TY - THES A1 - Alb, Miriam T1 - Tumorstroma-Immuntherapie und spontane Immunsuppression im Grm1-transgenen Melanom-Modell T1 - Tumor stroma immunotherapy and spontaneous immunosuppression in Grm1 transgenic murine melanoma N2 - 5.1 Immuntherapie mit vom Tumorstroma abgeleiteten Peptiden Tumore bestehen nicht nur aus Tumorzellen, sondern auch aus der sie umgebenden extrazellulären Matrix (EZM), und Stromazellen wie Fibroblasten (cancer-associated fibroblast; CAF) und Endothelzellen (tumor endothelial cell; TEC). Diese Stromazellen haben durch die Ausschüttung von Zytokinen, proteolytischen Enzymen, Wachstums- und Angiogenesefaktoren einen entscheidenden Einfluss auf die Tumorprogression. Sie unterscheiden sich von den Stromazellen der normalen Gewebe durch die Expression von sogenannten Tumorstroma-assoziierten Antigenen (TSAA). Damit sollten Therapien, die auf TSAA abzielen, universell einsetzbar und weniger anfällig gegenüber Resistenzentwicklungen (immune escape Mechanismen) sein, da Stromazellen im Gegensatz zu neoplastischen Zellen genetisch relativ stabil sind. Für eine Immuntherapie mit vom Tumorstroma abgeleiteten Peptiden wählten wir die TSAA Endoglin und Fap, welche während der Wundheilung und im Tumorstroma induziert werden. Dabei sollte überprüft werden, ob prophylaktische Vakzinierungen in C57Bl/6j Mäusen Peptid-reaktive T-Zellen induzieren können, und das Wachstum von transplantieren Grm1-transgenen Tumoren reduziert werden kann. In der Tat konnten wir sowohl bei Endoglin- als auch bei Fap Peptid vakzinierten Tieren in vivo Peptid-reaktive Lymphozyten im Blut und zu einem geringeren Anteil auch in der Milz nachweisen, welche Peptid-gepulste syngene Milzzellen lysieren konnten. Allerdings konnte in beiden Fällen keine Reduktion des Tumorwachstums gegenüber der Kontrollgruppe beobachtet werden. Bei der Fap-Peptid-vakzinierten Gruppe war das Tumorwachstum gegenüber der Kontrollgruppe sogar gesteigert. Dies könnte darauf hindeuten, dass die Induktion Fap-Peptid-reaktiver T-Zellen tumorpromovierend wirkt. Möglicherweise könnte aber durch eine Modifikation des Vakzinierungsprotokolls bzw. durch eine Kombination mit anderen Immuntherapeutika ein verbessertes Ansprechen auf eine Endoglin bzw. Fap basierte Immuntherapie erzielt werden. 5.2 Immunsuppressive Mechanismen im Grm1-transgenen Melanom-Modell Grm1-transgene Mäuse entwickeln spontan kutane Melanome. Dieses Modell erlaubte es uns in der vorliegenden Arbeit spontane Immunantworten im Laufe der Melanomentstehung zu untersuchen. Hierfür analysierten wir sowohl ex vivo als auch in vitro aus Milz und Lymphknoten gewonnene Lymphozyten von Mäusen, welche keine Tumorläsionen bzw. eine niedrige oder hohe Tumorlast aufwiesen. Dabei konnten wir ex vivo einen Anstieg der Frequenz aktivierter CD4+ und CD8+ Lymphozyten mit zunehmender Tumorlast zeigen. Bei tumortragenden Tieren exprimierten jedoch hauptsächlich CD4+ T-Zellen Aktivierungsmarker nach in vitro Stimulation. Interessanterweise waren diese Zellen tumortragender Tiere auch funktionell beeinträchtigt, was sich in einer verminderten Proliferationskapazität nach in vitro Stimulation zeigte. Weitere Analysen ergaben, dass die erhöhte Frequenz regulatorischer T Zellen bei tumortragenden Tieren ein frühes Ereignis im Laufe der Tumorentstehung ist. Gleichzeitig konnte auch ein starker Anstieg der immunsupprimierenden Zytokine Tgf-β1 und Il-10 sowohl in den Lymphknoten als auch im Tumorgewebe beobachtet werden. Dabei war die Tgf-β1-Expression sowohl im Tumor als auch im tumor-drainierenden Lymphknoten erhöht, während Il-10 im Tumor nur moderat exprimiert wurde, was eine komplexere Regulation der Il-10-Expression nahe legt. Dies bedeutet, dass in Grm1-transgenen Mäusen ähnlich wie auch bei Melanompatienten zelluläre und zytokinabhängige Mechanismen zur Tumorentstehung beitragen und dieses Modell daher geeignet ist, um präklinisch immunmodulierende Therapieansätze zu testen. N2 - 6.1 Immunotherapy with peptides derived from tumor stroma-associated antigens Tumors do not only comprise tumor cells but also stromal cells like fibroblasts (cancer associated fibroblast; CAF) and endothelial cells (tumor endothelial cell; TEC) and the surrounding extracellular matrix (ECM). These stromal cells impact on progression and invasion of tumors through release of cytokines, ECM-degrading enzymes, growth factors, and angiogenic factors. They differ from their normal counterparts through expression of so called tumor stroma-associated antigens (TSAA). Therefore, therapies targeting the tumor stroma should be universally applicable. Furthermore, such therapies should be less prone to resistance mechanisms as stromal cells are genetically more stable than neoplastic cells. We selected the TSAA Endoglin and Fap, which are both specifically induced during wound healing and in the tumor stroma, to test if vaccination with peptides derived from these TSAA induced peptide-reactive T cells, and could reduce the growth of transplanted Grm1 transgenic tumors in C57Bl/6j mice in a prophylactic setting. In mice vaccinated with Endoglin- and Fap-peptides, respectively, peptide-reactive lymphocytes from peripheral blood and spleen were able to lyse peptide-loaded syngeneic splenocytes in vivo. However, vaccination with Endoglin- and Fap-peptides, respectively, did not affect the growth of transplanted Grm1-transgenic tumors. In fact, tumor growth was enhanced in Fap peptide vaccinated mice compared to the control group. This suggests that Fap peptide reactive T cells promote tumor progression. Modification of the vaccination protocol or a combination with an immune-modulatory therapy could, however, increase the efficacy of an anti-Endoglin or anti-Fap therapy, respectively. 6.2 Immunosuppressive mechanisms of Grm1-transgenic murine melanoma Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increased frequency of activated CD4+ and CD8+ T lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4+ T cells, which could constitute both T helper as well as immune suppressive regulatory T cells, but not CD8+ T cells expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines Tgf-β1 and Il-10 became more evident with increased tumor burden. Notably, Tgf-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas Il-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of Il-10. Thus, similar to the situation in melanoma patients both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immune suppressed state of tumor-bearing Grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immune-modulatory therapies. KW - Stroma KW - Melanom KW - Immunsuppression KW - tumor KW - stroma KW - melanoma KW - immunosuppression KW - Tumorstroma Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78890 ER - TY - JOUR A1 - Biederer, Jürgen A1 - Mirsadraee, S. A1 - Beer, M. A1 - Molinari, F. A1 - Hintze, C. A1 - Bauman, G. A1 - Both, M. A1 - Van Beek, E. J. R. A1 - Wild, J. A1 - Puderbach, M. T1 - MRI of the lung (3/3)—current applications and future perspectives JF - Insights into Imaging N2 - Background MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. Methods Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. Results In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a “buffet” of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. Conclusion New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations. KW - functional imaging KW - magnetic resonance imaging KW - cystic fibrosis KW - pulmonary embolism KW - tumor KW - infiltrate Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124348 VL - 3 IS - 4 ER - TY - JOUR A1 - Graf, Nicolas A1 - Li, Zhoulei A1 - Herrmann, Ken A1 - Weh, Daniel A1 - Aichler, Michaela A1 - Slawska, Jolanta A1 - Walch, Axel A1 - Peschel, Christian A1 - Schwaiger, Markus A1 - Buck, Andreas K. A1 - Dechow, Tobias A1 - Keller, Ulrich T1 - Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma JF - Oncotargets and Therapy N2 - Background: Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[F-18] fluorothymidine (FLT). Methods: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects. Results: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue. Conclusion: Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy. KW - mammalian target of rapamycin KW - phosphatidylinositol-3-kinase KW - lymphoma KW - early response KW - NVP-BGT226 KW - non-hodgkins-lymphoma KW - signaling pathway KW - FDG-PET KW - in-vivo KW - target KW - tumor KW - imaging proliferation KW - inhibition KW - positron emission tomography Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117915 VL - 7 ER - TY - JOUR A1 - Grassinger, Julia Maria A1 - Floren, Andreas A1 - Müller, Tobias A1 - Cerezo-Echevarria, Argiñe A1 - Beitzinger, Christoph A1 - Conrad, David A1 - Törner, Katrin A1 - Staudacher, Marlies A1 - Aupperle-Lellbach, Heike T1 - Digital lesions in dogs: a statistical breed analysis of 2912 cases JF - Veterinary Sciences N2 - Breed predispositions to canine digital neoplasms are well known. However, there is currently no statistical analysis identifying the least affected breeds. To this end, 2912 canine amputated digits submitted from 2014–2019 to the Laboklin GmbH & Co. KG for routine diagnostics were statistically analyzed. The study population consisted of 155 different breeds (most common: 634 Mongrels, 411 Schnauzers, 197 Labrador Retrievers, 93 Golden Retrievers). Non-neoplastic processes were present in 1246 (43%), tumor-like lesions in 138 (5%), and neoplasms in 1528 cases (52%). Benign tumors (n = 335) were characterized by 217 subungual keratoacanthomas, 36 histiocytomas, 35 plasmacytomas, 16 papillomas, 12 melanocytomas, 9 sebaceous gland tumors, 6 lipomas, and 4 bone tumors. Malignant neoplasms (n = 1193) included 758 squamous cell carcinomas (SCC), 196 malignant melanomas (MM), 76 soft tissue sarcomas, 52 mast cell tumors, 37 non-specified sarcomas, 29 anaplastic neoplasms, 24 carcinomas, 20 bone tumors, and 1 histiocytic sarcoma. Predisposed breeds for SCC included the Schnauzer (log OR = 2.61), Briard (log OR = 1.78), Rottweiler (log OR = 1.54), Poodle (log OR = 1.40), and Dachshund (log OR = 1.30). Jack Russell Terriers (log OR = −2.95) were significantly less affected by SCC than Mongrels. Acral MM were significantly more frequent in Rottweilers (log OR = 1.88) and Labrador Retrievers (log OR = 1.09). In contrast, Dachshunds (log OR = −2.17), Jack Russell Terriers (log OR = −1.88), and Rhodesian Ridgebacks (log OR = −1.88) were rarely affected. This contrasted with the well-known predisposition of Dachshunds and Rhodesian Ridgebacks to oral and cutaneous melanocytic neoplasms. Further studies are needed to explain the underlying reasons for breed predisposition or “resistance” to the development of specific acral tumors and/or other sites. KW - canine KW - subungual KW - toe KW - tumor KW - inflammation KW - breed predisposition Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242690 SN - 2306-7381 VL - 8 IS - 7 ER - TY - THES A1 - Graulich, Michael T1 - Spinale Effekte von TNF-α am Modell des tumorinduzierten Knochenschmerzes der Maus T1 - Spinal effects of TNF-α in a mouse model of bone cancer pain N2 - Am Modell des tumorinduzierten Schmerzes der Maus wurden sowohl das Schmerzverhalten der Tiere als auch spezifische morphologische Veränderungen im Hinterhorn des Rückenmarks (Aktivierung von Astrozyten) und im tumorbefallenen Knochen analysiert. Durch Analyse von Mäusen mit Defizienz für TNF-Rezeptor 1, TNF-Rezeptor 2 oder für beide Rezeptoren konnte die Rolle von TNF-α seiner Rezeptoren bei der Entstehung von tumorinduziertem Schmerz untersucht werden. Im Unterschied zu neuropathischen Schmerzmodellen konnte gezeigt werden, dass beide TNF-Rezeptoren ausgeschaltet werden müssen, um eine signifikante Schmerzreduktion zu erzielen. Die systemische Behandlung mit dem TNF-neutralisierenden Fusionsprotein Etanercept konnte die im genetischen Modell gezeigte Reduktion der mechanischen Allodynie teilweise, aber nicht vollständig reproduzieren. Eine Hemmung der Mikrogliaaktivierung mittels Minocyclin erbrachte im Tumor-schmerzmodell keinen Effekt auf das Schmerzverhalten der Tiere. Die histologische Analyse der tumoraffizierten Knochen zeigte eine signifikante Zunahme der Osteoklastenaktivität in tumortragenden Tieren. Die Behandlung mit Minocyclin war ohne erkennbaren Effekt auf die Differenzierung und die Aktivität der Osteoklasten. Es ergaben sich jedoch Hinweise, dass TNF-α einen hemmenden Einfluss auf die Osteoklastenaktivität im Knochentumormodell hat, da sowohl in den TNFR-KO-Tieren als auch unter Gabe von Etanercept eine Steigerung der Osteoklastenaktivität nachgewiesen werden konnte. Die Ergebnisse dieser Arbeit zeigen, dass TNF-α eine wichtige Rolle, sowohl in der Entstehung, als auch in der Aufrechterhaltung von tumorinduziertem Schmerz spielt. Hier liegt der Ansatzpunkt für weitere Studien mit dem Ziel, eine spezifische Pharmakotherapie zu entwickeln mit wirksamer TNF-α Blockade auch bei Patienten mit Tumorschmerzen. Nach den Erkenntnissen dieser Arbeit mit Etanercept sollte ein spezielles Augenmerk auf die ZNS-Gängigkeit dieser Substanzen gelegt werden und die Gefahr der Möglichkeit eines vermehrten Tumorwachstum bedacht werden. N2 - Bone-cancer-related pain is one of the most disabling factors in patients suffering from primary bone cancer or bone metastases. Recent studies point toward an important role of proinflammatory cytokines, example tumor necrosis factor-alpha (TNF), for tumor growth and bone-cancer-associated pain. Mechanisms by which TNF, through its receptor subtypes, TNF receptor 1 (TNFR1) and -2 (TNFR2), elicits altered sensation and pain behavior, are still incompletely understood. To look for a potential role of TNF in bone cancer pain, cancer-related pain was analyzed in fibrosarcoma-bearing C57Bl/6J wild type mice after systemic antagonism of TNF. To further clarify the role of TNF receptor (TNFR) in bone-cancer pain, naive and fibrosarcoma-bearing C57Bl/ 6J wild type and transgenic mice with a deficiency of TNFR1 (TNFR1ko), TNFR2 (TNFR2ko), and TNFR1+2 (TNFR1+2ko) were compared regarding cancer-related pain and hyperalgesia, tumor growth, osteoclast activation, and spinal astrogliosis. Systemic antagonism of TNF significantly alleviated tactile hypersensitivity and spontaneous bone-cancer-related pain behavior. Most interestingly, combined deletion of the TNFR1 and TNFR2, but not of either gene alone, almost completely inhibited the development of tactile hypersensitivity, whereas spontaneous pain behavior was transiently increased. Accordingly, spinal astrogliosis was markedly reduced, whereas tumor growth was significantly increased in TNFR1+2ko mice. In contrast, deletion of the TNFR1 or TNFR2 gene alone did not change tumor growth or spinal astrogliosis. Our findings suggest that the combined absence of TNFR1 and TNFR2 is necessary for the attenuation of cancer-related tactile hypersensitivity and concomitant spinal astrogliosis, whereas tumor growth seems to be inhibited by combined TNFR activation. These findings support the hypothesis of cytokine-dependent pain development in cancer pain. Differential targeting of TNFR activation could be an interesting strategy in bone-cancer-related pain conditions. KW - Neuralgie KW - Schmerz KW - Schmerzforschung KW - Tumor-Nekrose-Faktor KW - Tumor-Nekrose-Faktor -Inhibitor KW - Experimentaltumor KW - Knochentumor KW - pain KW - tumor KW - bone KW - neuropathy KW - tnf KW - glia KW - minocycline KW - etanercept Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-54439 ER - TY - JOUR A1 - Grimm, Johannes A1 - Hufnagel, Anita A1 - Wobser, Marion A1 - Borst, Andreas A1 - Haferkamp, Sebastian A1 - Houben, Roland A1 - Meierjohann, Svenja T1 - BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1 JF - Oncogenesis N2 - Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application. KW - melanoma KW - senescence KW - BRAF KW - tumor Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177261 VL - 7 IS - 71 ER - TY - JOUR A1 - Götz, Lisa A1 - Rueckschloss, Uwe A1 - Balk, Gözde A1 - Pfeiffer, Verena A1 - Ergün, Süleyman A1 - Kleefeldt, Florian T1 - The role of carcinoembryonic antigen-related cell adhesion molecule 1 in cancer JF - Frontiers in Immunology N2 - The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin superfamily. CEACAM1 was shown to be a prognostic marker in patients suffering from cancer. In this review, we summarize pre-clinical and clinical evidence linking CEACAM1 to tumorigenicity and cancer progression. Furthermore, we discuss potential CEACAM1-based mechanisms that may affect cancer biology. KW - CEACAM1 KW - CEA KW - cancer KW - tumor KW - malignancy KW - metastasis KW - signaling Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357250 VL - 14 ER - TY - JOUR A1 - Herrmann, Thomas A1 - Karunakaran, Mohindar M. T1 - Butyrophilins: γδ T cell receptor ligands, immunomodulators and more JF - Frontiers in Immunology N2 - Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively studied molecule is BTN3A1, which binds via its cytoplasmic B30.2 domain, metabolites of isoprenoid synthesis, designated as phosphoantigen (PAg), The enrichment of PAgs in tumors or infected cells is sensed by Vγ9Vδ2 T cells, leading to the proliferation and execution of effector functions to remove these cells. This article discusses the contribution of BTNs, the related BTNL molecules and SKINT1 to the development, activation, and homeostasis of γδ T cells and their immunomodulatory potential, which makes them interesting targets for therapeutic intervention. KW - butyrophilin KW - immune therapy KW - T cell receptor KW - γδ T cell KW - BTN3A1 KW - BTN2A1 KW - phosphoantigen KW - tumor Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265944 SN - 1664-3224 VL - 13 ER - TY - THES A1 - Hilgarth, Markus T1 - Der aktuelle Stellenwert von Doppelkontrastpharyngographie und von Computertomographie bei der Detektion und bei der korrekten Stadienzuordnung von Tumoren des Oropharynx, Hypopharynx und des supraglottischen Larynx T1 - The current value of double contrast pharyngography and of computed tomography in detecting and correct staging of tumors of the oropharynx, hypopharynx and supraglottic larynx N2 - Retrospektive Analyse von Doppelkontrastpharyngographie (DkPh) und CT im Vergleich mit indirekter und direkter Laryngoskopie. Dazu wurden die Untersuchungsergebnisse von 151 Pat. mit Tumoren des Pharynx und des supraglottischen Larynx bezüglich Detektion und korrekter Stadienzuordnung nach dem TNM-System unter besonderer Berücksichtigung des subregionalen Befalls ausgewertet. Die DkPh stellt eine sinnvolle Ergänzung zur indirekten Laryngoskopie zur Tumordetektion dar, die Sensitivität wurde durch Kombination im Vergleich zu den einzelnen Verfahren signifikant verbessert. Zum Staging ist sie kein geeignetes Verfahren. Die CT Detektiert Tumoren zuverlässig. Bei der korrekten Stadienzuordnung liefert sie v.a. bzgl. Tiefeninfiltration wertvolle Zusatzinformationen. Fortgeschrittene Tumorstadien werden daher durch die CT signifikant besser dem korrekten T-Stadium zugeordnet als Tumor in frühen Tumorstadien. Durch Kombination von CT und direkter Laryngoskopie wurde die Sensitivität bzgl. einer korrekten Stadienzuornung im Vergleich zu den Einzelverfahren signifikant verbessert. N2 - The results of double contrast pharyngography (DCP) and CT where retrospectively analized and compared with the results of direct and indirect laryngoscopy. 151 patients with tumor of the oropharynx, hypopharynx and supraglottic larynx where included. DCP was a valuable technique in detecting tumors, espacially in the Hypopharynx. By combination of DCP and indirect laryngoscopy the sensitivity of detecting tumors was significantly improved. DCP was no suitable method in staging tumors. CT can reliable detect tumors of the pharynx and larynx. In correct staging CT staged T3/T4 tumors significantly correcter than T1/T2 tumors. Especially in detecting deep tumor infiltration CT can provide usefull additional information compared with the direct laryngoscopy.By combination the sensitivity in correct staging was significantly improved compared to the two single methods. KW - Tumor KW - Pharynx KW - Doppelkontrastpharyngographie KW - Computertomographie KW - Staging KW - Computed tomography KW - double-contrast pharyngography KW - tumor KW - pharynx Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-6099 ER - TY - THES A1 - Laufer, Antje T1 - Kombinierte zytogenetische und morphologische Analyse follikulärer Non-Hodgkin Lymphome : Eine neue rekurrente chromosomale Aberration bei prädominant diffusen follikulären Lymphomen T1 - Combined cytogenetic and morphologic analysis of follicular Non Hodgkin lymphomas. A new rekurrent chromosomal aberration with predominant diffuse follicular lymphomas. N2 - Das follikuläre Lymphom ist eines der häufigsten Non-Hodgkin Lymphome und überwiegend eine Erkrankung des erwachsenen Menschen. In der WHO-Klassifikation ist es als ein Lymphom von Keimzentrumszellen definiert, das follikulär und/oder diffus wachsen kann. Zur Subklassifikation follikulärer Lymphome empfiehlt die WHO-Klassifikation eine Unterscheidung der Grade 1, 2 und 3 durch Auszählen der Zentroblasten pro zehn Gesichtsfelder in starker Vergrößerung. Beim Grad 3A liegen neben Zentroblasten auch Zentrozyten vor. FL Grad 3B bestehen ausschließlich aus Zentroblasten. Hinsichtlich der Zytomorphologie, Immunhistologie und Genetik bestehen deutliche Unterschiede zwischen FL Grad 1, 2 und 3A gegenüber FL Grad 3B. In der vorliegenden Arbeit konnte gezeigt werden, dass die weit überwiegende Zahl der follikulären Lymphome Grad 1, 2 und 3A ein prädominant follikuläres Wachstumsmuster aufwies. Ein follikulärer und diffuser Wuchstyp lag seltener vor. Noch seltener war ein überwiegend bzw. „rein“ diffuses Wachstumsmuster. Die mitotische und proliferative Aktivität stieg mit dem Tumorgrad linear an. Hinsichtlich der CD10 Reaktivität, der BCL-2 und p53 Expression sowie des Nachweises einer sekretorischen Differenzierung ergaben sich beim Vergleich der FL Grad 1 bis 3A keine statistisch signifikanten Unterschiede. Die BCL-2 Expression nahm allerdings bei den FL1-3A mit zunehmendem Grad ab. In zytogenetischen Untersuchungen wurden in allen follikulären Lymphomen Grad 1 bis 3A primäre bzw. sekundäre Chromosomenaberrationen gefunden. Unter den rekurrenten chromosomalen Alterationen trat die Translokation t(14;18)(q32;q21) am häufigsten auf und war insbesondere bei follikulären Lymphomen Grad 1 und 2, in etwas geringerem Maße auch bei FL Grad 3A anzutreffen. Diese Translokation scheint also in einem frühen Stadium der B-Zell-Entwicklung aufzutreten und führt primär zu einem höher differenzierten (zentrozytenreichen) Lymphom. Die t(14;18) bedingt zumeist eine Überexpression des BCL-2 Gens, die sich auch immunhistochemisch nachweisen lässt und diagnostische Verwendung findet. Das BCL-2 Protein ist daher von Nutzen für die Unterscheidung neoplastischer von reaktiven Follikeln, nicht aber, um follikuläre von anderen „low grade“ B-Zell Lymphomen zu unterscheiden. Die sekundären Alterationen charakterisieren bestimmte undifferenzierte Stadien mit hohem Blastenanteil und einer hohen mitotischen und proliferativen Aktivität. In zytogenetischen Untersuchungen von überwiegend diffus wachsenden FL konnte keine Translokation t(14;18)(q32;q21) nachgewiesen werden. Die identische Morphologie dieser Lymphome und die identischen Veränderungen auch auf genetischer Ebene deuten auf die nahe Verwandtschaft der überwiegend diffus wachsenden FL mit den typischen Keimzentrums-lymphomen hin. Es handelt sich jedoch um eine eigenständige Identität, die differenzierten Keimzentrumslymphome, die wahrscheinlich aufgrund des Fehlens einer t(14;18)(q32;q21) ein primär und ausgeprägt diffuses Wachstumsmuster aufweisen. N2 - The follicular lymphoma is predominant one the most frequent Non Hodgkin of lymphomas and an illness of the adult humans. In the WHO classification it is defined as a lymphoma of germ center cells, which can grow follicular and/or vaguely. To the Subklassifikation of follicular lymphomas the WHO classification recommends a distinction of the degrees of 1, 2 and 3 by counting out the centroblasten per ten visual field in strong enlargement. With the degree of 3A also centrocyten are present beside centroblasten. Flat steel bars degrees of 3B exclusively consist of centroblasten. Regarding the cytomorphology, immunhistology and genetics clear differences between flat steel bar degrees 1, 2 and 3A exist opposite flat steel bar degree 3B. In the available work it could be shown that the number of the follicular lymphomas degrees of 1, 2 and 3A outweighing far predominant folliculars growth sample exhibited. A follicular and diffuse type of stature was present more rarely. Still more rarely a “diffuse growth sample was predominant and/or „pure. The mitotic and proliferative activity rose with the tumor degree linear. Regarding the CD10 reactivity, the BCL-2 and p53 Expression as well as the proof of a secretoric differentiation did not result in the case of the comparison of the flat steel bars degrees of 1 to 3A statistically significant differences. The BCL-2 Expression removed however with the FL1-3A with increasing degree. In cytogenetic investigations in all follicular lymphomas degrees of 1 to 3A primary and/or secondary chromosome aberrations were found. Under the recurrent chromosomalen old person rations the translokation t (14 stepped; 18) (q32; q21) most frequently up and was in particular with follicular lymphomas degree of 1 and 2 to find in somewhat smaller measure also with flat steel bar degree of 3A. This translokation seems to arise thus in an early stage of the B-cell-development and leads primarily to a more highly differentiated (centrocyt) lymphoma. The t (14; ) mostly a overexpression of the BCL-2 of gene, which can be proven also immune-histochemical, causes 18 and diagnostic use finds. The BCL-2 protein is from there of use for the distinction more neoplastic of reactive follicles, not however, in order to differentiated follicular from others „low degrees “B-cell lymphomas. The secondary old person rations characterize certain undifferentiated stages with high blowing portion and a high mitotic and proliferativen activity. In cytogenetic investigations of predominantly vaguely growing flat steel bar no Translokation t (14 could; 18) (q32; q21) to be proven. The identical morphology of these lymphomas and the identical changes also on genetic level point growing flat steel bar with the typical germ center lymphomas to the close relationship that predominantly vaguely. However the differentiated germ center lymphomas, those concern probably due to the absence of a t their own identity, (14; 18) (q32; q21) primarily and minted diffuse growth sample exhibit. KW - Lymphdrüse KW - Krebs KW - Tumor KW - Lymphknoten KW - Hodgkin KW - Lymphdrüse KW - Krebs KW - Tumor KW - Lymphknoten KW - Hodgkin KW - lymphoma KW - cancer KW - Hodgkin KW - tumor KW - lymph node Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-29701 ER -