TY - JOUR A1 - Almanzar, Giovanni A1 - Klein, Matthias A1 - Schmalzing, Marc A1 - Hilligardt, Deborah A1 - El Hajj, Nady A1 - Kneitz, Hermann A1 - Wild, Vanessa A1 - Rosenwald, Andreas A1 - Benoit, Sandrine A1 - Hamm, Henning A1 - Tony, Hans-Peter A1 - Haaf, Thomas A1 - Goebeler, Matthias A1 - Prelog, Martina T1 - Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis JF - International Archives of Allergy and Immunology N2 - Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype. KW - methylation KW - systemic sclerosis KW - suppression KW - Tregs KW - Th17 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196577 SN - 1018-2438 SN - 1423-0097 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 171 IS - 2 ER - TY - JOUR A1 - Vaiopoulos, Aristeidis G. A1 - Kanakis, Meletios A. A1 - Kapsimali, Violetta A1 - Vaiopoulos, Georgios A1 - Kaklamanis, Phedon G. A1 - Zouboulis, Christos C. T1 - Juvenile Adamantiades-Behçet disease JF - Dermatology N2 - Adamantiades-Behçet disease (ABD) is a chronic, multisystemic, recurrent, inflammatory vascular disorder of unknown etiology. Patients with symptoms initially appearing at the age of 16 or less are considered as cases of juvenile-onset ABD (JABD). JABD is relatively rare compared to ABD of adults, and only case reports and case studies have been published regarding this subtype of the disease. Epidemiology, clinical features, diagnosis and treatment of JABD are discussed in this review. KW - Aphthae KW - Childhood KW - Epidemiological study KW - Genitoanal region KW - Adamantiades-Behçet disease KW - Behçet’s disease KW - Uveitis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196616 SN - 1018-8665 SN - 1421-9832 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 232 IS - 2 SP - 129 EP - 136 ER - TY - JOUR A1 - Giampaolo, Sabrina A1 - Wójcik, Gabriela A1 - Serfling, Edgar A1 - Patra, Amiya K. T1 - Interleukin-2-regulatory T cell axis critically regulates maintenance of hematopoietic stem cells JF - Oncotarget N2 - The role of IL-2 in HSC maintenance is unknown. Here we show that Il2\(^{−/-}\) mice develop severe anomalies in HSC maintenance leading to defective hematopoiesis. Whereas, lack of IL-2 signaling was detrimental for lympho- and erythropoiesis, myelopoiesis was enhanced in Il2\(^{−/-}\) mice. Investigation of the underlying mechanisms of dysregulated hematopoiesis in Il2\(^{−/-}\) mice shows that the IL-2-T\(_{reg}\) cell axis is indispensable for HSC maintenance and normal hematopoiesis. Lack of T\(_{reg}\) activity resulted in increased IFN-γ production by activated T cells and an expansion of the HSCs in the bone marrow (BM). Though, restoring T\(_{reg}\) population successfully rescued HSC maintenance in Il2\(^{-/-}\) mice, preventing IFN-γ activity could do the same even in the absence of T\(_{reg}\) cells. Our study suggests that equilibrium in IL-2 and IFN-γ activity is critical for steady state hematopoiesis, and in clinical conditions of BM failure, IL-2 or anti-IFN-γ treatment might help to restore hematopoiesis. KW - immunity KW - hematopoietic stem cells KW - IL-2 KW - treg cells KW - IL-10 KW - IFN-γ KW - immunology and microbiology section KW - immune response Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170947 VL - 8 IS - 18 ER - TY - JOUR A1 - Effenberger, Madlen A1 - Bommert, Kathryn S. A1 - Kunz, Viktoria A1 - Kruk, Jessica A1 - Leich, Ellen A1 - Rudelius, Martina A1 - Bargou, Ralf A1 - Bommert, Kurt T1 - Glutaminase inhibition in multiple myeloma induces apoptosis via MYC degradation JF - Oncotarget N2 - Multiple Myeloma (MM) is an incurable hematological malignancy affecting millions of people worldwide. As in all tumor cells both glucose and more recently glutamine have been identified as important for MM cellular metabolism, however there is some dispute as to the role of glutamine in MM cell survival. Here we show that the small molecule inhibitor compound 968 effectively inhibits glutaminase and that this inhibition induces apoptosis in both human multiple myeloma cell lines (HMCLs) and primary patient material. The HMCL U266 which does not express MYC was insensitive to both glutamine removal and compound 968, but ectopic expression of MYC imparted sensitivity. Finally, we show that glutamine depletion is reflected by rapid loss of MYC protein which is independent of MYC transcription and post translational modifications. However, MYC loss is dependent on proteasomal activity, and this loss was paralleled by an equally rapid induction of apoptosis. These findings are in contrast to those of glucose depletion which largely affected rates of proliferation in HMCLs, but had no effects on either MYC expression or viability. Therefore, inhibition of glutaminolysis is effective at inducing apoptosis and thus serves as a possible therapeutic target in MM. KW - Multiple Myeloma KW - glutaminase inhibition KW - apoptosis KW - MYC Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170168 VL - 8 IS - 49 ER - TY - THES A1 - Keppler, Sarah T1 - Characterization of Novel Mutations in Receptor-Tyrosine Kinases in Multiple Myeloma T1 - Charakterisierung neuer Mutationen in Rezeptor-Tyrosin Kinasen im Multiplen Myelom N2 - Multiple myeloma (MM) is a disease of terminally differentiated B-cells which accumulate in the bone marrow leading to bone lesions, hematopoietic insufficiency and hypercalcemia. Genetically, MM is characterized by a great heterogeneity. A recent next-generation sequencing approach resulted in the identification of a signaling network with an accumulation of mutations in receptor-tyrosine kinases (RTKs), adhesion molecules and downstream effectors. A deep-sequencing amplicon approach of the coding DNA sequence of the six RTKs EPHA2, EGFR, ERBB3, IGF1R, NTRK1 and NTRK2 was conducted in a patient cohort (75 MM samples and 68 corresponding normal samples) of the “Deutsche Studiengruppe Multiples Myelom (DSMM)” to further elucidate the role of RTKs in MM. As an initial approach the detected mutations were correlated with cytogenetic abnormalities and clinical data in the course of this thesis. RTK mutations were present in 13% of MM patients of the DSMM XI trial and accumulated in the ligand-binding and tyrosine-kinase domain. The newly identified mutations were associated with an adverse patient survival, but not with any cytogenetic abnormality common in MM. Especially rare patient-specific SNPs (single nucleotide polymorphism) had a negative impact on patient survival. For a more comprehensive understanding of the role of rare RTK SNPs in MM, a second amplicon sequencing approach was performed in a patient cohort of the DSMM XII trial that included 75 tumor and 184 normal samples. This approach identified a total of 23 different mutations in the six RTKs EPHA2, EGFR, ERBB3, IGF1R, NTRK1 and NTRK2 affecting 24 patients. These mutations could furthermore be divided into 20 rare SNPs and 3 SNVs (single nucleotide variant). In contrast to the first study, the rare SNPs were significantly associated with the adverse prognostic factor del17p. IGF1R was among the most commonly mutated RTKs in the first amplicon sequencing approach and is known to play an important role in diverse cellular processes such as cell proliferation and survival. To study the role of IGF1R mutations in the hard-to-transfect MM cells, stable IGF1R-knockdown MM cell lines were established. One of the knockdown cell lines (L363-C/C9) as well as a IGF1R-WT MM cell line (AMO1) were subsequently used for the stable overexpression of WT IGF1R and mutant IGF1R (N1129S, D1146N). Overall, an impact on the MAPK and PI3K/AKT signaling pathways was observed upon the IGF1R knockdown as well as upon WT and mutant IGF1R overexpression. The resulting signaling pattern, however, differed between different MM cell lines used in this thesis as well as in a parallel performed master thesis which further demonstrates the great heterogeneity described in MM. Taken together, the conducted sequencing and functional studies illustrate the importance of RTKs and especially of IGF1R and its mutants in the pathogenesis of MM. Moreover, the results support the potential role of IGF1R as a therapeutic target for a subset of MM patients with mutated IGF1R and/or IGF1R overexpression. N2 - Das Multiple Myelom (MM) ist eine maligne Erkrankung ausdifferenzierter B-Zellen, den sogenannten Plasmazellen, welche sich im Knochenmark anhäufen. Symptome des MM sind, unter anderem, Knochenläsionen, Hyperkalzämie und hämatopoetische Insuffizienz. Zusätzlich ist das MM durch eine große genetische Heterogenität geprägt. In einer kürzlich durchgeführten Next-Generation Sequencing Studie wurde eine Akkumulation von Mutationen in Rezeptortyrosinkinasen (RTK), Adhesionmolekülen und den zugehörigen Effektoren identifiziert. Dies erlaubte die Definition eines inter- und intrazellulären Signalnetzwerkes. Um die Rolle der RTKs im MM genauer zu definieren, wurde die kodierende DNA Sequenz der sechs RTKs EPHA2, EGFR, ERBB3, IGF1R, NTRK1 und NTRK2 in einer einheitlich therapierten Patientenkohorte (75 Patienten) der „Deutschen Studiengruppe Multiples Myelom“ (DSMM) mittels eines Amplikonansatzes sequenziert. Die identifizierten Mutationen wurden im Rahmen dieser Arbeit validiert und anschließend mit zytogenetischen Anomalitäten und klinischen Daten korreliert. RTK Mutationen waren in 13 % der MM Patienten vorhanden und akkumulierten besonders in den Ligandenbindungs- und der Tyrosinkinase- Domänen. Die neu identifizierten RTK Mutationen hatten einen signifikant negativen Einfluss auf das Überleben, jedoch konnte kein Zusammenhang zwischen den Mutationen und zytogenetischen Alterationen festgestellt werden. Besonders seltene, Patienten-spezifische SNPs hatten einen negativen Einfluss auf die Gesamtüberlebenszeit, das ereignisfreie und das progressionsfreie Überleben. Um die Rolle dieser seltenen SNPs im MM besser zu verstehen, wurde ein zweiter Amplikonansatz in einer neuen Patientenkohorte der DSMM XII Studie durchgeführt. Hierbei wurden die sechs RTKs EPHA2, EGFR, ERBB3, IGF1R, NTRK1 und NTRK2 in 75 Tumor und 184 Normalproben sequenziert. Bei diesem Ansatz wurden 23 unterschiedliche Mutationen in 24 Patienten identifiziert. Diese Mutation konnten in 20 seltene SNPs und 3 SNVs (single nuleotide variant) unterteilt werden und waren, im Gegensatz zu Mutationen der ersten Studie, signifikant mit dem negativ prognostischen Faktor del17p assoziiert. IGF1R war bei der initialen Amplikon-Sequenzierstudie unter den am häufigsten mutierten RTKs und spielt eine wichtige Rolle in verschiedenen zellulären Prozessen, z. B. der Zellproliferation und dem Überleben. Um eine funktionelle Untersuchung der IGF1R Mutation in den schwer-zu-transfizierenden MM-Zellen zu ermöglichen, wurden stabile IGF1R-knockdown MM-Zelllinien etabliert. Eine dieser knockdown Zelllinien (L363-C/C9) sowie eine IGF1R WT MM-Zelllinie (AMO1) wurden anschließend für die stabile Überexpression von IGF1R WT, IGF1R D1146N und IGF1R N1129S verwendet. Funktionelle Analysen zeigten, dass sowohl IGF1R-knockdown als auch die Überexpression von IGF1R WT, IGF1R D1146N und IGF1R N1129S einen Einfluss auf den MAPK und den PI3K/AKT Signalweg haben. Der Einfluss des IGF1R WT, als auch der zwei Mutanten IGF1R D1146N und IGF1R N1129S unterschied sich jedoch in den in dieser Arbeit und in einer parallel durchgeführten Masterarbeit verwendeten Zelllinien. Diese Unterschiede verdeutlichen zusätzlich die große Heterogenität für die das MM bekannt ist. Zusammengenommen verdeutlichen die durchgeführten Sequenzier- und funktionellen Studien die wichtige Rolle der RTKs, besonders von IGF1R, im MM. Darüber hinaus unterstützen die erhaltenen Ergebnisse die potenzielle Rolle von IGF1R als therapeutisches Ziel für MM-Patienten mit mutiertem IGF1R und / oder IGF1R-Überexpression. KW - Plasmozytom KW - Rezeptor-Tyrosinkinasen KW - Multiple Myeloma KW - Amplicon Sequencing KW - Receptor-Tyrosine Kinases KW - IGF1R Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-155720 ER - TY - THES A1 - Frey, Lea Sarah T1 - Retrospektive Analyse zur Bedeutung des 21-Gen-Tests (OncotypeDX®) für die Indikationsstellung zu einer adjuvanten Chemotherapie bei Hormonrezeptor-positivem, Her2/neu-negativem Mammakarzinom T1 - Impact of OnctypeDX Recurrence Score on Treatment Recommendations for Patients with early Stage Breast Cancer N2 - Bei der postoperativen Therapieplanung des Mammakarzinoms treten immer wieder Entscheidungsgrenzfälle auf, bei denen keine sicheren Argumente für oder gegen eine adjuvante Chemotherapie gefunden werden können. Bei 50 Hormonrezeptor-positiven, Her2/neu-negativen Mammakarzinomen ohne oder mit nur geringer nodaler Metastasierung (max. pT1a) wurde zusätzlich zu den konventionellen klinisch-pathologischen Risikofaktoren der OncotypeDX®-Multigentest veranlasst. In der Tumorkonferenz wurde bereits vor Eingang des Testergebnisses ein Votum für oder gegen eine Chemotherapie auf Basis konventioneller Parameter protokolliert; die definitive Therapieempfehlung erfolgte nach Vorliegen des Multigentest-Ergebnisses. 32 Mammakarzinome (64 %) zeigten einen niedrigen, 26 (32 %) einen mittleren und 3 (6 %) einen hohen Recurrence-Score (RS). In vielen Fällen konnte das OncotypeDX®-Ergebnis eine auf der Basis konventioneller Parameter getroffene Therapieentscheidung stützen. In fünf Fällen wurde eine zunächst favorisierte Entscheidung für eine adjuvante Therapie revidiert. In drei Fällen wurde eine zunächst nicht geplante Chemotherapie empfohlen. Allerdings führte in einigen Fällen auch eine niedrige oder intermediäre Risikokonstellation in der OncotypeDX®-Testung nicht dazu, von einer adjuvanten Chemotherapie abzuraten. Insgesamt spricht das Ergebnis nicht dafür, einen Multigentest als Standardmethode einzusetzen. Vielmehr sollten zunächst die konventionellen, insbesondere die histopathologischen und immunhistochemischen Parameter mit großer Sorgfalt erhoben und analysiert werden. Im Zweifelsfall und nach Kosten-Nutzen-Abwägung kann ein Multigentest jedoch ein weiteres hilfreiches Argument für oder gegen eine bestimmte Therapieempfehlung liefern. N2 - Repeatedly in therapy planning of breast cancer there are decision borderline cases where no reliable arguments for or against adjuvant chemotherapy can be found. In 50 cases with hormone receptor-positive, Her2-negative, node-negative or low node-positive (max. pN1a) OncotypeDX® assay was induced additionally to conventional parameters. Before receiving results there was a vote in interdisciplinary tumor conference for or against chemotherapy based on conventional parameters. Final treatment recommendations were made after receiving test results. 32 breast cancer cases (64 %) showed low, 26 (32 %) intermediate and 3 (6 %) high recurrence score (RS). In many cases the test result supported the treatment recommendation based on conventional parameters. In five cases initially favoured decision for adjuvant chemotherapy was revised. In three cases there was a recommendation of chemotherapy which was initially not proposed. However, in some cases low or intermediate recurrence score didn´t cause to recommend against adjuvant chemotherapy. In conclusion, results do not suggest using OncotypeDX® as standard. Rather there should be a careful survey of conventional parameters, especially of histopathological and immunohistochemical parameters. In cases of doubt and after cost-benefit-consideration OncotypeDX® assay may provide an additional argument for or against a certain therapy management. KW - Mammakarzinom KW - Multigentests KW - OncotypeDX Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-156908 ER - TY - JOUR A1 - Shi, Yaoyao A1 - Kuai, Yue A1 - Lei, Lizhen A1 - Weng, Yuanyuan A1 - Berberich-Siebelt, Friederike A1 - Zhang, Xinxia A1 - Wang, Jinjie A1 - Zhou, Yuan A1 - Jiang, Xin A1 - Ren, Guoping A1 - Pan, Hongyang A1 - Mao, Zhengrong A1 - Zhou, Ren T1 - The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma JF - Oncotarget N2 - Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6. Therefore, we sought to explore the feedback loop between LITAF and BCL6 in B-NHL. Here, our data for the first time show that LITAF can repress expression of BCL6 by binding to Region A (−87 to +65) containing a putative LITAF-binding motif (CTCCC) within the BCL6 promoter. Furthermore, the regulation of BCL6 targets (PRDM1 or c-Myc) by LITAF may be associated with B-cell differentiation. Results also demonstrate that ectopic expression of LITAF induces cell apoptosis, activated by releasing cytochrome c, cleaving PARP and caspase 3 in B-NHL cells whereas knockdown of LITAF robustly protected cells from apoptosis. Interestingly, BCL6, in turn, could reverse cell apoptosis mediated by LITAF. Collectively, our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. Our study is expected to provide a possible biomarker as well as a target for clinical therapies to promote tumor cell apoptosis. KW - LITAF KW - BCL6 KW - apoptosis KW - lymphoma KW - B-cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166500 VL - 7 IS - 47 ER - TY - THES A1 - Brenner, Isabel Katharina T1 - Untersuchungen zu sekretorisch differenzierten Marginalzonen-Lymphomen unter besonderer Berücksichtigung primär kutaner Marginalzonen-Lymphome T1 - Marginal zone lymphomas with plasmacytic differentiation with special focus on primary cutaneous marginal zone lymphomas N2 - Marginalzonen-Lymphome (MZL) gehören zur Gruppe der indolenten Non-Hodgkin-Lymphome der B-Zell-Reihe, zu denen nach der aktuellen WHO-Klassifikation auch die primär kutane Marginalzonen-Lymphome (PCMZL) zählen. Eine klonale Leicht- und Schwerkettenexpression kann immunhistochemisch speziell in MZL mit sekretorischer/plasmozytoider Differenzierung (unabhängig von ihrer Primärlokalisation) nachgewiesen werden. In Voruntersuchungen war aufgefallen, dass von primär kutanen MZL ungewöhnlich häufig IgG bzw. IgG4 exprimiert wird, während extrakutane MZL auch nach Literaturangaben eine präferentielle IgM-Expression aufweisen. In der hier vorgelegten Arbeit wurde die Prävalenz einer IgG4-Expression an einer großen Kohorte von sekretorisch/plasmazellulär differenzierten MZL untersucht. Hierzu wurde die Immunglobulinschwerkettenexpression an 169 MZL unterschiedlicher Primärlokalisationen immunhistochemisch analysiert. Es konnte gezeigt werden, dass PCMZL überzufällig häufig IgG exprimieren (78 %, 35/49), wobei der Anteil IgG4-positiver PCMZL mit 54 % (19 von 35) sogar über dem der anderen drei IgG-Subklassen lag (46 %, 16/35). Unter den 120 anderen, nicht kutanen MZL war lediglich ein okuläres MZL positiv für die Schwerkette IgG4. Ferner wurde an dem in dieser Arbeit näher charakterisierten Kollektiv der PCMZL molekularbiologische Untersuchungen zur Frage einer MyD88 (L265P)-Mutation durchgeführt, die letztendlich in keinem der diesbezüglich auswertbaren 45 PCMZL nachgewiesen werden konnte. N2 - In this study the expression of IgG4 was investigated in a large cohort of marginal zone lymphoma specimens. We examined 169 marginal zone lymphomas of various primary sites with plasmacytic differentiation and light chain restriction, allowing for a detailed investigation of the immunoglobulin heavy chain expression in these lymphomas by immunohistochemistry. Unexpectedly, 19 of 49 (39%) primary cutaneous marginal zone lymphomas showed IgG4 expression and only 1 out of 120 noncutaneous marginal zone lymphomas (ocular adnexae) expressed IgG4. Furthermore we investigated the prevalence of MYD88 L265P mutations in a systematic manner in this cohort of PCMZL, however all of the 45 PCMZL exhibited a MYD88 wild type. KW - Primär kutane Marginalzonen-Lymphome KW - Marginalzonen-Lymphome KW - IgG4 KW - MyD88 KW - primary cutaneous marginal zone lymphomas KW - Marginal zone lymphomas Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147237 ER - TY - JOUR A1 - Fuchs, Andreas A1 - Hartmann, Stefan A1 - Ernestus, Karen A1 - Mutzbauer, Grit A1 - Linz, Christian A1 - Brands, Roman C. A1 - Kübler, Alexander C. A1 - Müller-Richter, Urs D. A. T1 - Mandibular intraosseous pseudocarcinomatous hyperplasia: a case report JF - Journal of Medical Case Reports N2 - Background Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases. Case presentation The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved. Conclusions Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment. KW - intraosseous KW - case report KW - pseudocarcinomatous hyperplasia KW - mandible Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146873 VL - 16 IS - 268 ER - TY - THES A1 - Zhi, Yingjun T1 - Immunhistochemische Analyse der Antikörper PAT-SM6 und PAT-LM1 auf Kolonkarzinomen und deren Metastasen T1 - Immunohistochemical analysis of the antibodies PAT-SM6 and PAT-LM1 of colon cancer and the metastases N2 - Das kolorektale Karzinom stellt die dritthäufigste Tumorerkrankung weltweit dar. Die Risikofaktoren sind vielseitig und werden in exogene und endogene Faktoren eingeteilt. Eine wichtige Präventionsmaßnahme von Kolonkarzinom ist die komplette endoskopische Koloskopie, die ab dem 55. Lebensjahr empfohlen wird. Der Goldstandard zur Behandlung von Kolonkarzinom ist nach wie vor die chirurgische Tumorresektion mit mikroskopisch nachgewiesener Tumorfreiheit. Eine chirurgische Sanierung der Fernmetastasen, welche am häufigsten in der Leber vorkommen, ist bei betroffenen Patienten anzustreben. Eine adjuvante Chemotherapie wird je nach UICC-Stadium des Tumors durchgeführt. Im Gegensatz zur Behandlung einiger maligner Tumorerkrankungen ist der Einsatz von Antikörpern noch kein fester Bestandteil der Therapie von Kolonkarzinomen. In dieser Arbeit wurde Untersuchungsmaterial von 41 Patienten mit Kolonkarzinom, die am Universitätsklinikum Würzburg in den Jahren 1997 bis 2012 behandelt wurden, analysiert. Dabei wurden Paraffinschnitte vom Primärtumor, regionalen Lymphknotenmetastasen und Lebermetastasen der einzelnen Patienten mit 2 verschiedenen monoklonalen IgM-Antikörpern, PAT-SM6 und PAT-LM1, gefärbt und mikroskopisch untersucht. Der Antikörper PAT-SM6 wurde aus einem an einem Magenkarzinom erkrankten Patienten isoliert und bindet an eine Isotyp-Form des 'Glucose-Regulated' Protein (GRP)-78PAT-SM6. Als Zielstruktur des PAT-LM1 Antikörpers wurde eine tumorspezifische Form von NONO (Non-POU domain-containing octamer-binding protein) identifiziert (NONOPAT-LM1). Für beide Rezeptor-Isoformen wurde nachgewiesen, dass sie nur auf malignen epithelialen Zellen, nicht aber auf gesunden Zellen exprimiert werden. Anhand dieser Arbeit konnte gezeigt werden, dass PAT-SM6 die Tumorzellen der Lebermetastasen stärker anfärbte als Zellen des Primärtumors. Für die PAT-LM1 Antikörperfärbung wurde ein ähnliches Resultat erzielt. In Bezug auf das Lebensalter der Patienten wiesen die Tumorzellen von älteren Patienten (ab dem 65. Lebensjahr) eine stärkere Antikörperbindung durch PAT-SM6 und PAT-LM1 auf. Interessant war auch die Feststellung, dass die Tumorzellen der Lebermetastasen von verstorbenen Patienten durch PAT-LM1 stärker gefärbt waren als die von zum Untersuchungszeitpunkt noch lebenden Patienten. Die Bindungsunterschiede zwischen PAT-SM6 und PAT-LM1 könnten neue diagnostische und therapeutische Möglichkeiten bei Kolonkarzinomen bieten und somit zukünftig eine individuelle Tumortherapie ermöglichen. N2 - Colorectal carcinoma is one of the most frequently malignant tumor disease worldwide. Two antibodies, PAT-SM6 and PAT-LM1 were used on primary tumor of colon cancer and metastases for the immunohistochemical analyses. It could been shown that both antibodies had a strong affinity to metastases and the tumorcells of older patients. KW - PAT-SM6 KW - PAT-LM1 KW - Kolonkarzinom Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150456 ER - TY - JOUR A1 - Franke, Katharina A1 - Vilne, Baiba A1 - da Costa, Olivia Prazeres A1 - Rudelius, Martina A1 - Peschel, Christian A1 - Oostendorp, Robert A. J. A1 - Keller, Ulrich T1 - In vivo hematopoietic Myc activation directs a transcriptional signature in endothelial cells within the bone marrow microenvironment JF - Oncotarget N2 - Cancer pathogenesis involves tumor-intrinsic genomic aberrations and tumor-cell extrinsic mechanisms such as failure of immunosurveillance and structural and functional changes in the microenvironment. Using Myc as a model oncogene we established a conditional mouse bone marrow transduction/transplantation model where the conditional activation of the oncoprotein Myc expressed in the hematopoietic system could be assessed for influencing the host microenvironment. Constitutive ectopic expression of Myc resulted in rapid onset of a lethal myeloproliferative disorder with a median survival of 21 days. In contrast, brief 4-day Myc activation by means of the estrogen receptor (ER) agonist tamoxifen did not result in gross changes in the percentage/frequency of hematopoietic lineages or hematopoietic stem/progenitor cell (HSPC) subsets, nor did Myc activation significantly change the composition of the non-hematopoietic microenvironment defined by phenotyping for CD31, ALCAM, and Sca-1 expression. Transcriptome analysis of endothelial CD45-Ter119-cells from tamoxifen-treated MycER bone marrow graft recipients revealed a gene expression signature characterized by specific changes in the Rho subfamily pathway members, in the transcription-translation-machinery and in angiogenesis. In conclusion, intra-hematopoietic Myc activation results in significant transcriptome alterations that can be attributed to oncogene-induced signals from hematopoietic cells towards the microenvironment, e. g. endothelial cells, supporting the idea that even pre-leukemic HSPC highjack components of the niche which then could protect and support the cancer-initiating population. KW - stem-cells KW - mutations KW - C-Myc KW - Rho-GTPases KW - niche KW - leukemia KW - target KW - growth KW - cycle KW - apoptosis, Myc KW - microenvironment KW - endothelial cells Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145844 VL - 6 IS - 26 SP - 21827 EP - 21839 ER - TY - JOUR A1 - Dietl, Sebastian A1 - Schwinn, Stefanie A1 - Dietl, Susanne A1 - Riedl, Simone A1 - Deinlein, Frank A1 - Rutkowski, Stefan A1 - von Bueren, Andre O. A1 - Krauss, Jürgen A1 - Schweitzer, Tilmann A1 - Vince, Giles H. A1 - Picard, Daniel A1 - Eyrich, Matthias A1 - Rosenwald, Andreas A1 - Ramaswamy, Vijay A1 - Taylor, Michael D. A1 - Remke, Marc A1 - Monoranu, Camelia M. A1 - Beilhack, Andreas A1 - Schlegel, Paul G. A1 - Wölfl, Matthias T1 - MB3W1 is an orthotopic xenograft model for anaplastic medulloblastoma displaying cancer stem cell- and Group 3-properties JF - BMC Cancer N2 - Background Medulloblastoma is the most common malignant brain tumor in children and can be divided in different molecular subgroups. Patients whose tumor is classified as a Group 3 tumor have a dismal prognosis. However only very few tumor models are available for this subgroup. Methods We established a robust orthotopic xenograft model with a cell line derived from the malignant pleural effusions of a child suffering from a Group 3 medulloblastoma. Results Besides classical characteristics of this tumor subgroup, the cells display cancer stem cell characteristics including neurosphere formation, multilineage differentiation, CD133/CD15 expression, high ALDH-activity and high tumorigenicity in immunocompromised mice with xenografts exactly recapitulating the original tumor architecture. Conclusions This model using unmanipulated, human medulloblastoma cells will enable translational research, specifically focused on Group 3 medulloblastoma. KW - cancer stem cells KW - anaplastic medulloblastoma KW - group 3 KW - orthotopic xenograft KW - animal model KW - brain tumor KW - children Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145877 VL - 16 IS - 115 ER - TY - JOUR A1 - Hertlein, Tobias A1 - Sturm, Volker A1 - Kircher, Stefan A1 - Basse-Lüsebrink, Thomas A1 - Haddad, Daniel A1 - Ohlsen, Knut A1 - Jakob, Peter T1 - Visualization of Abscess Formation in a Murine Thigh Infection Model of \(Staphylococcus\) \(aureus\) by (19)F-Magnetic Resonance Imaging (MRI) JF - PLoS ONE N2 - Background: During the last years, (19)F-MRI and perfluorocarbon nanoemulsion (PFC) emerged as a powerful contrast agent methodology to track cells and to visualize inflammation. We applied this new modality to visualize deep tissue abscesses during acute and chronic phase of inflammation caused by Staphylococcus aureus infection. Methodology and Principal Findings: In this study, a murine thigh infection model was used to induce abscess formation and PFC or CLIO (cross linked ironoxides) was administered during acute or chronic phase of inflammation. 24 h after inoculation, the contrast agent accumulation was imaged at the site of infection by MRI. Measurements revealed a strong accumulation of PFC at the abscess rim at acute and chronic phase of infection. The pattern was similar to CLIO accumulation at chronic phase and formed a hollow sphere around the edema area. Histology revealed strong influx of neutrophils at the site of infection and to a smaller extend macrophages during acute phase and strong influx of macrophages at chronic phase of inflammation. Conclusion and Significance: We introduce (19)F-MRI in combination with PFC nanoemulsions as a new platform to visualize abscess formation in a murine thigh infection model of S. aureus. The possibility to track immune cells in vivo by this modality offers new opportunities to investigate host immune response, the efficacy of antibacterial therapies and the influence of virulence factors for pathogenesis. KW - Soft-tissue infection KW - In-vivo KW - Iron-oxide KW - F-19 MRI KW - Inflammation KW - Particles KW - Tracking KW - Lesions KW - Images KW - Rats Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142846 VL - 6 IS - 3 ER - TY - JOUR A1 - Krebs, Markus A1 - Solimando, Antonio Giovanni A1 - Kalogirou, Charis A1 - Marquardt, André A1 - Frank, Torsten A1 - Sokolakis, Ioannis A1 - Hatzichristodoulou, Georgios A1 - Kneitz, Susanne A1 - Bargou, Ralf A1 - Kübler, Hubert A1 - Schilling, Bastian A1 - Spahn, Martin A1 - Kneitz, Burkhard T1 - miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro JF - Journal of Clinical Medicine N2 - Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition. KW - microRNA-221 KW - high-risk Prostate Cancer KW - angiogenesis KW - Sunitinib KW - Tyrosine kinase inhibition Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203168 SN - 2077-0383 VL - 9 IS - 3 ER - TY - JOUR A1 - Chopra, Martin A1 - Biehl, Marlene A1 - Steinfatt, Tim A1 - Brandl, Andreas A1 - Kums, Juliane A1 - Amich, Jorge A1 - Vaeth, Martin A1 - Kuen, Janina A1 - Holtappels, Rafaela A1 - Podlech, Jürgen A1 - Mottok, Anja A1 - Kraus, Sabrina A1 - Jordán-Garotte, Ana-Laura A1 - Bäuerlein, Carina A. A1 - Brede, Christian A1 - Ribechini, Eliana A1 - Fick, Andrea A1 - Seher, Axel A1 - Polz, Johannes A1 - Ottmueller, Katja J. A1 - Baker, Jeannette A1 - Nishikii, Hidekazu A1 - Ritz, Miriam A1 - Mattenheimer, Katharina A1 - Schwinn, Stefanie A1 - Winter, Thorsten A1 - Schäfer, Viktoria A1 - Krappmann, Sven A1 - Einsele, Hermann A1 - Müller, Thomas D. A1 - Reddehase, Matthias J. A1 - Lutz, Manfred B. A1 - Männel, Daniela N. A1 - Berberich-Siebelt, Friederike A1 - Wajant, Harald A1 - Beilhack, Andreas T1 - Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion JF - Journal of Experimental Medicine N2 - Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo. KW - Tumor-necrosis-factor KW - Regulatory-cells KW - Bone marrow transplantantation KW - Graft-versus-leukemia KW - Rheumatoid arthritis KW - Autoimmune diseases KW - Factor receptor KW - Alpha therapy KW - Expression KW - Suppression Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187640 VL - 213 IS - 9 ER - TY - THES A1 - Stumpf, Miriam T1 - Untersuchungen zum Ausbreitungsweg follikulärer Lymphome: Erhaltene reaktive Keimzentren sind ein deutlicher Hinweis auf ein (noch) lokales Erkrankungsstadium T1 - Preserved reactive germinal centers in follicular lymphoma is a strong histopathologic indicator of limited disease stage N2 - Follikuläre Lymphome (FL) zählen zu den Non-Hodgkin-Lymphomen und stellen die größte Untergruppe der B-Zell-Lymphome dar. Bedingt durch ihren meist indolenten Verlauf werden sie oft erst in einem fortgeschrittenen klinischen Stadium III/IV diagnostiziert und stellen dann eine systemische Erkrankung dar. Gelegentlich wird in der histopathologischen Untersuchung eines befallenen Lymphknotens eine nur partielle Infiltration beobachtet, die häufig auch in den angeschlossenen Stagingmaßnahmen mit einer nur lokalen Tumorausbreitung (klinisches Stadium I/II) assoziiert ist. Ein solches lokal begrenztes Stadium kann gemäß der Standard-Behandlungsprotokolle mit einer alleinigen Strahlentherapie ausreichend kontrolliert werden. Ziel der vorliegenden Arbeit war es zum einen, eine mögliche Assoziation einer nur partiellen Lymphknoteninfiltration beim FL mit einem lokal begrenzten klinischen Stadium zu untersuchen. Zum anderen sollte die Inzidenz einer nur partiellen Lymphknoten- Infiltration beim FL bestimmt werden. Der Vergleich der Studienkohorte mit einer nur partiellen Lymphknoteninfiltration, definiert als zumindest ein vollständig erhaltener Lymphfollikel, mit der Kontrollkohorte zeigte einen hochsignifikanten Unterschied: In der Studienkohorte befanden sich 38 von 40 Fälle (95%) in einem lokalen Stadium, wohingegen die Kontrollkohorte mit vollständiger Lymphknoteninfiltration nur bei 10 von 49 Patienten (20%) ein lokales Krankheitsstadium (p<0.001) aufwies. Um die erhaltenen Ergebnisse zu validieren, wurden alle FL Grad 1-3A aus dem exemplarischen Jahr 2001 untersucht. Hier zeigte sich in 34 Fällen (11 %) eine nur partielle Infiltration. In allen 18 Fällen mit mindestens einem vollständig erhaltenen reaktiven Keimzentrum lag in Übereinstimmung mit der initialen Studienkohorte ein lokales Krankheitsstadium I/II vor (p<0.001). Die erhaltenen Ergebnisse zeigen eindrücklich, dass follikuläre Lymphome mit einem nur partiellen Befall der Lymphknoten häufig mit einem (noch) lokalen klinischen Stadium assoziiert sind. In diesen Fällen käme eine alleinige Bestrahlung als Therapieoption in Betracht. N2 - Follicular lymphoma belongs to the non-Hodgkin lymphoma and represents the greatest subtype of B-cell-lymphomas. Due to their mostly indolent clinical course they are often diagnosed in clinical stages III/IV, i.e. as a systemic disease. We occasionally observed in cases with preserved reactive follicle structures (so called partial infiltration) an association with an only limited clinical stage I/II. According to standard protocolsthese cases can be controlled with radiotherapy alone. The purpose of this study was to analyze a possible association of a partial infiltration of follicular lymphoma with a limited stage I/II of disease and to determine the incidence of a partial infiltration in FL. Comparing the study group of 53 lymph node biopsies with a partial infiltration defined as at least one totally preserved follicle with the control group we found a highly significant difference: In the study group 38 of 40 cases (95%) showed a local clinical stage, while the control groupwith total infiltration of the lymph node only in 10 of 49 patients (20%) presented a local stage of disease (p<0.001). To validate these results all follicular lymphoma cases WHO grade1-3A in the exemplary year 2001 were examined. In 34 cases (11%) a partial lymph node infiltration was found. In all the 18 cases with at least one totally preserved reactive GC a local stage of disease I/II (p<0.001) was found according to the results of the initial study group. The results show impressively that follicular lymphoma with a partial infiltration of the lymph node are often associated with a (still) local clinical stage of disease. In these cases radiotherapy alone can be regarded as a treatment option. KW - follikulärer KW - Lymphknoten KW - Keimzentrum KW - follikuläre Lymphome erhaltene reaktive Keimzentren KW - follicular lymphoma reactive germinal centers Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170077 ER - TY - THES A1 - Braun, Klara T1 - Bedeutung der immunhistochemischen Expression von MAGE A3, NY-ESO 1 und STEAP-1 beim Harnblasenkarzinom T1 - The meaning of immunhistochemical expression of MAGE A3, NY-ESO 1 and STEAP-1 in bladder cancer N2 - Das Harnblasenkarzinom ist eine der häufigsten malignen Tumorarten weltweit, so dass ständig Fortschritte bei der Behandlung gesucht werden. Obwohl sich in den letzten Jahren die Therapie betroffener Patienten immer wieder verfeinert hat, ist die Prognose der Erkrankung im fortgeschrittenen Stadium schlecht. Das Ziel ist es, durch neue Detektionsmethoden und Therapieansätze die Prognose zu verbessern. CTA und andere spezielle biologische Marker bieten deshalb schon seit Längerem einen hochinteressanten Ansatzpunkt, da sie fast selektiv in Tumorgewebe exprimiert werden. Diese weiterhin als Zielantigene für Immuntherapien zu untersuchen kann zukünftig eine wichtige Säule der Krebstherapie darstellen. Ziel der vorliegenden Arbeit war es, das Expressionsmuster der CTA MAGE A3 und NY-ESO 1 sowie von STEAP-1 im Harnblasenkarzinom und ihre Korrelation mit pT-Stadium und Grading immunhistochemisch zu untersuchen. Dafür standen Karzinompräparate von insgesamt 93 Patienten der urologischen Klinik der Universität Regensburg aus dem Zeitraum 1994 bis 2009 für eine retroperspektive Analyse zur Verfügung. Die Präparate stammten von 76 männlichen und 17 weiblichen Patienten, der Median lag bei 68 Jahren. In 79,6 % der untersuchten Schnitte konnte wenigstens ein genanntes Antigen nachgewiesen werden. Dabei war als Kernergebnis NY-ESO 1 mit 90,3 % Expression in den untersuchten Präparaten am häufigsten vorhanden, im Gegensatz zu anderen Arbeiten. Bezüglich des Zusammenhangs zwischen Expression und T-Stadium konnte kein statistisch signifikantes Ergebnis erhoben werden. Es wurde allerdings gezeigt, dass starke Expression von NY-ESO 1 mit schlecht differenzierten Tumoren assoziiert war. Dies darf als eines der Kernergebnisse dieser Arbeit zählen. Bei MAGE A3 zeigte sich auf das Grading bezogen ein statistisch signifikanter Zusammenhang zwischen schlechterem Grading und Expression. Hinsichtlich der Prognose konnte bei MAGE A3 ein statistisch signifikantes Ergebnis bezüglich starker Färbereaktion und kürzerem progressionsfreien Überleben gezeigt werden. Auch dies stellen Kernergebnisse dieser Arbeit dar. Insgesamt stellten sich die untersuchten Marker, besonders MAGE A3, als verstärkt zu untersuchende Prognosefaktoren beim Harnblasenkarzinom dar. Weitere Untersuchungen auf diesem Gebiet scheinen sinnvoll. N2 - Bladder cancer is one of the most malignant tumors worldwide, there is a constant searching for improving treatment in progress. Although the therapy refined in the last years, the prognosis in advanced tumor stadium is poor. The target is to improve the prognosis with new detection methods and therapies. CTA and other biological markers are a very interesting targets because they are nearly selected expressed in several malignant tumors. So they are ideal as target antigens for immuntherapy. In this study we aimed to determine the prognostic value of the CTA MAGE-A3, NY-ESO 1 and STEAP-1 in bladder cancer. We collected archieved tumor slides of patients with NMIBC or MIBC who underwent treatment for bladder cancer at the department of urology in university hospital Regensburg and assessed them by immunohistochemistry The study population consisted of 93 patients. Median age was 68 years. 76 patients were male, 17 were female. There was at least one CTA in 79.6 % of the tumor slides. In 90.3 % of the slides we found the expression of NY-ESO-1. No statistical significance was reached for the correlation expression and higher tumor stages. For NY-ESO 1 we could find statistical significance with high-grade histology. Also for MAGE A3 we could find statistical significance with high-grade histology. Kaplan-Maier plots show statistically significant worse progression-free survival rates in tumors with high MAGE-A3 expression. In conclusion, CTAs are important markers for cancer immuntherapy that are needed to be analyzed more intensive. KW - Blasenkrebs KW - MAGE A3 KW - NY-ESO 1 KW - STEAP-1 KW - Cancer/Testis antigen Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168840 ER - TY - THES A1 - Oberski, Vanessa T1 - IMP3-Expression in Mantelzelllymphomen T1 - IMP3 expression in mantle cell lymphomas N2 - Das Mantelzelllymphom (MCL) gehört zu den aggressiven, mit bislang zur Verfügung stehenden Therapien nicht heilbaren, Non-Hodgkin-Lymphomen (NHL). Das MCL weist eine schlechte Prognose auf. Charakteristisch für das MCL ist die t(11,14)- Translokation, die das Cyclin D1- Gen betrifft. Darüber hinaus finden sich zahlreiche weitere genetische Alterationen mit Häufung bestimmter Zugewinne und Verluste von genetischem Material. Einer der am häufigsten chromosomal zugewonnene Abschnitte in MCL ist der kurze Arm von Chromosom 7 (7p). In Fällen mit dieser genetischen Veränderung fand sich das IMP3/IGF2BP3-Gen (Insulin-like growth factor 2 mRNAbinding protein 3) unter den am stärksten differentiell exprimierten Genen. In dieser Arbeit konnte in einer immunhistochemischen Analyse eine stark variable IMP3-Protein-Expression in einer Serie von insgesamt 172 primären MCL gezeigt werden. Darüber hinaus fand sich in diesem Kollektiv eine signifikante Korrelation der IMP3-Expression mit der Proliferationsfraktion (Ki67-Immunhistochemie) sowie auch eine Assoziation mit einer blastoiden Morphologie. Es konnte jedoch letztlich keine statistisch signifikante Assoziation der IMP-3-Protein-Expression mit einem chromosomalen Zugewinn von 7p, dem Genort von IMP3, nachgewiesen werden, so dass hier offenbar auch noch andere Mechanismen für die Regulation eine wichtige Rolle spielen. In einer darüber hinaus untersuchten Vergleichsgruppe von 20 Fällen von Lymphknoten mit Infiltraten durch ein small lymphocytic Lymphoma (SLL) zeigte sich insgesamt nur eine geringe IMP3-Expression. Der Befund einer vermehrten IMP3-Protein-Expression in einer Teilgruppe von MCL mit erhöhter Tumorzellproliferation unterstützt die Idee, dass eine Aktivierung des IGFSignalweges in MCL möglicherweise die Proliferation und biologische Aggressivität begünstigt. Daher könnte eine therapeutische Manipulation dieses Signalweges vermutlich eine zukünftige therapeutische Option für das MCL darstellen. N2 - The mantle cell lymphoma (MCL) is one of the most aggressive non-Hodgkin´s lymphomas (NHL) with poor prognosis. As of today, no therapy is capable to cure this lymphoma. One of the key MCL characteristics is the t(11,14)-translocation, involving the cyclin D1 gene. In addition, there are numerous further genetic alterations, especially gains and losses of genetic material. One of the most commonly affected chromosomal sections is the short arm of chromosome 7 (7p). IMP3/IGF2BP3 gene (insulin-like growth factor 2mRNAbinding protein3) is among the strongest differentially expressed genes in cases with this genetic alteration. This work analyses a series of 172 primary MCL cases with the help of immunohistochemistry. These cases have highly variable IMP3 protein expression. This thesis showed significant correlation between the IMP3 expression and the proliferation levels (Ki67 immunohistochemistry), as well with the blastoid morphology of these cases. However, no statistically significant association was found between the IMP3 protein expression and the chromosomal gains of 7p (the locus of IMP3), suggesting that other mechanisms can be responsible for the regulation of IMP3 in MCL. The analysis of the control group (20 cases of lymphnodes infiltrated with a small lymphocytic lymphoma - SLL) showed overall only a small IMP3 expression. The study of seven secondary MCL cases showed no major differences in IMP3 protein expression between the primary diagnoses and later relapses. The findings of the correlation between the IMP3 protein expression and the increased proliferation support the idea that the activation of the IGF signaling pathway possibly favors proliferation and biological aggressiveness in MCL. Therefore, future MCL therapy research could include therapeutic manipulation of the IGF signaling pathway. KW - IMP3 KW - Mantelzelllymphom KW - MCL KW - IGF2BP3 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168770 ER - TY - JOUR A1 - Lapa, Constantin A1 - Kircher, Stefan A1 - Schirbel, Andreas A1 - Rosenwald, Andreas A1 - Kropf, Saskia A1 - Pelzer, Theo A1 - Walles, Thorsten A1 - Buck, Andreas K. A1 - Weber, Wolfgang A. A1 - Wester, Hans-Juergen A1 - Herrmann, Ken A1 - Lückerath, Katharina T1 - Targeting CXCR4 with [\(^{68}\)Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma? JF - Oncotarget N2 - C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy. KW - PET KW - CXCR4 KW - [\(^{68}\)Ga] pentixafor KW - pleural mesothelioma KW - theranostics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-169989 VL - 8 IS - 57 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Weich, Alexander A1 - Higuchi, Takahiro A1 - Schmid, Jan S. A1 - Schirbel, Andreas A1 - Lassmann, Michael A1 - Wild, Vanessa A1 - Rudelius, Martina A1 - Kudlich, Theodor A1 - Herrmann, Ken A1 - Scheurlen, Michael A1 - Buck, Andreas K. A1 - Kropf, Saskia A1 - Wester, Hans-Jürgen A1 - Lapa, Constantin T1 - Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach JF - Theranostics N2 - C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors. KW - SSTR KW - peptide receptor radionuclide therapy KW - neuroendocrine tumor KW - [\(^{68}\)Ga]Pentixafor KW - CXCR4 KW - chemokine receptor KW - PET/CT KW - DOTATOC KW - PRRT KW - Positronen-Emissions-Tomografie Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158008 VL - 7 IS - 6 ER -