Neumann, Jens / Nieß, Hanno / Pretzsch, Charlotte M / Hofmann, F O / Kirchner, Thomas / Klauschen, Frederick / Werner, Jens / Angele, Martin / Kumbrink, Jörg

    Pathology, research and practice

    2024  Volume 254, Page(s) 155129

    Abstract: Epithelial-mesenchymal transition (EMT), angiogenesis, cell adhesion and extracellular matrix (ECM) interaction are essential for colorectal cancer (CRC) metastasis. Low grade mucinous neoplasia of the appendix (LAMN) and its advanced state low grade ... ...

    Abstract Epithelial-mesenchymal transition (EMT), angiogenesis, cell adhesion and extracellular matrix (ECM) interaction are essential for colorectal cancer (CRC) metastasis. Low grade mucinous neoplasia of the appendix (LAMN) and its advanced state low grade pseudomyxoma peritonei (lgPMP) show local aggressiveness with very limited metastatic potential as opposed to CRC. To better understand the underlying processes that foster or impede metastatic spread, we compared LAMN, lgPMP, and CRC with respect to their molecular profile with subsequent pathway analysis. LAMN, lgPMP and (mucinous) CRC cases were subjected to transcriptomic analysis utilizing Poly(A) RNA sequencing. Successfully sequenced cases (LAMN n = 10, 77%, lgPMP n = 13, 100% and CRC n = 8, 100%) were investigated using bioinformatic and statistical tests (differential expression analysis, hierarchical clustering, principal component analysis and gene set enrichment analysis). We identified a gene signature of 28 genes distinguishing LAMN, lgPMP and CRC neoplasias. Ontology analyses revealed that multiple pathways including EMT, ECM interaction and angiogenesis are differentially regulated. Fifty-three significantly differentially regulated gene sets were identified between lgPMP and CRC followed by CRC vs. LAMN (n = 21) and lgPMP vs. LAMN (n = 16). Unexpectedly, a substantial enrichment of the EMT gene set was observed in lgPMP vs. LAMN (FDR=0.011) and CRC (FDR=0.004). Typical EMT markers were significantly upregulated (Vimentin, TWIST1, N-Cadherin) or downregulated (E-Cadherin) in lgPMP. However, MMP1 and MMP3 levels, associated with EMT, ECM and metastasis, were considerably higher in CRC. We show that the different tumor biological behaviour and metastatic spread pattern of midgut malignancies is reflected in a different gene expression profile. We revealed a strong activation of the EMT program in non-metastasizing lgPMP vs. CRC. Hence, although EMT is considered a key step in hematogenous spread, successful EMT does not necessarily lead to hematogenous dissemination. This emphasizes the need for further pathway analyses and forms the basis for mechanistic and therapy-targeting research.
    MeSH term(s) Humans ; Pseudomyxoma Peritonei/genetics ; Transcriptome ; Colorectal Neoplasms/pathology ; Epithelial-Mesenchymal Transition/genetics ; Peritoneal Neoplasms/genetics ; Peritoneal Neoplasms/pathology ; Gene Expression Profiling ; Cell Line, Tumor ; Cell Movement
    Language English
    Publishing date 2024-01-14
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 391889-0
    ISSN 1618-0631 ; 0344-0338
    ISSN (online) 1618-0631
    ISSN 0344-0338
    DOI 10.1016/j.prp.2024.155129
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  9. Article ; Online: Identification of a gene expression signature associated with brain metastasis in colorectal cancer.

    Michl, Marlies / Taverna, Francesco / Woischke, Christine / Li, Pan / Klauschen, Frederick / Kirchner, Thomas / Heinemann, Volker / von Bergwelt-Baildon, Michael / Stahler, Arndt / Herold, Tobias Marcus / Jurinovic, Vindi / Engel, Jutta / Kumbrink, Jörg / Neumann, Jens

    Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico

    2024  

    Abstract: Purpose: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event with poor prognosis. Apart from (K)RAS status and lung and bone metastasis no biomarkers exist to identify patients at risk. This study aimed to identify a gene expression ... ...

    Abstract Purpose: Brain metastasis (BM) in colorectal cancer (CRC) is a rare event with poor prognosis. Apart from (K)RAS status and lung and bone metastasis no biomarkers exist to identify patients at risk. This study aimed to identify a gene expression signature associated with colorectal BM.
    Methods: Three patient groups were formed: 1. CRC with brain metastasis (BRA), 2. exclusive liver metastasis (HEP) and, 3. non-metastatic disease (M0). RNA was extracted from primary tumors and mRNA expression was measured using a NanoString Panel (770 genes). Expression was confirmed by qPCR in a validation cohort. Statistical analyses including multivariate logistic regression followed by receiver operating characteristic (ROC) analysis were performed.
    Results: EMILIN3, MTA1, SV2B, TMPRSS6, ACVR1C, NFAT5 and SMC3 were differentially expressed in BRA and HEP/M0 groups. In the validation cohort, differential NFAT5, ACVR1C and SMC3 expressions were confirmed. BRA patients showed highest NFAT5 levels compared to HEP/M0 groups (global p = 0.02). High ACVR1C expression was observed more frequently in the BRA group (42.9%) than in HEP (0%) and M0 (7.1%) groups (global p = 0.01). High SMC3 expressions were only detectable in the BRA group (global p = 0.003). Only patients with BM showed a combined high expression of NFAT5, ACVR1C or SMC3 as well as of all three genes. ROC analysis revealed a good prediction of brain metastasis by the three genes (area under the curve (AUC)  = 0.78).
    Conclusions: The NFAT5, ACVR1C and SMC3 gene expression signature is associated with colorectal BM. Future studies should further investigate the importance of this biomarker signature.
    Language English
    Publishing date 2024-03-17
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 2397359-6
    ISSN 1699-3055 ; 1699-048X
    ISSN (online) 1699-3055
    ISSN 1699-048X
    DOI 10.1007/s12094-024-03408-5
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  10. Article ; Online: Biomarker alterations associated with distinct patterns of metastatic spread in colorectal cancer.

    Michl, M / Taverna, F / Kumbrink, J / Schiergens, T S / Heinemann, V / Engel, J / Kirchner, T / Neumann, Jens

    Virchows Archiv : an international journal of pathology

    2020  Volume 478, Issue 4, Page(s) 695–705

    Abstract: Metastatic spread is the most important life-threatening feature of colorectal cancer and is supposed to be mainly driven by alterations in different carcinogenic pathways. The present study compared mutation and expression profiles of distinctive ... ...

    Abstract Metastatic spread is the most important life-threatening feature of colorectal cancer and is supposed to be mainly driven by alterations in different carcinogenic pathways. The present study compared mutation and expression profiles of distinctive biomarkers in colorectal cancer patients with different clinical metastatic patterns. As for a case-control study, patients were matched according to T category, grading and primary tumour site. Overall, 246 patients with either exclusive lung metastasis (N = 82), exclusive liver metastasis (N = 82) or non-metastatic colorectal cancer (N = 82) were identified. Paraffin-embedded specimens were examined for mutations in the RAS and RAF genes and for the expression of β-catenin and CD133. Clinical endpoints were presence or absence of distant metastasis, formation of metastasis in lungs versus the liver and survival. MAPK pathway mutations in either the KRAS, NRAS or BRAF gene were associated with the development of lung metastasis (63.4%) compared to the control group (47.6%; p = 0.04). MAPK pathway alterations plus high β-catenin expression were associated with metastasis to the lungs but not to the liver (28.0% vs. 13.4%; p = 0.02). High CD133 expression correlated with the development of liver metastasis compared to the control group (30.5% vs. 14.6%; p = 0.02). This data indicates that different patterns of distant spread are associated with specific biomarker alterations and may represent different molecular subtypes of colorectal cancer. However, underlying mechanisms of metastasis formation in different anatomic sites remains unclear. Since knowledge of the anticipated site of distant spread would substantially impact clinical management, further research is needed to identify solid biomarkers for different metastatic patterns.
    MeSH term(s) AC133 Antigen/metabolism ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Case-Control Studies ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/mortality ; Colorectal Neoplasms/pathology ; Female ; Follow-Up Studies ; GTP Phosphohydrolases/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/mortality ; Liver Neoplasms/secondary ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/mortality ; Lung Neoplasms/secondary ; Male ; Matched-Pair Analysis ; Membrane Proteins/genetics ; Middle Aged ; Mutation ; Neoplasm Grading ; Neoplasm Staging ; Prognosis ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Retrospective Studies ; Survival Analysis ; beta Catenin/metabolism
    Chemical Substances AC133 Antigen ; Biomarkers, Tumor ; KRAS protein, human ; Membrane Proteins ; PROM1 protein, human ; beta Catenin ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; NRAS protein, human (EC 3.6.1.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2020-12-09
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1184867-4
    ISSN 1432-2307 ; 0945-6317
    ISSN (online) 1432-2307
    ISSN 0945-6317
    DOI 10.1007/s00428-020-02983-6
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